CA2856946A1 - Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rory, nr1f3) activity and for the treatment of chronic inflammatory and autoimmunediseases - Google Patents
Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rory, nr1f3) activity and for the treatment of chronic inflammatory and autoimmunediseases Download PDFInfo
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Abstract
The invention provides modulators for the orphan nuclear receptor ROR? and methods for treating ROR? mediated diseases by administrating these novel ROR? modulators to a human or a mammal in need thereof. Specifically, the present invention provides pyrrolo carboxamide compounds of Formula (1) and the enantiomers, diastereomers, N-oxides, tautomers, solvates and pharmaceutically acceptable salts thereof.
Description
Pyrrolo carboxamides as modulators of orphan nuclear receptor RAR-related orphan receptor-gamma (RORy, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune diseases The invention provides pyrrolo carboxamide compounds as modulators for the orphan nuclear receptor RORy and methods for treating RORy mediated chronic inflammatory and autoimmune diseases by administrating these novel RORy modulators to a human or a mammal in need thereof.
The retinoid-receptor related orphan receptors consist of three family members, namely RORa (Beckerandre et al., Biochem. Biophys. Res. Commun. 1993, 194:1371), (Andre et at., Gene 1998, 516:277) and RORy (He et al., Immunity 1998, 9:797) and constitute the NR1F (ROR/RZR) subgroup of the nuclear receptor superfamily (Mangelsdorf et al., Cell 1995, 83:835).
The nuclear receptor superfamily shares common modular structural domains consisting of a hypervariable N-terminal domain, a conserved DNA binding domain (DBD), a hinge region and a conserved ligand-binding domain (LBD). The DBD targets the receptor to specific DNA
sequences (nuclear hormone response elements or NREs) and the LBD functions in the recognition of endogenous or exogenous chemical ligands. A constitutive transcriptional activation domain is found at the N-terminus (AF1) and a ligand regulated transcriptional activation domain is embedded within the C-terminal LBD of typical NRs. The nuclear receptors can exist in a transcriptional activating or repressing state when bound to their target NREs. The basic mechanism of gene activation involves ligand dependent exchange of co-regulatory proteins, namely co-activators and co-repressors (McKenna et at., Endocrine Rev. 1999, 20:321). A NR in the repressing state is bound to its DNA
recognition element and is associated with co-repressor proteins that recruit histone-deacetylases (HDACs). In the presence of an agonist, co-repressors are exchanged for coactivators that recruit transcription factors, which contribute to assembling of a chromatin-remodelling complex, which relieves transcriptional repression and stimulates transcriptional initiation via histone acetylation. The AF-2 domain of the LBD acts as a ligand dependant molecular switch presenting interaction surfaces for co-repressor or co-activator proteins and providing with a conserved mechanism for gene activation or repression that is shared by the members of the nuclear receptor superfamily.
The retinoid-receptor related orphan receptors consist of three family members, namely RORa (Beckerandre et al., Biochem. Biophys. Res. Commun. 1993, 194:1371), (Andre et at., Gene 1998, 516:277) and RORy (He et al., Immunity 1998, 9:797) and constitute the NR1F (ROR/RZR) subgroup of the nuclear receptor superfamily (Mangelsdorf et al., Cell 1995, 83:835).
The nuclear receptor superfamily shares common modular structural domains consisting of a hypervariable N-terminal domain, a conserved DNA binding domain (DBD), a hinge region and a conserved ligand-binding domain (LBD). The DBD targets the receptor to specific DNA
sequences (nuclear hormone response elements or NREs) and the LBD functions in the recognition of endogenous or exogenous chemical ligands. A constitutive transcriptional activation domain is found at the N-terminus (AF1) and a ligand regulated transcriptional activation domain is embedded within the C-terminal LBD of typical NRs. The nuclear receptors can exist in a transcriptional activating or repressing state when bound to their target NREs. The basic mechanism of gene activation involves ligand dependent exchange of co-regulatory proteins, namely co-activators and co-repressors (McKenna et at., Endocrine Rev. 1999, 20:321). A NR in the repressing state is bound to its DNA
recognition element and is associated with co-repressor proteins that recruit histone-deacetylases (HDACs). In the presence of an agonist, co-repressors are exchanged for coactivators that recruit transcription factors, which contribute to assembling of a chromatin-remodelling complex, which relieves transcriptional repression and stimulates transcriptional initiation via histone acetylation. The AF-2 domain of the LBD acts as a ligand dependant molecular switch presenting interaction surfaces for co-repressor or co-activator proteins and providing with a conserved mechanism for gene activation or repression that is shared by the members of the nuclear receptor superfamily.
The members of the NR1F family of nuclear receptors (such as RORy) have been considered to be constitutively active transcription factors in the absence of known ligands, which is similar to the estrogen-related receptor alpha (Vanacker et al., MoL
EndocrinoL
1999, 13:764). Most recently, 7-oxygenated oxysterols were identified to be high affinity ligands for RORa and RORy (Wang et al., J. BioL Chem. 2010, 285:5013). 7-Hydroxycholesterol is a key metabolite during the conversion of cholesterol into bile acids, but to date it is not clear whether it is a true endogenous ligand for the RORs. In any case it can be expected that inverse agonists of RORy should reduce the transcriptional activity of RORy and influence the biological pathways controlled by RORy.
The RORs are expressed as isoforms arising from differential splicing or alternative transcriptional start sites. So far, isoforms have been described that differ only in their N-terminal domain (NB-domain). In humans, four different RORa isoforms have been identified (RORa 1-4) while only two isoforms are known for both RORr3 (1 and 2) and RORy (1 and 2) (Andre et al., Gene 1998, 216:277; Villey et al., Eur. J. ImmunoL 1999, 29:4072). RORy is used herein as a term describing both, RORy1 and/or RORy2 (also called RORyt).
The ROR isoforms show different tissue expression patterns and regulate different target genes and physiological pathways. For example, the RORyt is highly restricted to CD4+CD8+
thymocytes and to interleukin-17 (IL-17) producing T cells while other tissues express RORy1 (Eberl et al., Science 2004, 305:248, Zhou and Littmann, Curr. Opin.
ImmunoL 2009, 21:146).
RORs exhibit a structural architecture that is typical of nuclear receptors.
RORs contain four major functional domains: an amino-terminal (NB) domain, a DNA-binding domain, a hinge domain and a ligand-binding domain (Evans et al., Science 1988, 240:889). The DBD
consists of two highly conserved zinc finger motifs involved in the recognition of ROR
response elements (ROREs) which consist of the consensus motif AGGTCA preceded by an AT-rich sequence (Andre et al., Gene 1998, 216:277) which is similar to that of the nuclear receptors Rev-ErbAa and Rev-Erb p (NR1D1 and D2, respectively) (Giguere et al., Genomics 1995, 28:596). These recognition elements do also show high similarity to those identified for the estrogen related receptors and in particular ERRa (ERRs, NR3B1, -2, -3) (Vanacker et al., Mol. EndocrinoL 1999, 13:764), steroidogenic factor 1 (SF-1, NR5A) and NGFI-B
(NR4A1, -2, -3) (Wilson et al., MoL CelL Biol. 1993, 13:5794).
EndocrinoL
1999, 13:764). Most recently, 7-oxygenated oxysterols were identified to be high affinity ligands for RORa and RORy (Wang et al., J. BioL Chem. 2010, 285:5013). 7-Hydroxycholesterol is a key metabolite during the conversion of cholesterol into bile acids, but to date it is not clear whether it is a true endogenous ligand for the RORs. In any case it can be expected that inverse agonists of RORy should reduce the transcriptional activity of RORy and influence the biological pathways controlled by RORy.
The RORs are expressed as isoforms arising from differential splicing or alternative transcriptional start sites. So far, isoforms have been described that differ only in their N-terminal domain (NB-domain). In humans, four different RORa isoforms have been identified (RORa 1-4) while only two isoforms are known for both RORr3 (1 and 2) and RORy (1 and 2) (Andre et al., Gene 1998, 216:277; Villey et al., Eur. J. ImmunoL 1999, 29:4072). RORy is used herein as a term describing both, RORy1 and/or RORy2 (also called RORyt).
The ROR isoforms show different tissue expression patterns and regulate different target genes and physiological pathways. For example, the RORyt is highly restricted to CD4+CD8+
thymocytes and to interleukin-17 (IL-17) producing T cells while other tissues express RORy1 (Eberl et al., Science 2004, 305:248, Zhou and Littmann, Curr. Opin.
ImmunoL 2009, 21:146).
RORs exhibit a structural architecture that is typical of nuclear receptors.
RORs contain four major functional domains: an amino-terminal (NB) domain, a DNA-binding domain, a hinge domain and a ligand-binding domain (Evans et al., Science 1988, 240:889). The DBD
consists of two highly conserved zinc finger motifs involved in the recognition of ROR
response elements (ROREs) which consist of the consensus motif AGGTCA preceded by an AT-rich sequence (Andre et al., Gene 1998, 216:277) which is similar to that of the nuclear receptors Rev-ErbAa and Rev-Erb p (NR1D1 and D2, respectively) (Giguere et al., Genomics 1995, 28:596). These recognition elements do also show high similarity to those identified for the estrogen related receptors and in particular ERRa (ERRs, NR3B1, -2, -3) (Vanacker et al., Mol. EndocrinoL 1999, 13:764), steroidogenic factor 1 (SF-1, NR5A) and NGFI-B
(NR4A1, -2, -3) (Wilson et al., MoL CelL Biol. 1993, 13:5794).
RORa is highly expressed in different brain regions and most highly in cerebellum and thalamus. RORa knock-out mice show ataxia with strong cerebellar atrophy, highly similar to the symptoms displayed in the so-called staggerer mutant mouse (RORasgisg).
This mouse carries mutations in RORa that results in a truncated RORa which does not contain a LBD
Analysis of RORasgisg staggerer-mice have revealed a strong impact on lipid metabolism beyond the CNS defects, namely significant decreases in serum and liver triglyceride, reduced serum HDL cholesterol levels and reduced adiposity. SREBP1c and the cholesterol transporters ABCA1 and ABCG1 are reduced in livers of staggerer mice and CHIP
analysis RORp knock-out mice display a duck-like gait and retinal degeneration which leads to blindness (Andre et al., EMBO J. 1998, 17:3867). The molecular mechanisms behind this retinal degeneration are still poorly understood.
RORy (particularly RORyt) null-mutant mice lack lymph nodes and Peyer's patches (Eberl 25 development.
Thymocyte development follows a complex program involving coordinated cycles of proliferation, differentiation, cell death and gene recombination in cell populations dedicated by their microenvironment. Pluripotent lymphocyte progenitors migrating from fetal liver or adult bone marrow to the thymus are being committed to the T-cell lineage.
They develop expressed in double negative and little expressed in immature single negative thymocytes (He et al., J. Immunol. 2000, 164:5668), while highly upregulated in double-positive thymocytes and downregulated during differentiation in single-positive thymocytes. RORy deficiency results in increased apoptosis in CD4+CD8+ cells and the number of peripheral blood thymocytes is decreased by 6-fold (10-fold CD4+ and 3-fold CD8+
thymocytes).
Recent experiments in a model of ovalbumin (OVA)-induced inflammation in mice, as a model for allergic airway disease, demonstrated a severe impairment of the development of the allergic phenotype in the RORy KO mice with decreased numbers of CD4+
cells and lower Th2 cytokine/chemokine protein and mRNA expression in the lungs after challenge with OVA (Tilley et al., J. Immunol. 2007, 178:3208). IFN-y and IL-10 production were increased in splenocytes following re-stimulation with the OVA antigen compared to wt splenocytes suggesting a shift towards a Th1 type immune response on cost of a reduction of Th2 type response. This suggests that down-modulation of RORy transcriptional activity with a ligand could result in a similar shift of the immune response towards a Th1 type response, which could be beneficial in the treatment of certain pulmonary diseases like asthma, chronic obstructive pulmonary disease (COPD) or allergic inflammatory conditions.
T-helper cells were previously considered to consist of Th1 and Th2 cells.
However, a new class of Th cells, the Th17 cells, which produce IL-17, were also identified as a unique class of T-cells that are considered to be pro-inflammatory. They are recognized as key players in autoimmune and inflammatory diseases since IL-17 expression has been associated with many inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and allograft rejection. (Tesmer et al., Immunol. Rev. 2008, 223:87).
RORyt is exclusively expressed in cells of the immune system and has been identified as a master regulator of Th17 cell differentiation. Expression of RORyt is induced by TGF-beta or IL-6 and overexpression of RORyt results in increased Th17 cell lineage and IL-expression. RORyt KO mice show very little Th17 cells in the intestinal lamina propria and demonstrate an attenuated response to challenges that usually lead to autoimmune disease (Ivanov et al., Cell 2006, 126:1121).
Inhibition of IL-17 production via inhibition of Th17 cell development may also be advantageous in atopic dermatitis and psoriasis where IL-17 is deeply involved. Interestingly, recent evidence was presented that IL-10 suppresses the expression of IL-17 secreted by both, macrophages and T-cells. In addition, the expression of the Th17 transcription factor RORyt was suppressed (Gu et al., Eur. J. Immunot 2008, 38:1807). Moreover, IL-deficient mice provide a good model for inflammatory bowel disease (IBD) where a shift towards a Th1 type inflammatory response is frequently observed. Oral IL-10 delivery poses a potential treatment option for IBD.
This mouse carries mutations in RORa that results in a truncated RORa which does not contain a LBD
Analysis of RORasgisg staggerer-mice have revealed a strong impact on lipid metabolism beyond the CNS defects, namely significant decreases in serum and liver triglyceride, reduced serum HDL cholesterol levels and reduced adiposity. SREBP1c and the cholesterol transporters ABCA1 and ABCG1 are reduced in livers of staggerer mice and CHIP
analysis RORp knock-out mice display a duck-like gait and retinal degeneration which leads to blindness (Andre et al., EMBO J. 1998, 17:3867). The molecular mechanisms behind this retinal degeneration are still poorly understood.
RORy (particularly RORyt) null-mutant mice lack lymph nodes and Peyer's patches (Eberl 25 development.
Thymocyte development follows a complex program involving coordinated cycles of proliferation, differentiation, cell death and gene recombination in cell populations dedicated by their microenvironment. Pluripotent lymphocyte progenitors migrating from fetal liver or adult bone marrow to the thymus are being committed to the T-cell lineage.
They develop expressed in double negative and little expressed in immature single negative thymocytes (He et al., J. Immunol. 2000, 164:5668), while highly upregulated in double-positive thymocytes and downregulated during differentiation in single-positive thymocytes. RORy deficiency results in increased apoptosis in CD4+CD8+ cells and the number of peripheral blood thymocytes is decreased by 6-fold (10-fold CD4+ and 3-fold CD8+
thymocytes).
Recent experiments in a model of ovalbumin (OVA)-induced inflammation in mice, as a model for allergic airway disease, demonstrated a severe impairment of the development of the allergic phenotype in the RORy KO mice with decreased numbers of CD4+
cells and lower Th2 cytokine/chemokine protein and mRNA expression in the lungs after challenge with OVA (Tilley et al., J. Immunol. 2007, 178:3208). IFN-y and IL-10 production were increased in splenocytes following re-stimulation with the OVA antigen compared to wt splenocytes suggesting a shift towards a Th1 type immune response on cost of a reduction of Th2 type response. This suggests that down-modulation of RORy transcriptional activity with a ligand could result in a similar shift of the immune response towards a Th1 type response, which could be beneficial in the treatment of certain pulmonary diseases like asthma, chronic obstructive pulmonary disease (COPD) or allergic inflammatory conditions.
T-helper cells were previously considered to consist of Th1 and Th2 cells.
However, a new class of Th cells, the Th17 cells, which produce IL-17, were also identified as a unique class of T-cells that are considered to be pro-inflammatory. They are recognized as key players in autoimmune and inflammatory diseases since IL-17 expression has been associated with many inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and allograft rejection. (Tesmer et al., Immunol. Rev. 2008, 223:87).
RORyt is exclusively expressed in cells of the immune system and has been identified as a master regulator of Th17 cell differentiation. Expression of RORyt is induced by TGF-beta or IL-6 and overexpression of RORyt results in increased Th17 cell lineage and IL-expression. RORyt KO mice show very little Th17 cells in the intestinal lamina propria and demonstrate an attenuated response to challenges that usually lead to autoimmune disease (Ivanov et al., Cell 2006, 126:1121).
Inhibition of IL-17 production via inhibition of Th17 cell development may also be advantageous in atopic dermatitis and psoriasis where IL-17 is deeply involved. Interestingly, recent evidence was presented that IL-10 suppresses the expression of IL-17 secreted by both, macrophages and T-cells. In addition, the expression of the Th17 transcription factor RORyt was suppressed (Gu et al., Eur. J. Immunot 2008, 38:1807). Moreover, IL-deficient mice provide a good model for inflammatory bowel disease (IBD) where a shift towards a Th1 type inflammatory response is frequently observed. Oral IL-10 delivery poses a potential treatment option for IBD.
5 The proinflammatory actions of IL-17 producing Th17 cells are counteracted by another T-helper cell type, so-called regulatory T-cells or Tregs. Naïve T-cells are differentiated into Tregs upon stimulation by TGFI3. This results in upregulation of the transcriptional modulator FoxP3 resulting in CD4+FoxP3+ Tregs. In case the naïve T-cells are co-stimulated by IL-6, FoxP3 expression is suppressed and RORyt expression is induced. These CD4+FoxP3-RORyt+ T-helper cells then differentiate into IL-17 producing Th17 cells.
(reviewed in Awasthi and Kuchroo, Int. Immunol. 2009, 21:489 and Zhou and Littmann, Curr.
Opin. Immunot 2009, 21:146). Several lines of evidence suggest that these Th17 cells are responsible for the etiology of a whole range of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, Crohn's disease and other types of inflammatory bowel disease, lupus erythematosus and asthma. The severity of disease seems to correlate with the presence of 1L-17+ Th17 cells and it is believed that interception of RORyt by a small molecule inverse agonist or antagonist should result in a reduction of these 1L-17+ Th17 cells ultimately leading to alleviation of disease symptoms and outcome (Crome et at., Clin. Exp. Immunot 2010, 159:109).
Lk:lands for the RORs:
It was reported that cholesterol and its sulfated derivatives might function as RORa ligands and in particular cholesterol-sulfate could restore transcriptional activity of RORa in cholesterol-depleted cells (Kalien et at., Structure 2002, 10:1697).
Previously, melatonin (Missbach et al., J. Biol. Chem. 1998, 271:13515) and thiazolidinediones were suggested to bind to RORa (Wiesenberg et al., Nucleic Acid Res. 1995, 23:327). However, none of these have been shown to be functional ligands of RORa or of any other of the RORs.
Certain retinoids including all-trans retinoid acid have been demonstrated to bind to RORIE1 and function as partial antagonists for RORI3 but not RORa (Stehlin-Gaon et at., Nat. Struct Biol.
2003, 10:820).
Recently, 7-oxygenated sterols such as 7-hydroxy-cholesterol and 7-keto-cholesterol were identified as highly potent modulators of RORy activity (Wang et al., J. Biol.
Chem. 2010, 285:5013) in in vitro assays. The same group of investigators also found that a known LXR
(reviewed in Awasthi and Kuchroo, Int. Immunol. 2009, 21:489 and Zhou and Littmann, Curr.
Opin. Immunot 2009, 21:146). Several lines of evidence suggest that these Th17 cells are responsible for the etiology of a whole range of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, Crohn's disease and other types of inflammatory bowel disease, lupus erythematosus and asthma. The severity of disease seems to correlate with the presence of 1L-17+ Th17 cells and it is believed that interception of RORyt by a small molecule inverse agonist or antagonist should result in a reduction of these 1L-17+ Th17 cells ultimately leading to alleviation of disease symptoms and outcome (Crome et at., Clin. Exp. Immunot 2010, 159:109).
Lk:lands for the RORs:
It was reported that cholesterol and its sulfated derivatives might function as RORa ligands and in particular cholesterol-sulfate could restore transcriptional activity of RORa in cholesterol-depleted cells (Kalien et at., Structure 2002, 10:1697).
Previously, melatonin (Missbach et al., J. Biol. Chem. 1998, 271:13515) and thiazolidinediones were suggested to bind to RORa (Wiesenberg et al., Nucleic Acid Res. 1995, 23:327). However, none of these have been shown to be functional ligands of RORa or of any other of the RORs.
Certain retinoids including all-trans retinoid acid have been demonstrated to bind to RORIE1 and function as partial antagonists for RORI3 but not RORa (Stehlin-Gaon et at., Nat. Struct Biol.
2003, 10:820).
Recently, 7-oxygenated sterols such as 7-hydroxy-cholesterol and 7-keto-cholesterol were identified as highly potent modulators of RORy activity (Wang et al., J. Biol.
Chem. 2010, 285:5013) in in vitro assays. The same group of investigators also found that a known LXR
agonist, TO901317 ([N-(2,2,2-trifluoroethyl)-N44-[2,2,2-trifluoro-1-hydroxy-1-(trifluoro-methypethyl]phenyli-benzenesulfonamide]) acts as a RORy inverse agonist at submicromolar potency (Kumar et al., MoL PharmacoL 2010, 77:228). In neither case, however, in vivo data were obtained that demonstrate a beneficial impact of these RORy modulating compounds. In case of the 7-oxysterols their endogenous presence as metabolites naturally produced by the body itself as well as their rapid turnover and their biological activities on many cellular proteins prevent a meaningful animal study that allows drawing conclusions on the role of RORy. In case of the T0901317 its polypharmacodynamic properties, acting on at least six different nuclear receptors (LXRa/13., FXR, PXR, RORa/y) prevents its usefulness as a drug candidate for the development in an autoimmune disease application (Houck et al., MoL Genet. Metab. 2004, 83:184; Xue et al., Bioorg.
Med. Chem.
2007, 15:2156).
W02004/060870 describes pyrrolo carboxamide compounds of structure (A) as modulators of the CB1 receptor useful for treating and preventing eating disorders, obesity, type II
diabetes and the like, (A) IRµJ N
(6H2)mR3 wherein R1 is H or lower alkyl;
R2 is limited to C1-8-alkyl, (CHO orroyclolalkyl or a (CH2)00r1 connected to a 5- or 6-membered saturated heterocycle or 5- or 6-membered heteroaromatic ring, wherein the corresponding ring can be optionally substituted. Remarkably, C1.8-alkyl can not be optionally substituted; R3 is limited to optionally substituted cycloalkyl or optionally substituted phenyl;
R4 is limited to optionally substituted phenyl, naphthyl or a 5- or 6-membered heteroaromatic ring. Possible substitutents for R4 are OH, C1_8-alkyl, 0-C1.8-alkyl, halogen, NO2, C1 -8' halogenated alkyl, 0-C1.8-halogenated alkyl, CN, S02-C1.8-alkyl and optionally alkylated amine. Remarkably, R4 can not be substituted e.g. with C0.8-alkyIene-CONR2, C0_8-alkylene-SO2NR2, C0_8-alkylene-NRCOR or C0_8-alkylene-NRSO2R.
W02005/108393 describes pyrrolo carboxamide compounds of structure (A) as modulators of the CB1 receptor, wherein 1:13 is limited to a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from N or 0, which is optionally substituted by OH, C1_8-alkyl, 0-C1.8-alkyl, C(.0)0-C1.8-alkyl or being condensed with a phenyl ring and R4 is limited to phenyl, optionally substituted only by OH, C1.8-alkyl, halo-C1-8-alkyl, 0-C1.8-alkyl, 0-halo-C1_6-alkyl and halogen.
W02004/060888 describes pyrrolo carboxamide compounds of structure (A) as modulators of the CBI receptor, wherein R4 is limited to optionally substituted 4-thiazolyl.
In none of the above mentioned publications a 4-membered heterocycle is claimed as substituent for R1 or R2. Furthermore there are no references, that these pyrrolo carboxamide compounds have RORy receptor modulating activity.
US2009/0036421 (equivalent to W02007/097276) describes pyrrolo carboxamide compounds of structure (B) as 5-HT2B and 5-HT7 receptor modulators for the treatment of irritable bowel syndrome / \ (B) R4 m R3 .,.
R2 .
However, there is no reference, that compounds have RORy receptor modulating activity.
In W02006/012642 are pyrrolo-3-carboxamides described, in particular compounds wherein a C1.3-alkylene-cycloalkyl group is connected to the pyrrolo nitrogen, e.g.
structures (C) and (C').
0, 0 z it 4.
N
NH H
N$ (C) N$ (C') W02004/103968 describes 2-phenylsulfopyrroles wherein the sulfonyl residue is restricted to optionally substituted phenyl.
Med. Chem.
2007, 15:2156).
W02004/060870 describes pyrrolo carboxamide compounds of structure (A) as modulators of the CB1 receptor useful for treating and preventing eating disorders, obesity, type II
diabetes and the like, (A) IRµJ N
(6H2)mR3 wherein R1 is H or lower alkyl;
R2 is limited to C1-8-alkyl, (CHO orroyclolalkyl or a (CH2)00r1 connected to a 5- or 6-membered saturated heterocycle or 5- or 6-membered heteroaromatic ring, wherein the corresponding ring can be optionally substituted. Remarkably, C1.8-alkyl can not be optionally substituted; R3 is limited to optionally substituted cycloalkyl or optionally substituted phenyl;
R4 is limited to optionally substituted phenyl, naphthyl or a 5- or 6-membered heteroaromatic ring. Possible substitutents for R4 are OH, C1_8-alkyl, 0-C1.8-alkyl, halogen, NO2, C1 -8' halogenated alkyl, 0-C1.8-halogenated alkyl, CN, S02-C1.8-alkyl and optionally alkylated amine. Remarkably, R4 can not be substituted e.g. with C0.8-alkyIene-CONR2, C0_8-alkylene-SO2NR2, C0_8-alkylene-NRCOR or C0_8-alkylene-NRSO2R.
W02005/108393 describes pyrrolo carboxamide compounds of structure (A) as modulators of the CB1 receptor, wherein 1:13 is limited to a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from N or 0, which is optionally substituted by OH, C1_8-alkyl, 0-C1.8-alkyl, C(.0)0-C1.8-alkyl or being condensed with a phenyl ring and R4 is limited to phenyl, optionally substituted only by OH, C1.8-alkyl, halo-C1-8-alkyl, 0-C1.8-alkyl, 0-halo-C1_6-alkyl and halogen.
W02004/060888 describes pyrrolo carboxamide compounds of structure (A) as modulators of the CBI receptor, wherein R4 is limited to optionally substituted 4-thiazolyl.
In none of the above mentioned publications a 4-membered heterocycle is claimed as substituent for R1 or R2. Furthermore there are no references, that these pyrrolo carboxamide compounds have RORy receptor modulating activity.
US2009/0036421 (equivalent to W02007/097276) describes pyrrolo carboxamide compounds of structure (B) as 5-HT2B and 5-HT7 receptor modulators for the treatment of irritable bowel syndrome / \ (B) R4 m R3 .,.
R2 .
However, there is no reference, that compounds have RORy receptor modulating activity.
In W02006/012642 are pyrrolo-3-carboxamides described, in particular compounds wherein a C1.3-alkylene-cycloalkyl group is connected to the pyrrolo nitrogen, e.g.
structures (C) and (C').
0, 0 z it 4.
N
NH H
N$ (C) N$ (C') W02004/103968 describes 2-phenylsulfopyrroles wherein the sulfonyl residue is restricted to optionally substituted phenyl.
W02011/042477 describes substituted pyrroles and imidazoles as estrogen receptor ligands. However no pyrrolo-3-carboxamides are disclosed, which have a C1_3-alkylene-cycloalkyl group connected to the pyrrolo nitrogen.
The Chemical Abstract database lists several pyrrolo carboxamides with no accompanying literature references, which are excluded via provisos form the presented claims, e.g.
0 I\
SV * N 011101 (D) (D') 0 (D") W02012/144661 describes substituted pyrroles as TRPV4 inhibitors with a very broad coverage of various substituents. However no pyrrolo-3-carboxamides are disclosed, which fall in the scope of the present invention. In particular, no compounds with a cycloalkyl group connected via a linker (e.g. alkylene or SO2) to the pyrrole nitrogen are specifically disclosed.
Modulators of the RORy receptor were recently disclosed in W02011/107248, W02011/112263, W02011/112264, W02011/115892, W02012/027965, W02012/028100, W02012/064744, W02012/100732, W02012/100734, W02012/106995, W02012/139775, W02012/147916 and W02012/158784, which are based upon other structural classes.
Summary of the invention It is therefore the object of the present invention to provide compounds, which bind to the orphan nuclear receptors RORy1 and/or RORyt and, thus, to open new methods for treating diseases associated with the modulation of RORy, such as autoimmune diseases, inflammatory skin diseases or multiple sclerosis.
This object is solved by claims 1 to 24.
Thus, the present invention provides pyrrolo carboxamides compounds as RORy modulators, which can be used for treating or preventing a disease or disorder associated with the inactivation or activation of the RORy receptor.
The Chemical Abstract database lists several pyrrolo carboxamides with no accompanying literature references, which are excluded via provisos form the presented claims, e.g.
0 I\
SV * N 011101 (D) (D') 0 (D") W02012/144661 describes substituted pyrroles as TRPV4 inhibitors with a very broad coverage of various substituents. However no pyrrolo-3-carboxamides are disclosed, which fall in the scope of the present invention. In particular, no compounds with a cycloalkyl group connected via a linker (e.g. alkylene or SO2) to the pyrrole nitrogen are specifically disclosed.
Modulators of the RORy receptor were recently disclosed in W02011/107248, W02011/112263, W02011/112264, W02011/115892, W02012/027965, W02012/028100, W02012/064744, W02012/100732, W02012/100734, W02012/106995, W02012/139775, W02012/147916 and W02012/158784, which are based upon other structural classes.
Summary of the invention It is therefore the object of the present invention to provide compounds, which bind to the orphan nuclear receptors RORy1 and/or RORyt and, thus, to open new methods for treating diseases associated with the modulation of RORy, such as autoimmune diseases, inflammatory skin diseases or multiple sclerosis.
This object is solved by claims 1 to 24.
Thus, the present invention provides pyrrolo carboxamides compounds as RORy modulators, which can be used for treating or preventing a disease or disorder associated with the inactivation or activation of the RORy receptor.
The present invention relates to a RORy modulator which is based on a pyrrolo carboxamide scaffold for use in the treatment or prophylaxis of a disease or disorder associated with the inhibition or activation of RORy.
When treating the disease or disorder associated with the modulation of the RORy receptor, the activity of said receptor is preferably reduced.
Preferably, the disease or disorder is selected from the group consisting of autoimmune diseases. Autoimmune diseases comprise a group of diseases with a similar etiology of an overshooting immune response against endogenous targets resulting in chronic inflammation and physical disabilities or other severe symptoms. Autoimmune diseases comprise e.g. rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD), infectious diseases such as mucosal leishmaniasis, multiple sclerosis, systemic sclerosis, type 1 diabetes, Kawasaki disease, Hashimoto's thyroiditis, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjorgren's syndrome, scleroderma, ulcerative colitis, epidermal hyperplasia, glomerulonephritis and amyotrophic lateral sclerosis. In a preferred embodiment, the disease or disorder is rheumatoid arthritis or psoriasis.
The present invention provides novel compounds to be used in the treatment of diseases or disorders associated with the inactivation or activation of the RORy receptor.
Moreover, the present provides a method for treating a disease or disorder associated with the modulation of the RORy receptor, wherein the method comprises administering an effective amount of a compound according to Formula (1) to a subject in need thereof. The disease or disorder is preferably selected from the group consisting of autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, espiratory diseases such as asthma or COPD, infectious diseases such as mucosal leishmaniasis, multiple sclerosis, systemic sclerosis, type 1 diabetes, Kawasaki disease, Hashimoto's thyroiditis, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjorgren's syndrome, scleroderma, ulcerative colitis, epidermal hyperplasia, glomerulonephritis and amyotrophic lateral sclerosis. In a certain embodiment the disorder is rheumatoid arthritis and psoriasis.
Detailed description of the invention The present invention provides a compound represented by Formula (1) ()Z6 R- N R-. (1) an enantiomer, diastereomer, tautomer, N-oxide, solvate, formulation and pharmaceutically acceptable salt thereof, wherein 10 R1 is selected from H, C1_10-alkyl, C2_10-alkenyl, C2_10-alkynyl, C3_6-cycloalkyl, C3.6-heterocycloalkyl, C1_10-alkylene-C3_10-cycloalkyl, C1_10-alkylene-C3_10-heterocycloalkyl, C1-10-alkylene-(5-membered monocyclic heteroaryl), S02-C1_10-alkyl, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR11, 0-C2_6-alkylene-OR11, C1.6-alkyl, halo-C1.6-alkyl, halogen, CO2R11, C0NR11R12, cow, soy-11, SO3H, SO2NR11R12, NR11COR11, NR11so2Ril, NRii_co_NRiiR12, N -0 1-SO2-NR11P
-12, C3_6-cycloalkyl, 0-C3-6-cycloalkyl, C3_6-heterocycloalkyl, 0-C3.6-heterocycloalkyl and NR11R12; and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S, wherein pyridinone and spiroheterocycle is optionally substituted with 1 to 4 groups independently selected from halogen, C1.6-alkyl, halo-C1.6-alkyl, OH, 0-C1.6-alkyl, 0-halo-C1_ 6-alkyl, oxo, =N-0R32, N(R32), Co_6-alkylene-C3_10-cycloalkyl, C0.6-alkylene-heterocycloalkyl, C0_6-alkylene-(5- or 6-membered monocyclic heteroaryl), C1.6-alkylene-0-R31, C0_6-alkylene-CN, 0-C3_10-cycloalkyl, 0-C1_6-alkylene-O-R32, 0-C3_10-heterocycloalkyl, Co_ 6-alkylene-COOR31, C0.6-alkylene-C(0)R31, C0_6-alkylene-C(0)N(R31)2, Co_6-alkylene-N(R31)C(0)R31, C0_6-alkylene-SO-R31, C0_6-alkylene-S02-R31, Co_6-alkylene-S02-N(R31)2, C0-6-alkylene-N(R31)S02-R31, C0_6-alkylene-S02-C3_10-heterocycloalkyl and C0_6-alkylene-S02-C3_ 10-heterocycloalkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1.3-alkyl, halo-C1_3-alkyl, OH, oxo, 0-C1_3-alkyl and 0-halo-C1_3-alkyl;
wherein aryl and heteroaryl is substituted with at least one group selected from C3-10-cycloalkyl, C4-heterocycloalkyl, C1.4-alkylene-C3.10-cycloalkyl, C1_4-alkylene-(C3-10-heterocycloalkyl), carbon atom linked 5- or 6-membered monocyclic heteroaryl, alkylene-(5- or 6-membered monocyclic heteroaryl), C1.4-alkylene-O-R31, C14-alkylene-CN, 0-C3.10-cycloalkyl, 0-C1_6-alkylene-O-R32, 0-C3.10-heterocycloalkyl, C0_6-alkylene-000R31, C0_ 6-alkylene-C(0)R31, C0_6-alkylene-C(0)N(R31)2, C0_6-alkylene-N(R31)C(0)R31, C0_6-alkylene-SO-R31, C1_6-alkylene-S02-R31, Co_calkylene-S02-N(R31)2, Co_6-alkylene-N(R31)S02-R31, SO2-C3_10-heterocycloalkyl, S02-C3.10-cycloalkyl, C0.6-alkylene-SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1_6-alkyl, C3_6-cycloalkyl, C3_6-heterocycloalkyl, oxo, =N-0R32, OH, 0-C1_6-alkyl and 0-halo-C1_6-alkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, halo-C1.3-alkyl, OH, oxo, =N-0R32, 0-C1.3-alkyl and 0-halo-C1_3-alkyl; and wherein aryl and heteroaryl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1_3-alkyl, halo-C1.3-alkyl, OH, 0-C1-3-alkyl and 0-halo-C1.3-alkyl;
or R1 is selected from a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0 and S, or C1_10-alkyl substituted with a group selected from halogen, ON, OR", SOyR11, SO3H, NR11s02-01, SO2NR11 iR co2R1 comv1R12, NRil_co_NRil R12, NRil_s02_ NR11R12 and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0 and S, or C0.1-alkylene-C3_10-cycloalkyl substituted with a group selected from halogen, ON, SOyR11, NR11s02-11, S02NR11 R12, 002R11, c0NR11R123 NR11_co-R11, NR11-CO_NR11 R12, NRil_sor NR11-ri 12 and NR11R12, or C2_10-alkylene-03_10-cycloalkyl, C2.10-alkylene-O-C3_10-cycloalkyl, 02.10-alkylene-05-10-heterocycloalkyl, C2.10-alkylene-O-C6_10-heterocycloalkyl and S02-C1_10-alkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, ON, 0-01_6-alkyl, 0-halo-01.6-alkyl, C1_6-alkyl, halo-C1_6-alkyl, halogen, CO2R11, coNR, 1 K-12, C0R11, S02R11, S02Nw1R12, NRiicoRii, NR11s02R11, 03_6-cycloalkyl, 0-C3.6-cycloalkyl, O36 heterocycloalkyl, 0-03.6-heterocycloalkyl, 0-C2_6-alkylene-0R11 and NR11R12;
and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S, wherein pyridinone, aryl and heteroaryl and spiroheterocycle is optionally substituted with 1 to 4 groups independently selected from halogen, 01_6-alkyl, halo-C1.6-alkyl, OH, 0-C1_6-alkyl, 0-halo-C1.6-alkyl, oxo, =N-0R32, N(R32), 00.6-alkylene-C3_10-cycloalkyl, 00_6-alkylene-03-10-heterocycloalkyl, C0_6-alkylene-(5- or 6-membered monocyclic heteroaryl), 01_6-alkylene-0-R31, 00_6-alkylene-ON, 0-03_10-cycloalkyl, 0-C1_6-alkylene-O-R32, 0-03_10-heterocycloalkyl, Co-6-alkylene-COOR31, C0.6-alkylene-C(0)R31, Co_6-alkylene-C(0)N(R31)2, 00.6-alkylene-N(R31)C(0)R31, 00.6-alkylene-SO-R31, C0_6-alkylene-S02-R31, Co_calkylene-S02-N(R31)2 and 00_6-alkylene-N(R31)S02-R31, and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, 01_6-alkyl, halo-C1.6-alkyl, 03-6-cycloalkyl, C3_6-heterocycloalkyl, oxo, =N-0R32, OH, 0-C1.6-alkyl and 0-halo-C1_6-alkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, ON, halo-01.3-alkyl, OH, oxo, =N-0R32, 0-C1_3-alkyl and 0-halo-C1.3-alkyl;
When treating the disease or disorder associated with the modulation of the RORy receptor, the activity of said receptor is preferably reduced.
Preferably, the disease or disorder is selected from the group consisting of autoimmune diseases. Autoimmune diseases comprise a group of diseases with a similar etiology of an overshooting immune response against endogenous targets resulting in chronic inflammation and physical disabilities or other severe symptoms. Autoimmune diseases comprise e.g. rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD), infectious diseases such as mucosal leishmaniasis, multiple sclerosis, systemic sclerosis, type 1 diabetes, Kawasaki disease, Hashimoto's thyroiditis, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjorgren's syndrome, scleroderma, ulcerative colitis, epidermal hyperplasia, glomerulonephritis and amyotrophic lateral sclerosis. In a preferred embodiment, the disease or disorder is rheumatoid arthritis or psoriasis.
The present invention provides novel compounds to be used in the treatment of diseases or disorders associated with the inactivation or activation of the RORy receptor.
Moreover, the present provides a method for treating a disease or disorder associated with the modulation of the RORy receptor, wherein the method comprises administering an effective amount of a compound according to Formula (1) to a subject in need thereof. The disease or disorder is preferably selected from the group consisting of autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, espiratory diseases such as asthma or COPD, infectious diseases such as mucosal leishmaniasis, multiple sclerosis, systemic sclerosis, type 1 diabetes, Kawasaki disease, Hashimoto's thyroiditis, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjorgren's syndrome, scleroderma, ulcerative colitis, epidermal hyperplasia, glomerulonephritis and amyotrophic lateral sclerosis. In a certain embodiment the disorder is rheumatoid arthritis and psoriasis.
Detailed description of the invention The present invention provides a compound represented by Formula (1) ()Z6 R- N R-. (1) an enantiomer, diastereomer, tautomer, N-oxide, solvate, formulation and pharmaceutically acceptable salt thereof, wherein 10 R1 is selected from H, C1_10-alkyl, C2_10-alkenyl, C2_10-alkynyl, C3_6-cycloalkyl, C3.6-heterocycloalkyl, C1_10-alkylene-C3_10-cycloalkyl, C1_10-alkylene-C3_10-heterocycloalkyl, C1-10-alkylene-(5-membered monocyclic heteroaryl), S02-C1_10-alkyl, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR11, 0-C2_6-alkylene-OR11, C1.6-alkyl, halo-C1.6-alkyl, halogen, CO2R11, C0NR11R12, cow, soy-11, SO3H, SO2NR11R12, NR11COR11, NR11so2Ril, NRii_co_NRiiR12, N -0 1-SO2-NR11P
-12, C3_6-cycloalkyl, 0-C3-6-cycloalkyl, C3_6-heterocycloalkyl, 0-C3.6-heterocycloalkyl and NR11R12; and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S, wherein pyridinone and spiroheterocycle is optionally substituted with 1 to 4 groups independently selected from halogen, C1.6-alkyl, halo-C1.6-alkyl, OH, 0-C1.6-alkyl, 0-halo-C1_ 6-alkyl, oxo, =N-0R32, N(R32), Co_6-alkylene-C3_10-cycloalkyl, C0.6-alkylene-heterocycloalkyl, C0_6-alkylene-(5- or 6-membered monocyclic heteroaryl), C1.6-alkylene-0-R31, C0_6-alkylene-CN, 0-C3_10-cycloalkyl, 0-C1_6-alkylene-O-R32, 0-C3_10-heterocycloalkyl, Co_ 6-alkylene-COOR31, C0.6-alkylene-C(0)R31, C0_6-alkylene-C(0)N(R31)2, Co_6-alkylene-N(R31)C(0)R31, C0_6-alkylene-SO-R31, C0_6-alkylene-S02-R31, Co_6-alkylene-S02-N(R31)2, C0-6-alkylene-N(R31)S02-R31, C0_6-alkylene-S02-C3_10-heterocycloalkyl and C0_6-alkylene-S02-C3_ 10-heterocycloalkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1.3-alkyl, halo-C1_3-alkyl, OH, oxo, 0-C1_3-alkyl and 0-halo-C1_3-alkyl;
wherein aryl and heteroaryl is substituted with at least one group selected from C3-10-cycloalkyl, C4-heterocycloalkyl, C1.4-alkylene-C3.10-cycloalkyl, C1_4-alkylene-(C3-10-heterocycloalkyl), carbon atom linked 5- or 6-membered monocyclic heteroaryl, alkylene-(5- or 6-membered monocyclic heteroaryl), C1.4-alkylene-O-R31, C14-alkylene-CN, 0-C3.10-cycloalkyl, 0-C1_6-alkylene-O-R32, 0-C3.10-heterocycloalkyl, C0_6-alkylene-000R31, C0_ 6-alkylene-C(0)R31, C0_6-alkylene-C(0)N(R31)2, C0_6-alkylene-N(R31)C(0)R31, C0_6-alkylene-SO-R31, C1_6-alkylene-S02-R31, Co_calkylene-S02-N(R31)2, Co_6-alkylene-N(R31)S02-R31, SO2-C3_10-heterocycloalkyl, S02-C3.10-cycloalkyl, C0.6-alkylene-SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1_6-alkyl, C3_6-cycloalkyl, C3_6-heterocycloalkyl, oxo, =N-0R32, OH, 0-C1_6-alkyl and 0-halo-C1_6-alkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, halo-C1.3-alkyl, OH, oxo, =N-0R32, 0-C1.3-alkyl and 0-halo-C1_3-alkyl; and wherein aryl and heteroaryl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1_3-alkyl, halo-C1.3-alkyl, OH, 0-C1-3-alkyl and 0-halo-C1.3-alkyl;
or R1 is selected from a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0 and S, or C1_10-alkyl substituted with a group selected from halogen, ON, OR", SOyR11, SO3H, NR11s02-01, SO2NR11 iR co2R1 comv1R12, NRil_co_NRil R12, NRil_s02_ NR11R12 and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0 and S, or C0.1-alkylene-C3_10-cycloalkyl substituted with a group selected from halogen, ON, SOyR11, NR11s02-11, S02NR11 R12, 002R11, c0NR11R123 NR11_co-R11, NR11-CO_NR11 R12, NRil_sor NR11-ri 12 and NR11R12, or C2_10-alkylene-03_10-cycloalkyl, C2.10-alkylene-O-C3_10-cycloalkyl, 02.10-alkylene-05-10-heterocycloalkyl, C2.10-alkylene-O-C6_10-heterocycloalkyl and S02-C1_10-alkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, ON, 0-01_6-alkyl, 0-halo-01.6-alkyl, C1_6-alkyl, halo-C1_6-alkyl, halogen, CO2R11, coNR, 1 K-12, C0R11, S02R11, S02Nw1R12, NRiicoRii, NR11s02R11, 03_6-cycloalkyl, 0-C3.6-cycloalkyl, O36 heterocycloalkyl, 0-03.6-heterocycloalkyl, 0-C2_6-alkylene-0R11 and NR11R12;
and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S, wherein pyridinone, aryl and heteroaryl and spiroheterocycle is optionally substituted with 1 to 4 groups independently selected from halogen, 01_6-alkyl, halo-C1.6-alkyl, OH, 0-C1_6-alkyl, 0-halo-C1.6-alkyl, oxo, =N-0R32, N(R32), 00.6-alkylene-C3_10-cycloalkyl, 00_6-alkylene-03-10-heterocycloalkyl, C0_6-alkylene-(5- or 6-membered monocyclic heteroaryl), 01_6-alkylene-0-R31, 00_6-alkylene-ON, 0-03_10-cycloalkyl, 0-C1_6-alkylene-O-R32, 0-03_10-heterocycloalkyl, Co-6-alkylene-COOR31, C0.6-alkylene-C(0)R31, Co_6-alkylene-C(0)N(R31)2, 00.6-alkylene-N(R31)C(0)R31, 00.6-alkylene-SO-R31, C0_6-alkylene-S02-R31, Co_calkylene-S02-N(R31)2 and 00_6-alkylene-N(R31)S02-R31, and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, 01_6-alkyl, halo-C1.6-alkyl, 03-6-cycloalkyl, C3_6-heterocycloalkyl, oxo, =N-0R32, OH, 0-C1.6-alkyl and 0-halo-C1_6-alkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, ON, halo-01.3-alkyl, OH, oxo, =N-0R32, 0-C1_3-alkyl and 0-halo-C1.3-alkyl;
and R2 is selected from the group consisting of H, halo-C1_6-alkyl and hydroxy-C1-6-alkyl, or 1:11 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR", SOyR11, SO3H, 11, NR11s02-1-tSO2NRil C0_6-alkylene-CO2R11, CONR11 R12, C0R11, NR11-CO-R11, NR11-CO-NR R12, NR-SO2-NRiiR12, NR11.-. 1112, C1_6-alkyl, hydroxy-C1_6-alkyl, C3-6-cycloalkyl, 0-C3.6-cycloalkyl, C3_6-heterocycloalkyl and 0-C3.6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1.3-alkyl, halo-C1.3-alkyl and oxo;
R4 is S02-(CR8R8)yR7, S02-NR12R7, (CR8R8),-R16 or C3_6-cycloalkyl, which is spirocyclic fused with C3_10-cycloalkyl;
R5 is selected from H, halo-C1.6-alkyl, CHO, CON(R62)2 or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of 0-C1_6-alkyl, 0-halo-C1_6-alkyl and OH;
R6 is selected from H, halo-C1_6-alkyl or halogen;
R7 is selected from C3_10-cycloalkyl and C3_10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, 0-C1 6-alkyl, 0-halo-C1_6-alkyl, cycloalkyl and heterocycloalkyl;
R8 is independently selected from H, F, halo-C1.3-alkyl or OH;
R1 is C3.10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, 0-C1_6-alkyl, 0-halo-C1_6-alkyl, C16-alkyl, halo-C16-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1.2-alkyl, halo-C1-2-alkyl;
R4 is S02-(CR8R8)yR7, S02-NR12R7, (CR8R8),-R16 or C3_6-cycloalkyl, which is spirocyclic fused with C3_10-cycloalkyl;
R5 is selected from H, halo-C1.6-alkyl, CHO, CON(R62)2 or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of 0-C1_6-alkyl, 0-halo-C1_6-alkyl and OH;
R6 is selected from H, halo-C1_6-alkyl or halogen;
R7 is selected from C3_10-cycloalkyl and C3_10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, 0-C1 6-alkyl, 0-halo-C1_6-alkyl, cycloalkyl and heterocycloalkyl;
R8 is independently selected from H, F, halo-C1.3-alkyl or OH;
R1 is C3.10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, 0-C1_6-alkyl, 0-halo-C1_6-alkyl, C16-alkyl, halo-C16-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1.2-alkyl, halo-C1-2-alkyl;
R11 is independently selected from H, C1.6-alkyl, C0_6-alkylene-C3.6-cycloalkyl, C0_6-alkylene-C3_6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C1.3-alkyl, halo-C1_3-alkyl, 0-C1_3-alkyl, 0-halo-C1.3-alkyl and S02-C1.3-alkyl;
R12 is independently selected from H, C1.6-alkyl and halo-C1_6-alkyl;
R31 is independently selected from H, C1_6-alkyl, halo-C1_6-alkyl, C0_6-alkylene-C3_6-cycloalkyl, C0.6-alkylene-C3_6-heterocycloalkyl, 5- or 6-membered heteroaryl and 6-membered aryl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, OH, oxo, C1.3-alkyl, halo-C1_3-alkyl, 0-C1_3-alkyl, 0-halo-C1_3-alkyl and S02-C1_3-alkyl;
and optionally wherein two R31 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1_4-alkyl and halo-C14-alkyl;
R32 is independently selected from H, C1_6-alkyl and halo-C1.6-alkyl;
R52 is independently selected from H, C1.3-alkyl and halo-C1.3-alkyl;
x is independently selected from 1 and 2;
y is independently selected from 0, 1 and 2;
with the proviso that R3 is not an unsubstituted or substituted ring selected from Me0 Me0 H
L/T-N
11.1,0 HFi S 0 OMe , F , 0 H , , , H HH Me Me lel -H, H and Me Me.
In a prefered embodiment, the present invention provides a compound of Formula (1) (1) an enantiomer, diastereomer, tautomer, solvate, formulation and pharmaceutically acceptable salt thereof, 5 wherein R1 is selected from H, C2_10-alkenyl, C2_10-alkynyl, Cm-cycloalkyl, C3_6-heterocycloalkyl, C1_10-alkylene-C3.10-cycloalkyl, C1_10-alkylene-C3_10-heterocycloalkyl, C1-10-alkylene-(5-membered monocyclic heteroaryl), S02-C1_10-alkyl, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted 10 with 1 to 7 substituents independently selected from oxo, CN, OR", 0-C2_6-alkylene-OR, C1_6-alkyl, halo-C1.6-alkyl, halogen, CO21:111, C0NR111112, cow, soy-113 SO3H, SO2NR11R12, NR11C0R11, NR11s02R11 , NR11-CO-NR11 R12, 11 S02-NR11R
-12, C3_6-CYCIOalkYl, 0-C3-6-cycloalkyl, C3_6-heterocycloalkyl, 0-C36-heterocycloalkyl and NR11R12; and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or 15 bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S, wherein pyridinone and spiroheterocycle is optionally substituted with a group selected from C3_10-cycloalkyl, C4-heterocycloalkyl, C1_4-alkylene-C3_1 0-cycloalkyl, C1_4-alkylene-C3-10-heterocycloalkyl, C06-alkylene-(5-membered monocyclic heteroaryl), C1_4-alkylene-O-R31, C1-4-alkylene-CN, 0-C3_10-cycloalkyl, 0-C1_6-alkylene-O-R32, 0-C3_10-heterocycloalkyl, C0_6-alkylene-000R31, C0_6-alkylene-C(0)R31, C0_6-alkylene-C(0)N(R31)2, C0_6-alkylene-N(R31)C(0)R31, C0_6-alkylene-S02-N(R31)2, Co_6-alkylene-N(R31)S02-R31, C0_6-alkylene-S02-C3_10-heterocycloalkyl and C06-alkylene-SO-R31, aryl and heteroaryl is substituted with at least one group selected from C3_10-cycloalkyl, C4-heterocycloalkyl, C1_4-alkylene-C3_10-cycloalkyl, C1.4-alkylene-C3_10-heterocycloalkyl, CO-6-alkylene-(5-membered monocyclic heteroaryl), C0_6-alkylene-(6-membered monocyclic heteroaryl), C1_4-alkylene-O-R31, C1_4-alkylene-CN, 0-C3_10-cycloalkyl, 0-C1_6-alkylene-O-R32, 0-C3.10-heterocycloalkyl, C06-alkylene-000R31, C06-alkylene-C(0)R31, Co.6-alkylene-C(0)N(R31)2, Co_6-alkylene-N(R31)C(0)R31, Cm-alkylene-S02-N(R31)2, C0_6-alkylene-N(R31)S02-R31, C0_6-alkylene-S02-C3_10-heterocycloalkyl, C0.6-alkylene-SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1_6-alkyl, halo-C1_6-alkyl, C3_6-cycloalkyl, C3_6-heterocycloalkyl, oxo, OH, 0-01_6-alkyl and 0-halo-01_6-alkyl, wherein pyridinone, aryl, heteroaryl, spiroheterocycle, alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1_6-alkyl, halo-C1_6-alkyl, C36-cycloalkyl, C3.6-heterocycloalkyl, OH, 0-C1_3-alkyl, 0-halo-C1_3-alkyl, 0-C3.6-cycloalkyl, 0-C3_6-heterocycloalkyl, oxo, N(R32)2, COOH, CON(R32)2, CN and NR32-00R32;
or R1 is selected from a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0 and S, or C1_10-alkyl substituted with a group selected from halogen, CN, OR11, SOyR11, SO3H, NR11s02-11, S02NR111312, co2Ril, coNR, 1R12, NR1l_co_R11, NR11-CO_NR11 R12, NR, l_s02_ NR11R12, NR11-rt12 and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0 and S, or C0.1-alkylene-C3_10-cycloalkyl substituted with a group selected from halogen, CN, SOyR11, NR11s02-11, S02NR11R12, co2Ril, c0NR11R12, CO-R11, NR11-CO-NR11 R12, NR11-s02-rt NR11.-.12 and NR11R12, or C2_10-alkylene-C3.10-cycloalkyl, C2_10-alkylene-O-C3_10-cycloalkyl, C2_10-alkylene-C6_10-heterocycloalkyl, C2_10-alkylene-O-C6_10-heterocycloalkyl and S02-C1_10-alkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, CN, 0-halo-C1_6-alkyl, C1_6-alkyl, halo-C1_6-alkyl, halogen, CO2R11, CONR11R12, C0R11, SO2R11, SO2NRi R12, NR11COR11, NR11s02R11, C3_6-cycloalkyl, 0-C3_6-cycloalkyl, C3-6-heterocycloalkyl, 0-C3.6-heterocycloalkyl, 0-C2_6-alkylene-OR11 and NR11R12;
and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S, wherein pyridinone, aryl, heteroaryl and spiroheterocycle are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, CN, C1_6-alkyl, C3.10-cycloalkyl, C3_10-heterocycloalkyl, C0_6-alkylene-(5-membered monocyclic heteroaryl), C0.6-alkylene-(6-membered monocyclic heteroaryl), C0.6-alkylene-O-R31, 0-C1_6-alkylene-O-R32, C0_6-alkylene-000R31, C0_6-alkylene-C(0)R31, C0.6-alkylene-C(0)N(R31)2, C0.6-alkylene-N(R31)C(0)R31, C0-6-alkylene-502-N(R31)2, Co_6-alkylene-N(1331)S02-R31, C0_6-alkylene-S02-R31, C0_6-alkylene-1 0 SO-R31 and C0.6-alkylene-N(R31)2, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1.3-alkyl, halo-C1_3-alkyl, C3_6-cycloalkyl, C3_6-heterocycloalkyl, OH, 0-C1_3-alkyl, 0-halo-C1_3-alkyl, 0-C3.6-cycloalkyl, 0-C3_6-heterocycloalkyl, oxo, N(R32)2, COOH, CON(R32)2, CN and NR32-COR32, and wherein optionally two adjacent substituents complete a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1.6-alkyl, cycloalkyl, C3_6-heterocycloalkyl, oxo, OH, 0-C1.6-alkyl and 0-halo-C1_6-alkyl;
and R2 is selected from the group consisting of H, C1_6-alkyl, halo-C1..6-alkyl and hydroxy-C1-6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, S0yR11, SO3H, NRils02-11, SO2NR11R12, CO21311, c0NR11-H12, C0R11, NRco_NRil R12, S02-NR,,R12, NRil -12, C1.6-alkyl, halo-C1.6-alkyl, hydroxy-C1_6-alkyl, C3_6-cycloalkyl, 0-C3_6-cycloalkyl, C3_6-heterocycloalkyl and 0-C3_6-heterocycloalkyl;
R4 is S02-(CR8R8)yR7, S02-NR12R7 or (CR8R8)x-R10;
R12 is independently selected from H, C1.6-alkyl and halo-C1_6-alkyl;
R31 is independently selected from H, C1_6-alkyl, halo-C1_6-alkyl, C0_6-alkylene-C3_6-cycloalkyl, C0.6-alkylene-C3_6-heterocycloalkyl, 5- or 6-membered heteroaryl and 6-membered aryl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, OH, oxo, C1.3-alkyl, halo-C1_3-alkyl, 0-C1_3-alkyl, 0-halo-C1_3-alkyl and S02-C1_3-alkyl;
and optionally wherein two R31 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1_4-alkyl and halo-C14-alkyl;
R32 is independently selected from H, C1_6-alkyl and halo-C1.6-alkyl;
R52 is independently selected from H, C1.3-alkyl and halo-C1.3-alkyl;
x is independently selected from 1 and 2;
y is independently selected from 0, 1 and 2;
with the proviso that R3 is not an unsubstituted or substituted ring selected from Me0 Me0 H
L/T-N
11.1,0 HFi S 0 OMe , F , 0 H , , , H HH Me Me lel -H, H and Me Me.
In a prefered embodiment, the present invention provides a compound of Formula (1) (1) an enantiomer, diastereomer, tautomer, solvate, formulation and pharmaceutically acceptable salt thereof, 5 wherein R1 is selected from H, C2_10-alkenyl, C2_10-alkynyl, Cm-cycloalkyl, C3_6-heterocycloalkyl, C1_10-alkylene-C3.10-cycloalkyl, C1_10-alkylene-C3_10-heterocycloalkyl, C1-10-alkylene-(5-membered monocyclic heteroaryl), S02-C1_10-alkyl, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted 10 with 1 to 7 substituents independently selected from oxo, CN, OR", 0-C2_6-alkylene-OR, C1_6-alkyl, halo-C1.6-alkyl, halogen, CO21:111, C0NR111112, cow, soy-113 SO3H, SO2NR11R12, NR11C0R11, NR11s02R11 , NR11-CO-NR11 R12, 11 S02-NR11R
-12, C3_6-CYCIOalkYl, 0-C3-6-cycloalkyl, C3_6-heterocycloalkyl, 0-C36-heterocycloalkyl and NR11R12; and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or 15 bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S, wherein pyridinone and spiroheterocycle is optionally substituted with a group selected from C3_10-cycloalkyl, C4-heterocycloalkyl, C1_4-alkylene-C3_1 0-cycloalkyl, C1_4-alkylene-C3-10-heterocycloalkyl, C06-alkylene-(5-membered monocyclic heteroaryl), C1_4-alkylene-O-R31, C1-4-alkylene-CN, 0-C3_10-cycloalkyl, 0-C1_6-alkylene-O-R32, 0-C3_10-heterocycloalkyl, C0_6-alkylene-000R31, C0_6-alkylene-C(0)R31, C0_6-alkylene-C(0)N(R31)2, C0_6-alkylene-N(R31)C(0)R31, C0_6-alkylene-S02-N(R31)2, Co_6-alkylene-N(R31)S02-R31, C0_6-alkylene-S02-C3_10-heterocycloalkyl and C06-alkylene-SO-R31, aryl and heteroaryl is substituted with at least one group selected from C3_10-cycloalkyl, C4-heterocycloalkyl, C1_4-alkylene-C3_10-cycloalkyl, C1.4-alkylene-C3_10-heterocycloalkyl, CO-6-alkylene-(5-membered monocyclic heteroaryl), C0_6-alkylene-(6-membered monocyclic heteroaryl), C1_4-alkylene-O-R31, C1_4-alkylene-CN, 0-C3_10-cycloalkyl, 0-C1_6-alkylene-O-R32, 0-C3.10-heterocycloalkyl, C06-alkylene-000R31, C06-alkylene-C(0)R31, Co.6-alkylene-C(0)N(R31)2, Co_6-alkylene-N(R31)C(0)R31, Cm-alkylene-S02-N(R31)2, C0_6-alkylene-N(R31)S02-R31, C0_6-alkylene-S02-C3_10-heterocycloalkyl, C0.6-alkylene-SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1_6-alkyl, halo-C1_6-alkyl, C3_6-cycloalkyl, C3_6-heterocycloalkyl, oxo, OH, 0-01_6-alkyl and 0-halo-01_6-alkyl, wherein pyridinone, aryl, heteroaryl, spiroheterocycle, alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1_6-alkyl, halo-C1_6-alkyl, C36-cycloalkyl, C3.6-heterocycloalkyl, OH, 0-C1_3-alkyl, 0-halo-C1_3-alkyl, 0-C3.6-cycloalkyl, 0-C3_6-heterocycloalkyl, oxo, N(R32)2, COOH, CON(R32)2, CN and NR32-00R32;
or R1 is selected from a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0 and S, or C1_10-alkyl substituted with a group selected from halogen, CN, OR11, SOyR11, SO3H, NR11s02-11, S02NR111312, co2Ril, coNR, 1R12, NR1l_co_R11, NR11-CO_NR11 R12, NR, l_s02_ NR11R12, NR11-rt12 and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0 and S, or C0.1-alkylene-C3_10-cycloalkyl substituted with a group selected from halogen, CN, SOyR11, NR11s02-11, S02NR11R12, co2Ril, c0NR11R12, CO-R11, NR11-CO-NR11 R12, NR11-s02-rt NR11.-.12 and NR11R12, or C2_10-alkylene-C3.10-cycloalkyl, C2_10-alkylene-O-C3_10-cycloalkyl, C2_10-alkylene-C6_10-heterocycloalkyl, C2_10-alkylene-O-C6_10-heterocycloalkyl and S02-C1_10-alkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, CN, 0-halo-C1_6-alkyl, C1_6-alkyl, halo-C1_6-alkyl, halogen, CO2R11, CONR11R12, C0R11, SO2R11, SO2NRi R12, NR11COR11, NR11s02R11, C3_6-cycloalkyl, 0-C3_6-cycloalkyl, C3-6-heterocycloalkyl, 0-C3.6-heterocycloalkyl, 0-C2_6-alkylene-OR11 and NR11R12;
and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S, wherein pyridinone, aryl, heteroaryl and spiroheterocycle are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, CN, C1_6-alkyl, C3.10-cycloalkyl, C3_10-heterocycloalkyl, C0_6-alkylene-(5-membered monocyclic heteroaryl), C0.6-alkylene-(6-membered monocyclic heteroaryl), C0.6-alkylene-O-R31, 0-C1_6-alkylene-O-R32, C0_6-alkylene-000R31, C0_6-alkylene-C(0)R31, C0.6-alkylene-C(0)N(R31)2, C0.6-alkylene-N(R31)C(0)R31, C0-6-alkylene-502-N(R31)2, Co_6-alkylene-N(1331)S02-R31, C0_6-alkylene-S02-R31, C0_6-alkylene-1 0 SO-R31 and C0.6-alkylene-N(R31)2, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1.3-alkyl, halo-C1_3-alkyl, C3_6-cycloalkyl, C3_6-heterocycloalkyl, OH, 0-C1_3-alkyl, 0-halo-C1_3-alkyl, 0-C3.6-cycloalkyl, 0-C3_6-heterocycloalkyl, oxo, N(R32)2, COOH, CON(R32)2, CN and NR32-COR32, and wherein optionally two adjacent substituents complete a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1.6-alkyl, cycloalkyl, C3_6-heterocycloalkyl, oxo, OH, 0-C1.6-alkyl and 0-halo-C1_6-alkyl;
and R2 is selected from the group consisting of H, C1_6-alkyl, halo-C1..6-alkyl and hydroxy-C1-6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, S0yR11, SO3H, NRils02-11, SO2NR11R12, CO21311, c0NR11-H12, C0R11, NRco_NRil R12, S02-NR,,R12, NRil -12, C1.6-alkyl, halo-C1.6-alkyl, hydroxy-C1_6-alkyl, C3_6-cycloalkyl, 0-C3_6-cycloalkyl, C3_6-heterocycloalkyl and 0-C3_6-heterocycloalkyl;
R4 is S02-(CR8R8)yR7, S02-NR12R7 or (CR8R8)x-R10;
R6 is selected from H, C1_6-alkyl, halo-C1_6-alkyl, CHO or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of 0-C1_6-alkyl, 0-halo-C1_6-alkyl and OH;
R6 is selected from H, C1_6-alkyl, halo-C1_6-alkyl or halogen;
R7 is selected from C3_10-cycloalkyl and C3_10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, 0-C1_6-alkyl, 0-halo-C1.6-alkyl, C1 _6-alkyl, halo-C1_6-alkyl, cycloalkyl and heterocycloalkyl;
R8 is independently selected from H, F, C1_3-alkyl, halo-C1_3-alkyl or OH;
1:113 is C3_10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, 0-C1_6-alkyl, 0-halo-C1_6-alkyl, C1_6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1_2-alkyl, halo-C1-2-alkyl;
R11 is independently selected from H, C1_6-alkyl, C0_6-alkylene-C3_6-cycloalkyl, C0_6-alkylene-C3_6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C1_3-alkyl, halo-C1_3-alkyl, 0-C1.3-alkyl, 0-halo-C1_3-alkyl and S02-C1_3-alkyl;
R12 is independently selected from H, C1_6-alkyl and halo-C1_6-alkyl;
R31 is independently selected from H, C1_6-alkyl, C0_6-alkylene-C3_6-cycloalkyl, C0_6-alkylene-C3_6-heterocycloalkyl, a 6-membered aryl wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl and aryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C1_3-alkyl, halo-C1.3-alkyl, 0-C1_3-alkyl, 0-halo-C1_3-alkyl and S02-C1-3-alkyl;
R32 is independently selected from H, C1_6-alkyl and halo-C1_6-alkyl;
x is independently selected from 1 and 2;
y is independently selected from 0, 1 and 2;
with the proviso that R3 is not an unsubstituted or substituted ring selected from Me0 R;¨N II 0 1-\H
/H
S , OMe 0 1.1 H H Me Me and Me Me.
In a first alternative, the invention provides a compound represented by Formula (1) 11 (1) an enantiomer, diastereomer, tautomer, N-oxide, solvate, formulation and pharmaceutically acceptable salt thereof, wherein R1 is selected from H, C3_6-cycloalkyl, C3_6-heterocycloalkyl, C1.10-alkylene-C3_10-cycloalkyl, C1.10-alkylene-C3_10-heterocycloalkyl, Cm0ralkylene-(5-membered monocyclic heteroaryl), wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR11, 0-C2_6-alkylene-01=1", halo-C1_6-alkyl, halogen, CO2Ru, CONR11R12, COW, SOyR11, SO3H, SO2NRiiR12, NRilcoRil, NR11S02R11, NRii-CO-NR11R123 NR11-S02-C3_6-cycloalkyl, 0-C3_6-cycloalkyl, C3_6-heterocycloalkyl, 0-C3_6-heterocycloalkyl and NR, R12;
R2 is selected from the group consisting of H, halo-C1.6-alkyl and hydroxy-C1-6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SOyR11, SO3H, NR11s02-H11, SO2NR11.-.1 C0.6-alkylene-CO2R11, coNR, R12, C0R11, NR-CO-R, NR-1-CO_NRil R12, N.-.11-S02-NR11R12, NR11.-. M12, C1_6-alkyl, halo-C1_6-alkyl, hydroxy-C1_6-alkyl, C3-6-cycloalkyl, 0-C3_6-cycloalkyl, C3.6-heterocycloalkyl and 0-C3_6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1.3-alkyl, halo-C1.3-alkyl and oxo;
5 R3 is a 6- or 10-membered mono- or bicyclic aryl or a 6- to 10-membered mono- or bicyclic heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N, 0 and S, wherein aryl and heteroaryl is substituted with at least one group selected from C3-6-cycloalkyl, C4-heterocycloalkyl, C1_4-alkylene-C3_10-cycloalkyl, carbon atom linked 5- or 6-membered monocyclic heteroaryl, C1.4-alkylene-O-R31, 0-C3_10-cycloalkyl, C(0)R31, CO-6-1 0 alkylene-C(0)N(R31)2, S02-N(R31)2, N(R31)S02-R31, S02-C3_10-heterocycloalkyl, SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1_6-alkyl, halo-C1_6-alkyl, C3_6-cycloalkyl, C3_6-heterocycloalkyl, oxo, 15 =N-0R32, OH, 0-C1.6-alkyl and 0-halo-C1_6-alkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and the carbon atom linked 5-or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1_3-alkyl, halo-C1-3-alkyl, OH, oxo, =N-OR32, 0-C1_3-alkyl and 0-halo-C1.3-alkyl; and 20 wherein aryl and heteroaryl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1_3-alkyl, halo-C1.3-alkyl, OH, 0-C1_3-alkyl and 0-halo-C1_3-alkyl; and R4 is S02-(CIVIR8)yR7, S02-NR121R7, (CR8R8)9-R1 or C3_6-cycloalkyl, which is spirocyclic fused with C3_10-cycloalkyl;
R6 is selected from H, C1_6-alkyl, halo-C1_6-alkyl, CHO, CON(R62)2 or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of 0-C1_6-alkyl, 0-halo-C1_6-alkyl and OH;
R6 is selected from H, C1_6-alkyl, halo-C1_6-alkyl or halogen;
R7 is selected from C3.10-cycloalkyl and C3_10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, 0-C1_6-alkyl, O-halo-C1_6-alkyl, C1.6-alkyl, halo-C1.6-alkyl, cycloalkyl and heterocycloalkyl;
R8 is independently selected from H, F, C1.3-alkyl, halo-C1_3-alkyl or OH;
R1 is C3.10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, 0-C1_6-alkyl, 0-halo-C1_6-alkyl, C1_6-alkyl, halo-C1_6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1_2-alkyl, halo-C1-2-alkyl;
R11 is independently selected from H, C1_6-alkyl, C0_6-alkylene-C3_6-cycloalkyl, C0_6-alkylene-C3_6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C1.3-alkyl, halo-C1_3-alkyl, 0-C1.3-alkyl, O-halo-C1_3-alkyl and S02-C1_3-alkyl;
R12 is independently selected from H, C1_6-alkyl and halo-C1_6-alkyl;
1331 is independently selected from H, C1_6-alkyl, halo-C1_6-alkyl, C0_6-alkylene-C3.6-cycloalkyl, C0.6-alkylene-C3.6-heterocycloalkyl, 5- or 6-membered heteroaryl and 6-membered aryl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, OH, oxo, C1_3-alkyl, halo-C1.3-alkyl, 0-C1_3-alkyl, 0-halo-C1_3-alkyl and S02-C1_3-alkyl;
and optionally wherein two R31 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1_4-alkyl and halo-C1_4-alkyl;
R32 is independently selected from H, C1_6-alkyl and halo-C1_6-alkyl;
R52 is independently selected from H, C1_3-alkyl and halo-C1_3-alkyl;
x is independently selected from 1 and 2;
y is independently selected from 0, 1 and 2.
In an additionally preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from phenyl, pyridinyl, pyrimidinyl, naphthyl, benzothiophenyl and quinolinyl, wherein phenyl, pyridinyl, pyrimidinyl, naphthyl, benzothiophenyl and quinolinyl is substituted with at least one group selected from C3-4-cycloalkyl, carbon atom linked 5- or 6-membered monocyclic heteroaryl, C14-alkylene-O-R31, C(0)R31, C(0)N(R31)2, S02-N(R31)2, S02-C3_10-heterocycloalkyl, SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, C1.3-alkyl, halo-C1_3-alkyl, C3_4-cycloalkyl, C3_4-heterocycloalkyl, oxo, OH, 0-C1.3-alkyl and 0-halo-C1.3-alkyl, wherein phenyl, pyridinyl, pyrimidinyl, naphthyl, benzothiophenyl, chinolinyl, alkyl, alkylene, cycloalkyl, heterocycloalkyl and the carbon atom linked 5- or 6-membered monocyclic heteroaryl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1_3-alkyl, halo-C1_3-alkyl, OH, 0-C1.3-alkyl and 0-halo-C1-3-alkyl.
In a further preferred embodiment in combination with any of the above or below embodiments of the first alternative R1 is selected from C1_10-alkyl, C3_6-cycloalkyl, C3-6-heterocycloalkyl, C1_10-alkylene-C3_10-cycloalkyl, C1_10-alkylene-C3.10-heterocycloalkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR11, 0-C2_6-alkylene-OR11, C1.6-alkyl, halo-C1.6-alkyl, halogen, CO2R11, c0NF11R12, coRil, SOyR11, SO3H, S02NR11R12, NFilicoRli, NR11s02R11, NRil_CO_NRii R12, N.-01_ S02-NR11 R12, C3.6-cycloalkyl, 0-C3-6-cycloalkyl, C3.6-heterocycloalkyl, 0-C3.6-heterocycloalkyl and NR11R12;
R2 is selected from the group consisting of H, C1_6-alkyl and halo-C1_6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SOyR11, SO3H, NR11SO2R11, SO2NR11.-.12, C0_6-alkylene-CO2R11, CONR11R12, C0R11, NR11-CO-R11, NR11-Co_NR11.-.12, NR11-S02-NRii R12, NR11.-. h1 C1_6-alkyl, halo-C1_6-alkyl, hydroxy-C1.6-alkyl, C3-6-cycloalkyl, 0-C3.6-cycloalkyl, C3_6-heterocycloalkyl and 0-C3.6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1_3-alkyl, halo-C1_3-alkyl and oxo.
In an additionally preferred embodiment in combination with any of the above or below embodiments of the first alternative R1 is selected from C1.10-alkyl, C3_6-cycloalkyl, C3-6-heterocycloalkyl, C1.10-alkylene-C3_10-cycloalkyl, more preferably C1_3-alkylene-C3-10-cycloalkyl, C1_10-alkylene-C3_6-heterocycloalkyl, more preferably C1.3-alkylene-C3-6-heterocycloalkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR", alkylene-0R11, C1_6-alkyl, halo-C1_6-alkyl, halogen, CO2H, C0NIVR12, C0R11, SOyR11, SO3H, SO2NRU R12, NRlicoRil, NR11S02R11, NR11-CO-NR11R12, NR11-S02-NR11R12, C3-6-cycloalkyl, 0-C3_6-cycloalkyl, Cm-heterocycloalkyl, 0-C34-heterocycloalkyl and NR11R12;
R2 is selected from the group consisting of H, C1_6-alkyl and halo-C1_6-alkyl, more preferably R2 is hydrogen;
or 1:11 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 6-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SOyR11, SO3H, NRuS02R11, SO2NR111R12, CMe2CO2H, CONR11 R12, C0R11, NR11-CO-R11, NR11-CO-NR11R12, NR11 SO2NRU R12, NR11R12, C1.6-alkyl, halo-Cwalkyl, hydroxy-C1.6-alkyl, C3_6-cycloalkyl, 0-C36-cycloalkyl, C3.6-heterocycloalkyl and 0-C3_6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1_3-alkyl, halo-C1_3-alkyl and oxo.
In an additionally preferred embodiment in combination with any of the above or below embodiments of the first alternative R1 contains 1(OH,J\I N 1\1- \
N , 0 or N , H H , more preferred R1 contains a carboxylic acid moiety and even more preferred R1 contains a secondary or tertiary carboxylic acid moiety.
In a preferred embodiment in combination with any of the above or below embodiments of the first alternative NR1R2 is selected from NH2, NHMe, NHEt, NH'Pr, NH1Bu, NHCH2CONH2, NHCH2CONMe2, NHCH2CH2OH, NHCH2CH(CF3)0H, NHCH2C(CF3)20H, NHCH2CH20Me, NHCH2CH2S02Me, NHCH2CH2S02NH2, NH(CH2)30H, NH(CH2)30Me, NH(CH2)40H, NH(CH2)40Me, NH(CH2)50H, NH(CH2)2CO2H, NH(CH2)3CO2H, NH(CH2)4CO2H, NH(CH2)5CO2H, NHCH2CMe2OH, NHCH(Me)CMe2OH, NHCH2CMe20Me, NHCH2CMe2CO2H, NHCH2CMe2CONH2, NHCH2CMe2CONHMe, NHCH2CMe2CONMe2, NHCH2CMe2NHSO2Me, NH(CH2)3SOMe, NH(CH2)5S02Me, NH(CH2)5S02NH2, NH(CH2)3NHSO2Me, NH(CH2)20(CH2)20H, NHCH2CHMe0H, NH(CH2)5SOMe, NC
HN--\
NH(CH2)3S02Me, HN-<, HN¨K HN-0 HN¨CN¨ HN¨C]
, HN
HN-)>. HN-\.:,H HN-\ /--\
\---\___Nr-\0 i\--NO
\ -- N 0 \ I NH
, HN- HN- HN OH HN OH
1---\
\ __I
HN-0 HN--\00 X
HN-CS HN-CS=0 HN-0=0 HN--<XH HN HN-CN-4-CS:C) O
HN-CNN N-H /-\
--/K
0 HN-X \50 HN-N 0 HN-----( \O
\ / `0 \/ ( \O N
, , , , HN-b 0 0HNo HN) HNI-C ) HN-K-\0 HNNCX 0 NH
HN---D, \H HN OH
HN-bo HN OH1,11--\_:))H HN OH
Q\
S,,.., \\*-1/4.) , S , \O , 0 , OH HN--JO
HN HN -K
p O
(JJ
HN ' 0 HN-õ. HN-b) HN--- -) r9 ----\_g_.
FIN' 03 HN.--03 II
H(N--?, 0 , , , X', , NH
HN--___ HN-3r1Ril \
NH2 \.1;) 0 , 0 , 0 , HN---) HN--) HN-\ c \----) \SC) ,4:0 -.0H --NH2 OH
, , , -)43 HN-X c HN-\ HN-\ c HN) __________________________________________________________________________ 0 OH NH2 N/ HN H HN-g%0 0 0 0 0 \
, , , , , HN N- N N"' 0 I
N'-.--)-LOH
HN -0 0-.<1 \r0 HO , OH, HO , OH , OH , HN,,, HN,,, HN,, HN HN,,,,,,N .
10<r0 0 Or0 OH, OH, OH, OH, OH, HN,,K---.1 , HN HN
HN'44.'"0 )(cf0 i'',/e OH, OH, OH, OH, HN- Nv'') --)-HN'a,,r0 HN'ON r 1 N,s/, HN-\ /<0 OH
OH, , HN --)A
HN--1 0 HN--__11 0 0 H
N
->H
5 OH, OH ,.....-OH , HN-)H0 HN--) e HN-b HN ________________________ \ _J) t)H 1 N-\ HN-\
14 \IDH
n -0 , \-0H, , 0 , 0, ,P FIND e FIN-3z, HNI\s,0 FIN --/ HN--\
HN-\
i t3 \--OH
N , , , , HN -\ HN---\ HN-\
.17-0 HN-)._____\ HN--) HN-\ NIIN) 1\1, I \ 1 N-NH
HN\____ , N\µ= No 0 HO 0 H2 0, N
, NN- , , N-NH \:)-CL N-0 HN HN
N-NH HN HN-----)N0 NO<OH
---\._ --)1\1-- N
N H , H , , , , N- N
0 I __ N
I 03na i'll-- T1 Nõ.3,,./L
OH
b , cy 10 OH, N") OH NTh S=0 and b .
, In a further preferred embodiment in combination with any of the above or below embodiments of the first alternative NI:111R2 is selected from NH2, NHMe, NHEt, NH'Pr, NHtBu, NHCH2CONH2, NHCH2CONMe2, NHCH2CH2OH, NHCH2CH(CF3)0H, NHCH2C(CF3)20H, NHCH2CH20Me, NHCH2CH2S02Me, NHCH2CH2S02NH2, NH(CH2)30H, NH(CH2)30Me, NH(CH2)40H, NH(CH2)40Me, NH(CH2)50H, NH(CH2)2CO2H, NH(CH2)3CO2H, NH(CH2)4CO2H, NH(CH2)5CO2H, NHCH2CMe2OH, NHCH(Me)CMe2OH, NHCH2CMe20Me, NHCH2CMe2CO2H, NHCH2CMe2CONH2, NHCH2CMe2CONHMe, NHCH2CMe2CONMe2, NHCH2CMe2NHSO2Me, NH(CH2)3SOMe, NH(CH2)5S02Me, NC
NH(CH2)3NHSO2Me, NH(CH2)20(CH2)20H, NHCH2CHMe0H, HN-<1, HNJ HN--<>, , HN->. HNH HN
-NO HN-\
CF3 ---N/---\0 HN- N- HN-\_____/ , HN
\----\_Nr-\0 n-N\ C /__\ HN-I...._.7 HN-y7 HN OH
/--- 0 \-N 0 \/ NH NH 0 , 0 , 14 , , , , HN---\,c-OH
LC) , HN-00 HN--\CO HN-CS HN-CS:=0 HN--<>=0 , , , , , ,0 HN HN-N-4 x 0 HN-CN-1(...._o -OCH , FIN-C% , 0 HN-CN ---\
, HN
HN-- HN ___Ng Nii_vE___I\
/--, HN-N 0 HN-( / \O --6 .__/ ___________ / / __ C__2, , Q, \
HN-Dt\I 0 OH HN-- JO
Q, HN ..-0 0 HN0 \0 , 0 P
, , , , HN-)._ , HN
--b1 HN HNI.=C
HNJ, , , , N, , HN-\ 1<0 0 0 1 HN-\ 9 HN HN->AI
\-- --).--NH H
0 , ..0 HN NH HN--Il HN--) HN--) HN--\ c \---- \S
0 HO \O /----OH
0 , --NH2 OH
, , , , HN-- e HN___\ 7 HN-) 0 HN I
C) i< 0 HN
-NH2 HN-g%0 ---0 10-1 \r 0, \ , HO , OH, HO
,, N NarHNõ HNõ HNõ, 0 0 '10,r0 ' OH OH , OH OH , OH, , , HN-\ e , HN--111 0 HNõ l HN '0 0 0 1 HN --\ 4) rOH , OH , OH , OH , HN--)r0 OH
HN
" lil HN-1:1, FIN---)A 0 \r HN--)_40 ....-- -\___ _.-OH ---"'"µc) , 0\ 0, OH , , HN-)0 HN -- 0, P HN-) HN--)ZHN-\ HN--\
Q--(-) OH lc---.. ---\--OH
\
, , 0 , 0 , HN1 HN --/ HN--)_\ HN HN-- HN-)._ \ , 0 oe-NH2 /
HN--\ HN--\ HN--\
HN---\ 1\le N f\le ),--0 N NN
I q Nx NO 0 HO 0 H2N 0 (:) H -OH , 0-- , N OH N N
i _______ / 1 S=0 , and b .
In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative NR1R2 is selected from HN---\..., HN¨v_ HN OH
HN--\___ HN-00 HN--\CO HN¨S.,---0 /OH , L-0, q , LC-) , , , HN---t:_)I)-1 HNI) HNZ
HN¨CS; HN--( \ s: HN---00 µ0 / , 0 , 0 , , , , HN--, HN OH \ HN-Ii, HN--C HNII-G
HNI C) r- 0 , HN NH2 HN) HN -\ ---)_>/_ HN
\ c HN, OH, NH2 OH
0 , \ OH
HN---\ / HN---\ c N N HNõ, 00 OH , OH
OH, , , , õ....\ HNõ, r HN,, 0 HNõ
HN , HN
0 0<0 0 0<r0 \---'y )',,, OH, OH , OH , OH , OH , HN
HN HN --b_ HN--bso N-NH
HN
,,--0 --------(N--N
OH, OH, 0 N-NI
HN
--).----NO N Q
OH 1-0 :--- =C) u , 0 ,o , I (:) and b .
, In an even more preferred embodiment in combination with any of the above or below embodiments of the first alternative NR1R2 is selected from HN-%
,0 HN-0 HN¨CS.--0 HN
\¨CS; HN¨( \SC' HN 0 HN OH
HNIDF_I HN OH HN NH2 HN-) /0 S. <
\\-0 0 , 0 0 , , 0 , OH
, HN---\ ( HN---\
\ c NH2 N HNõ, HN,, OH
.00 .<ro µ0õro 00 OH OH , OH
, , , , HN
N-NH HN-)___N-I N
0 0<r0 .--------(N,,N NO OH
N¨
I
I\l' Qz-0 NI S=0 b , and b .
In a most preferred embodiment in combination with any of the above or below embodiments of the first alternative NR1R2 is selected from HN OH HN--\ c 0 Nar OH HN
OH OH
HNõ 'O HNõ'1 HN
HN N-NH r0 00 10<r0 ------c OH OH OH
and , , , HN--)N-0 µ._ NO
H .
In another preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from 1 41 R-A -K=(N 4\ __ ( 93 /(\
R34 , R34 R34 , R34 R35 R33 R33 !NJ0,R36 "R36 R33 R33 , R33 , , , on i = R34 and , wherein R33 is independently selected from H, halogen, CN, C1_6-alkyl, fluoro-C1_6-alkyl, C1_4-alkylene-OH, C1-4-alkylene-O-C1_3-alkyl, C1.4-alkylene-0-fluoro-C1_3-alkyl, 0-C1_6-alkyl, 0-fluoro-C1-6-alkyl, NH-C1_6-alkyl, NH-fluoro-C1_6-alkyl, C3.10-cycloalkyl, C(0)N(R37)2, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C1_3-alkyl and fluoro-C1_3-alkyl;
R34 is independently selected from C14-alkylene-OH, C1.4-alkylene-O-C1_3-alkyl, C1-4-5 alkylene-0-fluoro-C1.3-alkyl, C3.10-cycloalkyl, C(0)N(R37)2, SO2N(R37)2, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C1_3-alkyl and fluoro-C1_3-alkyl;
R35 is C1.6-alkyl or fluoro-C1_6-alkyl;
10 R36 is independently selected from C1_6-alkyl, fluoro-C1_6-alkyl, C(0)N(R37)2 and SO2N(R37)2;
R37 is independently selected from H, C1_6-alkyl, halo-C1_6-alkyl, C0_4-alkylene-C3.6-cycloalkyl, C0.4-alkylene-C3.6-heterocycloalkyl, wherein alkyl and alkylene is unsubtituted or substituted with a substituent selected from halogen, OH, 0-C1_3-alkyl, CN; and cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently 15 selected from F, CN, OH, oxo, C1.3-alkyl and fluoro-C1_3-alkyl;
or wherein two R37 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1_4-alkyl and halo-C1_4-alkyl;
20 R38 is independently selected from H, C1_3-alkyl and fluoro-C1.3-alkyl;
R39 is H, F, OH, 0-C1.3-alkyl, 0-halo-C1.3-alkyl;
W is an annelated C5_8-cycloalkyl, an annelated 6-membered aryl or an annelated 5- to 6-membered heteroaryl, wherein cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 2 25 substituents selected from halogen, methyl and CF3, more preferably, W is an annelated aryl, unsubstituted or substituted with 1 to 2 substituents selected from fluoro, methyl and CF3;
X is an annelated saturated heterocycle selected from the group consisting of c.1-0 sss' ,rri- 0 õppsss'0 A-0 38 s&N-R38 sr\..A...\
ON(R37), (R4 (R37) (R37) ( n n 1:137) n ,0 tR37)n ) 1 9 µ
0 , cs5 0 .priss-[
ssss \ I
_38 (R37)n N and (R37)n =
, Y is an annelated 5- or 6-membered carbocycle, an annelated 6-membered aryl or an annelated 6-membered heteroaryl containing 1 to 2 nitrogen atoms, wherein the carbocycle, aryl or heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C1_3-alkyl and fluoro-C1_3-alkyl;
Z is an annelated 6-membered cycle forming a heteroaryl containing 1 to 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C1_3-alkyl and fluoro-C1_3-alkyl;
n is independently selected from 1 to 4.
In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from > ¨( 5 ¨ R33 / WR36 ------rR36 1 . R39 i¨( /NI ¨(___ 0 1¨</ I
1\1 411 R34 CI
N
R34 R34 , R35 9 9 9 *Ail VP
and , wherein R33 is selected from C1_6-alkyl, fluoro-C1_6-alkyl, C1.4-alkylene-OH, C1_4-alkylene-O-C1-3-alkyl, C1.4-alkylene-O-fluoro-C1.3-alkyl, 0-C1_6-alkyl, 0-fluoro-C1.6-alkyl, C3.10-cycloalkyl, C(0)N(R37)2, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C1_3-alkyl and fluoro-C1_3-alkyl, more preferably R33 is selected from fluoro, chloro, CF3, CHF2, OCF3, OCHF2, methyl, tbutyl and CMe2OH, 1-methylcyclopropyl;
R34 is selected from C1_4-alkylene-OH, C1_4-alkylene-O-C1_3-alkyl, C1_4-alkylene-O-fluoro-C1-3-alkyl, C3_10-cycloalkyl, C(0)N(R37)2, S(02)N(R37)2, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C1.3-alkyl and fluoro-C1-3-alkyl;
R35 is selected from C1_6-alkyl and fluoro-C1_6-alkyl;
R36 is selected from C1_6-alkyl, fluoro-C1_6-alkyl, C(0)N(R37)2, S(02)N(R37)2;
R37 is indenpedently selected from H, C1_6-alkyl, halo-C1_6-alkyl, C1_6-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C1_3-alkyl and fluoro-C1.3-alkyl, or wherein two R37 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, oxo, C1.4-alkyl and halo-C14-alkyl;
R35 is selected from H, C1.3-alkyl and fluoro-C1_3-alkyl;
R33 is selected from H, F or OH;
X is an annelated saturated heterocycle selected from the group consisting of sss' spr- 0 15-0 I¨N'R38 sPr N' R38 0 se\AJ
R37)n ss3 0 (R37)n Y-Lo R37)n f\lµ
(R37)n (R37)n (R37)n <5 0 sr, s R38 and (R37)n Y is an annelated 5- or 6-membered carbocycle, an annelated 6-membered aryl or an annelated 6-membered heteroaryl containing 1 to 2 nitrogen atoms, wherein the carbocycle, aryl or heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C1_3-alkyl and fluoro-C1_3-alkyl;
Z is an annelated 6-membered cycle forming a heteroaryl containing 1 to 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C1_3-alkyl and fluoro-C1_3-alkyl; and n is selected from 1 to 4.
In an equally more preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from 411, N(R37)2 N(R37)2 µN(R37)2 µN(R37)2 R33 , R33 and N(R37,2 , wherein R33 is independently selected from H, halogen, C1_6-alkyl, fluoro-C1_6-alkyl, C1_4-alkylene-OH, C1_4-alkylene-O-C1.3-alkyl, 0-C1_6-alkyl, 0-fluoro-C1_6-alkyl and C3_10-cycloalkyl, more preferably R33 is independently selected from fluoro, chloro, CF3, CHF2, OCF3, OCHF2, methyl, tbutyl and CMe2OH, 1-methylcyclopropyl;
one R37 is selected from H, C1.6-alkyl, halo-C1.6-alkyl and the other R37 is selected from C1_6-alkyl, halo-C1_6-alkyl, C0_4-alkylene-C3_6-cycloalkyl, C0_4-alkylene-C3_6-heterocycloalkyl, wherein, wherein alkyl and alkylene is unsubtituted or substituted with a substituent selected from halogen, OH, 0-C1_3-alkyl, CN; and cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, CN, OH, oxo, C1_3-alkyl and fluoro-C1_3-alkyl;
or wherein two R37 when taken together with the nitrogen to which they are attached may complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1_4-alkyl and halo-C1_4-alkyl;
W is selected from an annelated C5_8-cycloakyl, an annelated 6-membered aryl or an annelated 5- to 6-membered heteroaryl, wherein cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 2 substituents selected from halogen, methyl and CF3, more preferably, W is an annelated aryl, unsubstituted or substituted with 1 to 2 substituents selected from fluoro, methyl and CF3.
In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from OH
If g SF
g?0 10 0 1 li o i . s:::0 1 41 0 1\i(R37)2 , N(R37)2 , N(R37)2 , µN(R37)2 , CHF2 OCF3 OCHF2 .
1µ0_o II g:.-.0 'I, N(R37)2 IN(R37)2 , 1N(R37)2 , a P = CF3 a CF3 Cl Cl N(R37)2 F , 1 . gµNi--3(OR37)2 ' 1 II 4N9(C)R37)2 F2HC01. 4N( R37)2 ' = 0 CI
p N(R37)2 , N(R37)2 , µN(R37)2 , µN(R37)2 , iii N
/ \ . F
P 1 go = s,/?0 II s,-.0 .
N(R37)2 , N(R37)2 and µN(R37)2 , wherein N(R37)2 is selected from H H H H H l H
f\l< N H
I
N CF3 N1CF3 NCF3 N u3 NF N, , , , , NI NI f < 4 I ) < Ni 0 H Ni 0 NI I
N
OH and F, more preferably N(R37)2 is selected from H H H H H H
N N H N CF3 N CF3 N u3 NI<CF3 I
, , NCF3 , 1 X and , and most preferred N(R37)2 is NFII3u.
In an equally more preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from 5 ¨( N_=-( i __¨( /r\I ¨i /N N
( N--1( R34 , R34 , R34 , R34 , wherein R33 is selected from fluoro, chloro, CHMe2, CMe3, cyclopropyl, 1-methylcyclopropyl, CF3, CHF2, CMe2OH, CMe20Me, 0-CH2CMe3, 0-CH2CHMe3, OCF3 and OCHF2;
R34 is selected from C1_4-alkylene-OH, C1_4-alkylene-O-C1_3-alkyl, C3_10-cycloalkyl, 5 C(0)N(R37)2, SO2N(R37)2, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, methyl and CF3; and R37 is independently selected from H, C1_6-alkyl, halo-C1_6-alkyl.
10 In an equally more preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from V \ CF3 , , ¨0 0 HON
4 cF3 N
NH OH o o \ , cF3 41/ H I_Cro \ ir=___ y 1--( /11 y_ 1 \ /N1 %I 1 \ iNI
CI
411 V 141V ilk 14, i'll N NH N NH
15 o \ , o , o \ , o , 4 , 4 , OCF3 a O\
1 y 411 y CI NH . _iiky_111 /¨cF3 NH NH NH NH
0 0 0y 0 0 , cF3 cF3 .--cF 1 . _cF 1.y Iliky NH NH NH N NH
0 0 0 0 \ 0 , , , , , o ;- 1 . N 1 lik o i lik o NH NH
0 0 I $ CF3 , 111 , , OH OH 0...õ 0õ
411 ill 4,0 stko . 0 1.0 1.0 1.0 ,O
411 , Al , 4111 , , , , , 1.01,1101.01.014.01.=0 HN,õ<
411 , , , , iikg=0 = =,c) 1 . -,-0 i 11 :11= i * g' FIN f- , F3c ,, N---r -< 1 CF3, , o o i = -,c) i . s',0 1 * si-,0 ,c) i *$o Ny 1-114,,,6 4 41õ,z /
HN -....)CF3 , =
Br CI CI F CN
,0 9 si.-.0 i * 0 1 . si_-_-0 .
41,4 HN.,/..._ FIN , HIV 41 CI -\ ,,4... 1 HN,/__ /
V
i . . g=o ilk g'--.0 1 * go * $i=so HIVõ)z.... 41< FIN.< 141õ
rNi.< N
HN,..x..õ.
9 p 9 p 9 1 . =-,-,D 1 1, '----0 = ,----0 1 *Hto 1 = o HN/...._ , , HN..... 41 FFCIS.
HO\_1---HO-/ F--/ \O-Y----, $
, CF3 CF31 . gi?...0 ,0 CF3 ., f o .zo HN /5) CF3 HN,7 HN,,,p) HO--- FINNci 1 * (2/
NC , NH2 , -- $ , , CF3 0 CF3 9 CF3 1 * $0,z.0 p * s-,:o 1 = g%
1 * f-zo i * ',.--o 1 i HNyu3 HN
N , HN1 $ I , FIN rp ,,. 3 ' ,o o ,o ,o CF
1 . 7/--zo 1 * ,1-.-=o 1 * s,.-0 CF3 lik 7/--,-o . 9 Si =H
N
HN,,,CF3 HNNCF3 HN HN 1 I
CI
*$o 1 = s'--:o i *o 1 * sf FINI
1 '0 HINI FIN\ 1-k 1-k .< r,N1 F F i <
I
I
CHF2 0' F3C CI CI
0 p p ,0 ,5) 1 *3 *$o 1 *$o 1 Mk s0 *SNi z---y_.../0 HN HNN4 HN ..,. z Fkiz... H
, /
F2HC, F3C
CI c, CI CF3 0 b p o o p o o 1 . $i--=o * 4/--=o . o 1 = $i---,o * gi--.o 1 = e---=o Niz.... 1 FINN/..._ Hy FIN, FIN i/..._ HNiz FIN
i/_.
1 * Y 1 *
N,ssF1µ / 1 = / 1 N-N
NH
-----c o , C--0 , F 0' b \ , 0' b \
OH
1 . M / 1N / NH
/ N) N-N1 Wi N- 1 *
---c ----c --N i . /<
--N 1 * ---N
OH 0¨
/
1, ,0 N ¨ 1 * /NiNi- = 4= 1 . 7=9 * 7,0 i * , ,¨NH 0 HN - HNõ.<
¨N
N/ " / \ N N
/ \
"S
,0 s p * '-,o 1 * g'-=-o 1 * e---,o i * 10 i . $izzo i , FIN HNN4 Hti=IN4... FINiz._.. 1-IN
HisV...., / , . F
0 =
i . f.-zo 1 = y 1 * s--0 4. N"0 . NH 0 , i = 1\1/
FINiz....
NH
0 *, , 0 *0 i . HN-b = 0 1 * 0 ¨\ =
HN¨\ HN¨C) /
N-CF3, /
, , , o o i . o \---o * N 1 \ , /
0O 0µ 0 0 0 k "s-s-,s-NO N
No N 0 * 14-S___\
/--\ N U N H N
, \ i \ / /
and ' , .
In a further preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from 41 .4 .4 411 A A
i 11 i . i . i 4. * 1 11 Y 1 4.
, CF3, , \, o \ , o , V , NH OH
0 \, 0 0 ...Ø..õõ,, .S'N,,,-\ ( , , / )<
i----/N1 y ¨NH N N NH N NH
0 0 \ 0 \ 0 0 \ 0 O , , , , ilik y 141 y_ . ________________________________ lik Ili P 1. 0 N NH NH NH
0 \0 0 0 N.,y,,, , , , , I , , ilk() ilko 1.0 1.110 1.0 1.0 1.0 1 , 411 , ' ' , , , (3.
o O o o / II o 1 . o 1 . ,_0 i li, .,c) / 11 ..--rN---, 1 V
O cF3 cF3 cF3 cHF2 I, i sik ro 1 11 g.0 1 41 si.-.0 1 . g,-o 1 . g',0 i =
, 1 rõN,,,,..-r- --- HIV.,< HN., HN, HN.,<
I --' , , , , 1 . g=0 =1 II
11 =-C) 1 . S 1 lik N i . NH
H..<
L.< 0 0 ' 0 i . 0 4.
1 HNb 0 1 .
HN-\ i * 1 *
CF3 , H 0 \1.---) N-/
, 1 * 0 \-0 = 0 0 HN /- . 0 0 \ / 7_ -) i N ( , , , 0, 0 0 0 0 0 k ;s,--0 / i NO N
N N N
NO .
/
and \
\__/ , , .
More preferably, R3 is selected from i 411 . 1 lik II y 11 OH NH OH
CF3 , , 0 N--z--1 . '1 _CF3 1 * -CF3 1 .
NH NH NH NH
0411 , 0 0 0 , , , , cF3 V
lik y 11V 11, g=0 1..g=0 i 1 *;=o 1 = g.c, NH
HN.,,..
41.., 1 HIV.,<
0 , Al , cF3, , 1 . '-==c) 1 . p 1 * siz--o 1 * $1=0 FINI HN 1 =$o HicCF3 HN rp 1 N.,....... 3 ,CHF2 i * Si:L.-0 1 . ===10 CF3 * Siz=0 i * i *
'---:0 I-114NCF3 Hy 1 HN 41,1Z) "\ HNV._ , HNN jz_ H/V._ Hyy HNN/__ HNV__ CI CF3 '0 7 S
o 9 111 ,o ,o ilk IlL'.o 41 g=o ..
, 4V_ HIL< HrV HNV__ , N
/ \ * F
1 4I Hg'--o , - 1 = szo Firi,z 5 Z----- and Most preferred, R3 is selected from cF3 i li 1 lik y 1 ilk 0 1 * V.0 i . Lo 9 141 41, NH
41N<
CF3 110 CI CI CI a p 9 p p 9 *$o 1 *o * s',--o 1 = szo , HN., HNN/.._ HIV HNy_s/ 4V
-9 / 9 and / ¨.
10 In a preferred embodiment in combination with any of the above or below embodiments of the first alternative R5 is selected from H, C1_6-alkyl, halo-C1.6-alkyl or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of 0-C1_6-alkyl, 0-halo-C1_6-alkyl and OH; and R6 is selected from H or halogen.
More preferably, R5 is selected from H, C1.3-alkyl, fluoro or chloro, even more preferred R5 is 15 selected from H, methyl, fluoro or chloro. Most preferably, R5 is methyl.
In a preferred embodiment in combination with any of the above or below embodiments of the first alternative R6 is selected from H, fluoro or chloro, more preferably R6 is hydrogen.
In a further preferred embodiment in combination with any of the above or below embodiments of the first alternative R4 is CR8R8-R10 ; R- is independently selected from H, F, C1_3-alkyl or halo-C1.3-alkyl; R1 is C3_10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1.6-alkyl, halo-C1--alkyl6 and cycloalkyl.
In a preferred embodiment in combination with any of the above or below embodiments of the first alternative R4 is selected from 1>0 .Andv .01.Nv F
and HO.
In an equally preferred embodiment in combination with any of the above or below embodiments of the first alternative R4 is CH2-(C4.7-cycloalkyl), wherein C4.7-cycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from fluoro or methyl.
In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative R4 is 011V,, aVvV VVVy =An.n.f OW" aVtiv Ho '0 'c and Even more preferred, R4 is *NW
~AI
ayvy I:a H07 VVVV
F F
F F and HO, and most preferred, R4 is CH2-cyclohexyl.
In another preferred embodiment in combination with any of the above or below embodiments of the first alternative the compound of Formula (1) is selected from the group consisting of o Q
3 \-1 \-1 N 0 HO
)--7-IN
111"
/ \ /\ / \
N *
0 OH N *
0 N *
CI) 0) &
0, Q 0 ,s,....7 0 0 "----1 HN ------1\-1N HN
11, if N * HN /* N *
& t CI) 0) , , , \_f HN001\-iN
/ \
N * I-IN k / \
/ \
N *
O) Szo CY
CH
LI
A 0 HOT-IN )-1\-1N 0 k HN
11, lir /\ /\ N /\
N * N * H
CY , CF3 , o LI LI
o o 0 HN AT-IN HN
if / \ / \/ \
N *N 0 N * Firk- N *
CI) I
ci .0 (a 0 0 (Q
Hbn HN HN HN
11, k *
HN*
N *
0 N * HN
N
& g-& 0) CF36 --C) , , , CLq co_0_\H HO
HN HN
0 i \
N * ck N N *
N
\ C
11'0 ICH I ) O
005,0.__, o 0 HN HN
lir 0' HN iv 0,.HNt\iN
llr / \ /
-Si, 0 \
N .
0 / '0 N *
OH)/ = 0 L\) al CH
n Q (Q
HN HN HN
CF3 if / \
i i \ * "N
\ ( N 10 N*
N . N k s-0) ,s,-.0 cf , CY 0/
, OH , ((....) HN
lir k /\ / \ N I\ N
H \
N 10 N pN 110 0) OH
& 4 CD) 4 , , , V\nN HN HN
I\
N * 0 N * Fir-- N *
0) CI) CF36' 0 &
4 , HO-.(:7 0 HO
V)-7-IN FIN HN HN
11, N * N o0 / \
' I
*
10) 4 , 0) , 0) 4 , Q (a HN HN
if HO / \ / \ /\
N IP
0 N *
Sr---f- HN*
0) 0) b 0) 4 d , (a / -Th HO \____ 0 -( szNi___µ0 HN _________________ 0 7)-7-IN 0 Q HN
N
N N
V N'N[0N / b N \
N
Q0 H02cõ,0 o 0 N
/ \ H I \ * sc-O >CH I \ .
N 0 Htl* N NH CO2H N
NH
0) po , d -7( , d ---7c , (()0,,,, = p N ill ._.,õ 0 N p H 1 \ . sr H ( _) N H 1 \ a sr N NI-1 iN 'NH N d 1---- NH
o -7( --7c , , , Ho2cµ
a i __ , 0 u3 0 cF3 a , N 0 0 'N
H 1 H I \ * g: 0 ,:--0 N
\ M. g,:: 0 H I \ gi-, N NH N ' NH
N) M NH
---7( a -7( o -7( ,a I- F F
/
)-\N
H i \ Ake g_o \_---\ H I \ 410, g,i,o o2sON . 1 \ a c) ) m 'NH NI) NH N) NH
0 -7c 0 -7c 0 -7( CQ HO2C,k F\
i MO
o Fl o N
\---<
, N ,0 0 Cl Cl CI CI 0 CI N
H 1 \ Ai sµ,..:0 H j\ M 0 H 1 \ M si:õ.,_0 N M. NH NI) 1114-11F NH N M NH
c3 --7c HO2C,1/4_ H 02Ck L o v O, o E o . , 'N 'NI
H 1 \ / \ N N
H I \ * /1 H I\
d ----c , , , 00N 0 cõ H I \ * 0 4 a 0 4 0 0 i N,......N,....õ...-,N
N N
H I \ * g',:-0 H I \ . ID
N NH N N
d d dF
5 , , , 0 1 N:
HO000., 0 ,N,N
1 k.,..,,N 0 4 HOOC N
'N H N
H I \ * 0 0 Ill I \ * H I \ *
N N N
d d d H
N, _iiii...õ_., 0 V 0 , jc 0 V 0 jk....f.õ, V
V
I N N
N H N N
H I \ = H H I \ * H I \ .
N N N
d d d , , , HOOCõ \:\ _0-N
a 0 CI o cF3 0=\/Nici..,...N 0 V
N H N
H I \ H I \ H I
N \ *
OH
N I* N
y_ N I/
d 0 NH
d A
d , , , HO000o HO000 o H2N 0 0 OH
N N1=-Y
H I \ \,N h,--.i._._ Nzi\ 1 \
=
N \
N N
d A
d d A
OH
HOOC,.cl o V 0 OH Ao. 0 OH
N
N ,0 H I \ = \ = gs?õ, H I \ . 8:=0 N 0 OH N HN ( N NH
d d d A
O 0 0 v _,--;Nri 1 \ . bi 1 \ * =-b' 1 \ .
O v OH N y_ 0 OH N y 0 OH N
d 0 d NH
d 0 NH
---i o HOOC) V HOOC :\ o OCF3 1,..1-1 1----' "NN N-Y¨
N H I \ . H I
\ N
\ /
H I . y N N
d d d 0 NH A A
y y y Ni----N--1 (1-: i</i HN 1 \ * 1:1<0 HO
0 / \
N =
d d F F
0) lir OH ' OH
O -NH . 0 \ OSIN 0 ----7cOl I \ . N , --m-- i, NH
H I \ w S N
NH
H I \ * S,I
N
,o 011 N (r0 N Cr HO d 0 d u3 F3c d F3d , , , OH
HO"L 0 .0, 0 ONia 0 OH
N N NH N
H I \ *
N 0" '0 N
FdN
d d a , , , OH OH
..---1--J,,, OH
(21'''.0 o V 'CI 0 V ,..]
O" ".c.-1 0 N
H I \ . N
H HN j<
N N H I \ == =() d0 0 ldN 8 HN d HN
)-F3 , F3 C)<
, C * , A, ca0ci 4 HO
HN ==ci N N
H I \ ==o H I \ .
ad * 0 N
d , , and an enantiomer, diastereomer, tautomer, N-oxide, solvate and pharmaceutically acceptable salt thereof.
In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative the compound of Formula (1) is selected from the group consisting of (a HO
) HN
1 ----\-----1\-IN 0 -----11 110"
/\ so /\ \ / \
N
0 OH N *
0 0) *
0) , CH , , 0, Q
HO
HN ---.\--T-IN HN
1r ir / \
N * "N* / \
N .
0 /\
0)0:--(:) , CH 0) , , _,OH 0 0 oi HNel\-1N lir 0 (1\-1N
lir N * H1,1* N *C 0 N * ) OS' CH
?..4 0 0 SITiN )-7-IN 0 ir /\ /\ Nk HN i \
N * N ,H
N$
, , ' 0 HN -S Oq rl\-IN HN
11, i \ i \ i \
* N * FIN* N *
0) I
0) 0) = , , , a Q
o ( 0 0 Hbn HN H HN
lir i \ /N \ * HN* ICI / \
0)N * 7*
N *
0 d-CF 31 ....
o oq cot_\ 0 OH HO
HN HN
i \ * \ 0 i\
0 c-k--N N 'PN
0) 8'o , CI) N\
, '..k 0 OST-M__-\ 0 0 HN HN
ir 0,FIN-ti\lN
ir /\ `S, 0 0)N 110 N
*0 OHNI *0 0) , , , Q()......) Q
HN HN HN
CF3 111, / \ s (N* /
N N * N * "Nk s-0) 0 CI) 0/ 0) 0 Q HO HO
HN kl\-IN k V)-71N
if k / \ "N" * N / \ N
N *H N IP \
CI) OH
CI) A & A
n 0 HO
7)-7-IN HN HN
/ \ I\ I\
* 0 N *
N ET ----- N$
CI) 0) CF36 -C) 13) A , HO
HO
0 --/.3 I-IN HN HN
ir / " / \0 0 /\
'1 N * N *
0 N .
CY A , CD) 0) A , , Q Q
IF HN HN
HO / \ / \ / \
*
N * FIN*
d 6 & A d' , z 0 b 0 CI) ____________________________________________________________ /
N *
and an enantiomer, diastereomer, tautomer, solvate and pharmaceutically acceptable salt thereof.
5 In a second alternative, the present invention provides a compound of Formula (1) R4 (i) an enantiomer, diastereomer, tautomer, N-oxide, solvate, formulation and pharmaceutically 10 acceptable salt thereof, wherein R1 is selected from a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0 and S, or 15 C1.10-alkyl substituted with a group selected from halogen, CN, OR11, SOyR11, SO3H, NRiis02-11, S02NR11R12, co2R11, COW, CONR11R12, NR-CO-R, NRUCONRhlRl2, S02-NRiiR12, NR11R12 and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0 and S, or C0_1-alkylene-C3_10-cycloalkyl substituted with a group selected from halogen, CN, SOyR11, NR11s02-11, S02NR11R12; c02.-.m11;
CONR11R12, CO-R11, NR11-CO-NR11 R12, NR, -S02_ H and NR11R12, or C2.10-alkylene-C3_10-cycloalkyl, C2_10-alkylene-O-C3_10-cycloalkyl, C2.10-alkylene-C6-10-heterocycloalkyl and C2_10-alkylene-O-05_10-heterocycloalkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, CN, 0-C1_6-alkyl, 0-halo-C1.6-alkyl, halo-C1.6-alkyl, halogen, CO2R11, CONIT1R12, SO2R11, S02NR1 R12, NR11coRil, NR11S021111, C3.6-cycloalkyl, 0-C3_6-cycloalkyl, C36-heterocycloalkyl, 0-C3_6-heterocycloalkyl, 0-C2_6-alkylene-0R11 and NR11R12;
R2 is selected from the group consisting of H, C1_6-alkyl, halo-C1_6-alkyl and hydroxy-C1-6-alkyl;
or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR", SOyR1'1, SO3H, h SO2NR11.-. m1 C0_6-alkylene-0O2R11, coNRil R12, C0R11, NR11-c0_Rii, Co_NRii NR11-S02-NR,,R12, NR11 R12, C1_6-alkyl, halo-C1_6-alkyl, hydroxy-C1_6-alkyl, cycloalkyl, 0-C3_6-cycloalkyl, C3_6-heterocycloalkyl and 0-C3.6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1_3-alkyl, halo-C1_3-alkyl and oxo;
R3 is a 6- or 10-membered mono- or bicyclic aryl or a 6- to 10-membered mono-or bicyclic heteroaryl containing 1 or 2 heteroatom selected from the group consisting of N, 0 and S, wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, CN, C1_6-alkyl, C3_10-cycloalkyl, C0.6-alkylene-C3-10-heterocycloalkyl, C0.6-alkylene-0-R31, C0_6-alkylene-000R31, C0_6-alkylene-C(0)R31, CO-6-alkylene-C(0)N(R31)2, Co_calkylene-N(R31)C(0)R31, C0.6-alkylene-S02-N(R31)2, Co_6-alkylene-N(R31)S02-R31, C0_6-alkylene-S02-R31, C0_6-alkylene-S0-R31 and C0_6-alkylene-N(R31)2, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1_3-alkyl, C3_6-cycloalkyl, C3.6-heterocycloalkyl, OH, 0-C1_3-alkyl, 0-halo-C1_3-alkyl, 0-C3.6-cycloalkyl, 0-C3_6-heterocycloalkyl, oxo, N(R32)2, COOH, CON(R32)2, CN and NR32-COR32, and wherein optionally two adjacent substituents complete a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1_6-alkyl, halo-C1_6-alkyl, C3-6-cycloalkyl, C3.6-heterocycloalkyl, oxo, OH, 0-C1..6-alkyl and 0-halo-C1.6-alkyl;
R4 is S02-(CR8R8)yR7, S02-NR12R7, (CR8R8),-R1 or C3.6-cycloalkyl, which is spirocyclic fused with C3_10-cycloalkyl;
R6 is selected from H, halo-C1_6-alkyl, CHO, CON(R62)2 or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of 0-C1_6-alkyl, 0-halo-C1_6-alkyl and OH;
R6 is selected from H, C1_6-alkyl, halo-C1_6-alkyl or halogen;
R7 is selected from C3_10-cycloalkyl and C3_10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, 0-halo-C1..6-alkyl, C1_6-alkyl, halo-C1_6-alkyl, cycloalkyl and heterocycloalkyl;
R8 is independently selected from H, F, C1_3-alkyl, halo-C1_3-alkyl or OH;
R1 is C3_10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, 0-C1_6-alkyl, 0-halo-C1_6-alkyl, C1_6-alkyl, halo-C1_6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1_2-alkyl, halo-C1-2-alkyl;
R11 is independently selected from H, C0.6-alkylene-C3_6-cycloalkyl, C0_6-alkylene-C3_6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C1_3-alkyl, halo-C1_3-alkyl, 0-halo-C1_3-alkyl and S02-C1_3-alkyl;
R12 is independently selected from H, C1_6-alkyl and halo-C1_6-alkyl;
R31 is independently selected from H, C1_6-alkyl, C0_6-alkylene-C3_6-cycloalkyl, C0_6-alkylene-C3.6-heterocycloalkyl, 5- or 6-membered heteroaryl and 6-membered aryl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, OH, oxo, C1_3-alkyl, halo-C1_3-alkyl, 0-C1_3-alkyl, 0-halo-C1_3-alkyl and S02-C1_3-alkyl;
' 53 and optionally wherein two R31 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1.4-alkyl and halo-C1_4-alkyl;
R32 is independently selected from H, C1.6-alkyl and halo-C1.6-alkyl;
R52 is independently selected from H, C1.3-alkyl and halo-C1_3-alkyl;
x is independently selected from 1 and 2;
y is independently selected from 0, 1 and 2.
In a further preferred embodiment in combination with any one of the above or below embodiments of the second alternative NR1R2 is selected from NHCH2CONH2, NHCH2CONMe2, NHCH2CH2OH, NHCH2CH(CF3)0H, NHCH2C(CF3)20H, NHCH2CH20Me, NHCH2CH2S02Me, NHCH2CH2S02NH2, NH(CH2)30H, NH(CH2)30Me, NH(CH2)40H, NH(CH2)40Me, NH(CH2)50H, NH(CH2)2CO2H, NH(CH2)3CO2H, NH(CH2)4CO2H, NH(CH2)5CO2H, NHCH2CMe2OH, NHCH(Me)CMe2OH, NHCH2CMe20Me, NHCH2CMe2CO2H, NHCH2CMe2CONH2, NHCH2CMe2CONHMe, NHCH2CMe2CONMe2, NHCH2CMe2NHSO2Me, NH(CH2)3SOMe, NH(CH2)5S02Me, NH(CH2)5S02NH2, NH(CH2)3NHSO2Me, NH(CH2)20(CH2)20H, NHCH2CHMe0H, NH(CH2)5SOMe, NCNN--\
NH(CH2)3S02Me, HN-3<, HN--(rF HN-CN- CF3, \--N 0 C
HN HN-V/H \--N7-\0 C\--N
NH
, ,0 HN-00 HN--\CO HN-CS HNSO HN-CS;
, HN--) HN-\4 HN->21 N
NH
\
, , HN NH\------) HN---11-4 o HN--- HN- HN--\ /
\S
/)/---OH )rNH 2 -OH
, , , HN--( / HN----\ / HN--\ _.._ HN--) /<
ICIHN--) 0 --) g JP
00 0 0 , \, HN
, , , HN--.< Nil- N'-'= N 0 HN -0 0 \r0 /<r(3 N)-LOH
HO, HO OH OH L./
, , , , CD.,,r0 HN, HN,, ...\ HN,,, HN HN,,, OH, OH, OH, OH, OH, HN,,,,i HNo HN
Helk.0 )(r0 OH, OH, OH, OH, HN---) /<0 HN HNHNON / HNN7"--) HN--\ p 7N,s/, \
OH, 0/0 o'0 OH
HN-->_1;11 0 HN->_r\il 0 HN-)A HN--->_111 0 r z 0\ , OH, OH, OH, HN ---)A 0 HN-.) 0 HN--rrHN-- 4D
1 HN--\ \OH
0 , \-OH HN-\
CDI , , , HN-\_80 1 1-1\1--\N Nil-- N3 I
\--OH, OH 1 Nrc OH 0 OH
0, N- N
LCZ.-0 1\1Th I__(.--No 0H NI N'N) S=0 b ._.--c) o--/ Ni / and NO .
, In a more preferred embodiment in combination with any one of the above or below 5 embodiments of the second alternative NR1R2 is selected from NHCH2CONH2, NHCH2CONMe2, NHCH2CH2OH, NHCH2CH(CF3)0H, NHCH2C(CF3)20H, NHCH2CH20Me, NHCH2CH2S02Me, NHCH2CH2S02NH2, NH(CH2)30H, NH(CH2)30Me, NH(CH2)40H, NH(CH2)40Me, NH(CH2)50H, NH(CH2)2CO2H, NH(CH2)3CO2H, NH(CH2)4CO2H, NH(CH2)5CO2H, NHCH2CMe2OH, NHCH(Me)CMe2OH, NHCH2CMe20Me, 10 NHCH2CMe2CO2H, NHCH2CMe2CONH2, NHCH2CMe2CONHMe, NHCH2CMe2CONMe2, NHCH2CMe2NHSO2Me, NH(CH2)3SOMe, NH(CH2)5S02Me, NH(CH2)3NHSO2Me, F
NC HN--\
NH(CH2)20(CH2)20H, NHCH2CHMe0H, HN-\<1, HN-<r , HN-CN-, CF3, HN-r-\0 HN \---\_NrTho C-- \--NO r \--- NCO
HN-\____ \___/ \
HN-- HN-v...O_H HN---\L---OH
HN-CO HN-\CO HN-CS HN-CS-,---0 ,NO H -CN -4 x 0 -N-1(___ HN-CS; 0 HN-CN HN
HN--) \
HN- 0 qH HN-- JO HN--\-S- 9 HN
\ --)--NH2 HN----)1 Nr0 P 8 , HN OH HN NH2 HN NH HN--)___[\11 HN--)._>/_ \-----) µS"\C' zr34 o HO 0 HN) 4:) HN-- HN--\ / HN--\ / HN--\ p c__N-/ ( >--OH --NH2 HN-S:=0 - I tNH2 0 0 0 , \
, , , , HN--<, Nil- N Na HN,,, HN- 0 (j4 0 'Or10 0 0 \r rr HO OH HO OH OH OH
, , , , , HN,,, HN,,, i HNr0 0 OH , OH, OH , OH , 0 HN-)._1,71, HN--) HN-11 0 HN---...11 IN \r0 HN-\ 1 < r ...o--OH , OH , OH, HN->111 0 HN 0 0. P
---)Z
HN HN
)4) (C --IN--\
\
HN-\ \
0 , \--OH, OH, , HN--)ip 4c HN-).
HN-\
d>r-NH\--cm 1--( 1-1\ N pH OH, 0 2 , , H .
O 0', i) , , S=0 0 and \ib .
More preferably, NR1R2 is selected from HN---)(7,H ,0 HN-00 HN-CS--:--0 HN-CS
--\ ' \ c HN -\
c \ Nar HNõ, HN /<0 0 , HN
HNõ,or HN N-O 0<r0 N34 OH LO Le10 N
OH, OH, 0, 6 , 0 and N
S='-0 0;
and most preferred NR1R2 is HN OH HN-\ c 0 N
-4 N3)\A 0 OH HN C)H , OH
HNõ HN,,,Oro HN
.0,r0 101<r0 OH, OH and OH.
In another preferred embodiment in combination with any one of the above or below embodiments of the second alternative R3 is , --R33 R33 R33 ( 1 . R39 h (N i----K\ N
R34 , R34 , R34 and R34, wherein R33 is independently selected from C1_6-alkyl and fluoro-C1_6-alkyl;
R34 is independently selected from halogen, C1_6-alkyl, fluoro-C1.6-alkyl, 0-C1.6-alkyl, 0-fluoro-C1_6-alkyl, NH-C1_6-alkyl and NH-fluoro-C1_6-alkyl;
R39 is selected from H, F and OH.
In yet another preferred embodiment in combination with any one of the above or below embodiments of the second alternative R3 is selected from F 1 * OH 1 411 1 . OH
F
-( N _c=-( 1 \ N
3 , 5/ ( F2HCO 0N-x_ --( ----- . 3 /
y_ 7-HN-/ , HN , and .
More preferably, R3 is 4. 1 lik F =
1 * OH 1 11 -)<
1 'OH 1 \ '/NI i . F
, , , , 9 , CF3 1 i-( 0- -(CF3 --(.
\ 0-x (0 3 - -)\--\ /N i---=( 41%1 CF3,,CF3 and , , .
Even more preferably, R3 is N=?<
5 /N 1-= /N L- ?, and ?
5/¨
.
In a further preferred embodiment in combination with any one of the above or below embodiments of the second alternative R5 is selected from H, C1.6-alkyl, halo-C1_6-alkyl or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of 0-C1_6-alkyl, 0-halo-C1.6-alkyl and OH.
More preferably, R5 is selected from H, C1_3-alkyl, fluoro or chloro, even more preferred R5 is selected from H, methyl, fluoro or chloro. Most preferably, R5 is methyl.
In a preferred embodiment in combination with any of the above or below embodiments of the second alternative R6 is selected from H, fluoro or chloro, more preferably R6 is hydrogen.
In another preferred embodiment in combination with any one of the above or below embodiments of the second alternative R4 is S02-R7, S02-NR12R7, CHR8-R1 and (CH)2R10;
R7 is independently selected from C3_10-cycloalkyl and C3_10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, OH, alkyl, halo-C1_6-alkyl and cycloalkyl;
R8 is H, F, C1.3-alkyl or halo-C13-alkyl;
R1 is C3_10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C16-alkyl, halo-C1_6-alkyl and cycloalkyl.
In a further preferred embodiment in combination with any one of the above or below embodiments of the second alternative R4 is selected from vw vw 11140, vw 0-vvvb 0-s, y 0_1 0vw ' NI
N ob,00 0' N
or More preferably, R4 is CH2-C4.7-cycloalkyl, most preferably, R4 is CH2-cyclohexyl.
In yet another preferred embodiment in combination with any of the above or below embodiments of the second alternative, the compound of Formula (1) is selected from the group consisting of oq o ol--\
HN, HN HN F3C.,..\ HN
, 0' /S --O / \
N * N \ N
= N 1104 0) CY 0) 0 0 0 0 -1\-1N
)I-T-IN
H2N----1\1N
N * ---N \ N
z N CH * CI) 0) , OL.q HO
_________________________________________________________________ 9Th HN H.20 7)-7-iN
/\
N * N * N \ N
=
0) 0) , 0) , , , 0 0\
0," \S
SI___q i --7 L... 0 HN HO--N HN
/\ /\ /\
N * N 1110 N .
CI) 0) OL..q 0 0/-"\ 0 0 HN HN -------5F?N
0 /\
N \ N N * N *
0) oq (2.4 o o 0 HN HN )----\ --1\-IN
/ \ / \ 0 / \
*
ICI) CI) 0) , , , oL..q0 0 0 HN F HN HN
I\ / \ / \
N10 rij IP
0) Sr:--0 Cril b 0 1_ 4 1 . . ...q 0q 0 HN HN / \
/ \
\ CF3 *
N$
Olt oq L...q o o clq / \
10 / \ HN
Y
N
0, b )criN *
, OqOz_q (Lq HN HN HN
/\ CF3 /\ / \
NP N * N *
0) 0) F
C) HO2Ck El 0 HOOC, 0 H
--r I \ * ljCn ____ N-N
N
, d c3 , d , HOOCõ.0N ::01,,,.0, H I = \ /NI N
H \ \ \ /N
7---N ________________ N
d d and an enantiomer, diastereomer, tautomer, N-oxide, solvate and pharmaceutically acceptable salt thereof.
More preferred are compounds of Formula (1) selected from the group consisting of oq o ol--\
HN, HN HN F3C...._1 HN
O'70 / \ /\
N * N \ z N N 110 0) CI) Crj \i HN
/ \
N *
CI) 0) 0) 01..qHO
9""Th HN HSCN
kl\-IN
N 110 N * 0) \ z N
CY CI) 0 0, 0."
"-Si.q HN HO-C HN
/\ / \ / \
N * N 110, N *
Cf) 0) '/ OLq 0 HN HN
/\ 0 / \
0) 0) 0) OL..q01....q )Th 0"---\ 0 HN HN HN
/ \ \ 0 /\
*
or , , , 0 I:4 0 CL:14 HN F HN HN
N * 0 , 0 b ,s--0 , 0 b , , 0 OLq HN HN / \
/ \ / \ CF3 Ni 104 Y 10 N \ N ,S=0 Olt 0) / 9=1 lb, , , , cLq 0 ci_q HN HN (1..q / \
E / \ HN
Y * N . / \
,S=0 N *
b oq o oq o zq HN HN HN
/ \ CF3 0) N * ,0) N * Fande N #
.
The invention also provides the compound of the invention for use as a medicament.
Also provided is the compound of the invention for use in treating RORy mediated inflammatory and autoimmune diseases.
Preferably, the disease is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, psoriatic arthritis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, asthma, mucosal leishmaniasis, multiple sclerosis, systemic sclerosis, type 1 diabetes, Kawasaki disease, Hashimoto's thyroiditis, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thromobotic purpura, myasthenia gravis, Sjorgren's syndrome, scleroderma, ulcerative colitis, epidermal hyperplasia, glomerulonephritis, chronic obstructive pulmonary disease and amyotrophic lateral sclerosis. More preferably, the disease is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, psoriatic arthritis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, asthma, multiple sclerosis, type 1 diabetes, chronic obstructive pulmonary disease and amyotrophic lateral sclerosis. Most preferred, the disease is rheumatoid arthritis or psoriasis.
Also provided is a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier.
In the context of the present invention C1_12-alkyl means a saturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, which may be straight chained or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
The term "halo-C1.12-alkyl" means that one or more hydrogen atoms in the alkyl chain are replaced by a halogen. A subset of this term is "fluoro-C1_4-alkyl", wherein one or more hydrogen atoms in the alkyl chain are replaced by a fluorine atom. Preferred examples thereof are CF3, CH2CF3 and CH2CH2F.
C2-12-alkenyl means a hydrocarbon chain having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, which may be straight chained or branched, containing at least one carbon to carbon double bond. Examples thereof include ethenyl, propenyl, dodecenyl, 2-methylenehexyl and (2E,4E)-hexa-2,4-dienyl.
C2-12-alkynyl means a hydrocarbon chain having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, which may be straight chained or branched, containing at least one carbon to carbon triple bond. Examples thereof include ethynyl, propynyl and dodecynyl.
A "C0_6-alkylene" means that the respective group is divalent and connects the attached residue with the remaining part of the molecule. Moreover, in the context of the present invention, "Co-alkylene" is meant to represent a bond.
A C3_10-cycloalkyl group means a saturated mono-, bi- or multicyclic ring system comprising 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, pentacyclo[4.2Ø02=5.03'8.04Ioctyl and adamantyl.
A C3_10-heterocycloalkyl group means a saturated or partially unsaturated 3, 4, 5, 6, 7, 8, 9 or 10-membered carbon mono-, bi- or multicyclic ring wherein 1, 2 or 3 carbon atoms are replaced by 1, 2 or 3 heteroatoms, respectively, wherein the heteroatoms are independently selected from N, 0 and S. Examples thereof include epoxidyl, oxetanyl, pyrrolidinyl, 5 tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl, 4-quinuclidinyl, 1,4-dihydropyridinyl and 3,6-dihydro-2H-thiopyranyl. The C3_10-heterocycloalkyl group can be connected via a carbon or nitrogen atom, if not stated otherwise.
A 5- to 10-membered mono- or bicyclic heteroaryl system containing up to 4 heteroatoms means a monocyclic heteroaromatic ring such as pyrrolyl, imidazolyl, furanyl, thiophenyl, 10 pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and thiadiazolyl. It further means a bicyclic ring system wherein the heteroatom(s) may be present in one or both rings including the bridgehead atoms. Examples thereof include quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzisoxazolyl, benzodioxanyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl and pyrazolo[1,5-a]pyrimidinyl. The nitrogen 15 or sulphur atom of the heteroaryl system may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. If not stated otherwise, the heteroaryl system can be connected via a carbon or nitrogen atom. Examples for N-linked heterocycles are s, se, SN
1_/
and .
A 6- to 10-membered mono- or bicyclic aryl system means an aromatic carbon cycle such as 20 phenyl or naphthalenyl.
The term "N-oxide" denotes compounds, there the nitrogen in the heteroaromatic system (preferably pyridinyl) is oxidized. Such compounds can be obtained in a known manner by reacting a compound of the present invention (such as in a pyridinyl group) with H202 or a peracid in an inert solvent.
25 Halogen is selected from fluorine, chlorine, bromine and iodine. The preferred halogen is fluorine.
Furthermore, the compounds of the present invention are partly subject to tautomerism. For example, if a heteroaromatic group containing a nitrogen atom in the ring is substituted with a hydroxy group on the carbon atom adjacent to the nitrogen atom, the following 30 tautomerism can appear:
) When a substitution of a residue with cycloalkyl or heterocycloalkyl is described, it is understood that the substitution can be connected straight and, when the connecting carbon atom is sp3-hybridized, in addition spirocyclic. For example, when cyclohexan is substitued with the heterocycloalkyl group oxetan-3-yl, the following structures are possible:
aCj and It will be appreciated by the skilled person that when lists of alternative substituents include members which, because of their valency requirements or other reasons, cannot be used to substitute a particular group, the list is intended to be read with the knowledge of the skilled person to include only those members of the list which are suitable for substituting the particular group.
The compounds used in the present invention can be in the form of a pharmaceutically acceptable salt or a solvate. The term "pharmaceutically acceptable salts"
refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. In case the compounds of the present invention contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the present invention which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the present invention which contain one or more basic groups, i.e. groups which can be protonated, can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids known to the person skilled in the art. If the compounds of the present invention simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
The present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
In practical use, the compounds used in the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.
The tablets, pills, capsules and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
The compounds used in the present invention may also be administered parenterally.
Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral (including intravenous), ocular, pulmonary, nasal and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. Preferably compounds of the present invention are administered orally.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
When treating or preventing RORy-mediated conditions for which compounds of Formula (1) are indicated, generally satisfactory results are obtained when the compounds are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of mammal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligram to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
The present invention describes modulators, in the following also referred to as ligands, which bind to the RORy receptor. Surprisingly, it has been found that compounds of Formula (1) act as modulators of the RORy receptor.
The RORy receptor is considered to be involved in thymocyte development, thus the modulators described herein may be useful in the treatment of inflammatory skin diseases such as atopic eczema and psoriasis. It is further suggested that down-modulation of RORy transcriptional activity with a ligand could result in a shift of the immune response towards a Th2 type response which could be beneficial in the treatment of certain allergic inflammatory conditions such as rheumatoid arthritis, systemic lupus erythomatosis, inflammatory bowel disease (Crohn's Disease) and multiple sclerosis (Tesmer et. al., lmmunol.
Rev. 2008, 223:97).
The compounds of Formula (1) show antagonistic activity, with respect to the dose dependent modulation of the constitutive interaction of the RORy ligand binding domain with peptides derived from the co-activators such as SRC-1, TRAP 220 or TIF-2.
It has been surprisingly found that the interaction between RORy ligand binding domain and the peptides can be determined by a homogenous FRET based ligand-sensing assays. Even more surprising was the identification of compounds of Formula (1) as ligands for RORy.
The identification of high affinity ligands for RORy with agonistic and antagonistic properties is the basis to enable experts knowledgeable in the field to establish assays for the identification of novel agonistic and antagonistic RORy ligands from libraries of small molecules. The identification of ligands which bind to and modulate the activity of RORy1 and RORyt is the first mandatory step to develop new small molecule based medicines with a potential to be developed for the treatment of diseases which are directly or indirectly controlled by the activity of RORy1 or RORyt. Such diseases include but are not restricted to inflammatory diseases, asthma, rheumatoid arthritis, autoimmune diseases or diseases with an autoimmune component such as systemic lupus erythomatosis, inflammatory bowel disease (Crohn's disease), ulcerative colitis, inflammatory skin diseases such as atopic eczema or psoriasis, multiple sclerosis or similar diseases.
The compounds of the present invention can be prepared by a combination of methods known in the art including the procedures described in Schemes I to Ill below.
Pyrrole-3-esters of general structure A (Scheme I) can be N-derivatized by alkylation with alkyl halides, by reaction with sulfonyl chlorides or sulfamoyl chlorides in the presence of appropriate bases in appropriate solvents. The introduction of an aromatic or heteroaromatic substituents in the 5-position of intermediates B (Scheme I) can be achieved either by bromination with N-bromosuccinimide (NBS) and subsequent Suzuki cross coupling with boronic esters or boronic acids or by an Ir-catalyzed direct borylation (as described in J. Am.
Chem. Soc.
2007, 129:15434) of intermediate B (Scheme l), followed by boronic ester hydrolysis and Suzuki cross coupling with halo-aromatics or halo-heteroaromatics. The order of alkylation and bromination to prepare intermediates C can be inverted as depicted in Scheme I. The common intermediate E (Scheme I) can be further transformed into carboxamides by ester hydrolysis and amide formation using methods known to those skilled in the art.
Scheme I
0Alk 0Alk o R6 NBS oR6 ______________________ 1 Alk = alkyl RN ---1-1 R5 N Br ili A ill 1 xR4 I XR4 base, solvent base, solvent 0Alk 0Alk NBS
R5 Br ,....-0, 1. direct borylation" B¨R3 2. boronic ester hydrolysis -7-0 Suzuki coupling 0Alk 0Alk HNR1R2 Oi_.R...6 XR 0 _ . ....R 6 ester OH amide 3 .. hydrolysis 0 R6 formation 0 / \ ___________________ ... i \ ' R4 D Suzuki coupling 11 R4 E R5 R' ri R4 R' ri Alternatively, for purposes of tailored late stage derivatization, the formation of the amide can be performed first, followed by bromination and Suzuki cross-coupling as final step, as depicted in Scheme II.
Scheme II
0Alk OHNR1R2 0 o R6 6 ester hydrolysis R amide coupling 0 _ R:
R H R ''--H ________ .... / \
11 il N H
Alk = alkyl0 1 NBS
_.r.-' B¨R
NR1R2 0' NR1R2 0 _ _ R6 Suzuki coupling / \ , 11 \
IR' 11 R' R- Br In alternative to Pd-catalyzed cross coupling reactions the 2-position of pyrrole A (Scheme III) can be acylated and the resulting ketone intermediate B (Scheme III) can be further transformed into heteroaromatics containing analogues of the general formula C
in Scheme III, using methods described in Org. Lett. 2008, 10:2897. Again, intermediate C (Scheme III) can be further transformed into carboxamides by ester hydrolysis and amide formation using methods known to those skilled in the art.
Scheme III
0Alk 0Alk 0Alk R6 acylation / \
a ...
' / \ R6 R steps for hetero-romatic ring formation R r, R- N H R5 Ki R4 R4 0 R4 "
Alk = alkyl I
R' R, R', R", R"' = additional substituents 1. ester hydrolysis 2. amide formation R r, S¨
Y
D µ /
I
R' Abbreviations Ac acetyl ACN acetonitrile aq. aqueous B2Pin2 4,4,4',4',5,5,5',5'-octamethy1-2,2'-bi-1,3,2-dioxaborolane CC flash chromatography on silica gel COD cyclooctadiene Cy cyclohexyl dba dibenzylideneacetone DCE 1,2-dichlroroethane DCM dichloromethane DIPEA diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-dimethylformamide dppf 1,1'-bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane dtbpy 4,4'-di-tert-buty1-2,2'-bipyridine EA ethyl acetate HATU 0-(7-azabenzotriazole-1-y1)-N,N,N',N4etramethyluronium hexafluorophosphate MOM methoxymethyl MTBE tert-butylmethylether NBS N-bromosuccinimide NCS N-chlorosuccinimide Pin pinacolato (0CMe2CMe20) PE petroleum ether prep. preparative rt room temperature TBAB tertabutylammonium bromide Tf trifluoromethanesulfonyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Experimental Section Preparative Examples The synthesis of the following Preparative Examples is described in W02012/139775:
B
tk _(¨ ___________________________ ¨Y
B \ / / 76 N B¨(4N <
0' \ ,I3 \
-c,-\
P1 0 P2 0F3 , P3 0-7 , leL-'El 11 0 _______________________________________ V-NH ).- C)sB . V-N
N 0 HO' 0 cl 8 5, P6 , P10 , P11 , _________ -0 '0 02 g / NSõN - õ_,õµ CF3 ___________ :B *
L............õ kmanoi---00 (H0)2B¨Ce-0/ \
( / P13 . P14 \ ( P15 , ____________________________________________ _o\ -os 7\ V-os -=( 4 B * 0 _______________________________________________ .
)--Ci\B--C¨N/H B \ /N 0' -0 td \ rµli r--ci \
P16 P17 A, P20 P21 A , , , .4 V
_________ 13 lik ID (H0)2B 4I F __________ 'B 411 __ , ,I3 * )70,B *
-0' 1-0,/ _____________________________________________ -0 P22 0F3P24 p25 0F3 P26 0F3 P27 4 , , , , , )B * __ B B
:
-0 V-0, ['d * V-0, -T-0 411 -Os P28 4 P29 OH, P34 A , P35 A , , ________________ -0 ________________ B
: 41 -0 /--CF -0\ ? CF3 y_ _____________________________ sg 411, _.il 3 ) ,B * s-NHc-0' -0 ii 0 81 )\--P37 0 , P39 , P40 , )-Os 0 -0\
-.... ,B * g-Nb * ___)o'B II o )- B . 0 0 8 o' ) ____\-o 0 HO \-o, o c):E) ATL, :g- ,NH OH 13 11 -7 (5) B .
"-NH 0 S
P46 0F3 p47 0F3 P48 CF3 y 3 9 B cF, , . B * N 0 B * 0 P52 F , P68 0 P88 P98 OH , \ -o, o 7-o'B 11, Preparative Example P7 B . 0 \
Step 1: 4-Bromo-2-(tert-butvl)phenol (P7a) To a solution of 2-(tert-butyl)phenol (30.0 g, 200 mmol) in CHCI3 (600 mL) was added tetra-n-butyl ammonium tribromide (121 g, 250 mmol) and the solution was stirred for 2 h at rt, concentrated and the crude product was partitioned between Et20 and water. The organic layer was washed sequentially with 1M HCI twice and brine twice. The organic layer was separated and dried over MgSO4, concentrated and purified by CC (PE/EA = 7/1) to give compound P7a (39.9 g, 89%) as a colorless solid.
Step 2: 4-Bromo-2-(tert-butvI)-1-(methoxymethoxv)benzene (P7b) NaH (4.40 g, 110 mmol) and MOMCI (9.60 g, 120 mmol) were gradually added to a solution of compound P7a (22.8 g, 100 mol) in dry DMF (300 mL) while cooling on ice and the mixture was stirred at 0 C overnight, poured into ice water and extracted with EA (3x). The combined organic layer was washed with water (3x) and brine consecutively, dried over Na2SO4, concentrated and purified by CC (PE/EA = 100/1) to give compound P7b (24.9 g, 92%) as a light yellow oil.
Step 3: 2434 tert-Butv1)-4-(methoxvmethoxv)phenv1)-4,4,5,5-tetramethvI-1,3,2-dioxaborolane (P7) A solution of compound P7b (24.2 g, 89.0 mmol), B2Pin2 (24.1 g, 95.0 mmol), KOAc (9.31 g, 95.0 mmol) and Pd(dppf)Cl2 (4.00 g) in dry DMF (500 mL) was heated at 90 C
overnight under N2, concentrated and the residue was partitioned between water and EA.
The aq.
layer was extracted with EA and the combined organic layers were washed with water twice and brine consecutively. The organic layer was dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 5/1) to give compound P7 (15.4 g, 54%) as a colorless solid.
5 Preparative Example P8 )ckB /_ Step 1: 6-tert-Butv1-4-hydroxvpvridin-2(11-1)-one (P8a) A mixture of 6-tert-butyl-4-hydroxy-2H-pyran-2-one (38 g, 168 mmol) and aq.
NH4OH (150 mL, 30%) in dry toluene (200 mL) was heated at reflux for 1 h, concentrated and purified by 10 CC (PE/EA = 5/1) to give compound P8a (22.5 g, 80%) as a colorless solid.
Step 2: 4-Bromo-6-tert-butvlovridin-2(11-1)-one (P8b) To a solution of compound P8a (9.7 g, 60 mmol) in DMF (100 mL) was added POBr3 (17.2 g, 60 mmol) and the mixture was heated at 90 C for 2 h, was concentrated, diluted with water and extracted with EA. The organic layer was washed with brine (3x), concentrated and 15 purified by CC (PE/EA = 5/1) to give compound P8b (22.5 g, 80%) as a yellow solid.
Step 3: 4-Bromo-2-tert-butyl-6-(neopentvloxv)Pvridine (P8c) To a solution of compound P8b (2.0 g, 8.66 mmol) in dry DMF (20 mL) was added NaH
(0.62 g, 26.0 mmol) under N2 and the mixture was stirred at rt for 1 h. Then 1-bromo-2,2-dimethylpropane (2.37 g, 15.7 mmol) was added and the resulting mixture was heated at 20 80 C overnight, quenched with water (10 mL) and extracted with EA twice.
The combined organic layers were washed with brine (3x), concentrated and purified by CC
(PE/EA = 50/1) to give compound P8c (0.5 g, 20%) as an oil.
Step 4: 2-tert-Butyl-6-(neopentvloxv)-4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)pvridine (P8) 25 A mixture of compound P8c (2.2 g, 7.72 mmol), B2Pin2 (2.94 g, 11.6 mmol), KOAc (1.13 g, 11.6 mmol) and Pd(dppf)Cl2 (200 mg) in dry DMF (20 mL) was heated at 90 C
under N2 overnight, quenched with water and extracted with EA twice. The combined organic layers were washed with brine (3x), concentrated and purified by CC (PE/EA = 50/1) to give compound P8 (2.5 g, 97%) as an oil.
Preparative Example P9 os tB \ <¨_?/ o, /N
2,6-Di-tert-butyl-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)Pyridine (P9) Under N2 a catalyst stock solution was prepared by weighing [(COD)Ir(p-OMe)12 (104 mg, 0.312 mmol Ir), dtbpy (84 mg, 0.312 mmol) and B2Pin2 (2.64 g, 10.4 mmol) into a vial followed by the volumetric addition of degassed MTBE to make up a 25 mL
solution which upon shaking developed a deep red color. The solution was transferred to a vial and sealed with a rubber septum. Under N2, a vial was charged with 2,6-di- tert-butylpyridine (1.91 g, 10.0 mmol) followed by 25 mL of the catalyst stock solution. The reaction was heated at 80 C for 2 h, concentrated and purified by CC (PE/EA = 8/1) to give compound P9 (1.89 g, 60%) as a colorless solid.
Preparative Example P18a and Preparative Example P18 o o N \OH
dP18a d P18 Step 1: Ethyl 1-(cyclohexylmethyl)-2-methy1-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)-1H-pyrrole-3-carboxylate (P18a) To a solution of 1-(cyclohexylmethyl)-2-ethyl-1H-pyrrole-3-carboxylate (prepared according to Example 1d, 2.12 g, 8.51 mmol) in THF (20 mL) was added [(COD)Ir(p-OMe)]2 (167 mg, 0.25 mmol), dtbpy (137 mg, 0.51 mmol) and B2Pin2 (2.38 g, 9.37 mmol) and the solution was stirred overnight at 100 C under N2, concentrated and purified by CC (PE/EA =
50/1) to give compound P18a (2.24 g, 70%) as a colorless solid.
Step 2: 1-(Cyclohexylmethyl)-4-(ethoxycarbony1)-5-methyl-1H-pyrrol-2-ylboronic acid (P18) To a solution of P18a (1.50 g, 4.00 mmol) in a mixture of acetone (15 mL) and water (15 mL) was added sodium periodate (2.55 g, 12.0 mmol) and ammonium acetate (1.00 g, 13 mmol) at rt and the solution was stirred at reflux for 2 d, concentrated and extracted with EA. The organic layer was washed with 0.1M HCI and brine consecutively, dried over Na2SO4, filtered and concentrated to give intermediate P18 (1.17 g, quant.) as a colorless solid.
Preparative Example P19 -os 0 N
)10)3 41 o Step 1: 2-(tert-Butyl)-4-chlorophenol (P19a) To a mixture of 4-chlorophenol (50 g, 0.39 mol) and t-BuOH (57.6 g, 0.78 mol) was added conc. H2SO4 (40 mL) and the solution was stirred at rt for 48 h, poured into ice-water and extracted with EA twice. The combined organic layers were washed with water (3x) and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA =
40/1) to give compound P19a (48.5 g, 68%) as a colorless solid.
Step 2: 2-(tert-ButvI)-4-chlorophenvl trifluoromethanesulfonate (P19b) To a solution of compound P19a (32.0 g, 174 mmol) and pyridine (22.5 mL, 278 mmol) in dry DCM (500 mL) was added a solution of Tf20 (35.5 mL, 209 mmol) in dry DCM (150 mL) under ice cooling and the solution was stirred for 4 h at rt, poured into 1M
HCI and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 10/1) to give compound P19b (40.0 g, 82%) as a pale yellow solid.
Step 3: Methyl 2-(tert-butyI)-4-chlorobenzoate (P19c) A solution of compound P19b (40.0 g, 142 mmol), dppp (5.0 g, 12 mmol), Pd(OAc)2 (2.7 g, 12 mmol) and NEt3 (150 mL, 1.1 mol) in a mixture of Me0H (300 mL) and DMSO
(400 mL) was stirred overnight at 55 C under an atmosphere of CO. Water and EA were added and the organic layer was separated, washed with water twice and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 8/1) to give compound P19c (27.1 g, 84%) as a colorless solid.
Step 4: 2-(tert-Butyl)-4-chlorobenzoic acid (P19d) To a stirred solution of compound P19c (542 mg, 2.40 mmol) in a mixture of DMSO (6 mL) and H20 (2 drops) was added t-BuOK (538 mg, 4.8 mmol) and this mixture was stirred at 85 C for 4 h, adjusted to pH = 2-3 with 1N HCI and then extracted with EA
(3x). The combined organic layers were washed with water (3x) and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 2/1) to give compound P19d (404 mg, 80%) as a yellow solid.
Step 4: (2-(tert-Buty1)-4-chlorophenv1)(piperidin-1-yOmethanone (P19e) A solution of compound P19d (404 mg, 1.91 mmol), piperidine (244 mg, 2.87 mmol), HATU
(870 mg, 2.29 mmol) and DIPEA (616 mg, 4.78 mmol) in DMF (5 mL) was stirred at rt for 20 min, quenched with water and extracted with EA twice. The combined organic layers were washed with water (3x) and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by prep. TLC (PE/EA = 1/1) to give compound P19e (550 mg, 97%) as a yellow solid.
Step 5: (2-(tert-Butv1)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-v1)phenv1)(piperidin-1-vpmethanone (P19) A stirred solution of PCy3 (100 mg, 0.35 mmol) and Pd(dba)2 (200 mg, 0.35 mmol) in 1,4-dioxane (20 mL) was stirred at rt for 30 min, then compound P19e (550 mg, 1.97 mmol), P2Bin2 (767 mg, 2.17 mmol) and KOAc (546 mg, 1.90 mmol) was added and the solution was heated at 90 C for 3 h, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give compound P19 (159 mg, 22%) as a colorless solid.
Preparative Example P23 :B =
Step 1: 1-(3-BrOM0-5-(tert-butVOIDhenVOCyClObutan01(P23a) To an oven dried 100 mL 3-neck flask was added 1,3-dibromo-5-(tert-butyl)benzene (500 mg, 1.72 mmol) in dry THF (30 mL) under N2 and the mixture was cooled to ¨78 C. n-BuLi (2.5M, 1 mL) was added and the mixture was stirred at ¨78 C for 1 h. Then cyclobutanone (181 mg, 2.58 mmol) was added. After the reaction was complete (monitored by LC-MS) the mixture was quenched with aq. NH4CI and extracted with EA. The organic layer was dried over MgSO4, filtered and evaporated to give compound P23a (243 mg, 50%) as a yellow solid.
Step 2: 1-Bromo-3-(tert-butv1)-5-cyclobutvlbenzene (P23b) To the mixture of compound P23a (243 mg, 0.86 mmol) in DCM ( 20 mL) was added TFA (3 mL) and the mixture was stirred at rt. Triethylsilane (200 mg, 1.72 mmol) was added and the mixture was stirred overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL).
The organic layer was washed with brine, dried over Na2SO4 and concentrated to give compound P23b (150 mg, 66%) as a colorless solid.
Step 3: 2-(3-(tert-Butv1)-5-cyclobutvlphenv1)-4,4,5,5-tetramethvI-1,3,2-dioxaborolane (P23) To a mixture of compound P23b (133 mg, 0.50 mmol), B2Pin2 (152 mg, 0.60 mmol) and KOAc (98 mg, 1.00 mmol) in 1,4-dioxane (10 mL) under Ar was added Pd(dppf)Cl2 (0.03 eq) and the mixture was heated at 80 C overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (hexane/EA = 20/1) to give compound P23 (110 mg, 70%) as colorless solid.
Preparative Example P30 ___________________________________ -o :13 100 P30 ¨
Step 1: 1-Bromo-3-(tert-butv1)-5-(2-rnethoxvpropan-2-v1)benzene (P30a) To a mixture of 2-(3-Bromo-5-(tert-butyl)phenyl)propan-2-ol [synthesis described in W02012/139775] (190 mg, 0.7 mmol) in DMF (10 mL) was added NaH (60%, 20 mg, 1.2 mmol) and the mixture was stirred at rt for 10 min. Then Mel (423 mg, 3.0 mmol) was added and the mixture was stirred overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (hexane/EA = 10/1) to give compound P30a (125 mg, 64%) as a colorless solid.
Step 2: 2-(3-(tert-Butv1)-5-(2-methoxvproPan-2-Ophenv1)-4,4,5,5-tetramethvl-1,3,2-dioxaborolane (P30) To a mixture of compound P30a (128 mg, 0.45 mmol), B2Pin2 (137 mg, 0.54 mmol) and KOAc (88 mg, 0.9 mmol) in 1,4-dioxane (25 mL) was added Pd(dppf)C12 (0.03 eq) under Ar and the mixture was heated at 80 C overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (hexane/EA = 5/1) to give compound P30 (78 mg, 52%) as a colorless solid.
Preparative Example P31 :B N
Step 1: 4-(1-(3-Bromo-5-(tert-butvl)phenvI)ethvI)morpholine (P31a) A mixture of 1-(3-Bromo-5-(tert-butyl)phenyl)ethanone [synthesis as described in W02012/139775] (510 mg, 2.0 mmol) and morpholine (208 mg, 2.4 mmol) in DCE (30 mL) was stirred at 0 C for 1 h. Then NaBH(OAc)3 (845 mg, 4.0 mmol) was added at this temperature and the mixture was stirred overnight, diluted with aq. NH4C1 (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (hexane/EA = 8/1) to give compound P31a (172 mg, 26%) 5 as a colorless solid.
Step 2: 4-(1-(3-(tert-Butv1)-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)PhenvI)ethvI)morpholine (P31) To a mixture of compound P31a (163 mg, 0.5 mmol), B2Pin2 (152 mg, 0.6 mmol) and KOAc (98 mg, 1.0 mmol) in 1,4-dioxane (25 mL) under Ar was added Pd(dppf)Cl2 (0.03 eq). The 10 mixture was heated at 80 C overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (hexane/EA = 5/1) to give compound P31 (78 mg, 42%) as a colorless solid.
Preparative Example P32 4-o :13 110 15 P32 N \0 Step 1: 3-Bromo-5-(tert-butvl)benzaldehvde (P32a) To a mixture of 1,3-dibromo-5-(tert-butyl)benzene (876 mg, 3.0 mmol) in THF
(10 mL) was added tert-BuLi (2.5 M, 2.4 mL, 6.0 mmol) at ¨78 C and the mixture was stirred for 1 h at this temperature. Then DMF (222 mg, 3.0 mmol) was added at this temperature and stirred for 2 20 h., diluted with aq. NH4C1 (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC
(hexane/EA = 5/1) to give compound P32a (452 mg, 63%) as a colorless solid.
Step 2: 4-(3-Bromo-5-(tert-butvl)benzvl)morpholine (P32b) A mixture of compound P32a (450 mg, 1.87 mmol) and morpholine (194 mg, 2.24 mmol) in 25 DCE (30 mL) was stirred at 0 C for 1 h. Then NaBH(OAc)3 (561 mg, 2.66 mmol) was added at this temperature and then stirred overnight, diluted with aq. NH4CI (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by prep. TLC to give compound P32b (142 mg, 28%) as a colorless solid.
30 Step 3: 4-(3-(tert-Butv1)-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)benzyl)morpholine (P32) To a mixture of compound P32b (145 mg, 0.46 mmol) and B2Pin2 (152 mg, 0.6 mmol) and KOAc (98 mg, 1.0 mmol) in 1 ,4-dioxane (25 mL) was added Pd(dppf)C12 (0.03 eq) under Ar and the mixture was heated at 80 C overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by prep. HPLC to give P32 (80 mg, 54%) as a colorless solid.
Preparative Example P33 V
_o ____________________________________ :13 *
P33 o\
Step 1: Methyl 3-bromo-5-(prop-1-en-2-yl)benzoate (P33a) To a solution of methyl 3-bromo-5-iodobenzoate (3.40 g, 10 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh3)4 (300 mg, 0.26 mmol), prop-I-en-2-y' boronic acid (1.0 g, 12 mmol), K2CO3(2.8 g, 20 mmol) and H20 (1 mL) under N2. The mixture was stirred overnight at 90 C, concentrated and purified by CC (PE/EA = 6/1) to give compound P33a (1.9 g, 71%) as a solid.
Step 2: Methyl 3-bromo-5-(1-methylcyclopropyl)benzoate (P33b) To a solution of Et2Zn (4 mL of 1.0M solution in hexanes, 4.0 mmol) in dry DCM
(4 mL) at 0 C was added freshly distilled TFA (0.36 mL, 4.0 mmol) in DCM (4 mL) very slowly (ca. 30 min). The gray mixture was stirred at 0 C for 20 min at which time CH2I2 (0.4 mL, 4.0 mmol) dissolved in DCM (4 mL) was introduced by cannulation. The resulting slurry was stirred for 20 min before the addition of compound P33a (0.53 g, 2.0 mmol) dissolved in DCM (3 mL).
The slurry was allowed to warm to rt over 30 min, quenched by the addition of sat. aq. NH4CI
(5 mL) and the layers were separated. The aq. layer was extracted with hexane (2x) and dried over MgSO4. Evaporation and purification by CC (PE/EA = 7/1) afforded compound P33b (300 mg, 46%) as a colorless oil.
Step 3: 3-Bromo-5-(1-methylcyclopropyl)benzoic acid (P33c) Compound P33b (270 mg, 1.0 mmol) and LiOH (50 mg, 2.0 mmol) were mixed in THF
(3 mL) and H20 (3 mL). The mixture was stirred for 10 h, then the pH was adjusted to pH 3 with aq. HCI and extracted with EA (3x 10 mL). The organic layer was dried and concentrated to afford the crude product P33c (250 mg, quant.).
Step 4: 3-Bromo-N-(tert-buty1)-N-methy1-5-(1-methylcyclopropypbenzamide (P33d) To a solution of compound P33c (250 mg, 1.0 mmol) in DMF (5 mL) was added HATU
(380 mg, 1.0 mmol), MeNHtBu (174 mg, 2.0 mmol) and Et3N (202 mg, 2.0 mmol) and the mixture was stirred overnight. After removal of the solvents the crude product was purified with prep.
HPLC to afford compound P33d (300 mg, 95%).
Step 5: N-(tert-Butv1)-N-methyl-3-(1-methvIcyclopropv1)-5-(4,4,5,5-tetramethv1-1,3,2-dioxaborolan-2-yl)benzamide (P33) To a suspension of compound P33d (323 mg, 1.0 mmol), B2Pin2 (380 mg, 1.5 mmol), KOAc (290 mg, 3.0 mmol) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl2 (20 mg) under N2. The mixture was heated to 100 C for 16 h, concentrated and purified by CC (PE/EA =
4/1) to afford compound P33 (200 mg, 68%) as a colorless solid.
Preparative Example P33/1 to P33/2 Using similar procedures as described in Preparative Example P33, the following compounds were prepared:
# Structure # Structure ___\(-1) ___\6 0-.B
0 NHl< 0 H
Preparative Example P36 Br 4.
Step 1: 1-(3-Bromo-5-(trifluoromethoxv)phenvflethanone (P36a) To the solution of 1,3-dibromo-5-(trifluoromethoxy)benzene (654 mg, 2.06 mmol) in toluene (6 mL) were added tri-n-butyl-1-ethoxyvinyl tin (969 mg, 2.68 mmol) and Pd(PPh3)2Cl2 (147 mg 0.21 mmol) under N2. The mixture was stirred at 95 C for 3 h, concentrated and dissolved in 1,4-dioxane and 2M HCI. The mixture was stirred rapidly at 25 C
for 1 h and then extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC to give compound P36a (580 mg, 55%).
Step 2: 1-Bromo-3-(tert-butvI)-5-(trifluoromethoxv)benzene (P36) An oven dried flask was charged with DCM (5 mL) and TiCI4 (763 mg, 4.06 mmol), Zn(CH3)2 (1M, 4 mL) was added and the solution was cooled to ¨30 C and stirred at constant temperature for 0.5 h. Then a solution of compound P36a (572 mg, 2.03 mmol) in DCM was added dropwise and the mixture was allowed to warm to 0 C over a period of 40 min, stirred at rt for 2 h, 45 min at 45 C and 40 C overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give product P36 (180 mg, 30%) as a yellow oil.
Preparative Example P38 Step 1: 4-Bromo-2-(tert-butvl)aniline (P38a) To a solution of 2-(tert-butyl)aniline (14.9 g, 100 mmol) was added a solution of NBS (17.8 g, 100 mmol) in DMF at rt. The mixture was stirred overnight at rt, diluted with water (30 mL) and extracted with Et20 (3x 250 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC to give compound P38a (19 g, 83%).
Step 2: N-(4-Bromo-2-(tert-butvl)phenvI)-2-(hvdroxvimino)acetamide (P38b) To a solution of compound P38a (5.0 g, 21.9 mmol), hydroxylamine hydrochloride (5.48 g, 78.9 mmol) and sodium sulfate (24.9 g, 175 mmol) in H20 (150 mL) and 2M HCI
(7.4 mL) at rt under N2 was added chloral hydrate (3.88 g, 26.3 mmol). The resulting solution was stirred at 55 C for 18 h, cooled to rt, diluted with water (100 mL) and extracted with EA (3x 50 mL).
The combined organic layers were concentrated to give P38b (5 g) as a viscous oil.
Step 3: 5-Bromo-7-(tert-butvl)indoline-2,3-dione (P38c) A solution of compound P38b (5 g, 16.7 mmol) in conc. H2SO4 (30 mL) was stirred at 80 C
for 1 h, cooled to rt, poured onto crushed ice (200 mL) and allowed to stand for 30 min. The precipitate was collected by filtration, washed with water (3x) and dried under vacuum to yield compound P38c (2 g) as a yellow solid.
Step 4: 5-Bromo-7-(tert-butvl)indolin-2-one (P38d) KOH (796 mg, 14.2 mmol) was added into a mixture of compound P38c (2 g, 7.1 mmol), ethyleneglycol (20 mL) and hydrazine hydrate (0.5 g, 9.93 mmol). The mixture was stirred at 80 C for 3h, cooled to rt and poured into ice cold water. The pH of the mixture was adjusted to pH 1-2 with 12M HCI and the mixture was stirred at rt for 12 h and extracted with EA. The organic phase was evaporated to give compound P38d (1.5 g) as a yellow solid.
Step 5: 5-Bromo-7-(tert-butvI)-1,3,3-trimethvlindolin-2-one (P38e) To a solution of compound P38d (1.0 g, 3.73 mmol) in DMF (20 mL) was added a solution of CH3I (0.93 mL) in DMF at 0 C. The mixture was stirred overnight at rt, diluted with water (100 mL) and extracted with Et20 (3x 100 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC to give compound P38e (500 mg, 43% over 4 steps) as a light yellow solid.
Step 6: 7-(tert-Butv1)-1,3,3-trimethv1-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-vpindolin-2-one (P38) A solution of compound P38e (760 mg, 2.45 mmol) was treated as described for Example P33, Step 5 to give compound P38 (750 mg, 86%) as a colorless solid.
Preparative Example P45 =
,Sõ
P45 d Step 1: 4-Bromo-2-(difluoromethoxv)benzene-1-sulfonvl chloride (P45a) To a solution of 4-bromo-2-(difluoromethoxy)aniline (4.50 g, 18.9 mmol) in AcOH (20 mL) was added conc. HCI (10 mL) at rt and the solution was cooled to 5 C. Then a solution of NaNO2 (1.45 g, 21.0 mmol) in H20 (15 mL) was added and the solution was stirred at 0 C for 1 h. The resulting diazonium salt was added to a mixture of saturated solution of SO2 in AcOH (100 mL) and CuC12.2H0 (3.61 g, 21.0 mmol) in H20 (50 mL) at rt and the solution was stirred at rt for 30 min, poured into water and extracted with DCM twice.
The combined organic layers were purified by CC (PE) to give compound P45a (2.1 g, 35%) as an oil.
Step 2: 4-Bromo-N-(fert-butvI)-2-(difluoromethoxv)benzenesulfonamide (P45b) To a solution of compound P45a (2.10 g, 6.53 mmol) and pyridine (1.19 g, 15.1 mmol) in CH2Cl2 (20 mL) was added tert-butylamine (511 mg, 7.00 mmol) at rt and the mixture was stirred for 1 h, then washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 4/1) to give compound P45b (2.16 g, 92%) as a colorless solid.
Step 3: N-(tert-Butyl)-2-(difluoromethoxv)-4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-vl)benzenesulfonamide (P45) A solution of compound P45b (2.16 g, 6.03 mmol) was treated as described for Example P33, Step 5 to give compound P45 (1.25 g, 51%) as a colorless solid.
Preparative Example P45/1 to P45/17 Using similar procedures as described in Preparative Example P45, the following compounds were prepared:
# Structure # Structure F F F
F F
)-o, o P45/1 B 0 o k _____________________ P45/2 )70,B A--K l',,o -d ,== \4vH W
Br ________________________ 4.
______________________ 13 e , )-o 90 sE, * ss, P45/3 7-d \(1H P45/4 -o' \\IH
CN F F
) F
µ,-0,13 id& ,ss, \___os o P45/5 ___________________________ -0' W \vH P45/6 B 11 e X
\IH
F F
CNo F
)-(:), la .,,C) 0 P45/7 P45/8 )-0, AL g,..p -0,B g W NH ,13 F3C-1 ""0 W NH
F3C---c \_-0 1110 0 F3c b P45/9 '13 =
4. gs-P P45/10 \-0, 9 o __________________________________________________________ B 41/ µS
/ ___________________ -0' 1H [-0' \111 \--0 0 CI
________________________________ .B 41, e _os 9...o B . s\-P45/11 7--d NH P45/12 )---0' NH
7c CI a /--\
P45/13 ______________ -0µ *0 , ---(),B s\NH
A P45/14 \_-0 4.e 7--0' 0 0 s13 ,,iH
=
P45/15 _________________________ B 411 e P45/16 \_-0 0 .13 4. ko /---0' NH NH
---A 7c , N
i \
P45/17 ):_osi, AK g,0 -d W NH
---A
Preparative Example P49 cn 0 HBr P49 d Step 1: Methyl 5-bromo-1-(cyclohexylmethyl)-2-formyl-1H-pyrrole-3-carboxylate (P49a) To a solution of methyl 5-bromo-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (1.8 g, 6.0 mmol) (prepared similar as described in Example 1) and DMF (3 mL) in 1,2-dichloroethane (50 mL) was added POCI3 (1.38 g, 9.0 mmol) and the solution was stirred for 1 h, then warmed to 80 C overnight, diluted with water (50 mL), basified with 2M NaHCO3 and extracted with EA (3x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, evaporated and purified by CC (EA/PE = 1/10) to give compound P49a (1.1 g,58%).
Step 2: Methyl 5-bromo-1-(cyclohexylmethyl)-2-(hydroxymethyl)-1H-pyrrole-3-carboxylate (P49b) To a solution of P49a (1.1 g, 3.5 mmol) in Me0H (3 mL) at rt was added NaBH4 (152 mg, 4 mmol) and the resulting solution was stirred at this temperature for 20 min, diluted with water (50 mL) and extracted with EA (3x 50 mL). The combined layer was concentrated to give compound P49b (1.03 g, 89%).
Step 3: 5- Bromo-1-(cyclohexyl methyl)-2-(hyd roxymethyl)- N-(tetrahyd ro-2H-pyran-4-yI)-1 H-Pv r r ole -3-car boxamide (P49) Compound P49b (200 mg, 0.61 mmol) was saponified and then coupled with tetrahydro-2H-pyran-4-amine similar as described in Example 1 (Step 7 and 8) to give compound P49 (210 mg, 86%) as a colorless solid.
Preparative Example P50 oa 0 110-Br F N
P50 d Step 1: Methyl 5-bromo-1-(cyclohexylmethyl)-2-(fluoromethyl)-1H-pyrrole-3-carboxylate (P50a) To a solution of compound P49b (600 mg, 1.82 mmol) in CH2Cl2 at ¨70 C was added bis(2-methoxyethyl)aminosulfur trifluoride (400 mg, 1.82 mmol) and the resulting solution was stirred at this temperature for 1 h, then warmed to rt for additional 1 h, diluted with water (50 mL) and extracted with EA (3x 50 mL). The combined organic layer was concentrated and purified by CC (EA/PE = 1/10) to give compound P50a (90 mg, 15%).
Step 2: 5-Bromo-1-(cyclohexvImethvI)-2-(fluoromethvI)-N-(tetrahvdro-2H-pvran-4-v1)-1 H-p r r ol e -3- c arb oxamide (P50) Compound P50a (90 mg, 0.61 mmol) was saponified and then coupled with tetrahydro-2H-pyran-4-amine similar as described in Example 1 (Step 7 and 8) to give compound P50 (82 mg, 77%) as a colorless solid.
Preparative Example P51 a 0 11)70-Br CI N
P51 d 5-Bromo-2-chloro-1-(cyclohexvImethvI)-N-(tetrahvdro-2 H-pvran-4-vI)-1H-pvrrole-carboxamide (P51) To a solution of methyl 5-bromo-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (600 mg, 1.63 mmol) (prepared similar as described in Example 1) in dry THF (50 mL) was added NCS (250 mg, 1.87 mmol) at rt under nitrogen. The reaction was stirred at 55 C
for overnight and quenched with a cold aq. solution of NH4CI. The organic layer was separated and the aqueous layer extracted repeatedly with EA. The combined organic layer was washed with brine, dried over Na2SO4, filtered, evaporated and purified by CC (EA/PE =
1/3) to give compound P51 (510 mg, 80%).
Preparative Example P53 o cF3 "o I \ 411 N NI-I
2\
d P53 Step 1: 2-(4-lodo-2-(trifluoromethvl)phenvI)acetvl chloride (P53a) To a solution of 2-(4-iodo-2-(trifluoromethyl)phenyl)acetic acid (2.00 g, 6.06 mmol) in DCM
(20 mL) were added (C0C1)2 (1.54 g, 12.1 mmol) and DMF (1 drop) in one portion at rt and the mixture was stirred at rt for 1 h and concentrated to give compound P53a (2.00 g, 95%) as a colorless oil.
Step 2: N-(tert-Butv1)-2-(4-iodo-2-(trifluoromethvl)qhenynacetamide (P53b) To a solution of tert-butylamine (876 mg, 12.0 mmol) in DCM (10 mL) was added TEA (2.54 g, 24.0 mmol) and the mixture was stirred at rt for 30 min, then compound P53a (2.00 g, 5.85 mmol) in DCM (10 mL) was added and the mixture was stirred at rt overnight, concentrated and purified by CC (PE/EA = 1/5) to give compound P53b (1.20 g, 52%) as a yellow solid.
Step 3: Ethyl 5-(4-(2-(tert-butvlamino)-2-oxoethvI)-3-(trifluoromethvl)phenv1)-(cyclohexvImethvI)-2-methyl-1H-pwrole-3-carboxvlate (P53) A solution of compound P53b (500 mg, 1.30 mmol), compound 1218a (535 mg, 1.40 mmol) K2CO3 (450 mg, 3.38 mmol), TBAB (10 mg) and Pd(PPh3)2Cl2 (10 mg) in a mixture of 1,4-dioxane (10 mL) and water (5 mL) in a sealed tube was irradiated by microwaves at 100 C
for 100 min, concentrated and purified by CC (PE/EA = 1/10) to afford compound P53 (100 mg, 15%) as a colorless solid.
Preparative Example P54 cF3 \ 111N NH
d0 Step 1: Benzvl 2-(4-iodo-2-(trifluoromethvl)phenvpacetate (P54a) To a solution of BnOH (2.16 g, 20.0 mmol) in DCM (20 mL) was added TEA (3.54 g, 35.0 mmol) and the mixture was stirred at rt for 30 min. Then a solution of compound P53a (3.48 g, 10.0 mmol) in DCM (15 mL) was added and the mixture was stirred at rt overnight, concentrated and purified by CC (PE/EA = 1/15) to give compound P54a (2.65 g, 79%) as a yellow oil.
Step 2: Benzvl 2-(4-iodo-2-(trifluoromethvl)qhenv1)-2-methvIpropanoate (P54b) To a solution of NaH (880 mg, 22.1 mmol) in THF (30 mL) was added compound P54a (2.65 g, 6.30 mmol) and the mixture was stirred at rt for 30 min. Then Mel (3.10 g, 22.1 mmol) was added and the mixture was stirred at rt overnight, quenched with water and extracted with EA. The organic layer was dried with MgSO4, filtered, concentrated and purified by CC
(PE/EA = 1/15) to give compound P54b (900 mg, 32%) as a yellow oil.
Step 3: Ethyl 5-(4-(1-(benzyloxy)-2-methy1-1-oxopropan-2-y1)-3-(trifluoromethyl)pheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (P54c) A solution of compound P54b (900 mg, 2.00 mmol), compound 1218a (750 mg, 2.00 mmol) K2CO3 (690 mg, 5.00 mmol), TBAB (10 mg) and Pd(PPh3)2Cl2 (10 mg) in a mixture of dioxane (10 mL) and water (5 mL) in a sealed tube was irradiated with microwaves at 100 C
for 100 min, concentrated and purified by CC (PE/EA = 1/8) to afford compound P54c (400 mg, 36%) as a colorless solid.
Step 4: 2-(4-(1-(Cyclohexylmethyl)-4-(ethoxycarbony1)-5-methyl-1H-pyrrol-2-y1)-(trifluoromethyl)pheny1)-2-methylpropanoic acid (P54d) To a solution of compound P54c (400 mg, 0.75 mmol) in Et0H (10 mL) was added Pd/C
(10%, 40 mg) in one portion at rt and the mixture was stirred under H2 (50 psi) for 5 h, filtered; concentrated and purified by CC (PE/EA = 5/1) to give compound P54d (300 g, 90%) as a colorless solid.
Step 5: Ethyl 5-(4-(1-chloro-2-methy1-1-oxopropan-2-v1)-3-(trifluoromethyl)pheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pwrole-3-carboxylate (P54e) To a solution of compound P54d (300 mg, 0.63 mmol) in DCM (10 mL) were added (C0C1)2 (159 mg, 1.25 mmol) and DMF (1 drop) in one portion at rt and the mixture was stirred for 1 h and concentrated to give compound P54e (300 mg, 95%) as a colorless oil.
Step 6: Ethyl 5-(4-(1-(tert-butylamino)-2-methyl-1-oxopropan-2-y1)-3-(trifluoromethyl)pheny1)-1-(cyclohexylmethyl)-2-methy1-1H-pyrrole-3-carboxylate (P54) To a solution of tert-butylamine (91 mg, 1.25 mmol) in DCM (5 mL) was added TEA (190 mg, 1.88 mmol) and the mixture was stirred at rt for 30 min. Then a solution of compound P54e (300 mg, 0.63 mmol) in DCM (5 mL) was added and the mixture was stirred at rt overnight, concentrated and purified by CC (PE/EA = 1/5) to give compound P54 (100 mg, 30%) as a yellow solid.
Preparative Example P55 cF3 \ g=0 141, Step 1: 4-Acetyl-N-(tert-butyI)-2-(trifluoromethyl)benzenesulfonamide (P55a) To a solution of 4-bromo-N-(tert-butyl)-2-(trifluoromethyl)benzenesulfonamide (10.5 g, 29.2 mmol) in dry THF (100 mL) was added n-BuLi (2.5M in hexane, 12.0 mL, 30.0 mmol) drop-wise over 10 min at ¨78 C under N2, then the resulting solution was stirred at ¨78 C for 1 h.
N-Methoxy-N-methylacetamide (4.63 g, 45 mmol) Was added, after stirring for a further 10 min, the cooling bath was removed and the mixture was allowed to warm to rt and then stirred at rt for 2 h, quenched with 1M HCI and extracted with EA (3x 60 mL).
The combined 5 organic phase was washed with brine, dried qver Na2SO4, filtered, concentrated and purified by CC (PE/EA = 3/1) to give compound P55a (3.7 g, 39%) as a colorless solid.
Step 2: 4-(2-Bromoacetv1)-N-(tert-butv1)-2-(trifluoromethvl)benzenesulfonamide (P55b) To a solution of compound P55a (3.7 g, 11.5 mmol) in dry THF (100 mL) was added PhNMe3Br3 (4.32 g, 11.5 mmol) dropwise at 0 C and the solution was stirred for 4 h at rt, 10 partially concentrated, washed with water twice and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 2/1) to give compound P55b (2.9 g, 63%) as yellow oil.
Step 3: Benzvl 5-(4-(N-(tert-butvl)sulfamov1)-3-(trifluoromethvl)phenv1)-14(3,3-difluorocyclobutvpmethvI)-2-methvI-1H-pvrrole-3-carboxvlate (P55c) 15 A solution of 3,3-difluorocyclobutylmethylamine (0.40 g, 2.5 mmol), phenylmethyl 3-oxobutanoate (1.05 g, 5.5 mmol), DIEA (0.71g, 5.5 mmol) in DMF (5 mL) was placed in a sealed tube in a hot oil bath (150 C) and then stirred for 15 min. A solution of compound P55b (1.21 g, 3.0 mmol) in DMF (2 mL) was added to the hot resulting solution at 100 C.
The solution was heated to 180 C quickly and stirred for another 15 min at 180 C, cooled to 20 rt, diluted with water and extracted with EA. The organic layer was washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA =
5/1) to give compound P55c (140 mg, 9%) as a brown oil.
Step 4: 5-(4-(N-(tert-Butvpsulfamov1)-3-(trifluoromethAphenv1)-1-((3,3-difluorocyclobutvpmethvI)-2-methvI-1H-pwrole-3-carboxvlic acid (P55) 25 A suspension of compound P55c (130 mg, 0.22 mmol) and 10% Pd/C (50 mg) in Me0H (15 mL) was stirred under 1 atmosphere of H2 at rt for 2 h, filtered, concentrated and purified by CC (DCM/Me0H = 15/1) to give compound P55 (65 mg, 59%) as a colorless solid.
Preparative Example P55/1 to P55/3 30 Using similar procedures at those described in Preparative Example P55, the following compounds were prepared:
Structure # Structure HO
\ HO 0 I \ =
g=0 )= HN P55/2 \ = s=o P55/3 )1\I
Preparative Example P56 >%-o o B
Steg 1: N-(4-Bromo-2-(trifluoromethvl)phenvI)-2-(hvdroxvimino)acetamide (P56a) To a solution of 4-bromo-2-(trifluoromethyl)aniline (50 g, 22 mmol), hydroxylamine hydrochloride (5.48 g, 78.9 mmol) and sodium sulfate (24.9 g, 175 mmol) in H20 (150 mL) and 2M HCI (7.4 mL) at rt under N2 was added chloral hydrate (3.88 g, 26.3 mmol) and the solution was stirred at 55 C for 18 h, cooled to rt, diluted with water (100 mL) and extracted with EA (3x 50 mL). The combined layer was concentrated to give compound P56a (5.0 g) as a viscous oil.
Step 2: 5-Bromo-7-(trifluoromethvpindoline-2,3-dione (P56b) A solution of P56a (5.0 g, 16.7 mmol) in conc. H2SO4 (30 mL) was stirred at 80 C for 1 h, cooled to rt, poured into crushed ice (200 mL) and allowed to stand for 30 min. The precipitate was collected by filtration, washed with water (3x) and dried to yield compound P56b (2.0 g) as a yellow solid.
Step 3: 5-Bromo-7-(trifluoromethvpindolin-2-one (P56c) KOH (796 mg, 14.2 mmol) was added into a mixture of P56b (2.0 g, 7.09 mmol), ethyleneglycol (20 mL) and hydrazine hydrate (98%, 0.5 g, 10 mmol), stirred at 80 C for 3 h, cooled to rt and poured into ice cold water. The pH of the mixture was adjusted to pH 1-2 with 12M HCI and stirred at rt for 12 h and extracted with EA. The organic phase was collected and evaporated to give compound P56c (1.5 g) as a yellow solid.
Step 4: 5-Bromo-1,3,3-trimethvI-7-(trifluoromethAindolin-2-one (P56d) To a solution of compound P56c (1.0 g, 3.7 mmol) in DMF (20 mL) was added a solution of CH3I (0.93 mL) in DMF at 0 C. The mixture was stirred at rt overnight, diluted with water (100 mL) and extracted with Et20 (3x100 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC to give compound P56d (500 mg, 43%) as a light yellow solid.
Step 5: 1,3,3-Trimethv1-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)-7-(trifluoromethvpi ndol in-2-one (P56) A solution of compound P56d (760 mg, 2.45 mmol) was treated as described for Example P33, Step 5 to give compound P56 (750 mg, 86%) as a colorless solid.
Preparative Example P57 I
4- lodo-N-neopentv1-6-(trifluoromethvl)pvridi n-2-am i ne (P57) A solution of 2-fluoro-4-iodo-6-(trifluoromethyl)pyridine (100 mg, 0.34 mmol) and neopentyl amine (150 mg, 1.70 mmol) in MeCN (1 mL) in a sealed tube was irradiated by microwaves at 130 C for 30 min, cooled, diluted with water and extracted with EA. The organic layer was washed with brine, dried, concentrated and purified by CC (PE/EA = 20/1) to give compound P57 (100 mg, 83%) as a colorless solid.
Preparative Example P58 cF3 \ = 6'.-=-o d P58 Step 1: Neopentv1(2-arifluoromethvflphenyl)sulfane (P58a) To a solution of Na0Et in Et0H (prepared from sodium (1.29 g, 56.1 mmol) and Et0H (40 mmol)) was added 2-(trifluoromethyl)benzene-1-thiol (5.0 g, 28.1 mmol) and neopentyl 4-methylbenzenesulfonate (6.80 g, 28.1 mmol) and the solution was stirred at reflux under N2 for 20 h, cooled to rt and the formed solid was filtered off. The cake was washed with Et20 and the combined filtrate was concentrated and diluted with water and ether consecutively.
The organic phase was washed with water, dried over Na2SO4, filtered, concentrated and purified by CC (petroleum) to give compound P58a (4.55 g, 65%) as a colorless solid.
Step 2: (4-Bromo-2-(trifluoromethvl)phenv1)(neopentvpsulfane (P58b) To a solution of compound P58a (1.0 g, 4.0 mmol) in dry DCM (15 mL) was added Br2 (640 mg, 4.0 mmol) at rt and the solution was stirred for 2 h, washed with water, sat. sodium thiosulfate and brine consecutively, dried and concentrated to give compound P58b (1.27 g, 97%) as a colorless solid.
Step 3: 4-Bromo-1-(neopentvlsulfonvI)-2-(trifluoromethvl)benzene (P58c) To a solution of compound P58b (1.27 g, 3.9 mmol) in DCM (20 mL) was added 3-chloroperoxybenzoic acid (3.0 g, 11.7 mmol) at ¨10 C and the solution was stirred at rt overnight, diluted with DCM and water and the two layers were separated. The organic layer was washed with sat. NaHCO3 twice and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 25/1) to give compound P58c (700 mg, 47%) as a colorless solid.
Step 4: Ethyl 1-(cyclohexvImethvI)-2-methvI-5-(4-(neopentvlsulfonv1)-3-(trifluoromethvl)phenv1)-1H-pyrrole-3-carboxvlate (P58) Compound P58c (359 mg, 1.0 mmol) was treated similar as described in Preparative Example P54, Step 3 to give compound P58 (500 mg, 95%) as a yellow oil.
Preparative Example P59 Step 1: 2-(Dibenzvlamino)benzoic acid (P59a) To a solution of bisbenzylamine (140 g, 0.70 mol) in THF (1.0L) was added n-BuLi (2.5M, 280 mL, 0.7 mol) dropwise under N2 at ¨30 C, then the reaction solution was stirred at this temperature for 10 min. 2-Fluorobenzoic acid (50 g, 0.35 mol) in THF (500 mL) was added dropwise at ¨30 C and the solution was heated to 0 C for 2 h, quenched with water (100 mL), concentrated, treated with conc. HCI until pH 1 and extracted with DCM
(3x 500 mL).
The organic layer was concentrated and recrystallized from Et20 to give compound P59a (40 g, 36%) as colorless solid. 1H-NMR (300 MHz, CDCI3) 6: 4.16 (s, 4H), 7.15-7.61 (m, 13H), 8.15-8.18(m, 1H).
Step 2: Methyl 2-(dibenzvlamino)benzoate (P59b) The solution of compound P59a (20 g, 63 mmol), K2CO3 (26 g, 189 mmol), CH3I
(14 g, 94 mmol) and DMF (200 mL) was stirred at rt for 2 h, diluted with Et20 (1 L) and the organic phase was washed with water (3x 500 mL) and brine consecutively, dried over Na2SO4, filtered and concentrated to give compound P59b (20 g, 96%) as colorless oil.
1H-NMR (300 MHz, CDCI3) 6: 3.89 (s, 3H), 4.25 (s, 4H), 6.94-6.99 (m, 2H), 7.21-7.37 (m, 11H), 7.69-7.72 (m, 1H).
Step 3: 1-(2-(Dibenzvlamino)phenvI)cyclopropanol (P59c) To a solution of Ti(Oi-Pr)4 (99.6 g, 0.36 mol) in dry Et20 (1.0 L) was added EtMgBr (2M in THF, 540 mL, 1.08 mol) dropwise at ¨68 C under N2 and the solution was stirred at this temperature for 1.5 h. To the reaction solution was added compound P59b (60.0 g, 0.18 mol) in dry Et20 (0.5 L) at ¨68 C and then the solution was stirred overnight at rt, quenched carefully with 1M HCI (500 mL) at 0 C and separated. The aq. layer was extracted with Et20 (3x 300 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 100/1) to give compound P59c (9.0 g, 15%) as colorless oil. 1H-NMR (400 MHz, CDCI3) 6: 0.96-0.99 (m, 2H), 1.11-1.15 (m, 2H), 4.18 (s, 4H), 6.98-7.31 (m, 14H), 7.96 (s, 1H).
Step 4: N,N-Dibenzv1-2-(1-methoxycyclopropvl)aniline (P59d) To a solution of compound P59c (5.8 g, 17.6 mmol), CH3I (3.7 g, 26.4 mmol) in dry THF (20 mL) was added NaH (60%, 1.0 g, 26.4 mmol) in portions at 0 C under N2 and the solution was stirred at rt overnight, quenched with water (50 mL) and extracted with EA
(3x 150 mL).
The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 100/1) to give compound P59d (5.0 g, 83%) as colorless oil. 1H-NMR (300 MHz, CDCI3) 6: 0.95-0.99 (m, 2H), 1.22-1.26 (m, 2H), 3.24 (s, 3H), 4.32 (s, 4H), 6.96-7.45 (m, 14H).
Step 5: 2-(1-Methoxycyclopropvl)aniline (P59e) A solution of compound P59d (4.0 g, 11.6 mmol), HCO2NH4 (7.3 g, 116 mmol), Pd/C (0.5 g) in Me0H (20 mL) was heated to 45 C for 5 h, cooled to rt, filtered and the filtrate was concentrated. The residue was dissolved in EA (200 mL) and washed with water (3x 100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give crude product P59e (1.5 g, 75%) as colorless oil. 1H-NMR (300 MHz, CDCI3) 6: 0.90-0.93 (m, 2H), 1.09-1.13 (m, 2H), 3.16 (s, 3H), 6.66-6.69 (m, 2H), 7.10-7.14 (m, 2H).
Step 5: 4-Bromo-2-(1-methoxycyclopropvl)aniline (P59f) To a solution of compound P59e (2.0 g, 12.3 mmol) in MeCN (10 mL) was added NBS (2.18 g, 12.3 mmol) in three portions at 0 C under N2 and the solution was stirred at rt overnight, concentrated and purified by CC (PE/EA = 100/1) to give compound P59f (2.0 g, 70%) as yellow oil. 1H-NMR (400 MHz, CDCI3) 6: 0.87-0.90 (m, 2H), 1.07-1.11 (m, 2H), 3.14 (s, 3H), 4.32 (br s, 2H), 6.55-6.57 (d, J = 8.0 Hz, 1H), 7.16-7.20 (m, 2H).
Step 6: 4-Bromo-2-(1-methoxycyclopropvl)benzene-1-sulfonvl chloride (P59q) A solution of compound P59f (1.0 g, 4.0 mmol) in MeCN (40 mL) was cooled to 0-5 C, AcOH
(4.0 mL) and conc. HCI (2.0 mL) were added consecutively and then NaNO2 (304 mg, 4.4 mmol) in water (3 mL) over 10 min at 0-5 C. After stirring 20 min, SO2 was bubbled in over 5 40 min while keeping the temperature below 7 C. A solution of CuC12-2H20 (818 mg, 2.4 mmol) in water (3 mL) was added and the solution was allowed to warm to rt and stirred for 1 h, extracted with EA, washed with aq. NaHCO3 (2x 100 mL) and water (2x 100 mL) consecutively, dried over Na2SO4, filtered and concentrated to give product P59g (800 mg, 50%) as yellow solid.
10 Step 7: 4-Bromo-N-(tert-butv1)-2-(1-methoxycyclopropvl)benzenesulfonamide (P59h) A solution of compound P59g (800 mg, 2.46 mmol), 2-methylprop-2-ylamine (269 mg, 3.69 mmol), Et3N (497 mg, 4.92 mmol) and MeCN (5 mL) was stirred at rt overnight, concentrated and purified by CC (PE/EA = 80/1) to give compound P59h (400 mg, 46%) as yellow solid.
1H-NMR (300 MHz, CDCI3) 6:1.15-1.23 (m, 2H), 1.25 (s, 9H), 1.28-1.33 (m, 2H), 3.22 (s, 15 3H), 5.87 (s, 1H), 7.59 (s, 1H), 7.61-7.62 (m, 2H), 8.01-8.04 (d, J =
12.0 Hz, 1H).
Step 8: N-(tert-Butyl)-2-(1-methoxycyclopropv1)-4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-vnbenzenesulfonamide (P59) Compound P59h (200 mg, 0.55 mmol) was treated similar as described for Example P33, Step 5 to give compound P59 (150 mg, 67%) as colorless solid. 1H-NMR (400 MHz, CDCI3) 20 6:1.18-1.21 (m, 2H), 1.23 (s, 9H), 1.26-1.27 (m, 2H), 1.36 (s, 12H), 3.19 (s, 3H), 5.97 (s, 1H), 7.81 (s, 1H), 7.86-7.88 (d, J = 8.0 Hz, 1H), 8.12-8.14 (d, J = 8.0 Hz, 1H).
Preparative Example P60 B g=0 7"--0 25 Step 1: 4-Bromo-2-fluorobenzene-1-sulfonvl chloride (P60a) To the solution of 4-bromo-2-fluoroaniline (6.0 g, 31.6 mmol), AcOH (9 mL) and conc. HCI (5 mL) in MeCN (180 mL) was added NaNO2 (2.6 g, 37.9 mmol) over 10 min at < 5 C
and the solution was stirred for 30 min at this temperature. SO2 gas was bubbled in over 30 min.
Then a solution of CuC12+120 (6.4 g, 37.9 mmol) in H2O (5 mL) was added and the solution 30 was stirred for additional 2 h at rt, concentrated and diluted with EA.
The organic layer was washed with water and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 40/1) to give compound P60a (3.7 g, 43%) as colorless oil.
96 .
Step 2: 4-Bromo-N-(tert-butyI)-2-fluorobenzenesulfonamide (P60b) To a solution of compound P60a (3.7 g, 13.6 mmol) and pyridine (2 mL) in DCM
(40 mL) was added 2-methylprop-2-ylamine (3.0 g, 40.7 mmol) at 0 C and the solution was stirred at this temperature for 1 h, concentrated and purified by CC (PE/EA = 40/1) to give compound P60b (2.2 g, 53%) as a colorless solid.
Step 3: 4-Bromo-N-(tert-butyI)-2-(neopentyloxy)benzenesulfonamide (P60c) To a solution of 2,2-dimethylpropan-1-ol (1.14 g, 12.9 mmol) in dry DMF (15 mL) was added NaH (60% in oil, 413 mg, 10.3 mmol) at 0 C under N2 and the solution was stirred at this temperature for 40 min. Then compound P60b (800 mg, 2.58 mmol) was added and the solution was stirred at 90 C for additional 2 h, diluted with water and extracted with EA (3x).
The combined organic layers were washed with water (3x) and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 10/1) to give compound P60c (925 mg, 95%) as a colorless solid.
Step 4: N-(tert-Buty1)-2-(neopentyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (P60) A solution of compound P60c (600 mg, 1.59 mmol) was treated as described for Example P33, Step 5 to give compound P60 (380 mg, 60%) as a colorless solid.
Preparative Example P61 o cF3 I \ 441 g=0 N
NC HN, -.
d Step 1: Ethyl 2-bromo-5-(4-(N-(tert-butypsulfamoy1)-3-(trifluoromethyl)pheny1)-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (P61a) To a solution of ethyl 5-(4-(N-(tert-butyl)sulfamoy1)-3-(trifluoromethyl)pheny1)-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (2.6 g, 5.06 mmol) in dry THF (25 mL) was added a solution of NBS (0.9 g, 5.06 mmol) in dry THF (10 mL) at ¨78 C and the solution was stirred at ¨55 C for 2 h, quenched with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and carefully purified by CC (PE/EA = 5/1) to give compound P61a (1.08 g, 36%) as a colorless solid.
Step 2: Ethyl 5-(4-(N-(tert-butyl)sulfamoyI)-3-(trifluoromethyl)pheny1)-2-cyano-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (P61b) A solution of compound P61a (800 mg, 1.35 mmol), CuCN (145 mg, 1.62 mmol) and KI (10 mg) in DMF (10 mL) was stirred at 120 C overnight under N2, cooled to rt and diluted with 27% NH4OH (2 mL). The resulting solution was filtered and the filtrate was extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 3/1) to give compound P61b (496 mg, 68%) as a colorless solid.
Step 3: 5-(4-(N-(tert-Butyl)sulfamoy1)-3-(trifluoromethyl)pheny1)-2-cyano-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylic acid (P61) A mixture of compound P61b (100 mg, 0.19 mmol) and t-BuOK (38 mg, 0.40 mmol) in a mixture of DMSO and H20 (10/1, 2 mL) was stirred at 90 C for 1 h, cooled, diluted with water, acidified with 1M HCI to pH = 6 and extracted with EA. The organic layer was washed with water and brine consecutively, dried over Na2SO4, filtered and concentrated to give compound P61 (67 mg, 70%) as a colorless solid.
Preparative Example P62 cF3 HO
I \ g=0 HN N
HN
Step 1: Ethyl 5-(4-(N-(tert-Butyl)sulfamoyI)-3-(trifluoromethyl)pheny1)-2-carbamoyl-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (P62a) To a cooled (ice bath) solution of compound P61b (257 mg, 0.48 mmol) in DMSO
(5 mL) was added 30% H202 (0.07 mL) and K2CO3 (197 mg, 1.43 mmol) and the solution was stirred overnight at rt, quenched with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA =
1/1) to give compound P62a (145 mg, 54%) as a colorless solid.
Step 2: 5-(4-(N-(tert-Butyl)sulfamoy1)-3-(trifluoromethyl)pheny1)-2-carbamoy1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylic acid (P62) A mixture of compound P62a (145 mg, 0.26 mmol) and t-BuOK (89 mg, 0.79 mmol) in a mixture of DMSO and H20 (10/1, 2 mL) was stirred at 85 C for 1 h, cooled, diluted with water, acidified with 1M HCI to pH = 6 and extracted with EA. The organic layer was washed with water and brine consecutively, dried over Na2SO4, filtered and concentrated to give crude compound P62 (162 mg) as a colorless solid.
Preparative Example P63 HoJ
I \ ( N
N __ NH
d63 Step 1: 2-(Benzyloxy)-4-bromo-6-(tert-butyl)pyridine (P63a) To a mixture of 4-bromo-6-(tert-butyl)pyridin-2(1H)-one (1.15 g, 5.0 mmol) in benzene (65 mL) was added BnBr (855 mg, 5.0 mmol) and Ag2CO3 (689 mg, 2.5 mmol) successively and the mixture was stirred at 60 C overnight, cooled to rt and the solid was filtered off. The filtrate was washed with sat. NaHCO3, dried over Na2SO4, concentrated and purified by CC
(PE/EA = 10/1) to give compound P63a (1.39 g, 86%) as a colorless oil.
Step 2: 2-(Benzyloxy)-6-(tert-buty1)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine compound (P63b) A solution of compound P63a (320 mg, 1.0 mmol), 62Pin2 (508 mg, 2.0 mmol), KOAc (294 mg, 3.0 mmol) and Pd(dppf)Cl2 (73.2 mg, 0.10 mmol) in a mixture of 1,4-dioxane and DMSO
(50/1, 15 mL) was stirred at 80 C under N2 for 1 h, cooled to rt and diluted with H20 (15 mL), extracted with EA (3x). The combined organic layers were washed with brine twice, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 10/1) to give crude compound P63b (380 mg, quant.) as a colorless solid.
Step 3: Ethyl 5-(2-(benzyloxy)-6-(tert-butyl)pyridin-4-y1)-1-(cyclohexylmethy1)-2-methyl-1 H-pirr ole -3- carbon/late (P63c) A solution of compound P63b (141 mg, 0.38 mmol), ethyl 5-bromo-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (189 mg, 0.58 mmol), Cs2CO3 (375 mg, 1.15 mmol) and Pd(dppf)Cl2 (73.2 mg, 0.1 mmol) in a mixture of 1,4-dioxane and H20 (4/1, 5 mL) was stirred at 100 C under N2 for 2 h, diluted with H20 (15 mL) and extracted with EA
(3x). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 50/1) to give compound P63c (78 mg, 42%) as a colorless solid.
Step 4: Ethyl 5-(2-(tert-buty1)-6-hydroxypyridin-4-y1)-1-(cyclohexylmethyl)-2-methyl-1 H-pv r r ol e-3- carb oxv late (P63d) To a solution of compound P63c (700 mg, 1.43 mmol) in dry DCM (30 mL) at 5 C
was added anhydrous FeCl3 (1.93 g, 7.15 mmol) and the mixture was stirred at rt for 5 h under N29 diluted with water and extracted with EA twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC
(PE/EA = 10/1) to give compound P63d (470 mg, 82%) as a colorless oil.
Step 4: Ethyl 5-(2-(tert-butyl)-6-(((trifluoromethyl)sulfonyl)oxv)Ovridin-4-y1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (P63e) To a solution of compound P63d (470 mg, 1.18 mmol) and pyridine (186 mg, 2.36 mmol) in DCM (10 mL) was added Tf20 (499 mg, 1.77 mmol) and the solution was stirred at rt for 2 h under N2, diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by prep. TLC
(PE/EA = 50/1) to give compound P63e (250 mg, 41%) as a colorless oil.
Step 5: Ethyl 5-(2-(tert-buty1)-6-(neopentylamino)pyridin-4-y1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (P63f) A solution of compound P63e (250 mg, 0.48 mmol), 2,2-dimethylpropylamine (202 mg, 2.32 mmol), t-BuONa (178 mg, 1.86 mmol), Pd(OAc)2 (21 mg, 0.09 mmol) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (73 mg, 0.18 mmol) in toluene (10 mL) was stirred at 110 C under N2 for 2 h, diluted with H20 and extracted with EA (3x). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 50/1) to give compound P63f (240 mg, quant.) as a brown solid.
Step 6: 5-(2-(tert-Butyl)-6-(neopentylamino)pyridin-4-y1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylic acid (P63) To a solution of compound P63f (240 mg) in a mixture of DMSO and H20 (10/1, 11 mL) was added t-BuOK (288 mg, 2.57 mmol) and the solution was stirred at 90 C for 4 h, cooled to rt, acidified with sat. citric acid to pH = 3 and extracted with EA. The solution was dried over Na2SO4, filtered, concentrated and purified by prep. TLC to give compound P63 (200 mg, 89%) as a yellow oil.
Preparative Example P64 r S
Br 411 9-41, Step 1: 4-Bromobenzofblthiophen-7-amine (P64a) To a solution of benzo[b]thiophen-7-amine (4.65 g, 30 mmol) in DCM (100 mL) was added a solution of Br2 (4.99 g, 0.03 mL) in DCM (120 mL) at ¨78 C and the solution was stirred for 1.5 h at ¨78 C, quenched with water and extracted with DCM (3x). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 30/1) to give of compound P64a (2.38 g, 34%) as a colorless solid.
1H-NMR (400 MHz, CD30D) 6: 6.62 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.40 (d, J =
5.2 Hz, 1H), 7.62 (d, J = 6.0 Hz, 1H).
Step 2: 4-Bromobenzof blthiophene-7-sulfonyl chloride (P64b) To a solution of compound P64a (2.38 g, 10.5 mmol) in AcOH (8 mL) was added conc. HCI
(24 mL) at rt and the solution was cooled to -5 C. Then a solution of NaNO2 (1.08 g, 15.7 mmol) in H20 (8 mL) was added and the solution was stirred at 0 C for 1 h. The resulting diazonium salt was added to a premixed solution of SO2 in AcOH (sat., 30 mL) and CuC12-1120 (1.34 g, 7.86 mmol) in H20 (20 mL) at rt and the solution was stirred at rt for 2 h, poured into water and extracted with DCM twice. The combined organic layers were concentrated and purified by CC (PE/EA = 30/1) to give compound P64b (3.26 g, quant.) as a colorless oil.
Step 3: 4-Bromo-N-(tert-butyl)benzorblthiophene-7-sulfonamide (P64) The solution of compound P64b (3.26 g, 10.5 mmol), tert-butyl amine (2.5 mL) and pyridine (30 mL) in dry DCM (100 mL) was stirred for 1 h at rt, washed with water twice and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC
(PE/EA = 10/1) to give compound P64 (2.6 g, 71%) as a colorless solid. 111-NMR (400 MHz, CDCI3) 6: 1.19 (s, 9H), 7.59 (d, J = 6.4 Hz, 1H), 7.67 (d, J = 6.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.82 (d, J
= 8.0 Hz, 1H).
Preparative Example P65 OH
Os tO'B
Step 1: Ethyl 4-((arifluoromethyl)sulfonyl)oxy)-2-naphthoate (P65a) To a solution of ethyl 4-hydroxy-2-naphthoate (15.0 g, 58.1 mmol) and NEt3 (11.7 g, 116 mmol) in dry DCM (300 mL) was added a solution of Tf20 (24.5 g, 87.1 mmol) in DCM (50 mL) at 0 C and the solution was stirred for 4 h at rt, washed with H20 and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 8/1) to give compound P65a (18.0 g, 89%) as a colorless solid.
Step 2: 3-(2-Hydroxypropan-2-yl)naphthalen-1-yltrifluoromethanesulfonate (P65b) To a solution of compound P65a (13.2 g, 42.4 mmol) in dry THF (150 mL) was added MeMgBr (1M in THF, 51 mL, 51 mmol) dropwise at 0 C and the solution was stirred at 25 C
for 1 h, diluted with sat. NH4CI and extracted with DCM twice. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 2/1) to give compound P65b (16.7 g, quant.) as a yellow oil.
Step 3: 2-(4-(4,4,5,5-Tetramethv1-1,3,2-dioxaborolan-2-v1)naphthalen-2-v1)propan-2-ol (P65) A suspension of compound P65b (1.6 g, 4.8 mmol), KOAc (1.5 g, 14.4 mmol), B2Pin2 (1.5 g, 5.7 mmol) and Pd(dppf)Cl2 (176 mg, 0.24 mmol) in 1,4-dioxane (10 mL) was stirred at 80 C
under N2 overnight, concentrated and purified by CC (PE/EA = 4/1) to give compound P65 (1.2 g, 80%) as a colorless solid. 1H-NMR (400 MHz, CDCI3) 6: 1.42 (s. 3H), 1.69 (s, 6H), 1.89 (br s, 1H), 7.45-7.50 (m, 2H), 7.82 (dd, J = 8.0, 1.6 Hz, 1H), 8.02 (d, J
= 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 8.0 Hz, 1H).
Preparative Example P66 ) NH
____________________________________ -0 :E3 Step 1: N-(tert-Butyl)-4-hvdroxv-2-naphthamide (P66a) A solution of 4-hydroxy-2-naphthoic acid (2.0 g, 10.8 mmol), t-BuNH2 (1.5 g, 20.0 mmol), HATU (4.9 g, 13.0 mmol) and DIEA (1.4 g, 10.8 mmol) in DMF (10 mL) was stirred at 60 C
for 1.5 h, cooled to rt, diluted with water and extracted with EA (3x). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 1/1) to give compound P66a (2.1 g, 81%) as a colorless solid. 1H-NMR (400 MHz, CDCI3) 6: 1.56 (s, 9H), 7.26 (br s, 1H),7.62 (d, J = 1.6 Hz, 1H), 7.76-7.85 (m, 2H), 8.01 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H).
Step 2: 3-(tert-ButvIcarbamovOnaphthalen-1-vItrifluoromethanesulfonate (P66b) To a solution of compound P66a (3.80 g, 15.6 mmol) and TEA (4.73 g, 46.8 mmol) in DCM
(20 mL) was added Tf20 (6.60 g, 23.4 mmol) and the solution was stirred at rt for 2 h, diluted with DCM, washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC
(PE/EA = 4/1) to give compound P66b (5.0 g, 85%) as a colorless solid. 1H-NMR
(400 MHz, CDCI3) 6: 1.55 (s, 9H), 7.23 (br s, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.66-7.75 (m, 2H), 8.00 (d, J
= 8.2 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H).
Step 3: N-(tert-Butv1)-4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)-2-naphthamide (P66) Compound P66b (1.2 g, 3.2 mmol) was treated as described above in Example P65, Step 3 to give compound P66 (0.9 g, 80%) as a colorless solid. 1H-NMR (400 MHz, CDCI3) 6:1.42 (s, 12H), 1.53 (s, 9H), 1.88 (br s, 1H), 7.45-7.50 (m, 2H), 7.82 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 8.18 (d, J =1.6 Hz, 1H), 8.72 (d, J = 8.4 Hz, 1H).
Preparative Example P67 cF3 Step 1: 5-Bromo-3-(trifluoromethvl)pvridine-2(1H)-thione (P67a) The mixture of 5-bromo-3-(trifluoromethyl)pyridin-2-ol (2.0 g, 8.26 mmol) and Lawesson's reagent (2.3 g, 5.79 mmol) in toluene (30 mL) was refluxed overnight, concentrated and purified by CC (PE/EA = 20/1) to give compound P67a (1.5 g, 70%) as a yellow solid.
Step 2: 5-Bromo-N-(tert-butvI)-3-(trifluoromethvl)pvridine-2-sulfonamide (P67) The mixture of compound P67a (0.60 g, 2.33 mmol) and NCS (1.24 g, 9.30 mmol) in DCM
(30 mL) was stirred at 15 C for 2.5 h, washed with water, dried over Na2SO4 and filtered.
DIEA (0.60 g, 4.65 mmol) and tert-butylamine (0.20 g, 2.79 mmol) were added to the filtrate and the mixture was stirred at rt for 1 h, concentrated and purified by CC
(PE/EA = 10/1) to give compound P67 (0.10 g, 12%) as a pale brown solid.
Preparative Example P69 ____________________________________ -0 sI3 .
T ___________________________________ -0' Step 1: 2-Bromo-4-(tert-butvI)-6-methvlphenol (P69a) To a solution of 4-(tert-butyl)-2-methylphenol (10.6 g, 64.6 mmol) in dry CCI4 (100 mL) was added Br2 (10.9 g, 67.8 mmol) slowly and the solution was stirred at rt for 2 h, poured into sat. Na2S203 and extracted with MTBE twice. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (EA/PE =
1/100) to give compound P69a (15 g, 96%) as colorless oil.
Step 2: 1-Bromo-5-(tert-butyl)-2-(difluoromethoxv)-3-methvlbenzene (P69b) To a solution of compound P69a (10.0 g, 41.1 mmol) in isopropanol (120 mL) was added aq.
NaOH solution (20%, 120 mL) at -78 C, then CHCIF2 was bubbled into the solution and the solution was heated overnight at 40 C, cooled to rt, diluted with water and extracted with EA
twice. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (EA/PE = 1/50) to give compound P69b (5.1 g, 42%) as a colorless oil.
Step 3: 2-(5-(tert-Butv1)-2-(difluoromethoxv)-3-methylphenv1)-4,4,5,5-tetramethvI-1,3,2-dioxaborolane (P69) Compound P69b (4.8 g, 16.4 mmol) was treated as described above in Example P65, Step 3 to give compound P69 (3.2 g, 57%) as a colorless solid.
Preparative Example P70 F2Nco :13 2-(3,5-Di-tert-butv1-2-(difluoromethoxv)phenv1)-4,4,5,5-tetramethvI-1,3,2-dioxaborolane (P70) Compound P70 was prepared starting from 2-bromo-4,6-di-tert-butylphenol similar as described above in Example P69, Step 2 and 3.
Preparative Example P71 Br 11 NH
N-(4-Bromo-2-(trifluoromethvl)phenv1)-2-methvIpropane-2-sulfonamide (P71) To a solution of 2-methylpropane-2-sulfonamide (1.00 g, 7.30 mmol) in DMF (10 mL) was added NaH (60% w/t in mineral oil, 350 mg, 8.80 mmol) at 0 C and the solution was stirred for 30 min. Then a solution of 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (1.80 g, 7.30 mmol) in DMF (10 mL) was added and the solution was stirred at 120 C
overnight, cooled, diluted with H20 and extracted with EA (3x 20 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 8/1) to afford compound P71 (800 mg, 31%) as a colorless solid.
Preparative Example P72 Br 411 Br 11 4-1 cY
F
o- 0 P7272 N-(4-Bromo-2-fluoro-6-(trifluoromethvl)phenv1)-2-methvIpropane-2-sulfonamide (P72) To a solution of 2-methylpropane-2-sulfonamide (173 mg, 1.15 mmol) in DMF (10 mL) was added NaH (60% w/t in mineral oil, 56 mg, 1.39 mmol) at 0 C and the solution was stirred for 30 min. Then a solution of 5-bromo-1,2-difluoro-3-(trifluoromethyl)benzene (300 mg, 1.15 mmol) in DMF (5 mL) was added and the solution was stirred at 120 C for 2 h, cooled, quenched with H20 and extracted with EA (3x 20 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 10/1) to afford compound P72 (130 mg, 31%) as a colorless solid.
Preparative Example P73 cF3 __________________________________ _o -=() Step 1: 6-Chloro-3-nitro-2-(trifluoromethvl)pvridine (P73a) A mixture of 5-nitro-6-(trifluoromethyl)pyridin-2(1/-1)-one (3.54 g, 17.0 mmol), DMF (4.96 g, 68 mmol) and POCI3 (20.9 g, 136 mmol) was heated at 90 C for 16 h, evaporated, poured into ice-water (200 mL), neutralized to pH 5 with Na2CO3 and extracted with EA
(3x 100 mL).
The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC (EA/PE = 1/20) to give compound P73a (2.77 g, 72%) as a yellow solid. 1H-NMR (CDCI3, 300 MHz) 6: 7.74 (1H, d, J = 8.4 Hz), 8.22 (1H, d, J = 8.4 Hz).
Step 2: 6-Chloro-2-(trifluoromethvI)ovridin-3-amine (P73b) To a round bottom flask fitted with a centrally mounted stirrer, carrying a reflux condenser and a dropping funnel, was charged successively iron powder (2.18 g, 39 mmol) and ammonium chloride solution (65 mL, 1M, 65 mmol). A solution of compound P73a (2.95 g, 13 mmol) in Me0H (65 mL) was allowed to drop into the stirred slurry of iron powder-ammonium chloride solution over a duration of 10 min at rt. The mixture was stirred under reflux for 2h, filtrered hot followed by hot methanol wash (2x 30 mL) and the combined washings were concentrated to leave the product precipitating out from the solution. Re-crystallization from Me0H/DCM gave compound P62b (2.0 g, 79%) as yellow solid.
(CDCI3, 300 MHz) 6: 4.27 (2H, br s), 7.09 (1H, d, J = 8.4 Hz), 7.25 (1H, d, J
= 8.4 Hz).
Step 3: 6-Chloro-2-(trifluoromethvl)pvridine-3-sulfonvl chloride (P73c) Step (a): Thionyl chloride (42 mL) was added dropwise under ice cooling over 60 min to water (250 mL) maintaining the temperature of the mixture at 0-7 C. The solution was allowed to warm to 18 C and stirring was continued for 3 d. CuCI (151 mg) was added to the mixture and the resultant yellow-green solution was cooled to ¨3 C using an acetone/ice bath. Step (b): Hydrochloric acid (36% w/w, 12.2 mL) was added with agitation to compound P73b (1.65 g, 8.4 mmol), maintaining the temperature of the mixture below 30 C
with ice cooling. The mixture was cooled to ¨5 C using an ice/acetone bath and a solution of sodium nitrite (0.68 g, 9.8 mmol) in water (2.8 mL) was added dropwise over 30 min maintaining the temperature of the mixture between ¨5 to 0 C. The resultant slurry was cooled to ¨2 C and stirred for 10 min. Step (c): The slurry from step (b) was cooled to ¨5 C and added to the solution obtained from step (a) over 95 min, maintaining the temperature of the mixture between ¨3 to 0 C (the slurry from step (b) was maintained at ¨5 C throughout the addition).
As the reaction proceeded, a solid began to precipitate. When the addition was complete, the mixture was agitated at 0 C for 75 min. The solid was collected by vacuum filtration, washed with ice-cooled water (2x 25 mL) and dried under vacuum at below 25 C
to give compound P73c (1.53 g, 66%) as yellow solid. 1H-NMR (CDCI3, 300 MHz) 6: 7.81 (1H, d, J =
8.4 Hz), 8.57 (1H, d, J = 8.4 Hz).
Step 4: N-(tert-ButvI)-6-chloro-2-(trifluoromethyl)pvridine-3-sulfonamide (P73d) To a solution of 2-methylprop-2-ylamine (5 mL) in DCM (20 mL) was added a solution of compound P73c (1.53 g, 5.5 mmol) in DCM (10 mL) dropwise at 0 C and the solution was stirred at rt for 1 h, washed with water (3x 50 mL) and brine, dried over Na2504, filtered and concentrated to give compound P73d (1.2 g, 69%) as a yellow solid. 1H-NMR
(CDCI3, 300 MHz) 6:1.26 (9H, s), 4.87 (1H, s), 7.65 (1H, d, J = 8.4 Hz), 8.53 (1H, d, J =
8.4 Hz).
Step 5: N-(tert-butyl)-6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-2-(trifluoromethvl)pvridine-3-sulfonamide (P73) A solution of compound P73d (317 mg, 1.0 mmol), B2Pin2 (280 mg, 1.1 mmol), potassium acetate (294 mg, 3.0 mol) in 1,2-dimethoxyethane (5 mL) was sparged for 5 min with N2 and then Pd(dppf)Cl2 (82 mg, 0.1 mmol) was added. The mixture was heated under ref lux for 12 h, diluted with EA (20 mL) and concentrated to dryness. The residue was taken up in EA (30 mL) and water (20 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, concentrated and re-crystallized from EA/PE
= 1/8 to given compound P73 (200 mg, 46%) as a tan solid. 1H-NMR (CDCI3, 400 MHz) 6:1.24 (9H, s), 1.40 (12H, s), 4.83 (1H, s), 8.11 (1H, d, J = 8.0 Hz), 8.54 (1H, d, J = 8.0 Hz).
Preparative Example P74 cF3 -os ---,3=13 . /N-ki Step 1: 3-(4-Hydroxv-2-(trifluoromethvI)phenv1)-3-oxopropanal (P74a) Na0Me (5.4 g, 0.10 mol) was suspended in THF (100 mL) and treated at rt with ethyl formate (7.4 g, 0.10 mol) followed by dropwise addition of a solution 1-(4-hydroxy-2-(trifluoromethyl)phenyl)ethanone (16.3 g, 0.08 mol) in THF. The mixture was stirred for 2.5 h at rt, quenched with H20 (300 mL) and extracted with Et20 (100 mL). The extracts were discarded. The aqueous phase was acidified with 6M H2SO4 (18 mL) and extracted with Et20 (2x 100 mL). This extract was washed with water and brine, dried over Na2SO4, filtered and concentrated to afford compound P74a (12.5 g, 67%) as a yellow solid.
Step 2: 4-(1-lsopropv1-1H-pvrazol-5-v1)-3-(trifluoromethvl)phenol (P74b) A mixture of compound P74a (5.0 g, 22 mmol) and isopropylhydrazine hydrochloride (3.63 g, 33 mmol) in ethanol (80 mL) was stirred at 80 C for 2.5 h, concentrated and purified by CC
(PE/EA = 10/1) to afford compound P74b (4.8 g, 81%) as a pale solid.
Step 3: 4-(1-lsopropv1-1H-pvrazol-5-v1)-3-(trifluoromethvl)phenvl trifluoromethanesulfonate (P74c) To a P74b (4.0 g, 14.8 mmol) in DCM (80 mL) was added TEA (3.0 g, 29.6 mmol) and Tf20 (6.26 g, 22.2 mmol). The mixture was stirred at rt for 3.5 h and washed with water (30 mL).
The organic phase was dried over Na2SO4, concentrated and purified by CC
(PE/EA = 40/1) to afford product P74c (4.5 g, 76%) as a pale solid.
Step 4: 1-lsopropv1-5-(4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)-2-(trifluoromethvI)-phenvI)-1H-pvrazole (P74) A mixture of P74c (2.0 g, 5.00 mmol), Pd(dppf)2Cl2 (0.2g, 0.25 mmol), B2Pin2 (1.9 g, 7.50 mmol) and KOAc (1.47g, 15.0 mmol) in 1,4-dioxane (200 mL) was stirred at 90 C
under N2 for 3 h, washed with water (400 mL) and extracted with EA (3x 100 mL). The combined organic phase was dried over Na2SO4 and evaporated to obtain product P74 (1.8 g, 95%).
Preparative Example P75 \¨osB
NN
Step 1: 2-(tert-Butyl)-4-chlorophenyl trifluoromethanesulfonate (P75a) To a solution of 2-(tert-butyl)-4-chlorophenol (30 g, 0.163 mol) and pyridine (21 mL, 0.26 30 mol) in dry DCM (500 mL) was added a solution of Tf20 (33 ml, 0.19 mol) in dry DCM (150 mL) at 0 C and the solution was stirred for 4 h at rt, poured into 1M HCI and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 10/1) to give P75a (39 g, 87%) as a colorless liquid.
Step 2: Methyl 2-(tert-butyl)-4-chlorobenzoate (P75b) A solution of P75a (36 g, 0.13 mol), dppp (4.5 g, 11 mmol), Pd(OAc)2 (2.4 g, 11 mmol) and NEt3 (135 mL, 1.0 mol) in a mixture of Me0H (300 mL) and DMSO (400 mL) was stirred overnight at 55 C under an atmosphere of CO. Water and EA were added and the organic layer was separated, washed with water twice and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 8/1) to give compound P75b (25.7 g, 89%) as a colorless solid.
Step 3: 2-(tert-Butyl)-4-chlorobenzoic acid (P75c) To a solution of P75b (4.5 g, 20 mmol) in Me0H (30 mL) was added 3M NaOH (7 mL) and the mixture was ref luxed for 12 h, concentrated and poured into water (50 mL), adjusted to pH 3 by adding 3M HCI and extracted with EA (3x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to obtain crude product P75c (4.0 g, 95 /0).
Step 4: 2-(tert-Butv1)-4-chloro-1'f-pivalovlbenzohydrazide (P75d) A solution of P75c (2.1 g, 10 mmol), HATU (5.7 g, 15 mmol) and DIPEA (3.2 g, 25 mmol) in DMF (15 mL) was stirred at rt for 30 min. Then pivalohydrazide (1.7 g, 15 mmol) was added and the mixture was stirred for 12 h under rt, poured into H20 (50 mL) and extracted with EA
(3x 50 mL). The combined organic layer were dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to afford compound P75d (2.5 g, 80%).
Step 5: 2-(tert-Butyl)-5-(2-(tert-butv1)-4-chlorophenv1)-1,3,4-oxadiazole (P75e) To a slurry of compound P75d (1.2 g, 3.8 mmol) in DCM (15 mL) was added pyridine (0.6 g, 7.6 mmol). The mixture was cooled to ¨10 C and Tf20 (2.2 g, 7.6 mmol) was added dropwise. The mixture was stirred at ¨10 C for 1 h, at 0 C for 1 h and then warmed slowly to rt and stirred for 2 h, poured into H2O (50 mL) and extracted with EA (3x 50 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC
to afford compound P75e (660 mg, 60%).
Step 6: 2-(tert-Butyl)-5-(2-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-v1)phenv1)-1,3,4-oxadiazole (P75) Compound P75e was treated as described above in Example P65, Step 3 to give compound P75 as a colorless solid.
Preparative Example P76 0)t.,/c--N H2 StelD 1: Methyl 2,2-dimethy1-4-oxopentanoate (P76a) A solution of 4-methoxy-3,3-dimethy1-4-oxobutanoic acid (180 mg, 1.12mmol) in SOCl2 (6 mL) was stirred at rt for 2 h and concentrated. Cul (628 mg, 3.3 mmol) and Et20 (8 mL) in a separate flask was treated with MeLi (22 mL, 3M) and the solution was stirred for 5 min.
Then the resulting solution was cooled to ¨78 C. The acid chloride was added as a solution in Et20 (1 mL) and the solution was stirred for additional 30 min, quenched by Me0H and warmed to rt over 2 h. Aq. NHC14 was added and the mixture was extracted with EA. The organic layer was concentrated to give compound P76a (60 mg, 33%) as a colorless oil.
Step 2: 1-Benzv1-3,3,6-trimethylpiperidin-2-one (P76b) To a solution of compound P76a (100 mg, 0.63 mmol) in DCM (10 mL) was added BnNH2 (67 mg, 0.63 mmol), NaBH(Ac0)3 (186 mg, 0.88 mmol) and AcOH (0.04 mL) at 0 C.
The mixture was allowed to reach rt and stirred overnight. Aq. NaOH (1 mL, 10%) was added dropwise and the mixture was extracted with DCM. The organic layer was concentrated and purified by CC (PE/EA = 5/1) to give compound P76b (40 mg, 30%) as a colorless oil.
Step 3: 3,3,6-Trimethylpiperidin-2-one (P76c) Na (0.3 g, 13 mmol) was added to ammonia (10 mL) at ¨78 C, resulting in a dark blue solution. A solution of compound P76b (60 mg, 0.27 mmol) in THF (1 mL) was added and the solution was stirred at ¨40 C for 2 h, quenched with NHCI4 and concentrated. The residue was diluted with water (5 mL) and extracted with EA. The organic layer was concentrated and purified CC (PE/EA = 2/1) to give compound P76c (30 mg, 87%) as a colorless solid.
Step 4: Methyl 5-amino-2,2-dimethylhexanoate (P76) A mixture of compound P76c (400 mg, 3.14 mmol) in conc. HCI (10 mL) was stirred at 120 C
in a sealed tube for 48 h and concentrated. The obtained residue (300 mg, 1.63 mmol) was dissolved in Me0H (10 mL) and TMSCI (708 mg, 6.5 mmol) was added. The solution was stirred at rt for 24 h and concentrated to give compound P76 (350 mg, 57%) as an off-white solid.
Preparative Example P77 F3c _______________________________________ *
HN1<
Step 1: N-(2-Methv1-3-(trifluoromethvl)phenvpacetamide (P77a) 2-Methyl-3-(trifluoromethyl)aniline (1.95 g, 11.1 mmol) was dissolved in (Ac)20 (10 mL) and the mixture was stirred at rt overnight, partitioned between DCM (20 mL) and aq. NaHCO3 (20 mL) and the aq. phase was extracted again with DCM (3x 20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC to afford compound P77a (2.08 g, 86%).
Step 2: N-(4-Bromo-2-methv1-3-(trifluoromethvl)phenv1)acetamide (P77b) To a solution of compound P77a (2.08 g, 9.6 mmol) in HOAc (20 mL) was added under water-cooling a solution of bromine (1.8 mL) in HOAG (10 mL). The mixture was stirred at rt overnight and at 50 C for 2 h. Additional bromine (1.5 mL) was added under water-cooling and the mixture was stirred and heated to 50 C for 4 d, cooled to rt and poured into ice water. EA was added, followed by neutralization with K2CO3. The organic layer was separated, washed with aq. Na2S203 and brine, dried over Na2SO4 and concentrated to afford compound P77b (388 mg, 16%).
Step 3: 4-Bromo-2-methvI-3-(trifluoromethvpaniline (P77c) To a solution of compound P77b (338 mg, 1.33 mmol) in Et0H (20 mL) was added (1 mL). The mixture was heated to reflux overnight, cooled to rt, concentrated, adjusted to p14-4 with 4M HC1 and extracted with EA. The organic layer was washed with brine and dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to give compound P77c (186 mg, 56%) as colorless solid.
Step 4: N-(tert-Butv1)-2-methv1-4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)-3-(trifluoro-methvl)benzenesulfonamide (P77) Compound P77 was prepared from P77c similar as described for compound P45.
Preparative Example P77/1 to P77/2 Using similar procedures at that described in Preparative Example P77, the following compounds were prepared:
Structure # Structure 9,oCI F
-P77/1 -dB _\ scµNH P77/2 __ Preparative Example P78 ONfirs1H
Step 1: tert-Butvl 3-amino-3-(hydroxymethyl)azetidine-1-carboxylate (P78a) To a solution of 1-tert-butyl 3-ethyl 3-aminoazetidine-1,3-dicarboxylate (366 mg, 1.50 mmol) in THF (10 mL) was added LiBH4 (67 mg; 3 mmol) and the solution was ref luxed for 20 min, quenched with H20, acidified with 2M aq. HCI, neutralized again with 2M aq.
Na2CO3 and extracted with EA (3x). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated to give compound P78a (300 mg, 99%) as a yellow oil.
Step 2: tert- Butyl 6-oxo-8-oxa-2,5-diazaspirof3.51nonane-2-carboxylate (P78b) To a solution of compound P78a (400 mg, 1.98 mmol) and NEt3 (404 mg, 4.00 mmol) in DCM (10 mL) was added 2-chloroacetyl chloride (222 mg, 1.98 mmol) at 0 C and the solution was refluxed for 2 h, cooled to rt, washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA =5/1) to give of compound P78b (145 mg, 30%) as a colourless oil.
Step 3: 8-oxa-2,5-diazaspiro[3.51nonan-6-one (P78) A solution of compound P78b (145 mg, 0.60 mmol) and TFA (10 mL) was stirred for 6 h at rt and concentrated to give intermediate 78 (200 mg crude) as a TFA salt. 1H-NMR
(300 MHz, DMSO-d6) 6: 3.98-3.95 (m, 1H), 4.12-4.08 (m, 5H), 4.53 (s, 2H), 8.54 (m, 3H).
MS: 143 [M+1]+.
Preparative Example P79 OJNH
Step 1: 1-tert-Butyl 3-ethyl 3-(2-((tert-butoxycarbonyl)amino)acetamido)azetidine-1,3-dicarboxylate (P79a) The solution of of 1-tert-butyl 3-ethyl 3-aminoazetidine-1,3-dicarboxylate (400 mg, 1.64 mmol), 2-[(tert-butoxy)carbonylamino] acetic acid (431 mg, 2.46 mmol), HOBT
(332 mg, 2.46 mmol), EDCI (707 mg, 3.69 mmol) and DIEA (1 mL) in THF (20 mL) was stirred overnight at rt, washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC
(PE/EA = 2/1) to give compound P79a (500 mg, 76%) as a colorless solid.
Step 2: 2,5,8-Triazaspirof3.51nonane-6,9-dione (P79) A solution of compound P79a (500 mg, 1.25 mmol) and HCI in Me0H (3M, 10 mL) was stirred at rt for 1 h and then ref luxed overnight, concentrated and diluted with Et20. The formed solid was collected by filtration, washed with Et20 and dried in vacuum to give compound P79 (200 mg, 84%) as a mono HCI salt. 1H-NMR (300 MHz, D20) 6: 4.69-4.65 (m, 2H), 4.51-4.47 (m, 2H), 4.19 (s, 2H). MS: 156 [M+1]+.
Preparative Example P80 HN
Step 1: Methyl 4-acetyltetrahydro-2H-pyran-4-carboxylate (P80a) To a suspension of 2,2'-dichloroethyl ether (14.3 g, 100 mmol), K2CO3 (27.6 g, 200 mmol), KI
(1.0 g, 6.00 mmol) in DMF (60 mL) was added methyl 3-oxobutanoate (13.9 g, 120 mmol) and the solution was stirred for 8 h at 80 C, diluted with water and extracted with EA (6x).
The combined organic layers were dried over Na2SO4, filtered and the filtrate was distilled under reduced pressure (Kp 125 to 127 C, 1.3 kPa) to give compound P80a (8.0 g, 43%) as a pale yellow liquid.
Step 2: Methyl 4-(2-bromoacetyl)tetrahydro-2H-pyran-4-carboxylate (P80b) A suspension of compound P80a (8.0 g, 43 mmol) and CuBr2 (9.63 g, 43 mmol) in EA (100 mL) was stirred overnight at 40 C, filtered and the filtrate was concentrated and purified by CC (PE/EA = 20/1) to give compound P80b (2.0 g, 18%) as a colorless solid.
Step 3: 8-Oxa-2-azaspirof4.51decane-1,4-dione (P80c) A solution of compound P80b (2.0 g, 7.5 mmol) in Me0H/NH3 (10M, 100 mL) was stirred overnight at 50 C in a sealed tube, cooled to rt, concentrated and purified by CC (PE/EA =
8/1) to give compound P80c (800 mg, 63%) as a colorless solid.
Step 4: 4-amino-8-oxa-2-azaspirof4.51decan-1-one (P80) A suspension of compound P80c (800 mg, 4.7 mmol), K2CO3 (1.19 g, 8.6 mmol) and NH2OH=HCI (598 mg, 8.6 mmol) in Et0H (30 mL) was stirred for 6 h at rt and concentrated.
Et0H (15 mL) and Raney-Ni (1 g) were added consecutively and the suspension was stirred under 50 psi of H2 atmosphere for 3 h at 65 C, filtered and the filtrate was concentrated and purified by CC (PE/EA = 1/5) to give intermediate P80 (200 mg, 25%) as a colorless solid.
1H-NMR (300 MHz, DMSO-d6+ D20) 6: 3.87-3.81 (m, 1H), 3.75-3.69 (m, 1H), 3.59-3.48 (m, 2H), 3.42-3.36 (m, 1H), 3.29-3.26 (m, 1H), 2.86-2.81 (m, 1H), 1.58-1.43 (m, 4H). MS: 171 [M+1]+.
Preparative Example P81 C
N-N7 NH2.1-1C1 Step 1: tert-Butyl (2-methv1-2-(1H-tetrazol-5-v1)propvl)carbamate (P81a) To a solution of tert-butyl (2-cyano-2-methylpropyl)carbamate (915 mg, 4.62 mmol) in DMF
(25 mL) was added NaN3 (450 mg, 6.93 mmol) and NH4CI (367 mg, 6.93 mmol). The reaction mixture was stirred at 110 C for 24 h, cooled, diluted with EA (20 mL) and washed with water (100 mL). The combined organic extracts were dried over Na2SO4, evaporated and purified by prep. HPLC to give compound P81a (345 mg, 31%) as a colorless solid.
Step 2: 2-Methyl-2-(1H-tetrazol-5-v1)propan-1-amine hydrochloride (P81) A mixture of compound P81a (345 mg, 1.43 mmol) in HCl/Me0H (4M, 30 mL) was stirred at rt overnight and evaporated to give compound P81 (241 mg, 95%) as a colorless solid.
Preparative Example 82 dN.,(<NH2=HCI
Step 1: tert-Butvl (3-(hydroxvamino)-3-imino-2,2-dimethvIpropv1)carbamate (P82a) A mixture of tert-butyl (2-cyano-2-methylpropyl)carbamate (1.75 g, 8.85 mmol), NH2OH=HCI
(584 mg, 17.7 mmol) and Et0Na (1.80 g, 26.6 mmol) in Et0H (50 mL) was stirred at 60 C
overnight, poured into water and extracted with EA. The organic extracts were dried over Na2SO4 and evaporated to give compound P82a (1.53 g, 75%) as yellow oil.
Step 2: tea-Butyl (2-methvI-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-v1)propvl)carbamate (P82b) A mixture of P82a (1.53 g, 6.64 mmol), dimethyl carbonate (1.32 g, 13.3 mmol), Et0Na (903 mg, 13.3 mmol) in Et0H (50 mL) was stirred at 60 C overnight, poured into water and extracted with EA. The combined organic layers were dried and evaporated to afford compound P82b (700 mg, 41%) as yellow solid.
Step 3: 3-(1-Amino-2-methylpropan-2-y1)-1,2,4-oxadiazol-5(4H)-one hydrochloride (P82) A mixture of compound P82b (700 mg, 2.73 mmol) in HCl/Me0H (4M, 30 mL) was stirred at rt overnight and evaporated to give compound P82 (420 mg, 98%) as a colorless solid.
Preparative Example P83 NH2=HCI
Step 1: tert-Butyl (3-(hydroxyamino)-3-iminopropyl)carbamate (P83a) A mixture of tert-butyl (2-cyanoethyl)carbamate (763 mg, 4.49 mmol), NH2OH=FICI (296 mg, 8.98 mmol) and Et0Na (916 mg, 13.5 mmol) in Et0H (50 mL) was stirred at 60 C
overnight, poured into water and extracted with EA. The combined organic extracts were dried over Na2SO4 and evaporated to give compound P83a (775 mg, 85%) as yellow oil.
Step 2: tert-Butyl (2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yflethyl)carbamate (P83b) A mixture of compound P83a (772 mg, 3.80 mmol), 1,11-carbonyldiimidazole (1.23 g, 7.61 mmol), Et0Na (518 mg, 7.61 mmol) in Et0H (50 mL) was stirred at 60 C
overnight, poured into water and extracted with EA. The combined organic layers were dried and evaporated to afford compound P83b (540 mg, 62%) as yellow solid.
Step 3: 3-(2-Aminoethyl)-1,2,4-oxadiazol-5(4H)-one hydrochloride (P83) A mixture of compound P83b (540 mg, 2.36 mmol) in HCl/Me0H (4M, 30 mL) was stirred at rt overnight and evaporated to give compound P83 (301 mg, 99%) as a colorless solid.
Peparative Example P84 *NH
Ci Step 1: 3-Bromo-N-(tert-butyl)-5-chlorobenzamide (P84a) A mixture of 3-bromo-5-chlorobenzoic acid (2.3 g, 10 mmol), HATU (3.7 g, 10 mmol) and DIPEA (2 g, 15 mmol) in DMF (30 mL) was stirred at rt for 30 min. Then 2-methylbutan-2-amine (1.0 g, 10 mmol) was added and the mixture was stirred for 12 h under rt, poured into water (100 mL) and extracted with EA (3x 50 mL). The combined organic layer was dried over Na2SO4, filtered, evaporated and purified by CC to give compound P84a (2.3 g, 80%).
Step 2: N-(tert-Butv1)-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-v1)benzamide (P84) The mixture of compound P84a (2.0 g, 6.0 mmol), B2Pin2 (2.0 g, 8.5 mmol), KOAc (1.0 g, 10.5 mmol) and Pd(dppf)C12 (100 mg) in 1,4-dioxane (50 mL) was stirred at 90 C
under N2 for 12 h, concentrated, poured into water (50 mL) and extracted with EA (3x 50 mL). The combined organic layer was dried over Na2SO4, filtered, evaporated and purified by CC to give compound P84 (1.1 g, 53%).
Preparative Example P85 A
:B * P85 Compound P85 was prepared using similar procedures as described in W02012/139775, Preparative Example P28, starting with 1,3-dibromo-5-chlorobenzene.
Preparative Example P86 ocF3 _________________________________ -o V
Step 1: 3-Bromo-N-methoxv-N-methyl-5-(trifluoromethoxv)benzamide (P86a) To a solution of 3-bromo-5-(trifluoromethoxy)benzoic acid (5.00 g, 17.5 mmol), N,0-dimethylhydroxylamine=HCI (4.20 g, 43.9 mmol), HATU (14.7 g, 38.7 mmol) in DMF
(50 mL) was added TEA (9.8 mL, 70.2 mmol) in portions at 0 C and the solution was stirred overnight at rt, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2504, filtered and concentrated to give compound P86a (5.5 g, 96%) as a yellow oil. 1H-NMR (400 MHz, CDCI3) 6: 3.37 (s, 3H), 3.56 (s, 3H), 7.48 (s, 1H), 7.52 (s, 1H), 7.80 (s, 1H).
Step 2: 1-(3-Bromo-5-(trifluoromethoxv)phenvnethanone (P86b) To a solution of compound P86a (4.5 g, 13.7 mmol) in dry THF (50 mL) was added CH3MgBr (3M in Et20, 9.2 mL, 27.6 mmol) in portions at ¨15 C and the solution was stirred for 15 min at this temperature and then at rt for 1 h, diluted with 1M HCI and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give compound P86b (3.5 g, 90%) as a yellow oil. 1H-NMR (400 MHz, CDCI3) 6: 2.62 (s, 3H), 7.60 (s, 1H), 7.74 (s, 1H), 8.02 (m, 1H).
Step 3: 1-Bromo-3-(prop-1-en-2-yI)-5-(trifluoromethoxv)benzene (P86c) To a suspension of methyltriphenylphosphonium bromide (7.60 g, 21.2 mmol) in dry THF
(150 mL) was added NaHMDS (1M in THF, 10.6 mL, 10.6 mmol) at ¨15 C and the solution was stirred further for 30 min. A solution of compound P86b (3.0 g, 10.6 mmol) in THF (5 mL) was added at ¨15 C and the mixture was stirred at rt for 1 h, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE) to give compound P86c (2.4 g, 81%) as a yellow oil.
1H-NMR (400 MHz, CDCI3) 6: 2.11 (d, J = 1.6 Hz, 3H), 5.19 (s, 1H), 5.38 (s, 1H), 7.22 (s, 1H), 7.29 (s, 1H), 7.52 (m, 1H).
Step 4: 1-Bromo-3-(1-methvIcyclopropv1)-5-(trifluoromethoxv)benzene (P86d) To a suspension of Pd(OAc)2 (1.0 g, 4.45 mmol) and compound P86c (3.0 g, 10.7 mmol) was added a solution of CH2N2 in Et20 (1M, 20 mL, 20 mmol) at ¨10 C and the solution was stirred for 30 min, filtered and the filtrate was concentrated to give compound P86d (1.9 g, 60%) as a yellow oil. 1H-NMR (400 MHz, CDCI3) 6: 0.78-0.81 (m, 2H), 0.84-0.88 (m, 2H), 1.39 (s, 3H), 7.00 (s, 1H), 7.18 (s, 1H), 7.30 (m, 1H).
Step 5: 4,4,5,5-Tetramethv1-2-(3-(1-methvIcyclopropy1)-5-(trifluoromethoxv)phenv1)-1,3,2-dioxaborolane (P86) To a suspension of compound P86d (1.0 g, 3.4 mmol), KOAc (1.40 g, 13.8 mmol) and B2Pin2 (1.80 g, 7.08 mmol) in 1,4-dioxane (40 mL) was added Pd(dppf)Cl2 (250 mg, 356 pmol) at rt under N2 and the solution was heated overnight at 80 C, cooled to rt and filtered. The filtrate was concentrated and purified by CC (PE/EA = 50/1) to give compound P86 (1.0 g, 91%) as yellow oil. 1H-NMR (300 MHz, CDCI3) 6:0.73-0.76 (m, 2H), 0.86-0.90 (m, 2H), 1.34 (s, 12H), 1.41 (s, 3H), 7.17 (s, 1H), 7.43 (s, 1H), 7.60 (s, 1H).
Preparative Example P87 ocF3 y P87 NH
Compound P87 was prepared using similar procedures as described in Preparative Example P84.
Preparative Example P89:
\--0, B N/¨\N¨
Step 1: 1-(2-(tert-Butvl)phenv1)-4-methvIpiperazine (P89a) A mixture of 2-(tert-butyl)aniline (1.0 g, 6.71 mmol), Nal (3.0 g, 20.1 mmol), K2CO3 (2.78 g, 20.1 mmol) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine (1.04 g, 6.71 mmol) in diglyme (150 mL) was stirred at 170 C for 24 h, poured into water and extracted with EA.
The organic layers were dried over Na2SO4, evaporated and purified by CC
(DCM/Me0H =
19/1) to afford compound P89a (500 mg, 32%).
Step 2: 1-(4-Bromo-2-(tert-butvl)phenvI)-4-methylpiperazine (P89b) Compound P89a (200 mg, 0.86 mmol) and Na0Ac (210 mg, 2.58 mmol) were dissolved in AcOH (5 mL) and the mixture was stirred at it Bromine (165 mg, 1.03 mmol) was added dropwise and the mixture was stirred for 2 h at rt, diluted with 2M NaOH (150 mL) and extracted with EA. The combined organic phases were dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to afford compound P89b (40 mg, 15%).
Step 3: 1-(2-(tert-Butv1)-4-(4,4,5,5-tetramethv1-1,3,2-dioxaborolan-2-v1)phenv1)-4-methvIpiperazine (P89) This compound was prepared using a similar procedure as described in Preparative Example P86, Step 5.
Preparative Example P90 OH
___________________________________ :B P90 f'0 F F
Step 1: 2-(3-Bromo-5-(trifluoromethvl)phenvI)propan-2-ol (P90a) A mixture of 1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (0.5 g, 1.8 mmol) in THF (10 mL) was cooled to 0 C and treated dropwise with MeMgBr (1M in Et20, 10 mmol, 10 mL). Upon completion of addition, the resulting suspension was allowed to warm to rt and was stirred for 5 h, slowly diluted with saturated aq. NH4C1 (10 mL) and EA (10 mL). The layers were separated and the aq. layer was extracted with EA (3x 30 mL). The combined organic layers were dried over MgSO4, evaporated and purified by CC to afford compound P90a (0.47 g, 93%).
Step 2: 2-(3-(4,4,5,5-Tetramethy1-1,3,2-dioxaborolan-2-v1)-5-(trifluoromethvl)phenv1)propan-2-01 (P90) Compound P90 was prepared using a similar procedure as described in Preparative Example P86, Step 5.
Preparative Example P91 Br ¨\ P91 N),\
Step 1: 2,6-Di- tert-butvlpvrimidin-4-ol (P91a) To a mixture of pivalimidamide (586 mg, 5.86 mmol) and ethyl 4,4-dimethy1-3-oxopentanoate (1.21 g, 7.03 mmol) in Me0H (30 mL) was added Na0Me (623 mg, 11.7 mmol) under Ar.
The mixture was refluxed at 75 C overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give compound P91a (1.04 g, 85%) as colorless solid.
Step 2: 4-Bromo-2,6-di-tert-butvIrwrimidine (P91) Compound P91a (1.04 g, 4.99 mmol) and POBr3 (10 g) was stirred at 65 C for 1 h, poured into ice/water and extracted with EA. The organic layer was dried over MgSO4, filtered and concentrated to give compound P91 (1.20 g, 89%) as a yellow oil.
Preparative Example P92 Br¨CY--; P92 Step 1: 1-MethvIcyclopropanecarboximidamide (P92a) NH4C1 (129 mg, 2.43 mmol) was suspended in toluene (10 mL) and the slurry cooled to 0 C.
AlMe3 (2M in toluene, 2.43 mmol) was added at 0 C and the mixture was allowed to warm to rt and stirred until gas evolution had ceased. Methyl 1-methylcyclopropanecarboxylate (114 mg, 1.62 mmol) was added and the mixture stirred at 80 C overnight, cooled to rt, diluted with Me0H and stirred at rt for 1 h. The solution was filtered, the solids washed with Me0H
and the solvent was removed in vacuo to afford the compound P92a (100 mg, 63%).
Step 2: 6-(tert-Butyl)-2-(1-methvIcyclopropvl)pvrimidin-4-ol (P92b) To a mixture of compound P92a (63 mg, 0.64 mmol) and methyl 4,4-dimethy1-3-oxopentanoate (121 mg, 0.77 mmol) in Me0H (30 mL) was added Na0Me (86 mg, 1.61 mmol) under Ar. The mixture was refluxed at 75 C overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give compound P92b (112 mg, 85%) as a colorless solid.
Step 3: 4-Bromo-6-(tert-buty1)-2-(1-methylcyclopropyl)pyrimidine (P92) Compound P92b (105 mg, 0.51 mmol) and POBr3 (200 mg) was stirred without solvent at 65 C for 1 h, poured into ice/water and extracted with EA. The organic layer was dried over MgSO4, filtered and concentrated to give compound P92 (121 mg, 89%) as yellow oil.
Preparative Example P93 TfO¨Cr p93 Nlv.
Step 1: Methyl 3-(1-methylcyclopropyI)-3-oxopropanoate (P93a) To a solution of 1-(1-methylcyclopropyl)ethanone (328 mg, 3.35 mmol) in THF
(90 mL) was added LiHMDS (1M in THF, 2.5 mL) at ¨78 C. The cooling bath was removed and the mixture was stirred at rt for 30 min. Dimethyl carbonate (452 mg, 5.03 mmol) was added and the mixture stirred at rt overnight, evaporated, diluted with water and EA, acidified with AcOH
and extracted with EA. The organic layer was dried over MgSO4, filtered, concentrated and purified by CC (EA/PE = 1/9) to give compound P93a (68 mg, 13%) as a yellow oil.
Step 2: 2-(tert-ButyI)-6-(1-methylcyclopropyl)pyrimidin-4-ol (P93b) To a mixture of compound P93a (60 mg, 0.38 mmol) and pivalimidamide (46 mg, 0.46 mmol) in Me0H (30 mL) was added Na0Me (51 mg, 0.95 mmol) under Ar. The mixture was ref luxed at 75 C overnight, diluted with water (20 mL) and extracted with EA
(3x 20 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give compound P93b (63 mg, 80%) as a colorless solid.
Step 3: 2-(tert-Butyl)-6-(1-methylcyclopropyl)pyrimidin-4-yltrifluoromethanesulfonate (P93) To a mixture of compound P93b (57 mg, 0.28 mmol) in DCM (10 mL) was added Tf20 (118 mg, 0.42 mmol) and TEA (71 mg, 0.70 mmol) and the mixture was stirred at rt overnight, poured into water and extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated to afford compound P93 (81 mg, 86%) as a yellow oil.
Preparative Example P94 o _ \B it Nx_H
\_ 0 7'6 P94 OMe Step 1: 3-Bromo-5-(methoxvcarbonvl)benzoic acid (P94a) To a solution of dimethyl 5-bromoisophthalate (5.0 g, 18.3 mmol) in a mixture of THF (25 mL) and Me0H (25 mL) was added NaOH (740 mg, 18.4 mmol) and the mixture was stirred at rt overnight, concentrated, diluted with 2M HCI (20 mL) and extracted with EA. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was washed with a mixture of PE/EA (10:1, 10 mL) to give compound P94a (4.2 g, 88%) as a colorless solid.
Step 2: Methyl 3-bromo-5-(tert-butvIcarbamovl)benzoate (P94b) A solution of compound P94a (400 mg, 1.54 mmol) in SOCl2 (10 mL) was heated at reflux for 2 h, concentrated and coevaporated with toluene twice. The residue was dissolved in dry DCM (6 mL). TEA (0.2 mL) and tert-butylamine (0.15 mL) were added and the solution was stirred for further 40 min, concentrated and purified by CC (PE/EA = 10:1) to give compound P94b (360 mg, 76%) as a colorless oil.
Step 3: Methyl 3-(tert-butvIcarbamov1)-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)benzoate (P94) A flask was charged with compound P94b (360 mg, 1.15 mmol), B2Pin2 (1.57 g, 5.4 mmol), KOAc (0.72 g, 7.3 mmol), Pd(dppf)C12 (60 mg) and DMF (10 mL) and the mixture was stirred at 90 C for 12 h, cooled, concentrated and purified by CC (PE/EA = 10/1) to give compound P94 (315 mg, 76%) as a colorless solid.
Preparative Example P95 OH
* p95 OMe Step 1: Methyl 3-bromo-5-(methoxv(methvI)carbamovnbenzoate (P95a) A solution of compound P94a (3.8 g, 14.7 mmol) in SOCl2 (40 mL) was heated at reflux for 2 h, concentrated and diluted with dry DCM (200 mL). Then the solution was added to a stirring solution of N,0-dimethylhydroxylamine hydrochloride (1.69 g, 17.6 mmol) and NEt3 (6 mL) in dry DCM (60 mL) slowly at 0 C and the solution was stirred for 1 h at rt, poured into water. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated to give crude compound P95a (4.2 g, 94%) as a light brown oil.
Step 2: Methyl 3-acetyl-5-bromobenzoate (P95b) To a solution of compound P95a (4.2 g, 14.0 mmol) in dry THF (120 mL) was added MeMgBr (3M in Et20, 5.5 mL, 16.7 mmol) dropwise at 0 C and the solution was stirred for 4 h at rt, quenched with aq. NHCI4 and extracted with EA twice. The combined organic layers were washed with water and brine consecutively, dried over Na2SO4, filtered and concentrated to give crude compound P95b (2.5 g) which contains 15% compound P95c (based on LCMS) as a colorless oil Step 3: Methyl 3-bromo-5-(2-hydroxvpropan-2-v1)benzoate (P95c) To a solution of crude compound P95b (2.5 g, 9.7 mmol) in dry THF (50 mL) was added MeMgBr (3M in Et20, 3.7 mL, 11.1 mmol) dropwise at 0 C and the solution was stirred for 4 h at rt, quenched with aq. NHCI4 and extracted with EA twice. The combined organic layers were washed with water and brine consecutively, dried over Na2SO4, filtered and concentrated to give crude compound P95c (2.1 g, 79% over two steps) as pale yellow oil.
Step 4: Methyl 3-(2-hydroxvpropan-2-v1)-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-0benzoate (P95) A flask was charged with compound P95c (900 mg, 3.3 mmol), B2Pin2 (4.5 g, 17.8 mmol), KOAc (2.3 g, 23.1 mmol), Pd(dppf)Cl2 (100 mg) and DMF (200 mL) and the solution was stirred at 100 C for 12 h, concentrated and purified by CC (PE/EA = 10/1) to give compound P95 (650 mg, 62%) as a colorless solid.
Preparative Example P96 OMe :B P96 OMe Step 1: Methyl 3-bromo-5-(2-methoxvproPan-2-v1)benzoate (P96a) To a solution of compound P95c (1.1 g, 4.0 mmol) in dry THF (20 mL) was added NaH (195 mg, 8.0 mmol) under N2 and the suspension was stirred for 1 hat rt. Then Mel (1.72 g, 12.0 mmol) was added and the solution was stirred at 70 C in a sealed tube overnight, poured into water and extracted with Et20. The organic layer was washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE) to give compound P96a (600 mg, 52%) as a colorless oil.
Step 2: Methyl 3-(2-methoxypropan-2-y1)-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-vl)benzoate (P96) A flask was charged with compound P96a (600 mg, 2.1 mmol), B2Pin2 (1.07 g, 4.2 mmol), KOAc (1.44 g, 14.7 mmol), Pd(dppf)Cl2 (60 mg) and DMF (10 mL) and the solution was Preparative Example P97 ___________________________________ B I/ 0 P97 -(5 To a solution of 2-(spiro[chroman-4,1'-cyclopropan]-8-yl)propan-2-ol (prepared as described in W02012/139775, Preparative Example P39) (1.0 g, 4.58 mmol) in dry THF (10 mL) was added NBS (980 mg, 5.5 mmol) and the mixture was heated at reflux overnight, cooled, poured into water and extracted with EA twice. The combined organic layers were washed Step 2: 4,4,5,5-tetramethy1-2-(8-(prop-1-en-2-yl)spirorchroman-4,11-cyclopropan1-6-y1)-1,3,2-dioxaborolane (P97) (30 mg) and KOAc (150 mg, 1.52 mmol) in DMF (5 mL) under N2 atmosphere was stirred at 95 C overnight, concentrated and purified by CC (PE/EA = 10/1) to give compound P97 (128 mg, 36%) as a colorless solid.
HN
N
Step 1: 1-Cyclohexylethyl methanesulfonate (la) A solution of 1-cyclohexylethanol (1.28 g, 10 mmol) in DCM (50 mL), mesylchloride (15 mmol), Et3N (30 mmol) was added under 0 C. The mixture was stirred for additional 2 h, quenched with ice water and extracted with EA. The organic layer was separated, washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and the crude intermediate la was used in the next step.
Step 2: 1,2-Dibromoethvl acetate (1b) Under N2, vinyl acetate (86 g, 1.0 mol) was dissolved in dry CCI4 (200 mL) and bromine (160 g, 1 mol) in dry CCI4 (100 mL) was added dropwise over 2 h with vigorous stirring in an ice-water bath below 10 C. The mixture was stirred for additional 30 min and solvent was removed to give crude product lb, which was used for the next step without further purification.
Step 3: Ethyl 2-methyl-1H-pyrrole-3-carboxvlate (1c) NH3 (gas) was bubbled to a stirred solution of compound lb (24.6 g, 10 mmol) and ethyl 3-oxobutanoate (13.0 g, 0.1 mol) in dry THF for 15 min. The solid was filtered off and solvent was removed to give crude product lc.
Step 4: Ethyl 1-(1-cyclohexvIethvI)-2-methyl-1H-pvrrole-3-carboxvlate (1d) To a solution of compound lc (1.53 g, 10 mmol) in dry DMF (10 mL) was added NaH (60%
in mineral oil, 1.2 g, 0.03 mol) in an ice-water bath below 0 C. The mixture was stirred for 30 min and then compound la (3.09 g, 15 mmol) was added to the mixture. The mixture was stirred for additional 12 h, quenched with ice water and extracted with EA.
The organic layer was separated and washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by CC (EA/PE = 1/60) to give compound id (1.63 g, 62%) as a pale yellow oil.
Step 5: Ethyl 5-bromo-1-(1-cyclohexvIethvI)-2-methyl-1H-pvrrole-3-carboxvlate (le) To a solution of compound id (1.32 g, 5.0 mmol) in dry THF (25mL) was added NBS (0.89 g, 5 mmol) at ¨78 C under N2. The reaction was stirred 5 min (monitored by TLC) and quenched with cold aq. NH4CI. The organic layer was separated and the aq.
layer extracted repeatedly with EA. The combined organic layer was washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by CC
(EA/PE= 1/60) to give compound le (1.57 g, 92%).
Step 6: Ethyl 1-(1-cyclohexvIethvI)-5-(3,5-di-tert-butvlphenv1)-2-methyl-1H-pyrrole-3-carboxvlate (1f) A suspension of compound le (1.71 g, 5 mmol), Cs2CO3 (3.25 g 10 mmol), 2-(3,5-di-tert-butylpheny1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.37 g, 7.5 mmol), Pd(dppf)Cl2 (30 mg) in 1,4-dioxane/H20(10:1, 50 mL) was heated overnight under N2 at 90 C. After cooling, the mixture was concentrated and extracted with EA. The organic layer was washed with brine, dried over magnesium sulfate, filtered, concentrated and purified by CC (EA/PE
= 1/50) to give compound if (903 mg, 40%).
Step 7: 1-(1-CyclohexvIethvI)-5-(3,5-di-tert-butvlphenv1)-2-methyl-1H-pyrrole-3-carboxylic acid (1q) To a solution of compound if (902 mg, 2 mmol) in Et0H (20 mL) was added 5M KOH
(10 mL). The mixture was ref luxed overnight, the solvent was removed under reduced pressure and the residue was adjusted to pH<2 with 4M HCI. The mixture was extracted with EA three times and the combined organic layer was washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep. HPLC to give pure product 1g as a colorless solid.
Step 8: 1-(1-CyclohexvIethvI)-5-(3,5-di-tert-butvlphenv1)-2-methyl-N-(oxetan-3-v1)-1H-pyrrole-3-carboxamide (1) To a solution of compound 1g (85 mg, 0.2 mmol) in DMF (5 mL) was added HATU
(152 mg, 0.4 mmol) and DIPEA (129 mg, 1 mmol). The mixture was stirred for 60 min and then oxetan-3-amine (110 mg, 1.5 mmol) was added to the mixture. The mixture was stirred overnight and quenched with ice water and extracted with EA. The organic layer was separated washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep. HPLC to give compound 1 (40 mg, 42%) as a colorless solid. 1H-NMR (500 MHz, DMSO-d6) 6: 0.63 (m, 2H), 1.01 (m, 4H), 1.13-1.31 (m, 20H), 1.47 (m, 6H), 2.57 (s, 3H), 3.86 (m, 1H), 4.52 (m, 2H), 4.70 (m, 2H), 4.95 (m, 1H), 6.50 (s, 1H), 7.09 (s, 2H), 7.39 (s, 1H), 8.19 (d, 1H). MS: 479.4 (M+1).
Example 1/1 to 1/132 The following Examples were prepared similar as in Example 1:
Structure Analytical data 1H-NMR (400 MHz, DMSO-d6) 6: 7.88 (t, J = 5.6 o, P Hz, 1H), 7.36 (s, 1H), 7.15 (d, J =
1.6 Hz, 1H), / N41.
H I 6.46 (s, 1H), 3.77 (d, J = 7.2 Hz, 2H), 3.60-3.55 (m, 2H), 3.31 (t, J = 7.0 Hz, 2H), 3.01 (s, 3H), 2.53 (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.21 (m, 21H), 0.93-0.88 (m, 3H), 0.68-0.62 (m, 2H). MS:
515.1 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.80 (t, J = 6.0 Hz, 1H), 7.36 (t, J = 1.8 Hz, 1H), 7.16 (d, J = 1.6 ofIr\-11 = Hz, 2H), 6.53 (s, 1H), 4.47 (d, J =
5.6 Hz, 2H), 1/2 4.15 (d, J = 5.6 Hz, 2H), 3.76 (d, J =
7.2 Hz, 2H), 3.34 (d, J = 6.0 Hz, 2H), 2.52 (s, 3H), 1.46-1.44 (m, 3H), 1.34-1.23 (m, 24H), 0.95-0.89 (m, # Structure Analytical data 3H), 0.66-0.60 (m, 2H). MS: 493.4 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.36-7.31 (m, o 2H), 7.20 (s, 1H), 7.15 (d, J = 1.6 Hz, 2H), 6.84 1 /3 \ . (s, 1H), 6.42 (s, 1H), 3.75 (d, J = 7.2 Hz, 2H), H2N 081 3.29 (s, 2H), 2.51 (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.22 (m, 21H), 1.07 (s, 6H), 0.95-0.89 (m, 3H), 0.67-0.60 (m, 2H). MS: 508.2 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.65 (t, J = 6.2 H o Hz, 1H), 7.36 (s, 1H), 7.16 (d, J = 1.6 Hz, 2H), 7.CN 0 fli 7.04 (s, 1H), 6.50 (s, 1H), 3.76 (d, J = 7.2 Hz, 1/4 , 0 N 2H), 3.28 (d, J = 6.4 Hz, 2H), 2.95 (s, 3H), 2.52 d (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.15 (m, 27H), 0.95-0.87 (m, 3H), 0.68-0.59 (m, 2H). MS: 558.1 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.81 (t, J = 5.8 o Hz, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 7.17 (d, J =
H2Nr \ 1.6 Hz, 1H), 6.96 (s, 1H), 6.53 (s, 1H), 3.78 (d, J
il git 1 /5 N = 7.2 Hz, 2H), 3.72 (d, J = 5.6 Hz, 2H), 2.53 (s, O 3H), 1.46-1.43 (m, 3H), 1.31-1.15 (m, 21H), 0.93-0.86 (m, 3H), 0.69-0.61 (m, 2H). MS: 466.1 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.65 (t, 1H), I o 7.36 (s, 1H), 7.17 (d, J = 1.6 Hz, 2H), 6.51 (s, \
1H), 3.99 (d, J = 5.2 Hz, 2H), 3.77 (d, J = 7.2 -Nr 1 it 1 /6 H N Hz, 2H), 3.00 (s, 3H), 2.84 (s, 3H), 2.52 (s, 3H), O 1.46-1.43 (m, 3H), 1.35-1.23 (m, 21H), 0.94-0.85 (m, 3H), 0.67-0.61 (m, 2H). MS: 494.2 (M+1).
o 1H-NMR (400 MHz, DMSO-d6) 6: 7.35 (t, J = 2.0 C.N \
Hz, 1H), 7.15 (d, J = 2.0 Hz, 2H), 6.18 (s, 1H), 1 .
1/7 HOi N 4.47-3.68 (m, 8H), 2.46 (s, 3H), 1.46-1.43 (m, d 3H), 1.31-1.21 (m, 21H), 0.98-0.85 (m, 3H), 0.68-0.60 (m, 2H). MS: 465.1 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6:7.36 (t, J = 1.6 o Hz, 1H), 7.15 (d, J = 1.6 Hz, 2H), 6.21 (s, 1H), o'Cir\I \ = 4.43-3.69 (m, 7H), 3.21 (s, 3H), 2.47 (s, 3H), 1/8 N 1.46-1.35 (m, 3H), 1.31-1.15 (m, 21H), 1.00-0.85 (m, 3H), 0.68-0.60 (m, 2H). MS: 479.1 (M+1).
# Structure Analytical data 1H-NMR (400 MHz, DMSO-d6) 6: 7.80 (t, J = 5.8 H2N o Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 1.6 Hz, 2H), ',sõ, \ , it 6.92 (s, 2H), 6.44 (s, 1H), 3.76 (d, J = 7.2 Hz, 1/9 N 2H), 3.56 (q, 2H), 3.18 (t, J = 7.4 Hz, 2H), 2.53 d (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.21 (m, 21H), 0.94-0.88 (m, 3H), 0.68-0.60 (m, 2H). MS: 516.1 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 8.18 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), o 6.26 (s, 1H), 5.89 (m, 1H), 4.56 (s, 1H), 4.00 (m, 1/10 c(Dy[Nil 1 \ /it sp2* 2H), 3.77 (d, J = 7.2 Hz, 2H), 3.38 (m, 2H), 3.30 N
N H (111, 2H), 2.63 (s, 3H), 1.86 (m, 1H), 1.66 (m, d 11H), 1.55-1.51 (m, 3H), 1.42-1.24 (m, 14H), 1.01-0.92 (m, 3H), 0.60 (m, 2H). MS: 586.1 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.12 (d, J =
o o 8.4 Hz, 1H), 7.74 (s, 1H), 7.63 (m, 1H), 7.52 (s, 1H)' 7.40 (m, 1H), 6.62 (s, 1H), 3.84 (m, 2H), H I \ it sPN24-- 3.56 (m, 4H), 3.27 (m, 2H), 2.52 (s, 3H), 2.38 d (m, 6H), 1.54 (s, 9H), 1.43 (m, 3H), 1.22-1.12 (m, 12H), 0.99-0.82 (m, 3H), 0.59 (m, 2H). MS:
601.1 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.45 (s, 1H), A4c,NN o 7.36 (t, J = 1.6 Hz, 1H), 7.15 (d, J = 1.6 Hz, 2H), H 1 \ = 6.48 (s, 1H), 3.77 (d, J = 6.8 Hz, 2H), 2.54 (s, 1/12 N 3H), 1.50-1.43 (m, 5H), 1.30-1.14 (m, 22H), d 0.94-0.86 (m, 3H), 0.67-0.60 (m, 2H). MS:
474.1 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 8.21 (d, J = 8.4 o Hz, 1H), 7.59 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), H2N \ II SO2 /_ 6.31 (s, 1H), 5.52 (br s, 2H), 4.67 (s, 1H), 3.80 H (d, J = 6.8 Hz, 2H), 2.63 (s, 3H), 1.62 (s, 9H), d 1.53 (m, 3H), 1.35-1.29 (m, 12H), 1.02-0.95 (m, 3H), 0.61 (m, 2H). MS Found: 488.5 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 5: 8.19 (d, J =
sa o 8.0 Hz, 1H), 7.36 (s, 1H), 7.16 (d, J = 1.6 Hz, 2H), 6.53 (s, 1H), 5.22-5.16 (m, 1H), 3.76 (d, J =
11 1 \ = 6.8 Hz, 2H), 3.50 (t, J = 9.0 Hz, 2H), 3.19 (t, J =
N
d 10.4 Hz, 2H), 2.43 (s, 3H), 1.45-1.40 (m, 3H), 1.31-1.15 (m, 21H), 0.97-0.87 (m, 3H), 0.67-0.58 (m, 2H). MS: 481.1 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 8.12 (d, J =
>LolNa 0 7.2 Hz, 1H), 7.36(t, J = 1.6 Hz, 1H), 7.16(d, J =
1.6 Hz, 2H), 6.56 (s, 1H), 4.63-4.58 (m, 1H), N \
H . 4.06-4.02 (m, 2H), 3.81-3.76 (m, 4H), 2.51 (s, d 3H), 1.45-1.43 (m, 3H), 1.38 (s, 9H), 1.31 (s, 18H), 1.27-1.15 (m, 3H), 0.92-0.84 (m, 3H), 0.67-0.59 (m, 2H). MS: 564.2 (M+1).
# Structure Analytical data 1H-NMR (300 MHz, CDCI3) 6: 0.66-0.72 (m, 2H), o\_3 cF3 0.97-1.04 (m, 9H), 1.25-1.43 (m, 4H), 1.58-1.63 (m, 4H), 2.60 (s, 3H), 3.85 (d, J = 7.2 Hz, 2H), d 1/16 N 4.07 (s, 2H), 4.57 (t, J = 6.6 Hz, 2H), 4.98 (t, J = o--)c.
7.2 Hz, 2H), 5.15-5.23 (m, 1H), 6.23-6.25 (m, 1H), 6.45 (s, 1H), 6.86 (s, 1H), 7.21 (s, 1H). MS:
508 (M+1)+.
1H-NMR (300 MHz, CDCI3) 6: 0.66-0.72 (m, 2H), 0.98-1.06 (m, 3H), 1.23-1.40 (m, 12H), 1.51-oa o 1.58 (m, 3H), 2.59 (s, 3H), 3.83 (d, J = 7.2 Hz, 2H), 4.57 (t, J = 6.6 Hz, 2H), 4.82 (q, J = 8.7 Hz, d 2H), 4.99 (t, J = 7.2 Hz, 2H), 5.15-5.23 (m, 1H), -\cF, 6.19 (d, J = 7.2 Hz, 2H), 6.35 (s, 1H), 6.62 (d, J
= 0.9 Hz, 1H), 6.93 (d, J = 0.9 Hz, 1H). MS: 508 (M+1)+.
11-I-NMR (400 MHz, DMSO-d6) 6: 8.23-8.20 m o\.3 N \ . NH (2H), 7.18 (s, 1H), 7.17 (s, 1H), 6.57 (s, 1H), 4.97-4.92 (m, 1H), 4.71 (t, 2H), 4.54 (t, 2H), 3.75 1/18 N (d, 2H), 2.42 (s, 3H), 1.48-1.46 (m, 3H), 1.41 (s, d 9H), 1.36-1.24 (m, 9H), 0.97-0.92 (m, 3H), 0.73-0.64 (m, 2H). MS: 506.3 (M+1).
1H-NMR (400 MHz, CDCI3) 6:7.32 (d, 1H), 7.04 (d, 1H), 6.23 (s, 1H), 6.20 (d, J = 7.2 Hz, 2H), oa / 5.23-5.20 (m, 1H), 5.00 (t, 2H), 4.57 (t, 2H), 3.74 Hi 1 \ = N
1/19 N (d, J = 6.8 Hz, 2H), 3.29 (s, 3H), 2.60 (s, 3H), d 2.50 (br s, 2H), 1.56-1.54 (m, 3H), 1.45 (s, 9H), 1.42-1.18 (m, 9H), 1.02-1.00 (d, 3H), 0.69-0.65 (m, 2H). MS: 520.3 (M+1).
S\ 0 o -- - ----NH
H, O \--= n.d.
d sa 0 N \ =
1/21 N n.d.
d 1H-NMR (300 MHz, DMSO-d6) 6: 8.31 (d, J =
oa 0 Aiik P 6.6 Hz, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 6.78 (s, 1H), 4.98-4.92 (m, 1H), 4.73 (t, J = 6.8 Hz, 2H), 1/22 N ii 4.55 (t, J = 6.2 Hz, 2H), 3.94-3.84 (m, 3H), 3.58-d 3.51 (m, 1H), 2.53 (s, 3H), 1.54-1.44 (m, 15H), 1.31-1.20(m, 9H), 0.95-0.88 (m, 3H), 0.70-0.62 (m, 2H). MS: 556.4 (M+1).
# Structure Analytical data sn 0 0 \--I 1 \
1/23 N Nt- n.d.
d 1H-NMR (400 MHz, CDCI3,) 5: 7.26 (s, 1H), 7.22 (d, 1H, J = 2.0 Hz), 7.10 (t, 1H, J = 2.0 Hz), 6.16 oaN 0 (s, 1H), 6.15 (s, 1H), 5.28 (s, 2H), 5.18-5.23 (m, H \ 41k \--0 1H), 4.98 (t, 2H, J = 9.6 Hz), 4.57 (t, 2H, J =
8.8 N
d \
Hz), 3.70 (d, 2H, J = 7.2 Hz), 3.54 (s, 3H), 2.60 (s, 3H), 1.55-1.51 (m, 3H), 1.45-1.31 (m, 12H), 1.03-0.97 (m, 3H), 0.68-0.64 (m, 2H). MS: 469 (M+1).
(-))CN \ it, 0 1/25 N n.d.
d 4 1H-NMR (500 MHz, CDCI3) 5: 8.14 (d, J = 8.5 o o Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.36 (dd, J =
H0x,N 1 \ 41"o ----INJH 8.5, 2.0 Hz, 1H), 6.44 (s, 1H), 6.89 (s, 1H), 6.02 1/26 , , N
r3k,d 0 ic- (t, J = 6.0 Hz, 1H), 4.53 (s, 1H), 3.86 (d, J = 7.5 Hz, 2H), 3.34 (d, J = 6.0 Hz, 2H), 1.71 (m, 6H), 1.61 (s, 9H), 1.31 (s, 9H), 1.26 (m, 3H), 1.17 (s, 6H), 0.97 (m, 2H). MS: 614.2 (M+1).
1H-NMR (500 MHz, CDCI3) 5: 8.13 (d, J = 8.0 o Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.35 (dd, J =
OH 9 8.0, 2.0 Hz, 1H), 6.89 (s, 1H), 6.89 (s, 1H), 5.97 1/27 "
µi-1\____ (t, J = 6.0 Hz, 1H), 4.46 (s, 1H), 3.87 (d, J = 7.5 F3C j U Hz, 2H), 3.74 (dd, J = 7.5, 3.0 Hz, 4H), 3.38 (d, J = 6.0 Hz, 2H), 1.78 (m, 5H), 1 .6p (s, 9H), 1.57 (m, 4H), 1.47 (m, 2H), 1.33 (s, 9H), 1.29 (m, 4H), 1.00 (m, 2H). MS: 656.2 (M+1).
1H-NMR (500 MHz, CDCI3) 5: 8.21 (d, J = 8.0 o Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.29 (dd, J =
Ho.,...,,N \ . 's-NH 8.0, 2.0 Hz, 1H), 6.88 (s, 1H), 6.49 (s, 1H), 4.80 A H 1 6 i\-- (s, 2H), 4.63 (s, 1H), 3.92 (d, J = 6.0 Hz, 2H), ..õ0 d 3.46 (m, 5H), 1.62 (s, 9H), 1.56 (m, 3H), 1.29 (m, 21H), 0.98 (m, 3H), 0.65 (m, 2H). MS: 558.3 (M-OCH3)+.
1H-NMR (500 MHz, CDCI3) 5: 8.21 (d, J = 8.0 o'. o o Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.29 (d, 2.0 41" k-NH Hz, 1H), 6.53 (d, J = 8.0, 1H), 6.49 (s, 1H), 4.72 1/29 ,,C) N b iv d (s, 3H ), 4.19 (m, 1H), 4.00 (m, 2H), 3.90 (d, J =
6.0 Hz, 2H), 3.57 (t, J = 6.0 Hz, 2H), 2.03 (d, J =
12.5 Hz, 2H), 1.75 (s, 2H), 1.62 (s, 9H), 1.58 (m, 5H), 1.30 (m, 13H), 0.99 (m, 3H), 0.64 (m, 2H).
Structure= Analytical data MS: 570.3 (M¨OCH3)+.
1H-NMR (CDCI3, 300 MHz) 6: 7.40 (d, 1H, J =
1.5 Hz), 7.25 (d, 1H, J = 7.5 Hz ), 7.13 (dd, 1H, J = 7.5 Hz, 1.5 Hz), 6.19-6.16 (m, 2H), 5.57 (s, M \ 110 HN-(- 1H), 5.22-5.17 (m, 1H), 4.99 (t, 2H, J = 6.6 Hz), 4.58 (t, 2H, J = 6.6 Hz), 3.75 (d, 2H, J = 7.2 Hz), 2.59 (s, 3H), 1.55-1.51 (m, 3H), 1.50-1.47 (m, 18H), 1.43-1.33 (m, 3H), 1.02-0.93 (m, 12H), 0.68-0.64 (m, 2H). MS: 508 (M+1) 1H-NMR (CDCI3, 400 MHz) 6: 7.40 (d, 1H, J =
2.4 Hz), 7.14 (dd, 1H, J = 10.0 Hz, 2.0 Hz), 7.04 NI* (1H, d, J = 10.0 Hz), 6.22 (s, 1H), 6.20-6.18 (m, 11 0 1H), 5.23-5.19 (m, 1H), 4.99 (t, 2H, J = 6.8 Hz), 4.57 (t, 2H, J = 6.4 Hz), 3.75 (d, 2H, J = 6.0 Hz), 2.76 (s, 3H), 2.59 (s, 3H), 1.57-1.52 (m, 12 H), 1.41 (s, 9H), 1.36-1.25 (m, 3H), 1.03-0.97 (m, 3H), 0.68-0.64 (m, 2H). MS: 522 (M+1).
1H-NMR (CDCI3, 400 MHz) 6: 7.43 (d, 1H, J =
1.2 Hz), 7.29 (d, 1H, J = 8.0 Hz), 7.16 (dd, 1H, J
= 7.6 Hz, 1.6 Hz), 6.21-6.19 (m, 2H), 5.82-5.79 \(m, 1H), 5.20-5.19 (m, 1H), 4.99 (t, 2H, J = 6.8 HN--)\-- Hz), 4.58 (t, 2H, J = 6.4 Hz), 3.76 (d, 2H, J = 7.2 Hz), 3.28 (d, 2H, J = 6.4 Hz), 2.60 (s, 3H), 1.59-1.56 (m, 3H), 1.44 (s, 9H), 1.42-1.33 (m, 3H), 1.02-0.93 (m, 12H), 0.68-0.64 (m, 2H). MS: 522 (M+1) 1H-NMR (CDCI3, 400 MHz) 6: 7.43 (d, 1H, J =
1.6 Hz), 7.17-7.10 (m, 2H), 6.24-6.17 (m, 2H), N0 5.24-5.19 (m, 1H), 4.99 (t, 2H, J = 6.8 Hz), 4.57 H N (t, 2H, J = 6.4 Hz), 4.20 (d, 1H, J = 14.0 Hz), 1/33 3.75 (d, 2H, J = 6.0 Hz), 3.14 (s, 3H), 2.63 (d, 1H, J = 14.4 Hz), 2.60 (s, 3H), 1.57-1.52 (m, 3H), 1.43-1.31 (m, 12H), 1.08 (s, 9H), 1.03-0.97 (m, 3H), 0.68-0.64 (m, 2H). MS: 536 (M+1).
1H-NMR (CDCI3, 400 MHz) 6: 7.43 (s, 1H), 7.16 /Th (d, 1H, J = 8.0 Hz), 7.09 (1H, d, J = 7.6 Hz), \N--/ 6.24(s, 1H), 6.19 (d, 1H, J = 7.6 Hz), 5.23-5.19 (m, 1H), 4.99 (t, 2H, J = 6.8 Hz), 4.57 (t, 2H, J =
\
1/34 M 0 6.4 Hz), 4.12 (m, 1H), 3.75 (d, 2H, J = 6.0 Hz), 3.38-3.35 (m, 1H), 3.27-3.23 (m, 1H), 3.07-3.05 (m, 1H), 2.60 (s, 3H), 1.76-1.67 (m, 4H), 1.63-1.45 (m, 5H), 1.41 (s, 9H), 1.36-1.25 (m, 3H), 1.03-0.97 (m, 3H), 0.68-0.64 (m, 2H). MS: 520 # Structure Analytical data (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.35 (s, 1H), O 7.32-7.28 (t, J = 6.2 Hz, 1H), 7.16-7.15 (d, J=
,c5cm \ \ ik, 1.6 Hz, 2H), 6.53 (s, 1H), 3.77-3.74 (d, J =
7.2 Hz, 2H), 3.25-3.23 (d, J = 6.0 Hz, 2H), 3.13 (s, d 3H), 2.52 (s, 3H), 1.46-1.43 (d, J = 10.4 Hz, 3H), 1.31-1.22 (m, 21H), 1.08 (s, 6H), 0.99-0.86 (m, 3H), 0.68-0.60 (m, 2H). MS: 495.2 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 7.36-7.34 (t, J =
1.6 Hz, 1H), 7.15-7.14 (d, J = 2.0 Hz, 2H), 7.01-o 6.98 (d, J = 8.8 Hz, 1H), 6.50 (s, 1H), 4.37 (s, HON \ 1 N \ = 1H), 3.93-3.89 (m, 1H), 3.76-3.73 (d, J =
7.2 Hz, 1/36 N 2H), 2.51 (s, 3H), 1.46-1.44 (t, J = 4.6 Hz, 3H), d 1.31-1.23 (m, 21H), 1.09-1.07 (t, J = 3.8 Hz, 3H), 0.95-0.89 (m, 3H), 0.66-0.60 (m, 2H). MS:
495.2 (M+1).
11-I-NMR (400 MHz, DMSO-d6) 6: 7.34-7.33 (d, J
o = 1.6 Hz, 1H), 7.16-7.15 (d, J = 2.0 Hz, 2H), _Ciji 1 \ fa 6.04 (s, 1H), 3.77-3.29 (m, 7H), 2.26 (d, 3H), 1/37 N 1.46-1.40 (m, 7H), 1.30-1.22(m, 18H), 1.14(s, HO d3H), 0.94-0.88 (m, 3H), 0.66-0.63 (m, 2H). MS:
507.2 (M+1).
11-I-NMR (CDCI3, 400 MHz) 6: 0.70 (2H, m), 0.86 oiq o (2H, m), 1.02 (5H, m), 1.39 (12H, s), 1.57 (3H, HN
=m), 1.91 (2H, t, J = 4.8 Hz), 2.57 (3H, s), 3.64 (2H, d, J = 7.2 Hz), 4.34 (2H, t, J = 4.8 Hz), 4.57 /
0 (2H, t, J = 6.4 Hz), 4.98 (2H, t, J = 7.2 Hz), 5.21-5.24 (1H, m), 6.11 (1H, s), 6.15 (1H, d, J = 7.2 1/38 N" *
0) Hz), 6.43 (1H, d, J = 2.0 Hz), 6.97 (1H, d, J =
1.6 Hz). MS: 491 (M+1).
\i_OH 1H-NMR (CDCI3, 400 MHz) 6: 0.70 (2H, m), 0.85 O (2H, m), 1.01 (5H, m), 1.23 (7H, s), 1.38 (12H, = s), 1.56 (3H, m), 1.90 (2H, t, J = 5.2 Hz), 2.59 / \ (3H, s), 3.28 (1H, s), 3.38 (2H, d, J = 6.0 Hz), 1/39 N lip 6.11-6.13 (2H, m), 6.43 (1H, d, J = 1.6 Hz), 6.97 0 3.64 (2H, d, J = 7.2 Hz), 4.33 (2H, t, J =
5.2 Hz), 0) (1H, d, J = 1.6 Hz). MS: 507 (M+1).
o 4 1H-NMR (CDCI3, 400 MHz) 6: 0.64-0.72 (2H, m), HO--N.---"Nõ--NN 0.83-0.88 (2H, m), 0.98-1.03 (5H, m), 1.35-1.49 H I \ . 0 (12H, s), 1.57-1.65 (12H, m), 1.90 (2H, t, J
= 5.2 d Hz), 2.59 (3H, s), 3.39 (2H, d, J = 6.8 Hz), 3.63 (4H, d, J = 7.2 Hz), 4.33 (2H, t, J = 4.8 Hz), 5.75 (1H, t, J = 6.0 Hz), 6.06 (1H, s), 6.43 (1H, d, J =
# Structure Analytical data 2.0 Hz), 6.97 (1H, d, J = 2.0 Hz). MS: 521 (M+1).
1H-NMR (CDCI3, 400 MHz) 6: 0.68-0.70 (2H, m), o' o 4 0.84-0.87 (2H, m), 1.00-1.03 (5H, m), 1.39 (12H, s), 1.59 (9H, s), 1.90 (2H, t, J = 5.6 Hz), 2.48 N"---NN (2H, d, J = 4.0 Hz), 2.55 (2H, t, J = 6.0 Hz), 2.60 H I \ * o (3H, s), 3.48 (2H, d, J = 5.6 Hz), 3.63 (2H, d, J =
d 7.6 Hz), 3.70 (4H, t, J = 4.4 Hz), 4.34 (2H, t, J =
5.2 Hz), 6.11 (1H, s), 6.30 (1H, d, J = 3.6 Hz), 6.45 (1H, d, J = 2.0 Hz), 6.99 (1H, d, J = 2.0 Hz). MS: 548 (M+1).
11-I-NMR (CDCI3, 400 MHz) 6: 0.64-0.74 (6H, m), cLq o 0.85-0.88 (2H, m), 1.00-1.03 (5H, m), 1.33-1.42 HN
lif (6H, m), 1.56 (3H, m), 1.90-1.92 (2H, t, J =
10.0 Hz), 2.57 (3H, s), 3.64-3.66 (2H, d, J = 7.2 Hz), 1/42 / \
N *
0 4.38-4.40 (2H, t, J = 10.4 Hz), 4.55-4.58 (2H, t, J
0) 4 = 13.2 Hz), 4.96-5.00 (2H, t, J = 14.4 Hz), 5.20-5.22 (1H, m), 6.10 (1H, s), 6.13-6.15 (1H, m), 6.43 (1H, s), 6.97 (1H, s). MS: 489 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 0.63-0.66 (m, 2H), 0.76-0.77 (m, 2H), 0.86-0.89 (m, 2H), 0.98-0.99 00, 0 1 (m, 3H), 1.33-1.43 (m, 3H), 1.47 (s, 3H), 1.52-N 1.56 (m, 5H), 1.58 (s, 6H), 1.75 (s, 2H), 2.61 (s, H
1/43 N I \ .=
OH 3H), 3.49-3.55 (t, 2H, J = 12.0 Hz), 3.72-3.74 (d, d 2H, J = 8.0 Hz), 3.96-3.99 (m, 2H), 4.15-4.17 (m, 1H), 5.60-5.62 (d, 1H, J = 8.0 Hz), 6.17 (s, 1H), 7.07 (s, 1H), 7.20 (s, 1H), 7.39 (s, 1H). MS:
493 (M+1).
1H-NMR (CDCI3, 400 MHz) 6: 0.61-0.64 (m, 2H), a 0 4 0.75-0.77 (m, 2H), 0.86-0.89 (m, 2H), 0.98-0.99 (m, 3H), 1.32-1.37 (m, 3H), 1.43 (s, 3H), 1.47-N 1.53 (m, 11H), 1.96-2.00 (m, 2H), 2.61 (s, 3H), H I \ ilk 1/44 N OMe 3.08 (s, 1H), 3.49-3.55 (t, 2H, J = 12.0 Hz), d 3.73-3.75 (d, 2H, J = 8.0 Hz), 3.96-3.99 (m, 2H), 4.15-4.17 (m, 1H), 5.60-5.62 (d, 1H, J = 8.0 Hz), 6.17 (s, 1H), 7.07 (s, 1H), 7.15 (s, 1H), 7.26 (s, 1H). MS: 507 (M+1).
O
1H-NMR (DMSO-d6, 400 MHz) 6: 8.74 (s, 1H), 2 I \ * OH 7.72 (d, 2H), 7.52 (d, 2H), 7.17 (m, 1H), 6.66 (m, 1/45 N CF3 1H), 6.60 (s, 1H), 3.85 (m, 2H), 2.53 (s, 3H), d 1.55-1.40 (m, 3H), 1.35-1.20 (m, 3H), 1.00-0.80 (m, 3H), 0.70-0.55 (m, 2H). MS: 463 (M+1).
# Structure Analytical data o 1H-NMR (CDCI3, 400 MHz) 6: 7.09 (s, 2H), 6.16 ONNN (s, 1H), 6.12 (m, 1H), 5.26 (s, 1H), 3.68-3.62 (m, H I \ 4. OH 2H), 3.61-3.56 (m, 2H), 3.54-3.51 (m, 2H), 3.36 1/46 N (s, 3H), 2.61 (s, 3H), 1.65-1.50 (m, 3H), 1.45 (s, d 18H), 1.40-1.30 (m, 3H), 1.05-0.95 (m, 3H), 0.75-0.60 (m, 2H). MS: 483 (M+1).
F3c OH
CF3 1H-NMR (CDCI3, 400 MHz) 6: 7.75-7.70 (m, 2H), 1 \ lik 7.51 (m, 1H), 7.44-7.42 (m, 1H), 6.25 (s, 1H), 1/47 N 5.40 (br s, 2H), 3.74 (d, 2H), 2.60 (s, 3H), 1.60-C) 1.45 (m, 3H), 1.35-1.20 (m, 3H), 1.00-0.90 (m, 3H), 0.65-0.50 (m, 2H). MS: 463 (M+1).
F 0 1H-NMR (400 MHz, CDCI3) 6: 7.08 (s, 2H), 6.15 F,I, T -N (s, 1H), 5.88-5.92 (t, 1H), 5.28 (s, 1H), 4.01-4.08 F H I \ = OH (m, 2H), 3.65-3.67 (d, 2H, J = 8.0 Hz), 2.60 (s, d 3H), 1.52-1.56 (m, 4H), 1.45(s, 18H), 1.34-1.37 (m, 2H), 0.96-1.03 (m, 3H), 0.67-0.73 (m, 2H).
MS: 507 (M+1).
O 1H-NMR (400 MHz, CDCI3) 6: 7.57-7.59 (d, 2H, ---N J = 8.0 Hz), 7.48-7.50 (d, 1H, J = 8.0 Hz), 6.24 H2N \ * 6 1 (s, 1H), 5.39-5.43 (m, 2H), 3.74-3.76 (d, 2H, J =
d8.0 Hz), 2.56-2.63 (m, 6H), 1.54-1.57 (m, 4H), 1.25-1.39 (m, 2H), 1.28 (t, 3H), 0.83-1.05 (m, 3H), 0.58-0.64 (m, 2H). MS: 352 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 6.91-6.93 (d, 1H, O J = 8.0 Hz), 6.87-6.89 (d, 1H, J = 8.0 Hz), 6.15 H2N \ *
I 0 (s, 1H), 5.36-5.39 (m, 2H), 4.28 (s, 2H), 3.68-1/50 N 3.70 (d, 2H, J = 8.0 Hz), 2.61-2.65 (q, 2H), 2.60 d (s, 3H), 1.50-1.59 (m, 4H),1.40-1.45 (m, 2H), 1.38 (s, 6H), 1.28 (m, 3H), 0.98-1.18 (m, 3H), 0.60-0.69 (m, 2H). MS: 395 (M+1).
0õ0 0 ;SN 1H-NMR (400 MHz, CDCI3) 6: 7.90 (s, 1H), 7.40 (m, 1H), 7.10 (m, 1H), 6.18 (s, 1H), 3.70 (d, 1H), N 3.38 (s, 3H), 2.60 (s, 3H), 1.57-1.50 (m, 3H), C) 1.38-1.25 (m, 21H), 1.00-0.90 (m, 3H), 0.70-0.60 (m, 2H). MS (m/z): 487 (M+1).
o 1H-NMR (400 MHz, CDCI3) 6: 7.30 (s, 1H), 7.08 1/52 (1\1 I \ 4.
C:IN
N (n, 2H), 6.04 (s, 1H), 3.63 (m, 10H), 2.32 (s, 3H), 1.75 (m, 1H), 1.45 (m, 3H), 1.26 (s, 21H), d 0.93 (m, 3H), 0.57 (m, 2H). MS (m/z): 479.2 (M+1).
# Structure Analytical data N
1H-NMR (500 MHz, CDCI3) 6: 7.33 (s, 1H), 7.07 o3, (m, 2H), 6.16 (s, 1H), 6.13 (m, 1H), 5.15 (al, 1/53 H µ I N41 1H), 4.91 (t, J = 7.0 Hz, 2H), 4.51 (t, J =
6.5 Hz, N 2H), 3.64 (d, J = 7.0 Hz, 2H), 2.53 (s, 3H), 1.45 d (m, 3H), 1.28 (s, 21H), 0.92 (m, 3H), 0.57 (m, 2H). MS (m/z): 465.2 (M+1).
HO 1H-NMR (500 MHz, CDCI3) 6: 7.31 (s, 1H), 7.07 ..-----1µ1 1/54 H \ (m, 2H), 6.18 (m, 1H), 6.15 (s, 1H), 3.71 (m, I ilk N 2H), 3.64 (d, J = 7.0 Hz, 2H), 3.48 (m, 2H), 2.54 d (s, 3H), 1.45 (m, 3H), 1.27 (s, 21H), 0.92 (m, 3H), 0.57 (m, 2H). MS (m/z): 453.2 (M+1).
OH 0 1H-NMR (400 MHz, CDCI3) 6: 7.31 (s, 1H), 7.07 1/55 ri 1 \ 4. (m, 2H), 6.16 (m, 2H), 3.64 (d, J = 7.2 Hz, 2H), N 3.32 (d, J = 6.0 Hz, 2H), 2.54 (s, 3H), 1.45 (m, d 3H), 1.27 (s, 21H), 1.18 (s, 6H), 0.92 (m, 3H), 0.57 (m, 2H). MS (m/z): 481.2 (M+1).
O 1H-NMR (500 MHz, CDCI3) 6: 7.38 (m, 1H), 7.14 (NN (m, 2H), 6.87 (br s, 1H), 6.35 (s, 1H), 3.70 (d, J
1/56 ,N H I \ 41 N = 7.5 Hz, 2H), 3.60 (m, 2H), 3.01 (m, 2H), 2.67 d (s, 6H), 2.57 (s, 3H), 1.52 (m, 3H), 1.33 (s, 21H), 0.98 (m, 3H), 0.64 (m, 2H). MS (m/z):
480.2 (M+1).
O
1H-NMR (500 MHz, CDCI3) 6: 7.26 (s, 1H), 7.01 oN
1/57 HO H \ (m, 2H), 6.26 (br s, 1H), 6.14 (s, 1H), 4.05 (m, I ilik N 2H), 3.58 (d, J = 7.5 Hz, 2H), 2.47 (s, 3H), 1.40 d (m, 3H), 1.20 (s, 21H), 0.87 (m, 3H), 0.52 (m, 2H). MS (m/z): 467.2 (M+1).
HO
6, 0 11-1-NMR (400 MHz, CDCI3) 6: 7.32 (s, 1H), 7.05 N (m, 2H), 6.25 (br s, 1H), 6.05 (s, 1H), 5.18 (br s, 1/58 H I \ .
N 1H), 3.64 (d, J = 6.8 Hz, 4H), 2.54 (s, 3H), 1.45 d (m, 3H), 1.24 (s, 21H), 0.92 (m, 7H), 0.57 (m, 2H). MS (m/z): 479.2 (M+1).
HO 1H-NMR (400 MHz, CDCI3) 6: 7.32 (s, 1H), 7.07 1/59 I il I \ * (m, 2H), 6.15 (m, 2H), 3.64 (d, J = 6.8 Hz, 2H), N 3.28-3.48 (m, 4H), 2.54 (s, 3H), 1.45 (m, 3H), d 1.24 (m, 24H), 0.92 (m, 3H), 0.57 (m, 2H). MS
(m/z): 467.2 (M+1).
o 1H-NMR (400 MHz, CDCI3) 6: 7.31 (s, 1H), 7.07 HO,, (m, 2H), 6.20 (br s, 1H), 6.15 (s, 1H), 3.93 (m, N
1/60 H I \ . 1H), 3.64 (d, J = 7.2 Hz, 2H), 3.45 (m, 2H), 3.22 N OM 1H), 2.53 (s, 3H), 1.45 (m, 3H), 1.27 (s, d 21H), 1.14 (m, 3H), 0.91 (m, 3H), 0.55 (m, 2H).
MS (m/z): 467.2 (M+1).
Structure Analytical data 4F 1H-NMR (400 MHz, CDCI3) 6: 7.40 (m, 1H), 7.12 (m, 2H), 6.18 (s, 1H), 6.10 (br s, 1H), 3.71 (d, J
1/61 H I \ = 7.2 Hz, 2H), 3.47 (m, 1H), 2.59 (s, 3H), 1.86 (rrl, 1H), 1.52 (m, 3H), 1.30 (s, 22H), 0.98 (m, 3H), 0.64 (m, 2H). MS (m/z): 585.2 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.72-7.69 (t, J
= 5.4 Hz, 1H), 7.47 (s, 1H), 7.23 (s, 2H), 6.57 (s, o 1H), 3.85-3.83 (d, J = 6.8 Hz, 2H), 3.65-3.62 (t, J = 6.0 Hz, 1H), 3.51-3.48 (t, J = 6.0 Hz, 2H), 1/62 H I \
3.39-3.36 (t, J = 6.0 Hz, 2H), 2.60 (s, 3H), 1.54-d 1.51 (d, J = 8.8 Hz, 3H), 1.39-1.29 (m, 21H), 1.17-1,16 (d, J = 6.0 Hz, 6H), 0.99-0.96 (d, J =
12.4 Hz, 3H), 0.76-0.70 (t, J = 10.6 Hz, 2H). MS
(m/z): 495 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.65-7.62 (t, J
= 4.8 Hz, 1H), 7.34 (s, 1H), 7.15 (s, 2H), 6.49 (s, (-NN 1H), 4.61-4.59 (t, J = 5.0 Hz, 1H), 3.76-3.74 (d, 1/63 0 H I \ 411 J = 6.4 Hz, 2H), 3.51-3.43 (m, 6H), 3.34 (s, 2H), 2.52 (s, 3H), 1.44-1.42 (d, J = 4.4 Hz, 3H), 1.30 HO (s, 18H), 1.24-1.21 (d, J = 13.2 Hz, 3H), 0.93-0.87 (t, J = 10.4 Hz, 3H), 0.64-0.61 (d, J = 10.8 Hz, 2H). MS (m/z): 497 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.67-7.64 (t, J
O = 5.2 Hz, 1H), 7.35 (s, 1H), 7.16 (s, 2H), 6.51 (s, 1H), 3.77-3.76 (d, J = 6.8 Hz, 2H), 3.42-3.39 (t, 1/64 H I \ .11 J = 5.6 Hz, 2H), 3.35 (s, 2H), 3.26 (s, 3H), 2.53 (s, 3H), 1.45-1.43 (d, J = 8.8 Hz, 3H), 1.31 (s, 18H), 1.25-1.22 (d, J = 13.2 Hz, 3H), 0.94-0.89 (t, J = 10.6 Hz, 3H), 0.68-0.60 (m, 2H). MS
(m/z): 467 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.70-7.68 (d, J
O = 4.8 Hz, 1H), 7.42 (s, 1H), 7.23 (s, 2H), 6.60 (s, 1H), 4.57-4.54 (t, J = 5.0 Hz, 1H), 3.84-3.82 (d, 1/65 H I \ J = 7.2 Hz, 2H), 3.54-3.49 (m, 2H), 3.32-3.28 (m, 2H), 2.58 (s, 3H), 1.71-1.68 (t, J = 6.4 Hz, 2H), 1.53-1.51 (d, J = 9.6 Hz, 3H), 1.38-1.29 (m, 21H), 1.01-0.96 (t, J = 10.0 Hz, 3H), 0.75-0.70 (t, J = 10.4 Hz, 2H). MS (m/z): 467 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.60-7.58 (d, J
HO 0 = 5.2 Hz, 1H), 7.35 (s, 1H), 7.15 (s, 2H), 6.48 (s, 1H), 4.39-4.37 (t, J = 5.2 Hz, 1H), 3.77-3.75 (d, N
1/66 H I \ J = 7.2 Hz, 2H), 3.43-3.38 (m, 2H), 3.18-3.14 (m, 2H), 2.52 (s, 3H), 1.48-1.43 (t, J = 10.0 Hz, 7H), 1.31-1.21 (m, 21H), 0.94-0.89 (t, J = 10.4 Hz, 3H), 0.65-0.62 (d, J = 11.2 Hz, 2H). MS
(m/z): 481 (M+1).
# Structure Analytical data 11-1-NMR (400 MHz, DMSO-d6) 6: 7.58 (s, 1H), o 7.33 (s, 1H), 7.14 (s, 2H), 6.48 (s, 1H), 4.34 (s, 1H), 3.75-3.74 (d, J = 6.0 Hz, 2H), 3.39-3.38 (d, CNN \ .
OH J = 5.2 Hz, 2H), 3.12-3.14 (d, J = 6.0 Hz, 2H), N
d2.51 (s, 3H), 1.45-1.43 (d, J = 5.6 Hz, 7H), 1.30 (s, 20H), 1.24-1.21 (d, J = 12.4 Hz, 3H), 0.91-0.88 (d, J = 11.2 Hz, 3H), 0.64-0.61 (d, J = 10.4 Hz, 2H). MS (m/z): 495 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6:12.13 (s, 1H), o 7.70-7.67 (t, J = 5.2 Hz, 1H), 7.35 (s, 1H), 7.15 HO-jc---N (s, 2H), 6.47 (s, 1H), 3.77-3.75 (d, J = 6.8 Hz, 1/68 H I \ . 2H), 3.38-3.35 (t, J = 6.0 Hz, 2H), 2.52-2.45 (m, N 5H), 1.46-1.43 (d, J = 4.6 Hz, 3H), 1.31-1.21 (t, d J = 9.8 Hz, 21H), 0.94-0.89 (t, J = 5.0 Hz, 3H), 0.65-0.62 (d, J = 10.8 Hz, 2H). MS (m/z): 481 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6:12.03 (s, 1H), HO 0 7.66-7.63 (t, J = 5.2 Hz, 1H), 7.35 (s, 1H), 7.15 (s, 2H), 6.49 (s, 1H), 3.77-3.75 (d, J = 6.8 Hz, 1/69 0 H I \ . 2H), 3.20-3.15 (m, 2H), 2.52-2.50 (d, J =
6.8 Hz, N 3H), 2.26-2.23 (t, J = 7.2 Hz, 2H), 1.73-1.66 (m, d 2H), 1.46-1.44 (d, J = 4.4 Hz, 3H), 1.31-1.15 (m, 21H), 0.98-0.89 (m, 3H), 0.65-0.62 (m, 2H). MS
(m/z): 495 (M+1).
OTh c....N 0 1H-NMR (400 MHz, DMSO-d6) 6:7.60 (s, 1H), 7.35 (s, 1H), 7.15 (s, 2H), 6.46 (s, 1H), 3.77-3 .75 (d, J = 7.2 Hz, 2H), 3.60 (s, 4H), 3.32 (s, 1/70 H I \ *
N 4H), 2.52-2.40 (t, 7H), 1.46-1.44 (d, J =
9.2 Hz, d 3H), 1.31 (s, 18H), 1.24-1.21 (d, J = 13.6 Hz, 3H), 0.91-0.88 (m, 3H), 0.68-0.60 (m,2H). MS
(m/z): 522 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.68-7.66 (t, J
= 5.4 Hz, 1H), 7.35 (s, 1H), 7.15 (s, 2H), 6.46 (s, o 1H), 3.77-3.75 (d, J = 6.8 Hz, 2H), 3.58-3.57 (d, NH 1 \ = J = 4.0 Hz, 4H), 3.22-3.18 (m, 2H), 2.52-2.50 (d, N J = 6.0 Hz, 3H), 2.39-2.34 (t, J = 10.6 Hz, 6H), d 1.66-1.62 (t, J = 6.6 Hz, 2H), 1.46-1.43 (d, J =
9.2 Hz, 3H), 1.31-1.21 (m, 21H), 0.91-0.88 (d, J
= 12.0 Hz, 3H), 0.67-0.62 (t, J = 10.8 Hz, 2H).
MS (m/z): 536 (M+1).
Ori 1H-NMR (400 MHz, DMSO-d6) 6:11.97 (s, 1H), O 7.63-7.60 (t, J = 5.6 Hz, 1H), 7.37 (s,1H), 7.18-7.17 (d, J = 1.2 Hz, 2H), 6.50 (s, 1H), 3.79-3.77 1/72 N , H 1 \ * (d, J = 7.2 Hz, 2H), 3.19-3.15 (m, 2H), 2.54-2.52 N (m, 3H), 2.25-2.21 (t, J = 7.4 Hz, 2H), 1.56-1.46 d (m, 7H), 1.33-1.24 (m, 23H), 0.96-0.88 (m, 3H), 0.69-0.67 (m, 2H). MS (m/z): 523 (M+1).
# Structure Analytical data 1H-NMR (400 MHz, DMSO-d6) 6:12.01 (s, 1H), o 7.63-7.60 (t, J = 5.6 Hz, 1H), 7.35 (s, 1H), 7.16-7.15 (d, J = 1.2 Hz, 2H), 6.48 (s, 1H), 3.77-3.75 N \
1/73 0 oiXi " I N. 11 (d, J = 6.8 Hz, 2H), 3.18-3.15 (t, J = 6.2 Hz, 2H), d 2.52-2.51 (d, J = 4.8 Hz, 3H), 2.25-2.21 (t, J =
6.8 Hz, 2H), 1.50-1.43 (m, 7H), 1.31-1.25 (m, 21H), 0.94-0.85 (m, 3H), 0.63-0.60 (m, 2H). MS
(m/z): 509 (M+1).
Ncl 1H-NMR (400 MHz, DMSO-d6) 6: 7.67 (s, 1H), c Nx./ 0 7.39 (s, 1H), 7.20 (s, 2H), 6.54 (s, 1H), 3.81-1/74 N , H I = . 3.80 (d, J = 6.0 Hz, 2H), 3.62 (s, 4H), 3.23 (s, 2H), 2.57 (s, 3H), 2.45 (s, 4H), 2.39 (s, 2H), 1.52 N
d (s, 7H), 1.35-1.26 (m, 21H), 0.96 (s, 3H), 0.69-0.67 (d, J = 10.4 Hz, 2H). MS (m/z): 550 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.61-7.58 (t, J
= 5.8 Hz, 1H), 7.35 (s, 1H), 7.15-7.15 (d, J = 1.6 o Hz, 2H), 6.48 (s, 1H), 3.77-3.75 (d, J = 6.8 Hz, 1/75 Ci--11 I \ .
NTh N
c,0 d 2H), 3.55-3.54 (d, J = 4.4 Hz, 4H), 3.18-3.13 (m, 2H), 2.51-2.51 (d, J = 3.2 Hz, 3H), 2.33 (s, 4H), 2.28-2.24 (t, J = 7.2 Hz, 2H), 1.49-1.40 (m, 7H), 1.31-1.21 (m, 23H), 0.92-0.88 (d, J = 12.8 Hz, 3H), 0.67-0.62 (t, J = 10.4 Hz, 2H). MS (m/z):
564 (M+1).
o ' = 1H-NMR (500 MHz, CDCI3) 6: 0.59 (m, 2H), 0.80 H2N \ . (m, 3H), 1.11 (m, 14H), 1.47 (m, 3H), 1.80-2.54 N
1/76 I (m, 8H), 3.67 (d, 2H), 5.40 (br s, 2H), 6.14 (s, d 1H), 6.94 (s, 1H), 7.08 (m, 2H). MS (m/z):
(M+1).
o\.3, 0 1H-NMR (300 MHz, DMSO-d6) 6: 8.22 (d, J =
N 6.6 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H), 6.59 (s, 1/77 H I \ Mk F 1H), 4.96 (m, 1H), 4.74 (m, 2H), 4.56 (m, 2H), N 3.74 (d, J = 6.6 Hz, 2H), 2.50 (s, 3H), 1.49 (m, d 24H), 0.98 (m, 3H), 0.71 (m, 2H). MS (m/z): 483 (M+1).
0 1H-NMR (400 MHz, CDCI3) 6: 7.60 (s, 1H), 7.53 N (s, 1H), 7.41 (s, 1H), 6.28 (s, 1H), 6.17 (d, 1H), 1/78 H I \ . 5.23 (m, 1H), 4.99 (m, 2H), 4.58 (t, 2H), 3.73 (d, dN CF 3 2H), 2.61 (s, 3H), 1.56 (s, 6H), 1.32 (m, 9H), 1.00 (m, 3H), 0.63 (m, 2H). MS (m/z): 477 (M+1).
op, 0 V 1H-NMR (400 MHz, CDCI3) 6: 7.47 (s, 1H), 7.37 N (s, 2H), 6.27 (s, 1H), 6.16 (d, 1H), 5.21 (m, 1H), 1/79 H I \ . 4.99 (m, 2H), 4.58 (m, 2H), 3.73 (d, 2H), 2.60 (s, N 3H), 1.54 (m, 4H), 1.46 (s, 3H), 1.33 (m, 3H), d u3 1.01 (m, 2H), 1.00 (m, 2H), 0.84 (m, 2H), 0.66 (m, 2H). MS (m/z): 475 (M+1).
# Structure Analytical data oa o V 1H-NMR (CDCI3, 300 MHz) 5:7.07 (s, 1H), 6.92 (d, J = 1.5 Hz, 2H), 6.10 (m, 2H), 5.15 (m, 1H), N
1/80 H I \ 411 4.91 (t, 2H), 4.50 (t, 2H), 3.64 (d, J = 6.9 Hz, N
d A 2H), 2.52 (s, 3H), 1.47 (m, 3H), 1.18-1.46(m, 9H), 0.94 (m, 3H), 0.76-0.81 (m, 10H). MS
(m/z): 461 (M+1).
1H-NMR (DMSO-d6, 400 MHz) 6:8.22 (d, 1H), 7.20 (s, 1H), 7.16 (s, 1H), 6.99 (s, 1H), 6.59 (s, N \ 1H), 4.93 (m, 1H), 4.72 (t, 2H), 4.55 (t, 2H), 3.76 N (t, 2H), 2.50 (s, 3H), 1.45 (m, 3H), 1.40 (s, 3H), d 1.31 (s, 9H), 1.23 (m, 3H), 0.95 (m, 3H), 0.84 (m, 2H), 0.76 (m, 2H), 0.65 (m, 2H). MS (m/z):
463 (M+1).
o V 1H-NMR (400 MHz, DMSO-d6) 6: 7.58 (t, 1H), HO----\,..--NN 7.19 (s, 1H), 7.14 (s, 1H), 6.97 (s, 1H), 6.48 (s, 1/82 H I \ * 1H), 4.34 (t, 1H), 3.75 (d, 2H), 3.69 (m, 2H), N 3.15 (m, 2H), 2.50 (m, 3H), 1.40-1.48 (m, 10H), d 1.27 (m, 14H), 0.77-0.96 (m, 9H). MS (m/z):
(M+1).
LN o V 1H-NMR (400 MHz, DMSO-d6) 6: 7.57 (t, 1H), 1/83 H I \ Mk 7.19 (s, 1H), 7.13 (s, 1H), 6.96 (s, 1H), 6.46 (s, N 1H), 3.75 (d, 2H), 2.73 (m, 1H), 2.50 (m, 3H), d 1.21-1.47 (m, 18H), 0.74-0.95 (m, 13H). MS
(m/z): 447 (M+1).
oaN o V 1H-NMR (400 MHz, DMSO-d6) 6:7.41 (d, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 6.97 (s, 1H), 6.53 (s, N
1/84 H I \ * 1H), 3.95 (m, 1H), 3.87 (d, 2H), 3.85 (d, 2H), N 3.35 (d, 2H), 2.56 (m, 3H), 1.71 (d, 2H), 1.45-d 1.68 (m, 8H), 1.22-1.30 (m, 12H), 0.59-0.96 (m, 9H). MS (m/z): 491 (M+1).
o . -1C1.----N 0 V 1H-NMR (400 MHz, DMSO-d6) 6: 7.33 (t, 1H), 1/85 H \
7.19 (d, 2H), 7.13 (s, 1H), 6.96 (s, 1H), 6.85 (s, I .
N 1H), 6.41 (s, 1H), 3.74 (d, 2H), 3.28 (d, 2H), d 2.50 (m, 3H), 1.22-1.46 (m, 18H), 0.75-0.95 (m, 15H). MS (m/z): 506 (M+1).
o V 1H-NMR (400 MHz, DMSO-d6) 6: 7.80 (t, 1H), 1/86 oi--- hi I \ = 7.20 (d, 2H), 6.98 (s, 1H), 6.53 (s, 1H), 4.47 (d, N 2H), 4.15 (d, 2H), 3.75 (d, 2H), 3.33 (s, 2H), d 2.50 (m, 3H), 1.23-1.47 (m, 21H), 0.63-0.96 (m, 9H). MS (m/z): 491 (M+1).
OH 0 V 1H-NMR (400 MHz, DMSO-d6) 6: 7.46 (t, 1H), 1/87 NhN 1 \ * 7.19 (d, 2H), 6.98 (s, 1H), 6.53 (s, 1H), 4.66 (s, N 1H), 3.76 (d, 2H), 3.16 (d, 2H), 2.51 (m, 3H), d 1.24-1.47 (m, 18H), 0.63-1.08 (m, 15H). MS
(m/z): 479 (M+1).
# Structure Analytical data OTh 0 V 1H-NMR (400 MHz, DMSO-d6) 6: 7.56 (t, 1H), N---NN \ 7.19 (d, 2H), 6.97 (s, 1H), 6.45 (s, 1H), 3.75 (d, 1/88 H I \ * 2H), 3.57 (m, 4H), 3.28 (m, 2H), 2.50 (m, 3H), N
d 2.40 (m, 6H), 1.22-1.47 (m, 18H), 0.75-0.96 (m, 9H). MS (m/z): 520 (M+1).
o V
1H-NMR (400 MHz, DMSO-d6) 6: 7.14 (m, 3H), Fi2N , .
1/89 I \ 6.97 (s, 1H), 6.49 (d, 2H), 3.77 (d, 2H), 2.50 (m, N 3H), 1.23-1.48 (m, 18H), 0.66-0.96 (m, 9H). MS
d(m/z): 407 (M+1).
o 1 11-I-NMR (400 MHz, CDCI3) 6: 6.96 (s, 1H), 6.42 o (s, 1H), 6.32 (m, 1H), 6.07 (s, 1H), 4.34 (t, 2H), 1/90 H 1= \ 4. 0 3.67 (m, 4H), 2.72 (t, 2H), 2.58 (s, 3H), 1.91 (t, N 2H), 1.53 (m, 3H), 1.44 (m, 12H), 1.02 (m, 5H), d 0.84 (m, 2H), 0.67 (m, 2H). MS (m/z): 507 (M+1).
oo 4 11-1-NMR (400 MHz, CDCI3) 6: 6.97 (s, 1H), 6.43 1/91 HO)N (s, 1H), 6.29 (m, 1H), 6.09 (s, 1H), 4.34 (t, 2H), H I \ * 0 3.63 (d, 2H), 3.52 (d, 2H), 2.59 (s, 3H), 1.90 (t, N 2H), 1.57 (m, 3H), 1.38 (m, 12H), 1.25 (m, 6H), d 1.01 (m, 5H), 0.83 (m, 2H), 0.67 (m, 2H). MS
(m/z): 534 (M+1).
4 1H-NMR (400 MHz, CDCI3) 6: 6.96 (s, 1H), 6.42 (s, 1H), 6.00 (s, 1H), 5.83 (br s, 1H), 4.33 (t, 1/92 H I - . 0 2H), 3.64 (d, 2H), 2.81 (s, 1H), 2.60 (s, 3H), N 1.91 (t, 2H), 1.57 (m, 3H), 1.39 (m, 12H), 1.02 d (m, 5H), 0.85 (m, 4H), 0.77 (m, 2H), 0.57 (m, 2H). MS (m/z): 475 (M+1).
a 0 4 1H-NMR (400 MHz, CDCI3) 6: 6.97 (s, 1H), 6.43 (s, 1H), 6.06 (s, 1H), 5.57 (d, 1H), 4.34 (t, 2H), N
1/93 H I \ . 0 4.17 (s, 1H), 3.96 (m, 2H), 3.63 (d, 2H), 3.49 (t, N 2H), 2.59 (s, 3H), 1.99 (d, 2H), 1.95 (t, 2H), 1.52 d (m, 5H), 1.38 (m, 12H), 1.02 (m, 5H), 0.86 (m, 2H), 0.64 (m, 2H). MS (m/z): 519 (M+1).
o 4 1H-NMR (400 MHz, CDCI3) 6: 6.97 (s, 1H), 6.43 (s, 1H), 6.05 (s, 1H), 5.83 (s, 1H), 4.34 (t, 2H), N
1/94 COF1 \ I \ II 0 3.99 (d, 2H), 3.64 (d, 2H), 3.37 (t, 2H), 3.26 (t, N 2H), 2.59 (s, 3H), 1.91 (t, 3H), 1.84 (m, 2H), d 1.57 (m, 3H), 1.34 (m, 12H), 1.02 (m, 5H), 0.86 (m, 2H), 0.69 (m, 2H). MS (m/z): 533 (M+1).
# Structure Analytical data so, 4 1H-NMR (400 MHz, CDCI3) 6: 6.96 (s, 1H), 6.42 < o (s, 1H), 6.06 (s, 1H), 5.85 (d, 1H), 4.69 (s, 1H), µ
1/95 H I \ . 0 4.34 (t, 2H), 3.94 (m, 2H), 3.84 (m, 2H), 3.71 (d, N 2H), 2.58 (s, 3H), 2.31 (m, 1H), 1.90 (m, 3H), d 1.56 (m, 3H), 1.38 (m, 12H), 1.02 (m, 5H), 0.84 (m, 2H), 0.65 (m, 2H). MS (m/z): 505 (M+1).
/o¨ o 4 1H-NMR (400 MHz, CDCI3) 6: 6.96 (s, 1H), 6.43 N (s, 1H), 6.06 (s, 1H), 5.85 (d, 1H), 4.69 (s, 1H), 1/96 H I \ = 0 4.34 (t, 2H), 3.94 (m, 2H), 3.84 (m, 2H), 3.71 (d, N 2H), 2.58 (s, 3H), 2.31 (m, 1H), 1.90 (m, 3H), d 1.56 (m, 3H), 1.38 (m, 12H), 1.02 (m, 5H), 0.84 (m, 2H), 0.64 (m, 2H). MS (m/z): 505 (M+1).
OMe ID 4 1H-NMR (400 MHz, CDCI3) 6: 6.91 (s, 1H), 6.38 (s, 1H), 6.06 (s, 1H), 5.97 (d, 1H), 4.27 (t, 2H), NIH I \ . 0 3.57 (d, 2H), 3.35 (d, 2H), 3.71 (d, 2H), 3.13 (s, N 3H), 2.52 (s, 3H), 1.84 (m, 2H), 1.50 (m, 3H), d 1.36 (m, 12H), 1.19 (s, 6H), 0.95 (m, 5H), 0.78 (m, 2H), 0.63 (m, 2H). MS (m/z): 521 (M+1).
o o 4 1H-NMR (400 MHz, CDCI3) 6: 6.89 (s, 1H), 6.31 1-12NN (m, 3H), 6.03 (s, 1H), 5.19 (s, 1H), 4.26 (t, 2H), 1/98 H I \ . 0 3.55 (d, 2H), 3.45 (d, 2H), 2.51 (s, 3H), 1.84 (t, N 2H), 1.50 (m, 3H), 1.37 (m, 12H), 1.25 (s, 6H), d 0.96 (m, 5H), 0.79 (m, 2H), 0.60 (m, 2H). MS
(m/z): 534 (M+1).
OH 0 4 ' H-N MR (400 MHz, CDCI3) 6: 6.97 (s, 1H), 6.43 (s, 1H), 6.08 (d, 2H), 4.35 (t, 2H), 3.85 (m, 4H), N
v99 aNH i \ ili 0 3.77 (d, 211), 3.44 (s, 2H), 2.59 (s, 3H), 1.90 (t, N 2H), 1.63 (m, 7H), 1.44 (m, 12H), 1.02 (m, 5H), d 1.00 (m, 2H), 0.72 (m, 2H). MS (m/z): 549 (M+1).
O 4 1H-NMR (400 MHz, CDCI3) 6: 6.89 (s, 1H), 6.36 (s, 1H), 5.99 (s, 1H), 5.84 (t, 1H), 4.73 (t, 2H), 1/100 11 I \ . o 4.40 (t, 2H), 4.25 (t, 2H), 3.58 (m, 4H), 3.20 (m, N 1H), 2.51 (s, 3H), 1.83 (m, 2H), 1.51 (m, 3H), d 1.33 (m, 12H), 0.95 (m, 5H), 0.79 (m, 2H), 0.60 (m, 2H). MS (m/z): (M+1).
O 4 1H-NMR (400 MHz, CDCI3) 6: 6.97 (s, 1H), 6.43 r------NN (s, 1H), 6.10 (s, 1H), 6.00 (t, 1H), 4.54 (d, 2H), 1/101 0,/ H 1 \ 0111 0 4.38 (d, 2H), 4.32 (t, 2H), 3.63 (d, 2H), 3.55 (d, N 2H), 2.59 (s, 3H), 1.90 (m, 2H), 1.56 (m, 3H), d 1.26 (m, 15H), 1.01 (m, 5H), 0.85 (m, 2H), 0.68 (m, 2H). MS (m/z): 519 (M+1).
o 4 1H-NMR (400 MHz, CDCI3) 6: 6.98 (s, 1H), 6.44 1/102 .7Nri 1 \ ip 0 (s, 1H), 6.10 (s, 1H), 5.81 (s, 1H), 4.33 (t, 2H), N 3.63 (d, 2H), 3.24 (d, 2H), 2.59 (s, 3H), 1.91 (m, d 2H), 1.58 (m, 3H), 1.37 (m, 12H), 1.01 (m, 6H), 0.85 (m, 2H), 0.67 (m, 2H), 0.25 (m, 2H), 0.21 # Structure Analytical data (m, 2H). MS (m/z): 489 (M+1).
H 0 4 1H-NMR (400 MHz, CDCI3) 6: 6.90 (s, 1H), 6.37 sl\INNN (s, 1H), 6.21 (t, 1H), 6.06 (s, 1H), 5.56 (s, 1H), 1/103 o"o I H I \ . 0 4.25 (t, 2H), 3.56 (d, 2H), 3.38 (d, 2H), 2.94 (s, N 3H), 2.51 (s, 3H), 1.83 (m, 2H), 1.50 (m, 3H), d 1.33 (m, 18H), 0.96 (m, 5H), 0.78 (m, 2H), 0.61 (m, 2H). MS (m/z): 584 (M+1).
0,õo o 1 1H-NMR (400 MHz, CDCI3) 6: 6.89 (s, 1H), 6.35 sN (m, 2H), 6.03 (s, 1H), 4.27 (t, 2H), 3.84 (m, 2H), 1/104 H I \ . 0 3.57 (d, 2H), 3.27 (t, 2H), 2.90 (s, 3H), 2.51 (s, N 3H), 1.84 (m, 2H), 1.58 (m, 3H), 1.30 (m, 12H), d 0.97 (m, 5H), 0.78 (m, 2H), 0.61 (m, 2H). MS
(m/z): 541 (M+1).
o 4 1H-NMR (400 MHz, CDCI3) 6: 6.91 (s, 1H), 6.37 H2N = .
1/105 I o (s, 1H), 6.04 (t, 1H), 5.45 (s, 2H), 4.27 (t, 2H), \
N 3.37 (d, 2H), 2.52 (s, 3H), 1.84 (m, 2H), 1.51 (m, d 3H), 1.29 (m, 12H), 0.94 (m, 5H), 0.79 (m, 2H), 0.61 (m, 2H). MS (m/z): 435 (M+1).
cz.o, o 1H-NMR (400 MHz, DMSO-d6) 6: 8.22 (d, 1H), N \ 7.49 (s, 1H), 7.18 (d, 2H), 6.59 (s, 1H), 5.05 (s, \
1/106 H I # 1H), 4.94 (m, 1H), 4.71 (t, 2H), 4.55 (t, 2H), 3.77 N OH (d, 2H), 2.50 (s, 3H), 1.44 (s, 9H), 1.31 (s, 9H), d 1.21 (m, 3H), 0.92 (m, 3H), 0.59 (m, 2H). MS
(m/z): 467 (M+1).
ca o 1H-NMR (400 MHz, CDCI3) 6: 7.42 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 6.25 (s, 1H), 6.18 (d, 1H), N \
1/107 H I \ * 5.24 (m, 1H), 4.97 (t, 2H), 4.56 (t, 2H), 3.73 (d, N OMe 2H), 3.09 (s, 3H), 2.60 (s, 3H), 1.53 (m, 9H), d 1.37 (m, 12H), 0.97 (m, 3H), 0.61 (m, 2H).
MS
(m/z): 481 (M+1).
o 1H-NMR (400 MHz, DMSO-d6) 6: 8.22 (d, 1H), 7.26 (s, 2H), 7.13 (s, 1H), 6.61 (s, 1H), 4.98 (m, N µ
1/108 H I \ * 1H), 4.73 (t, 2H), 4.53 (t, 2H), 3.78 (d, 2H), 3.57 N r--\ (t, 3H), 3.51 (s, 2H), 2.36 (s, 4H), 1.45 (d, 3H), d N0 1.24 (m, 12H), 0.86 (m, 3H), 0.56 (m, 2H). MS
(m/z): 508 1H-NMR (400 MHz, DMSO-d6) 6: 7.48 (t, 1H), OH 7.24 (s, 2H), 7.10 (s, 1H), 6.54 (s, 1H), 4.64 (m, 1/109 I \ . 1H), 3.78 (t, 2H), 3.55 (m, 4H), 3.40 (m, 1H), N 3.16 (d, 2H), 2.52 (s, 3H), 2.29 (m, 2H), 2.26 (m, ,_\
d N 0 2H), 1.45 (m, 3H), 1.31 (m, 12H), 1.23 (m, 3H), 1.08 (s, 6H), 0.92 (m, 3H), 0.59 (m, 2H). MS
(m/z): 538 (M+1).
# Structure Analytical data OH 0 A 1H-NMR (400 MHz, DMSO-d6) 6: 7.47 (t, 1H), 1/110 NN 1\ =11 v 7.23 (s, 1H), 7.16 (s, 1H), 7.11 (s, 1H), 6.61 (s, dN 7 1H), 3.81 (d, 2H), 3.17 (d, 2H), 2.81 (s, 3H), 2.50 (s, 3H), 1.41 (m, 15H), 1.24 (m, 3H), 1.07 0N\ (s, 6H), 0.63-0.89 (m, 8H). MS (m/z): 536 (M+1).
OH 0 A 1H-NMR (400 MHz, DMSO-d6) 6: 7.82 (s, 1H), Nt---NN 7.64 (s, 1H), 7.59 (s, 1H), 7.47 (m, 1H), 7.32 (s, 1/111 H I \ = 1H), 6.62 (s, 1H), 4.64 (s, 1H), 3.82 (d, 2H), N 3.16 (d, 2H), 2.54 (s, 3H), 1.46 (m, 15H), 1.30 d NH
0 (m, 3H), 1.11 (s, 6H), 0.63-0.97 (m, 8H). MS
(m/z): 522 (M +1).
OH 0 A 1H-NMR (400 MHz, DMSO-d6) 6: 8.28 (d, 1H), 1/112 NhN 7.68 (d, 2H), 7.48 (t, 1H), 7.34 (s, 2H), 6.63 (s, H I \ . \ 1H), 4.64 (s, 1H), 4.13 (m, 1H), 3.83 (d, 2H), N )---NH 3.16 (d, 2H), 2.49 (s, 3H), 1.17-1.48 (m, 15H), d o 1.08 (s, 6H), 0.63-0.90 (m, 9H). MS (m/z):
(M+1).
1H-NMR (400 MHz, CDCI3) 6: 8.05 (s, 1H), 7.43 N (s, 1H), 7.16 (s, 2H), 6.25 (t, J = 5.6 Hz, 1H), \
1/113 F3c H I ' ID' 6.23 (s, 1H), 3.93 (d, J = 6.0 Hz, 2H), 3.74 (d, J
N = 7.2 Hz, 2H), 2.61 (s, 3H), 1.56-1.51 (m, 4H), d 1.36 (s, 18H), 1.40-1.25 (m, 4H), 1.02-0.87 (m, 3H), 0.67-0.64 (m, 2H). MS: 589 (M+1).
oaN 0 1H-NMR (400 MHz, CD30D) 6: 7.34 (s, 1H), H I \ = 7.10 (m, 2H), 6.41 (s, 1H), 4.96 (m, 1H), 4.62 1/114 N (m, 2H), 4.58 (t, J = 6.8 Hz, 2H), 3.93-3.70 (m, 2H), 2.44 (m, 3H), 1.47-1.26 (m, 1H), 1.26-1.02 (m, 24H), 0.70-0.42 (m, 6H). MS: 479.4 (M+1)+.
0 1H-NMR (400 MHz, CDCI3) 6: 7.42 (s, 1H), 7.18 oaN
(s, 2H), 6.29-6.26 (m, 2H), 5.26 (m, 1H), 5.01 (t, H 1 \ =
1/115 N J = 6.8 Hz, 2H), 4.61 (t, J = 6.4 Hz, 2H), 3.73 (d, d J = 7.6 Hz, 2H), 2.62 (s, 3H), 1.27-1.55 (m, 27H), 0.89-1.21 (m, 4H). MS: 479.4 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.23 (d, J =
5.2 Hz, 1H), 7.40 (s, 1H), 7.17 (s, 2H), 6.58 (s, 11 1\ = 1H), 4.97 (m, 1H), 4.72 (t, J = 6.8 Hz, 2H), 4.55 N
alp (t, J = 6.4 Hz, 2H), 3.84 (m, 2H), 2.53 (m, 3H), 1.35-1.56 (m, 27H), 0.84 (m, 2H). MS: 465.4 (M+1)+.
# Structure Analytical data a 1H-NMR (400 MHz, CDCI3) 6: 7.29 (s, 1H), 7.05 oaN
(s, 2H), 6.26 (m, 1H), 6.16 (m, 1H), 5.10 (m, H \ .
1/117 N 1H), 4.85 (t, J = 6.8 Hz, 2H), 4.47 (m, 2H), 3.53-0-1 3.84 (m, 2H), 2.50 (m, 3H), 1.12-1.89 (m, 23H), 0.27-0.85 (m, 6H). MS: 477.1 (M+1)+.
o 1H-NMR (400 MHz, CDCI3) 6: 7.28 (m, 1H), 7.09 oaN
(m, 2H), 6.95 (m, 4H), 6.22-6.18 (m, 2H), 5.18 H I \ .
N (m, 1H), 4.93 (t, J = 6.8 Hz, 2H), 4.51 (t, J = 6.8 1/118 Hz, 2H), 3.94 (d, J = 7.6 Hz, 2H), 2.65 (m, 2H), ijk 2.56-2.48 (m, 4H), 2.29 (m, 2H), 1.24 (s, 18H).
IW MS: 499.4 (M+1)+.
oa a 1H-NMR (400 MHz, CDCI3) 5:7.40 (m, 1H), 7.17 H1 \ it (m, 2H), 6.20 (m, 2H), 5.24 (m, 1H), 4.99 (t, J =
6.8 Hz, 2H), 4.58 (m, 2H), 3.70-3.91 (m, 2H), 2.60 (s, 3H), 1.31-1.62 (m, 22H), 0.23-0.98 (m, 9H). MS: 479.6 (M+1)t o\.... o 1H-NMR (CDCI3, 300 MHz) 6: 0.67-0.68 (2H, m), 0.87-1.03 (12H, m), 1.33-1.36 (12H, m), 1.56-N
1.57 (2H, m), 2.59 (3H, s), 3.82-3.84 (2H, d, J =
1/120 N --( 7.2 Hz), 4.06 (2H, s), 4.57 (2H, t, J = 6.6 Hz), d 0 5/ 5.20 (2H, t, J = 6.6Hz), 5.18-5.23 (1H, m), 6.17-6.19 (1H, m), 6.32 (1H, s), 6.50 (1H, s), 6.80 (1H, s). MS: 496.5 (M+1).
v3.
1H-NMR (CDCI3, 300 MHz) 6: 0.65-0.74 (2H, m), 0.97-1.06 (6H, m), 1.29-1.34 (9H, m), 1.53-1.58 N
H (4H, m), 1.96-2.00 (2H, m), 2.06-2.13 (1H, m), 1/121 N --( 2.61 (3H, s), 3.48-3.56 (2H, m), 3.82 (2H, d, J =
d 0 9.9 Hz), 3.99-4.01 (2H, m), 4.11-4.17 (3H, m), 5.58-5.61 (1H, m), 6.26 (1H, s), 6.48 (1H, s), 6.80 (1H, s). MS: 482.5 (M+1).
ov.3N o 1H-NMR (CDCI3, 400 MHz) 6: 0.67-0.69 (2H, m), N 0.98-1.02 (3H, m), 1.36 (18H, m), 1.57 (6H, m), H-11--) ______________ / \ N 2.60 (3H, s), 3.78-3.80 (2H, d, J = 7.2 Hz), 4.58 0õ __.? (2H, t, J = 6.8 Hz), 4.99 (2H, t, J = 6.8 Hz), 5.21-5.23 (1H, m), 6.19-6.21 (1H, m), 6.32 (1H, s), 7.05 (2H, s). MS: 466.2 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 8.18 (d, J = 8.4 H o Hz, 1H), 7.59 (s, 1H), 7.27 (m, 1H), 6.43 (m, S'N1H) 6.35 (s 1H) 4.52 (s 1H) 3.79 (d J = 7.2 o2 /\ N \ = s92* , , , , , , 1/123 N N Hz, 2H), 3.49 (d, J = 6.4 Hz, 2H), 3.04 (s, 3H), H
d 2.62 (s, 3H), 1.62 (m, 9H), 1.54 (m, 3H), 1.46 (m, 6H), 1.26 (m, 12H), 0.97 (m, 3H), 0.60 (m, 2H). MS: 637.3 (M+1).
# Structure Analytical data 1H-NMR (400 MHz, CDCI3) 6: 8.18 (d, J = 8.0 o HoxNN Hz, 1H), 7.58 (s, 1H), 7.24 (m, 1H), 6.30 (s, 1H), H 1 \ ii sp2*
H 6.17 (m, 1H), 4.49 (s, 1H), 3.86-3.72 (m, 6H), 1/124 o 1 N
3.45 (m, 2H), 2.62 (s, 3H), 1.53-1.70 (m, 16H), 1.34-1.31 (m, 12H), 0.98 (m, 3H), 0.60 (m, 2H).
MS: 602.3 (M+1).
o 1H-NMR (400 MHz, CDCI3) 6: 8.17 (d, J = 8.4 Fi2N-15N Hz, 1H), 7.58 (s, 1H), 7.24 (m, 1H), 6.52 (m, s924_ 1H), 6.30 (s, 1H), 6.17 (br s,1H), 5.28 (br s, 1H), 1/125 N H 4.54 (m, 1H), 3.76 (m, 2H), 3.54 (m, 2H), 2.61 d (s, 3H), 1.45-1.62 (m, 12H), 1.35-1.31 (m, 18H), 0.98 (m, 3H), 0.60 (m, 2H). MS: 587.4 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.14 (d, J =
O 8.0 Hz, 1H), 7.85 (m, 1H), 7.82 (s, 1H), 7.52 (s, ol-DNIF1 1 \. s 24_ 1H), 7.42 (m, 1H), 6.64 (s, 1H), 4.60 (m, 2H), 1/126 N N 4.32 (t, J = 6.0 Hz, 2H), 3.82 (m, 2H), 3.42 (m, H
d 2H), 3.10 (m, 1H), 2.52 (s, 3H), 1.54 (s, 9H), 1.43 (m, 3H), 1.18 (m, 12H), 0.88 (m, 3H), 0.59 (m, 2H). MS: 558.7 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.17 (d, J =
O 8.4 Hz, 1H), 7.89 (m, 1H), 7.86 (s, 1H), 7.56 (s, of-JNIE'ilsp24_ 1H), 7.46 (m, 1H), 6.73 (s, 1H), 4.50 (d, J = 5.6 1/127 N N Hz, 2H), 4.18 (d, J = 5.6 Hz, 2H), 3.87 (m, 2H), H
d 3.39 (m, 2H), 2.58-2.54 (m, 3H), 1.58 (s, 9H), 1.46 (m, 3H), 1.26-1.22 (m, 6H), 1.23 (s, 9H), 0.89 (m, 3H), 0.66 (m, 2H). MS: 572.2 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.13 (d, J =
/OH 0 8.4 Hz, 1H), 7.73 (s, 1H), 7.65 (m, 1H), 7.52 (s, \ ii, so24_ 1H), 7.40 (m, 1H), 6.65 (s, 1H), 4.34 (m, 1H), H i N 3.82 (m, 2H), 3.37 (m, 2H), 3.12 (m, 2H), 2.52 d (s, 3H), 1.54 (s, 9H), 1.51-1.38 (m, 7H), 1.31 (m, 2H), 1.22-1.06 (m, 12H), 0.89 (m, 3H), 0.65 (m, 2H). MS: 574.1 (M+1)+.
1H-NMR (400 MHz, CDCI3) 6: 8.16 (d, J = 8.4 o Hz, 1H), 7.57 (s, 1H), 7.25 (m, 1H), 6.39 (11, NN' \ 4, SP24_ 1H), 6.27 (s, 1H), 4.83 (s, 1H), 3.77 (m, 2H), 1/129 N H 3.53 (m, 2H), 2.60 (s, 3H), 1.61 (s, 9H), 1.58 (m, d 3H), 1.29 (m, 18H), 0.98 (m, 3H), 0.59 (m, 2H).
MS: 588.3 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.12 (d, J =
02 8.4 Hz, 1H), 7.95 (m, 1H), 7.74 (s, 1H), 7.52 (s, -sNs924_ 1H), 7.40 (m, 1H), 6.62 (s, 1H), 3.85 (m, 2H), N N
H 3.59 (m, 2H), 3.29 (m, 2H), 3.01 (s, 3H), 2.53 (s, d 3H), 1.54 (s, 9H), 1.45 (m, 3H), 1.16 (m, 12H), 0.87 (m, 3H), 0.56 (m, 2H). MS: 594.0 (M+1)+.
Structure Analytical data 11-1-NMR (400 MHz, DMSO-d6) 6: 8.14 (d, JLJ =
o 8.4 Hz, 1H), 7.74 (s, 1H), 7.52 (s, 1H), 7.46 (m, N \ =s924_ 1H), 7.40 (m, 1H), 6.69 (s, 1H), 4.01-3.81 (m, 5H), 3.35 (m, 2H), 2.52 (s, 3H), 1.71 (m, 2H), 1.60-1.40 (m, 14H), 1.25-1.05 (m, 12H), 0.92-0.81 (m, 3H), 0.59 (m, 2H). MS: 572.1 (M+1)+.
1H-NMR (CDCI3, 300 MHz) 6: 0.68-0.69 (2H, m), oa 0 cF3 0.85-0.96 (2H, m), 0.99-1.08 (3H, m), 1.20-1.42 N , 411, 1 (5H, m), 1.59-1.62 (3H, m), 1.94 (2H, t, J = 5.1 \
H
Hz), 2.57 (3H, s), 3.65 (2H, d, J = 7.2 Hz), 4.44 1/132 (2H, t, J = 5.1 Hz), 4.56 (2H, t, J =
6.9 Hz), 4.98 4 (2H, t, J = 6.9 Hz), 5.20 (1H, m), 6.14-6.15 (2H, m), 6.73 (1H, d, J = 1.8 Hz), 7.28 (1H, d, J = 1.8 Hz). MS: 503 (M+1)+.
Example 2 o, sa 0 H 1 \
d2 Step 1: 1-(CvclohexvImethyl)-5-(3,5-di-tert-butvlphenv1)-2-methvl-N-(1-oxidothietan-3-v1)-1 H-pvrrole-3-carboxamide (2) A solution of compound of Example 1/14 (96 mg, 0.2 mmol) in DCM (6 mL) was treated with m-chloroperoxybenzoic acid (99 mg, 0.4 mmol) in an ice-bath for 1 h and then allowed to warm to rt and stirred for 3 h. The mixture was quenched with aq. Na2S03and extracted with EA (3x 30 mL). The organic layer was separated and washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep.
HPLC to give the target compound 2 (38 mg, 40%). 11-1-NMR (400 MHz, DMSO-d6) 6: 8.15 (d, J =
8.0 Hz, 1H), 7.36 (s, 1H), 7.16 (d, J = 1.6 Hz, 2H), 6.53 (s, 1H), 4.40-4.33 (m, 1H), 4.04-3.99 (m, 2H), 3.77 (d, J = 6.8 Hz, 2H), 3.30-3.27 (m, 2H), 2.50 (s, 3H), 1.45-1.38 (m, 3H), 1.31-1.16 (m, 21H), 0.97-0.85 (m, 3H), 0.67-0.57 (m, 2H). MS: 497.1 (M+1).
Examples 2/1 to 2/3 The following Examples were prepared from the corresponding thioether similar as described in Example 2:
# Structure Analytical data oõsa N 0 1H-NMR (400 MHz, CDCI3) 6: 8.19 (d, J =
8.4 Hz, 1H), nn õ, 7.58 (d, 1H), 7.24 (d, 1H), 6.37-6.34 (m, 2H), 4.74-4.67 1 \ . 'S(1\i 0 )\---- (m, 2H), 4.21-4.16 (m, 2H), 3.78 (d, J - 6.8 Hz, 2H), 3.35-2/1 N " 3.30 (m, 2H), 2.60 (s, 3H), 1.61 (s, 9H), 1.58-1.53 (m, d 3H), 1.34-1.25 (m, 12H), 0.99-0.96 (d, 3H), 0.68-0.60 (m, 2H). MS: 576.0 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 7.28-7.27 (m, 1H), 7.13 (t, o,,sa o 4 1H), 7.00 (t, 1H), 6.18 (s, 1H), 6.02 (d, J = 7.2 Hz, 1H), 11 1 \ = 4.66-4.59 (m, 1H), 4.19-4.13 (m, 2H), 3.72 (d, J = 7.2 Hz, 2H), 3.22-3.16 (m, 2H), 2.59 (s, 3H), 1.53 (m, 3H), 1.42 d (m, 3H), 1.41-1.31 (m, 12H), 1.00-0.98 (m, 3H), 0.89-0.86 (m, 2H), 0.77-0.74 (m, 2H), 0.66-0.63 (m, 2H). MS: 595.0 (M+1).
o o 1H-NMR (400 MHz, CDCI3) 6: 7.31(s, 1H), 7.10 (s, 1H), 1------,,,, 1g,-..o 6.31 (s, 1H), 6.26 (d, J = 8.0 Hz, 1H), 4.69-4.63 (m, 1H), , d2/3 NN,r 4.19-4.14 (m, 2H), 3.80-3.73 (m, 4H), 3.28-3.22 (m, 2H), 2.60 (s, 3H), 1.66-1.55 (m, 15H), 1.38-1.30 (m, 9H), 1.02-0.98 (m, 3H), 0.65-0.61 (m, 2H). MS: 588.3 (M+1).
Example 3 9, o.-13, o N
H I \ .=
N
d 3 Step 1: 1-(CyclohexvImethvI)-5-(3,5-di-tert-butvlphenv1)-N-(1,1-dioxidothietan-3-v1)-2-methvI-1H-ovrrole-3-carboxamide (3) To a solution of compound 2 (67 mg, 0.14 mmol) in DCM (2 mL), cooled to 0 C, was added titanium isopropoxide (42 pL, 0.14 mmol) followed by hydrogen peroxide (58 pL, 0.56 mmol) and the solution was stirred at 0 C for 15 min. The ice-bath was removed and stirring was continued at rt for 1 h. The mixture was diluted with DCM (10 mL) and quenched by addition of H20 (10 mL). The organic layers was separated and washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep.
HPLC to give the target compound 3 (40 mg, 56%). 1H-NMR (400 MHz, DMSO-d6) 6: 8.20 (d, J = 3.6 Hz, 1H), 7.37 (s, 1H), 7.16 (d, J = 1.6 Hz, 2H), 6.55 (s, 1H), 4.53-4.47 (m, 3H), 4.28-4.23 (m, 2H), 3.77 (d, J = 7.2 Hz, 2H), 2.52 (s, 3H), 1.45-1.43 (m, 3H), 1.31-1.20 (m, 21H), 0.94-0.86 (m, 3H), 0.66-0.61 (m, 2H). MS: 513.3 (M+1).
Example 4 InN 0 H I= \ *
d 4 Step 1: N-(Azetidin-3-v1)-1-(cyclohexvImethvI)-5-(3,5-di-tert-butvlphenv1)-2-methvI-1H-pvrrole-3-carboxamide hydrochloride (4a) Compound of Example 1/15 (400 mg, 0.71 mmol) was treated with HCl/CH3OH (20 mL) at rt for 18 h. The solvent was evaporated to give intermediate 4a (355 mg, 100%) as a colorless solid, which was used without further purification.
Step 2: 1-(CyclohexvImethvI)-5-(3,5-di-tert-butvlphenv1)-N-(1-(2-methoxvacetvl)azetidin-3-v1)-2-methyl-1H-pyrrole-3-carboxamide (4) To a mixture of compound 4a (100 mg, 0.2 mmol) and DIPEA (78 mg, 0.6 mmol) in DCM (15 mL) was added 2-methoxyacetyl chloride (26 mg, 0.24 mmol) at 0 C and the mixture was stirred for 2 h. Then it was quenched with H20 (20 mL) and extracted with DCM
(3x 20 mL).
The organic layer was separated and washed with brine and dried over Na2SO4.
After filtration, the filtrate was evaporated and purified by prep. HPLC to give the target compound 4 (56 mg, 52%). 1H-NMR (400 MHz, CDCI3) 6: 7.38 (t, J = 1.8 Hz, 1H), 7.17 (d, J = 1.6 Hz, 2H), 6.96 (br s, 1H), 6.50 (s, 1H), 4.39 (br s, 2H), 4.04 (s, 1H), 3.96-3.87 (m, 2H), 3.73 (d, J =
7.2 Hz, 2H), 3.66-3.63 (m, 1H), 3.48-3.43 (m, 1H), 3.38 (s, 3H), 2.58 (s, 3H), 1.53-1.49 (m, 3H), 1.37-1.28 (m, 21H), 0.99-0.95 (m, 3H), 0.68-0.61 (m, 2H). MS: 536.2 (M+1).
Example 5 ---1NoN 0 H I= \ 411 d ste,D1: N-(1-Acetvlazetidin-3-v1)-1-(cyclohexvImethvI)-5-(3,5-di-tert-butvlphenyl)-2-methyl-1H-pvrrole-3-carboxamide (5) To a mixture of compound 4a (100 mg, 0.2 mmol) and DIPEA (78 mg, 0.6 mmol) in DCM (15 mL) was added acetyl chloride (19 mg, 0.24 mmol) at 0 C and the mixtures was stirred for 2 h. Then it was quenched with H20 (20 mL) and extracted with DCM (3x 20 mL).
The organic layer was separated and washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep. HPLC to give the target compound 5 (59 mg, 54%).
1H-NMR (400 MHz, DMSO-d6) 6: 7.98 (t, J = 5.6 Hz, 1H), 7.36 (t, J = 1.6 Hz, 1H), 7.15 (d, J
= 1.6 Hz, 2H), 6.29 (s, 1H), 4.27-4.18 (m, 2H), 3.99-3.96 (m, 1H), 3.79 (d, J
= 7.2 Hz, 2H), 3.31-3.27 (m, 1H), 3.10-3.03 (m, 1H), 2.53 (s, 3H), 1.83 (s, 3H), 1.46-1.43 (m, 3H), 1.30 (s, 18H), 1.24-1.15 (m, 3H), 0.97-0.85 (m, 3H), 0.68-0.60 (m, 2H). MS: 506.1 (M+1).
Example 6 oaN jo__, y NH
d os-Step 1: Methyl 6-(tert-butyl)-4-(1-(cyclohexylmethyl)-5-methyl-4-(oxetan-3-ylcarbamoy1)-1 H-pyr r ol-2-v1) picolinate (6a) To a mixture of compound P1(3.0 g, 9.4 mmol), 5-bromo-1-(cyclohexylmethyl)-2-methyl-N-(oxetan-3-y1)-1H-pyrrole-3-carboxamide (similar prepared as in Example 1) (4.3 g, 10.6 mmol), K2CO3 (3.12 g, 22.6 mmol) and TBAB (180 mg, 0.54 mmol) in 1,4-dioxane (10 mL) and H20 (4 mL) was added Ph(PPh3)2Cl2 (180 mg, 0.24 mmol) under N2. Under microwave conditions, the solution was heated at 100 C for 1.5 h. Water was added and the solution was extracted with EA. The organic layer was washed with brine, dried over NaSO4, filtered, concentrated and purified by CC (PE/EA = 3/1) to give compound 6a (1.8 g, 41%) as a colorless solid.
Step 2: 6-(tert-Buty1)-4-(1-(cyclohexylmethyl)-5-methyl-4-(oxetan-3-ylcarbamoy1)-1H-pyrrol-2-vl)picolinic acid (6b) To a stirred solution of compound 6a (1.65 g, 3.54 mmol) in a mixture of THF
(15 mL) and H20 (5 mL) was added LiOH=H20 (300 mg, 5.64 mmol) and this mixture was stirred at 60 C
for 3 h. The solution was adjusted to pH = 2-3 with 1M HCI. Then the mixture was extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (PE/EA = 2/1) to give compound 6b (1.3 g, 81%) as a colorless powder.
Step 3: N,6-Di-tert-butyl-4-(1-(cyclohexylmethyl)-5-methyl-4-(oxetan-3-ylcarbamoy1)-1 H-p g r ol-2-v1)picolinamide (6) A mixture of compound 6b (150 mg, 0.33 mmol), tert-butylamine (36 mg, 0.48 mmol), HATU
(207 mg, 0.54 mmol) and DIPEA (146 mg, 1.14 mmol) in DMF (5 mL) was stirred at rt for 20 min. The mixture was washed with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (PE/EA =
2/1) to give compound 6 (42 mg, 30%) as a colorless powder. 1H-NMR (CDCI3, 300 MHz) 6:
8.19 (s, 1H), 7.94 (s, 1H), 7.39 (s, 1H), 6.45 (s, 1H), 6.38 (d, J = 6.9 Hz, 1H), 5.20 (q, J = 6.9 Hz, 1H), 4.97 (t, J = 6.9 Hz, 2H), 4.60 (t, J = 6.9 Hz, 2H), 3.84 (d, J = 6.9 Hz, 2H), 2.60 (s, 3H), 1.66 (m, 2H), 1.51 (s, 9H), 1.40 (s, 9H), 1.38-1.29 (m, 3H), 1.03-0.97 (m, 3H), 0.68-0.61 (m, 2H).
MS: 509 (M+1).
Examples 6/1 to 6/9 The following Examples were prepared similar as in Example 6:
# Structure Analytical data ojN o 1H-NMR (CDCI3, 300 MHz) 6: 7.33 (s, 1H), 7.26 (s, 1H), 6.42 N (s, 1H), 6.33 (d, J = 6.9 Hz, 1H), 5.20 (q, J
= 6.9 Hz, 1H), H I \ \ /N \ / 4.96 (t J = 6.9 Hz, 2H), 4.58 (t, J = 6.9 Hz, 2H), 3.84 (d, J =
,'N6/1 -s-N ' Y 6.9 Hz', 2H), 2.92 (s, 3H), 2.59 (s, 3H), 1.73-1.62 (m, 2H), c:,r-N\ 1.53 (s, 9H), 1.43 (s, 9H), 1.38-1.30 (m, 4H), 1.03-0.97 (m, 0) 3H), 0.72-0.63 (m, 2H).MS: 523 (M+1).
n1H-NMR (CDCI3, 400 MHz) 6: 7.44 (d, 1H, J = 1.6 Hz), 7.25 o (d, 1H, J = 8.0 Hz), 7.16 (dd, 1H, J = 8.0 Hz, 1.6 Hz), 6.17 (S, N
= \ mt 1H), 6.09-6.07 (m, 1H), 5.60 (d, 1H, J = 8.0 Hz), 4.18-4.09 H I
6/2N NH (m, 3H), ' .(m' ' 3.75 " - 3 3 99-3 96 2H) (d 2H J 7.2 Hz)' ' 3 55-W-d ( 3.49 (m, 2H), 3.29 (t, 2H, J = 6.4 Hz), 2.62 (s, 3H), 2.00-1.96 cF3 (m, 2H), 1.58-1.47 (m, 5H), 1.44 (s, 9H), 1.41-1.33 (m, 3H), 1.06-1.00 (m, 3H), 0.67-0.62 (m, 2H). MS: 562 (M+1).
n1H-NMR (CDCI3, 400 MHz) 6: 7.43 (d, 1H, J = 1.6 Hz), 7.33 O (d, 1H, J = 7.6 Hz), 7.16 (dd, 1H, J = 7.6 Hz, 1.6 Hz), 6.17 (s, NN \ * 0 1H), 5.75 (m, 2H), 5.60 (t, 2H, J = 7.2 Hz), 4.19-4.14 (m, 1H), H I =
N NH 3.99-3.96 (m, 2H), 3.75 (d, 2H, J = 7.6 Hz), 3.55-3.48 (m, d 22H), 2.61 (s, 3H), 2.04-1.96 (m, 5H), 1.54-1.46 (m, 5H), 1.44 (s, 9H), 1.41-1.36 (m, 3H), 1.03-1.05 (m, 3H), 0.67-0.62 (m, 2H). MS: 480 (M+1).
n1H-NMR (CDCI3, 400 MHz) 6: 7.40 (d, 1H, J = 1.2 Hz), 7.24 o (d, 1H, J = 7.6 Hz), 7.13 (dd, 1H, J = 8.0 Hz, 1.2 Hz), 6.15 (s, NN \ M 1H), 5.74 (d, 1H, J = 4.8 Hz), 5.60 (d, 1H, J = 7.2 Hz), 4.18-H
6/4 I =
4.15 (m, 1H), 3.99-3.96 (m, 2H), 3.75 (d, 2H, J = 7.2 Hz), dN W /NH 3.55-3.49 (m, 2H), 3.01-3.00 (d, 3H, J = 4.8 Hz), 2.61 (s, 3H), 1.56-1.53 (m, 5H), 1.47 (s, 9H), 1.41-1.36 (m, 3H), 1.01-0.99 (m, 3H), 0.62-0.87 (m, 2H). MS: 494 (M+1).
n1H-NMR (CDCI3, 400 MHz) 6: 7.43 (d, 1H, J = 1.6 Hz), 7.24 o (dd, 1H, J = 8.0 Hz, 1.6 Hz), 7.08 (d, 1H, J = 8.0 Hz), 6.18 (s, N
= \ * 1H),5.61 (t, 2H, J = 7.2 Hz), 4.18-4.14 (m, 1H), 3.99-3.96 (m, H I
6/5 2H), 3.75 75 (d 2H J - 8.0 Hz) 3 55-3 49 (m 2H) 3.12 (s 3H) d , 2.82 (s, 3H), 2.61 (s, 3H), 1.99-1.96 (m, 2H), 1.53-1.48 (m, 5H), 1.42-1.23 (m, 12H), 1.01-1.00 (m, 3H), 0.64-0.61 (m, 2H). MS: 508 (M+1).
# Structure Analytical data 1H-NMR (CDCI3, 400 MHz) 6:7.40 (d, 1H, J = 1.2 Hz), 7.22 a 0 (d, 1H, J = 8.0 Hz), 7.13 (dd, 1H, J = 8.0 Hz, 1.2 Hz), 6.14(s, 0 1H), 5.60 (t, 2H, J = 7.2 Hz), 4.18-4.14 (m, 1H), 4.00-3.96 (m, N
H I \ 41 3H), 3.73 (d, 2H, J = 7.2 Hz), 3.55-3.48 (m, 2H), 2.61 (s, 3H), 6/6 N NH 2.09-1.96 (m, 5H), 1.78-1.74 (m, 2H), 1.68-1.65 (m, 1H), d a 11..2569-.11..5139 rim; 44HH)): 11..5031-.11..4035 ((mm:
312HH)),016.46.10-16.396(m 2H). MS:
562 (M+1).
1H-NMR (CDCI3, 400 MHz) 6:7.41 (d, 1H, J = 1.6 Hz), 7.25 a0 (d, 1H, J = 8.0 Hz), 7.14 (dd, 1H, J = 8.0 Hz, 1.6 Hz), 6.15 (s, N 0 1H), 5.79 (t, 2H, J = 6.0 Hz), 5.60 (d, 1H, J = 8.0 Hz), 4.18-H I \ . 4.15 (m, 1H), 4.00-3.95 (m, 2H), 3.75 (d, 2H, J = 7.6 Hz), 6/7 N NH 3.55-3.49 (m, 2H), 3.29 (t, 2H, J = 6.4 Hz), 2.61 (s, 3H), 2.00-d 1.96 (m, 2H), 1.82-1.74 (m, 4H), 1.71-1.67 (m, 4H), 1.51-1.43 (m, 12H), 1.41-1.32 (m, 6H), 1.19-1.05 (m, 5H), 0.66-0.69 (m, 2H). MS: 576 (M+1).
n 0 0,3 1H-NMR (400 MHz, DMSO-d6) 6: 8.14 (s, 1H), 7.80-7.67 (m, 2H), 7.55-49 (m, 2H), 6.72 (s, 1H), 4.01-3.82 (m, 5H), 3.35 H I \
6/8 N NH (111, 2H), 2.55 (s, 3H), 1.75-1.67 (m, 2H), 1.59-1.44 (m, 5H), d \ 1.36 (s, 9H), 1.34-1.24 (m, 3H), 0.98 (m, 3H), 0.63 (m, 2H).
MS: 548.3 (M+1)+.
a 0 CF 1H-NMR (400 MHz, DMSO-d6): 68.41 (d, J = 8.0 Hz, 1H), 0 7.80-7.67 (m, 2 H), 7.52 (d, J = 8.0 Hz, 2H), 6.73 (s, 1H), I-I I \ * 3.99-3.83(m, 5H), 3.72 (m, 1H), 3.40-3.32 (m, 2H), 2.55 (s, 6/9 N NH 3H), 1.86-1.80 (m, 2H), 1.76-1.67 (m, 4H), 1.62-1.47 (m, 6H), d0 (1m.4+01_ )õ.1 0 (m, 8H), 0.98 (s, 3H), 0.65 (m, 2H). MS: 574.3 Example 7 o\.._ 0 N
N
Step 1: Ethyl 2-methyl-1-(piperidin-1-ylsulfony1)-1H-ovrrole-3-carboxylate (7a) To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (1.0 g, 6.52 mmol) in dry DMF (10 mL) was added NaH (172 mg, 7.17 mmol) in portions and the resulting mixture was stirred at rt for 30 min. A solution of piperidine-1-sulfonyl chloride (1.32 g, 7.17 mmol) in dry DMF (4 mL) was added and the resulting mixture was stirred at rt for 3 h. The mixture was quenched with aq. NH4CI and diluted with EA. The organic phase was washed with water and brine and Step 2: Ethyl 5-bromo-2-methy1-1-(piperidin-1-ylsulfony1)-1H-pyrrole-3-carboxylate (7b) To a solution of compound 7a (600 mg, 2 mmol) in dry DMF (8 mL) was added NBS
(409 mg, 2.3 mmol) in portions at 0 C and this mixture was stirred at rt for 3 h.
The mixture was diluted with EA and washed with water and brine. The organic phase was dried over Na2SO4, concentrated and purified by CC (PE/EA = 15/1) to give compound 7b (700 mg) as a pale-yellow solid.
Step 3: Ethyl 5-(3,5-di-tert-butylpheny1)-2-methy1-1-(piperidin-1-ylsulfony1)-1H-pyrrole-3-carboxylate (7c) A mixture of compound 7b (700 mg, 1.85 mmol), 2-(3,5-di-tert-butylphenyI)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (519 mg, 2.22 mmol) and Pd(PPh3)4 (107 mg) in degassed 1,2-dimethoxyethane (5 mL) and 2M Na2CO3 (8 mL) was heated to 100 C for 30 min under microwave irradiation. The mixture was cooled and diluted with EA and washed with water and brine. The organic phase was dried over Na2SO4, concentrated and purified by CC
(PE/EA = 100/1 to 80/1) to give compound 7c as a colorless solid (500 mg).
Step 4: 5-(3,5-Di-tert-butylpheny1)-2-methy1-1-(piperidin-1-ylsulfony1)-1H-pyrrole-3-carboxylic acid (7d) A mixture of compound 7c (300 mg, 0.614 mmol), Li0H-1120 (503 mg, 12.3 mmol) and NaOH (125 mg) in 1,4-dioxane (5 mL) and water (3 mL) was stirred and heated to 120 C for min under microwave irradiation. The mixture was cooled and acidified by 2M
HCI to 20 pH-2 and then extracted with EA. The combined extracts were washed with water and brine, dried over Na2SO4, concentrated and purified by CC (PE/EA = 10/1 to 2/1) to give compound 7d (250 mg) as a colorless solid.
Step 5: 5-(3,5-Di-tert-butylpheny1)-2-methyl-N-(oxetan-3-y1)-1-(piperidin-1-ylsulfony1)-1 H-pv r r ole -3- carboxamide (7) 25 To a solution of compound 7d (100 mg, 217 pmol), oxetan-3-amine (18 mg, 238 pmol) and HATU (124 mg, 326 pmol) in dry DMF (2 mL) at 0 C was added DIPEA (42 mg, 326 pmol) and the resulting mixture was stirred at rt overnight. The mixture was diluted with water, extracted with EA and the combined extracts were washed with water and brine.
The organic phase was dried over Na2SO4, concentrated and purified by CC (PE/EA = 3/1 to 2/1) to give compound 7 (80 mg, 72%) as a colorless solid. 1H-NMR (400 MHz, CDCI3) 6: 7.41 (1H, s), 7.28 (2H, s), 6.22 (1H, s), 6.19 (1H, d, J = 7.2 Hz), 5.23-5.17 (1H, m), 4.99 (2H, t, J = 6.8 Hz), 4.55 (2H, t, J = 6.4 Hz), 2.81 (3H, s), 2.74 (4H, m), 1.34 (23H, m), 0.85 (1H, m). MS:
516.4 (M+1)+.
Examples 7/1 to 7/8 The following Examples were prepared similar as in Example 7:
# Structure Analytical data oa o 11-I-NMR (400 MHz, CDCI3) 5: 7.41 (1H, s), 7.26 (2H, s), 6.22 N
H I \(1H, s), 6.20 (1H, d, J = 8.0 Hz), 5.21-5.18 (1H, m), 4.99 (2H, 7/1 N 411 t, J = 7.2 Hz), 4.55 (2H, t, J = 6.4 Hz), 3.28 (2 H, m), 2.81 :SO2 (3H, s), 2.20 (2H, m), 1.42 (2H, m), 1.34 (18H, s), 1.23 (1H, pm), 0.95 (2H, m), 0.83 (3H, d, J = 6.8 Hz). MS: 530.3 (M+1)+.
0 1H-NMR (400 MHz, CDCI3) 5: 7.42 (1H, s), 7.28 (2H, m), 6.22 N (1H, s), 6.19 (1H, m), 5.21-5.17 (1H, m), 4.99 (2H, t, J = 6.8 H I \ II Hz), 4.55 (2H, t, J = 6.4 Hz), 3.23 (1H, m), 3.14 (1H, m), 2.81 7/2 N (3H, s), 2.15 (1H, m), 1.68 (1H, m), 1.61-1.57 (1H, m), 1.50-0:S 2 1.45 (1H, m), 1.34 (20H, s), 0.90 (1H, m), 0.69 (3H, d, J = 6.4 ......01 Hz). MS: 530.3 (M+1)+.
0\3N 0 N 1H-NMR (400 MHz, DMSO-d6) 5: 8.53 (1H, d, J = 6.4 Hz), H 1 \ II 7.42 (1H, s), 7.24 (2H, s), 6.56 (1H, s), 4.98-4.92 (1H, m), N 4.72 (1H, t, J = 6.8 Hz), 4.53 (1H, t, J = 6.4 Hz), 3.13 (2H, m), 7/3 2so2 2.71 (3H, s), 1.68-1.49 (3H, m), 1.34-1.20 (19H, m), 0.68 .....91 (6H, m), 0.40-0.36 (1H, m). MS: 544.4 (M-i-1).
N
H , * 1H-NMR (400 MHz, DMSO-d6) 5: 8.50 (1H, d, J =
6.4 Hz), I \
7/4 N7.41 (1H, s), 7.21 (2H, s), 6.63 (1H, s), 4.95-4.91 (1H, m), 4.72 (1H, t, J = 6.8 Hz), 4.52 (1H, t, J = 6.4 Hz), 2.71-2.69 :S02 (7H, m), 1.40 (8H, s), 1.34 (18H, s). MS: 530.3 (M+1)+.
a 0\._3 0 N
H , . 1H-NMR (400 MHz,DMSO-d6) 5: 8.53 (1H, d, J
= 6.4 Hz), I \ 7.41 (1H, s), 7.23 (2H, s), 6.65 (1H, s), 4.98-4.92 (1H, m), N 4.73 (1H, t, J = 6.4 Hz), 4.53 (1H, t, J = 6.4 Hz), 3.11 (1H, m), 7/5 ,So2 2.71 (3H, s), 2.36 (3H, s), 1.63 (2H, m), 1.48 (1H, m), 1.32 ----N
b(18H, s), 1.27-0.95 (5H, m). MS: 544.4 (M+1)+.
0\3N 0 N \ .
H 1H-NMR (400 MHz, CDCI3) 6:8.52 (1H, d, J = 6.8 Hz), 7.42 I\
N (1H, s), 7.25 (2H, s), 6.66 (1H, s), 4.94 (1H, m), 4.72 (2H, t, J
7/625o2 = 6.8 Hz), 4.53 (2H, t, J = 6.4 Hz), 2.93 (2H, t, J = 6.8 Hz), MS: 556.5 (M+1).
2.71 (3H, s), 2.62 (2H, s), 1.52-1.40 (6H, m), 1.31 (22H, m).
+
# Structure Analytical data o HON 1H-NMR (400 MHz, DMSO-d6): 6 7.75 (1H, t, J = 6.4 Hz), H I \ II 7.39 (1H, s), 7.24 (2H, s), 6.62 (1H, s), 4.50 (1H, br s), 3.17 7/7 N (2H, d, J = 6.0 Hz), 2.77-2.68 (7H, m), 1.30 (19H, m), 1.21 01:SO2 (5H, m), 1.07 (6H, s). MS: 532.4 (M+1)+.
o H2 N , \ .
I ` 1H-NMR (400 MHz,CDCI3): 6 7.41 (s, 1H), 7.28 (s, 2H), 6.22 7/8 N (s, 1H), 5.59 (br, s, 2H), 2.84 (s, 3H), 2.76-2.73 (m, 4H), 1.34 :SO2 (s, 18H), 1.26 (m, 6H). MS: 460.2 (M+1)+.
Example 8 ?rij 0 j 5-0 d ,/
Step 1: Ethyl 5-acetyl-1-(cyclohexylmethyl)-2-methy1-1H-pyrrole-3-carboxylate (8a) To a stirred solution of ethyl 1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (8.0 g, 32.1 mmol, prepared according to Example "Id) and 1-methylvinyl acetate (6.4 g, 64.2 mmol) in 1,2-dichloroethane (100 mL) was added p-toluenesulfonic acid monohydrate (250 mg, 1.45 mmol) under N2 and the mixture was stirred and heated to ref lux overnight. After cooling rt the mixture was diluted with water and extracted with DCM twice. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC
(PE/EA = 30/1) to give compound 8a (5.7 g, 61%) as a yellow solid.
Step 2: (E)-Ethyl 1-(cyclohexylmethyl)-2-methyl-5-(3-(pyridin-2-ynacryloy1)-1H-pyrrole-3-carboxylate (8b) To a solution of compound 8a (5.4 g, 18.5 mmol) and picolinaldehyde (4.0 g, 37.4 mmol) in THF (60 mL) was added DBU (3.1 g, 20.4 mmol) and the solution was stirred at rt for 3 d.
The solution was quenched with aq. NH4CI and extracted with EA twice. The combined organic layers were washed with brine and dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 20/1) to give compound 8b (3.8 g, 54%) as a yellow solid.
Step 3: Ethyl 1-(cyclohexylmethyl)-2-methy1-5-(3-(pyridin-2-y1)propanoy1)-1H-pyrrole-3-carboxylate (8c) To a solution of compound 8b (3.7 g, 9.7 mmol) in Me0H (100 mL) was added Pd/C
(370 mg) and the mixture was stirred at rt under H2 (15 psi) overnight. The solution was filtered, concentrated and purified by CC (PE/EA = 20/1) to give compound 8c (3.2 g, 86%) as a colorless solid.
Step 4: Ethyl 1-(cyclohexylmethyl)-5-(1-(N-(methoxycarbonyl)sulfamoypindolizin-3-y1)-2-methyl-1H-pyrrole-3-carboxylate (8d) A solution of compound 8c (3.0 g, 7.8 mmol) in dry toluene (50 mL) was refluxed with a Dean-Stark tube to remove water under N2 for 10 min and then (methoxycarbonyl-sulfamoyl)triethylammonium hydroxide inner salt (Burgess reagent, 3.8 g, 15.9 mmol) was added to the mixture. The mixture was heated to ref lux for further 30 min and cooled to rt.
The solution was quenched with aq. NH4CI and extracted with EA twice. The combined organic layers were washed with brine and dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 3/1) to give compound 8d (2.1 g) as a yellow solid.
Step 5: Ethyl 1-(cyclohexylmethyl)-2-methy1-5-(1-(piperidin-1-ylsulfonyl)indolizin-3-y1)-1 H-pyrrole-3-carboxylate (8e) To a solution of compound 8d (700 mg, 1.4 mmol) in ACN (20 mL) was added 1,5-dibromopentane (383 mg, 1.68 mmol) and K2CO3 (483 mg, 3.5 mmol) and the mixture was stirred overnight at ref lux. The resulting solution was cooled to rt and further K2CO3 (483 mg, 3.5 mmol) was added. The solution was stirred again overnight at ref lux.
After cooling to rt the mixture was diluted with water and extracted with EA twice. The combined organic layers were washed brine, dried over Na2SO4, filtered and concentrated to dryness. CC
(PE/EA =
10/1) afforded compound 8e (610 mg, 85%) as an oil.
Step 6: 1-(Cyclohexylmethyl)-2-methyl-5-(1-(piperidin-1-ylsulfonyl)indolizin-3-y1)-1H-pyrrole-3-carboxylic acid (8f) To a stirred solution of compound 8e (600 mg, 1.17 mmol) in a mixture of DMSO
(15 mL) and H20 (2 drops) was added KOtBu (655 mg, 5.85 mmol) and the mixture was stirred at 85 C for 4 h. After cooling to rt the pH was adjusted to pH 2-3 with 1M HCI
and then the mixture was extracted with EA. The organic layer was washed with water and brine, dried over Na2SO4, concentrated and purified by CC (PE/EA = 2/1) to give compound 8f (450 mg, 80%) as a yellow solid.
Step 7: 1-(Cyclohexylmethyl)-2-methyl-N4(3-methyloxetan-3-y1)methyl)-5-(1-(piperidin-1-vlsulfonypindolizin-3-y1)-1H-pyrrole-3-carboxamide (8) A mixture of compound 8f (150 mg, 0.31 mmol), (3-methyloxetan-3-yl)methanamine (62 mg, 0.62 mmol), HATU (207 mg, 0.54 mmol) and DIPEA (146 mg, 1.14 mmol) in DMF (5 mL) was stirred at rt for 20 min. The resulting solution was diluted with water and extracted with EA twice. The combined organic layers were washed with water three times and brine consecutively, dried over Na2SO4, concentrated and purified by prep. TLC
(PE/EA = 1/1) to give compound 8 (30 mg, 16%) as a pale yellow powder. 1H-NMR (CDCI3, 400 MHz) 6: 8.05 (d, 1H, J = 9.2 Hz), 7.81 (d, 1H, J = 6.8 Hz), 7.10-7.05 (m, 2H), 6.77-6.73 (m, 1H), 6.47 (s, 1H), 6.10 (t, 1H, J = 6.0 Hz), 4.55 (d, 2H, J = 6.0 Hz), 4.42 (d, 2H, J = 6.0 Hz), 3.56 (d, 2H, J
= 6.0 Hz), 3.52 (d, 2H, J = 7.2 Hz), 3.00 (m, 4H), 2.64 (s, 3H), 1.67-1.62 (m, 4H), 1.57-1.53 (m, 5H), 1.37-1.25 (m, 6H), 0.99-0.95 (m, 3H), 0.61-0.57 (m, 2H). MS: 567.1 (M+1)+.
Examples 8/1 to 8/2 The following Examples were prepared similar as in Example 8:
Structure Analytical data HO 1H-NMR (CDCI3, 400 MHz) 6: 8.06 (d, 1H, J
= 8.8 Hz), / SO2Ni\--) 7.82 (d, 1H, J = 6.8 Hz), 7.10-7.05 (m, 2H), 6.77-6.73 (m, 1H), 6.48 (s, 1H), 6.20(m, 1H), 3.52 (d, 2H, J = 7.2 8/1 d N Hz), 3.41 (d, 2H, J = 6.0 Hz), 3.00 (m, 4H), 2.63 (s, 3H), \I 1.67-1.63 (m, 4H), 1.60-1.53 (m, 3H), 1.44-1.37 (m, 15H), 0.99-0.95 (m, 3H), 0.61-0.57 (m, 2H). MS: 555.1 (M+1)+.
01H-NMR (CDCI3, 400 MHz) 6: 8.06 (d, 1H, J = 8.8 Hz), / SO2Nr--) 7.82 (d, 1H, J = 6.8 Hz), 7.11-7.06 (m, 2H), 6.76 (t, 1H, J
= 5.4 Hz), 6.49 (s, 1H), 6.22 (d, 1H, J = 7.2 Hz), 5.24-8/2 N 5.19(m, 1H), 5.00 (t, 1H, J = 7.2 Hz), 4.57 (t, 1H, J = 7.2 d NI Hz), 3.52 (d, 2H, J = 7.2 Hz), 3.00 (m, 4H), 2.62 (s, 3H), 1.67-1.52 (m, 9H), 1.39-1.24 (m, 4H), 0.99-0.95 (m, 3H), 0.61-0.57 (m, 2H). MS: 539.1 (M+1).
Example 9 oo\ 0 H \ /11 Step 1: 1-(CyclohexvImethvI)-2-methvI-1H-ovrrole-3-carboxvlic acid (9a) To a solution of 1-(cyclohexylmethyl)-2-ethyl-1H-pyrrole-3-carboxylate (prepared according to Example 1d, 875 mg, 3.5 mmol) in Et0H (50 mL) was added 5M KOH (10 mL). The mixture was stirred and heated to reflux overnight. After cooling to rt the solvent was concentrated and the pH of the remaining aq. mixture was adjusted to <2 with 4M HCI. The mixture was extracted with EA three times and the combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep. HPLC to give pure product 9a as a colorless solid.
Step 2: 1-(CyclohexylmethvI)-2-methvl-N-(oxetan-3-v1)-1H-pyrrole-3-carboxamide (9b) To a solution of 9a (505 mg, 2.29 mmol) in DMF (15 mL) was added HATU (1.74 mg, 4.58 mmol) and DIPEA (1.48 mg, 11.5 mmol). The mixture was stirred for 60 min and then oxetan-3-amine (185 mg, 2.52 mmol) was added. The mixture was stirred for additional 18 h, quenched with ice water and extracted with EA. The organic layer was separated, washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep. HPLC to give 9b (398 mg, 63%) as a colorless solid.
Step 3: 5-Bromo-1-(cyclohexvImethvI)-2-methyl-N-(oxetan-3-v1)-1H-pyrrole-3-carboxamide To a solution of 9b (555 mg, 2 mmol) in dry THF (10 mL) was added NBS (374 mg, 2.1 mmol) at ¨78 C under N2. The mixture was stirred for 5 min and quenched with a cold aq.
solution of NH4CI. The organic layer was separated and the aq. layer extracted repeatedly with EA. The combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by CC (EA/PE = 1/60) to give compound 9c (630 mg, 89%).
Step 4: 5-(3-tert-Butv1-5-(N-tert-butyl-N-methvIsulfamovl)phenv1)-1-(cyclohexvImethvI)-2-methyl-N-(oxetan-3-v1)-1H-pwrole-3-carboxamide (9) Compound 9c (86 mg, 244 pmol), compound P12 (100 mg, 244 pmol) and Cs2CO3 (238 mg, 732 pmol) in 1,4-dioxane/water (10:1, 2.2 mL) were stirred at rt. Pd(PPh3)4 (0.03 eq) was added under N2 and the mixture was stirred and heated under microwave irradiation to 120 C for 2 h. The mixture was cooled to rt, filtered and purified by prep.
HPLC to give target 9 (81.5 mg, 60%) as a colorless solid. 11-1-NMR (400 MHz, DMSO-d6) 6: 8.32-8.30 (d, J = 6.4 Hz, 1H), 7.69 (m, 2H), 7.54-7.53 (t, J = 1.4 Hz, 1H), 6.75 (s, 1H), 4.96 (m, 1H), 4.74-4.70 (t, J
= 7.0 Hz, 1H), 4.57-4.53 (t, J = 6.2 Hz, 1H), 3.85-3.82 (m, 1H), 2.97 (s, 3H), 2.53 (s, 3H), 1.48-1.45 (m, 3H), 1.35 (s, 9H), 1.24-1.20 (m, 12H), 0.92 (m, 3H), 0.61 (m, 2H). MS: 558.3 (M+1)+.
Examples 9/1 to 9/15 The following Examples were prepared similar as in Example 9, using the corresponding borononic ester building blocks prepared as or similar as described above:
# Structure Analytical data ojN o 0, p 1H-NMR (400 MHz, DMSO-d6) 6: 8.33 (d, J = 6.8 Hz, ;S=NO 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.76 (s, 1H), N
H I \ / 1'1 7.65 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 3.8 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 4.98 (d, J = 6.8 Hz, 1H), 4.75-4.71 9/1 di .
(t, J = 7.0 Hz, 2H), 4.58-4.54 (t, J = 6.6 Hz, 2H), 3.85 (d, J = 7.2 Hz, 2H), 3.19-3.16 (m, 4H), 2.54 (s, 3H), 1.46 (s, 7H), 1.35 (m, 5H), 0.92 (d, J = 5.2 Hz, 3H), 0.64-0.60 (t, J = 6.6 Hz, 2H). MS: 539.2 (M+1)+.
0 0õ0 HO 1H-NMR (400 MHz, DMSO-d6) 6: 7.95 (d, J = 8.0 Hz, / \ N I \ / N? s'._ No 1H), 7.75 (s, 1H), 7.63-7.61 (m, 1H), 7.56 (s, 1H), 7.41-7.39 (m, 1H), 7.35-7.33 (m, 1H), 6.73 (s, 1H), 3.84-3.82 9/2 di *
(d, J = 7.6 Hz, 2H), 3.59 (br s, 1H), 3.19-3.17 (m, 6H), 2.56 (s, 3H), 1.46 (s, 7H), 1.35 (m, 5H), 1.08 (s, 6H), 0.91 (m, 3H), 0.64-0.61 (m, 2H). MS: 555.1 (M+1)+.
HO 1H-NMR (400 MHz, DMSO-d6) 6: 7.68 (m, 2H), 7.55 ?r N I \ . (m, 2H), 6.69 (s, 1H), 3.99 (s, 1H), 3.84-3.82 (d, J = 6.8 Hz, 2H), 3.17-3.16 (d, J = 6.0 Hz, 2H), 2.96 (s, 3H), 9/3 N /2.54 (s, 3H), 1.48-1.46 (m, 3H), 1.34 (s, 9H), 1.24 (s, d 02s-N),_ 12H), 1.08 (s, 6H), 0.93 (m, 3H), 0.62 (m, 2H). MS:
574.2 (M+1)+.
0\3N 0 1H-NMR (400 MHz, DMSO-d6) 6: 8.36 (d, J=6.4Hz, N 0 1H), 8.22 (d, J=8.4Hz, 1H), 7.84 (s, 1H), 7.61 (s, 1H), H
( 7.51 (m, 1H), 6.83 (s, 1H), 5.03 (m, 1H), 4.79 (m, 2H), 9/4 N 41 4.61 (m, 2H), 3.90 (m, 2H), 2.58 (s, 3H), 1.62 (s, 9H), d 1.50 (m, 3H), 1.30-1-20 (m, 12H), 0.95 (m, 3H), 0.67 (m, 2H). MS: 544.2 (M+1)+.
Ov3N 0 1H-NMR (400 MHz, DMSO-d6) 6: 8.31 (d, J=7.2Htz, N 0 1H), 7.79 (d, J=8.4Hz, 1H), 7.57 (s, 1H), 7.43 (m, 1H), Hg':=0 ( 6.76 (s, 1H), 4.98 (m, 1H), 4.73 (m, 2H), 4.56 (m, 2H), 'N
C / 3.84 (m, 2H), 3.09 (s, 3H), 2.51 (s, 3H), 1.54 (s, 9H), 1.43 (m, 3H), 1.21 (s, 9H), 0.91 (m, 3H), 0.89 (m, 3H), 0.61 (m, 2H). MS: 558 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.31 (d, J=6.4Hz, N,0 1H), 7.81 (d, J=8.0Hz, 1H), 7.58 (s, 1H), 7.43 (m, 1H), H I \ *
9/6 N ( 6.76 (s, 1H), 4.96 (m, 1H), 4.72 (m, 2H), 4.54 (m, 2H), N __ 3.83 (d, 2H), 3.59 (m, 2H), 2.51 (s, 3H), 1.55 (s, 9H), d 1.43 (m, 3H), 1.27 (m, 12H), 1.18 (m, 3H), 0.88 (m, 3H), 0.60 (m, 2H). MS: 572.3 (M+1)+.
9-\ 0 1H-NMR (400 MHz, DMSO-d6) 6: 8.30 (d, J=6.4Hz, Np 1H), 8.17 (d, J=8.0Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), H I \ *
, __ 7.42 (m, 1H), 6.77 (s, 1H), 4.97 (m, 1H), 4.74 (m, 2H), 9/7 N HN 4.55 (m, 2H), 3.84 (d, 2H), 2.52 (s, 3H), 1.55 (m, 11H), d 1.44 (m, 3H), 1.19 (d, 3H), 1.08 (s, 6H), 0.89 (m, 6H), 0.63 (m, 2H). MS: 558.3 (M+1).
# Structure Analytical data HO 1H-NMR (400 MHz, DMSO-d6) 6: 8.14 (d, J=8.4Hz, ?Chi I \ Art ,o 1H), 7.75 (s, 1H), 7.55-7.45 (m, 2H), 7.42 (m, 1H), 6.71 s, (s, 1H), 4.61 (s, 1H), 3.85 (m, 2H), 3.15 (m, 2H), 2.52 9/8 N W HN ( (s, 3H), 1.54 (s, 9H), 1.45-1.40 (m, 3H), 1.20-1.06 (m, d 12H), 1.07 (s, 6H), 0.92-0.80 (m, 3H), 0.56 (m, 2H).
MS: 560.3 (M+1)+.
HO 1H-NMR (400 MHz, DMSO-d6) 5: 7.78 (d, J=8.4Hz, N
?CH I\ 0 jõic, 1H), 7.60-7.45 (m, 2H), 7.41 (m, 1H), 6.71 (s, 1H), 4.61 N li 6IN ( (s, 1H), 3.84 (m, 2H), 3.17 (m, 2H), 3.08 (s, 3H), 2.53 i (s, 3H), 1.54 (s, 9H), 1.46-1.40 (m, 3H), 1.22 (s, 9H), d 1.27-1.18 (m, 3H), 1.04 (s, 6H), 0.93-0.80 (m, 3H), 0.62 (m, 2H). MS: 574.3 (M+1)+.
HO 1H-NMR (400 MHz, DMSO-d6) 6: 7.80 (d, J=8.4Hz, ?Ch I \ M2o, 1H), 7.62-7.44 (m, 2H), 7.41 (m, 1H), 6.71 (s, 1H), 4.61 N W SsN ( (s, 1H), 3.84 (m, 2H), 3.62 (m, 2H), 3.15 (m, 2H), 2.52 (s, 3H), 1.54 (s, 9H), 1.45-1.41 (m, 3H), 1.35-1.16 (m, d c 15H), 1.07 (s, 6H), 0.96-0.80 (m, 3H), 0.63 (m, 2H).
MS: 588.3 (M+1)+.
HO 1H-NMR (400 MHz, DMSO-d6) 6: 8.14 (d, J=8.4Hz, ?(Ni I \ e2o 1H),7.62(s, 1H)1,7.543-76.50 (m,2H),.7.42 (m,1H),63.72 9/11 N W HN ____ (s, 1H), 4.61 ), 61 H .8 (s, ), (m, 2H), 318 (m, 2H), 2.6 (s, 3H), 1.560-1.50 (m, 11H), 1.49-1.40 (m, 3H), 1.25-d 1.21 (m, 3H), 1.08 (s, 12H), 0.93-0.81 (s, 6H), 0.61 (m, 2H). MS: 574.1 (M+1)+.
Oa 0 1H-NMR (400 MHz, CDCI3) 6: 0.68-0.71 (2H, m), 1.01-( 1.07 (12H, m), 1.37-1.45 (3H, m), 1.58 (3H, m), 2.58 (3H, s), 3.41 (2H, d, J = 5.6 Hz), 3.65 (2H, d, J = 7.2 9/1 2 N - Hz), 4.57 (2H, t, J = 6.4 Hz), 4.97-5.00 (2H, t, J = 6.4 0) F Hz), 5.04 (1H, s), 5.20-5.22 (1H, m), 6.17 (2H, d, J =
F F
7.6 Hz), 6.20 (1H, s), 7.58 (1H, d, J = 2.4 Hz), 8.20 (1H, d, J = 2.0 Hz). MS: 507.1 (M+1)+.
Oa 0 K 1H-NMR (400 MHz, DMSO-d6) 6: 0.67-0.69 (2H, m), 0.86-1.02 (12H, m), 1.29-1.36 (3H, m), 1.51-1.53 (3H, 9/13 N - m), 2.45 (3H, s), 3.76 (2H, m), 4.12 (2H, s), 4.54 (2H, 0) F m), 4.72 (2H, m), 4.94 (1H, m), 6.72 (1H, s), 8.07 (1H, F F
m), 8.28 (1H, m), 8.45 (1H, m). MS: 508.1 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.24 (m, 1H), 8.03 (m, 1H), 7.92 (m, 1H), 6.64 (s, 1H), 4.94 (m, 1H), 4.71 N , N
(m, 2H), 4.53 (m, 2H), 3.94 (s, 2H), 3.71 (m, 2H), 2.49 9/14 N - (s, 3H, partial overlay with solvent signal), 1.59-1.52 0) F FF (m, 2H), 1.50-1.25 (m, 4H), 1.10-1.00 (m, 2H), 0.94 (s, 9H), 0.76 (m, 2H); MS: 508.1 (M+1)+.
Structure Analytical data ojN o 1H-NMR (300 MHz, CDCI3) 5: 7.45-7.42 (m, 2H), 6.43 (s, 1H), 6.35 (d, 1H, J = 6.9 Hz), 5.20 (m, 1H), 4.99 (t, 11)11 \N 2H, J = 6.9 Hz), 4.58 (t, 2H, J = 6.9 Hz), 3.84 (d, 2H, J
9/15 N --( =6.9 Hz), 2.61 (s, 3H), 1.66 (m, 3H), 1.41 (s, 9H), 1.30-1.38 (m, 3H), 0.97-1.03 (m, 3H), 0.63 (m, 2H).
MS: 478.2 (M+1).
Example 10 n H I \ I H
V--"N N
dNI
Step 1: Indolizine-1-carboxylic acid (10a) 5 A solution of ethyl indolizine-1-carboxylate (1.3 g, 6.88 mmol, prepared according J. Org.
Chem. 1999, 64:7618) and 10% aq. NaOH (120 mL) in THF (10 mL) was heated to 50 C
overnight. The resulting solution was concentrated and adjusted to pH 1 by conc. HCI. The solution was extracted twice with EA. The combined organic layers were washed with brine, dried with Na2SO4, filtered and concentrated to give intermediate 10a (0.50 g, 45%) as a 10 colorless solid.
Step 2: N-tert-Butvlindolizine-1-carboxamide (10b) A solution of intermediate 10a (500 mg, 3.11 mmol), HATU (1.42 g, 3.73 mmol) and DIPEA
(1.2 g, 9.33 mmol) in DMF (10 mL) was stirred at rt for 30 min, then tert-butylamine (273 mg, 3.73 mmol) was added and the solution was stirred for another 0.5 h. The mixture was quenched with water and extracted three times with EA. The combined organic layers were washed with water and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 5/1) to give intermediate 10b (410 mg, 61%) as a colorless solid.
Step 3: 3-Bromo-N-tert-butvlindolizine-1-carboxamide (10c) A solution of intermediate 10b (100 mg, 463 pmol) and CuBr2.2 H20 (124 mg, 556 pmol) in ACN (10 mL) was stirred at rt for 1.5 h. The mixture was quenched with sat.
aq. NH4CI and extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 20/1) to give intermediate 10c (50 mg, 37%) as a yellow solid.
Step 4: Ethyl 541-(tert-butvIcarbamovpindolizin-3-v1)-1-(cyclohexylmethvI)-2-methvI-1 H-pyr r ol e -3- carboxyl ate (10d) To a solution of intermediate 10c (50 mg, 169 pmol), P18 (59.5 mg, 203 pmol), K2CO3 (58 mg, 423 pmol) and TBAB (10 mg) in a mixture of 1,4-dioxane (1 mL) and water (0.5 mL) was added Pd(PPh3)2Cl2 (10 mg) under N2 and the solution was heated to 85 C for 1 h under microwave irradiation (120 W). After cooling to rt the resulting solution was poured into a mixture of water and EA and the aq. phase was extracted twice with EA. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 5/1) to give intermediate 10d (30 mg, 38%) as a colorless solid.
Step 5: 5-(14 tert-ButvIcarbamovI)indolizin-3-v1)-1-(cyclohexvImethvI)-2-methvl-1H-pwrole-3-carboxylic acid (10e) To a solution of intermediate 10d (156 mg, 337 pmol) in a mixture of DMSO (1.5 mL) and water (one drop) was added KOtBu (76 mg, 674 pmol) and the solution was stirred at 80 C
overnight. The mixture was quenched with water, the pH was adjusted to 5 with 1M HCI and extracted twice with DCM. The combined organic layers were washed with water three times and brine consecutively, dried over Na2SO4, filtered and concentrated to give intermediate 10e (143 mg, 98%) as a colorless solid.
Step 6: N-tert-Butv1-3-(1-(cyclohexvImethvI)-5-methyl-4-(tetrahvdro-2H-pvran-4-vIcarbamov1)-1H-pwrol-2-v1)indolizine-1-carboxamide (10) A solution of intermediate 10e (143 mg, 329 pmol), HATU (150 mg, 394 pmol) and DIPEA
(127 mg, 986 pmol) in dry DMF (2 mL) was stirred for 30 min at rt, then 4-aminotetrahydropyran (40 mg, 394 pmol) was added and the solution was stirred for another 0.5 h. The mixture was quenched with water and extracted twice with EA. The combined organic layers were washed with water three times and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to give 10 (25 mg, 15%) as a colorless solid. 1H-NMR (CDCI3, 400 MHz) 6: 0.54-0.60 (2H, m), 0.96-0.98 (3H, m), 1.25-1.28 (4H, m), 1.44-1.51 (13H, m), 1.97-2.01 (2H, m), 2.64 (3H, s), 3.50-3.55 (4H, m), 3.97-3.99 (2H, m), 4.15-4.4.19 (1H, m), 5.58-5.60 (1H, d, J = 8.0 Hz), 5.67 (1H, s), 6.35 (1H, s), 6.63-6.67 (1H, m), 6.83 (1H, s), 6.99-7.03 (1H, m), 7.73 (1H, d, J = 7.6 Hz), 8.37 (1H, d, J =
9.2 Hz). MS: 519.2 (M+1).
Example 10/1 The following Example was prepared similar as in Example 10:
Structure Analytical data 01 0 0 1H-NMR (CDCI3, 400 MHz) 6: 0.61-0.63 (2H, m), 0.96-0.98 0 ((36HH: mm)),, 21 ..3624-(13.3H6 s(4) F13,.51111):315.533(-21H.55d(2J1-1., m7 1H.z6)4-31..7702 z I _ 1 Oil N 3.73 (4H, m), 4.56-4.59 (2H, m), 4.98-5.01 (2H, m), 5.20-d \I 5.22 (1H, m), 6.21-6.22 (1H, m), 6.43 (1H, s), 6.60-6.64 (1H, m), 6.87 (1H, s), 6.93-6.97 (1H, m), 7.70-7.72 (1H, m), 7.90-7.92 (1H, m). MS: 503.1 (M+1)+.
Example 11 N J,N
0\õ..) c 111 H \
d 5484 tert-Butyl)spi roich roman-4,1'-cyclopropan1-6-0-1-(cyclohexvImethvI)-N-(2,2-dimethvl-3-morpholino-3-oxopropv1)-2-methyl-1H-pyrrole-3-carboxamide (11) To a solution of Example 1/91 (106 mg, 0.2 mmol) in DMF (5 mL) was added HATU
(152 mg, 0.4 mmol) and DIPEA (129 mg, 1 mmol). The mixture was stirred for 60 min and then morpholine (87 mg, 1 mmol) was added into the mixture. The mixture was stirred overnight and quenched with ice water and extracted with EA. The organic layer was separated and washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep. HPLC to give compound 11(54 mg, 45%) as a colorless solid.
(400 MHz, DMSO-d6) 6: 7.26 (t, 1H), 6.89 (s, 1H), 6.48 (s, 1H), 6.26 (s, 1H), 4.28 (t, 2H), 3.65 (d, 2H), 3.57 (s, 8H), 3.37 (m, 2H), 2.47 (s, 3H), 1.84 (t, 2H), 1.51 (m, 3H), 1.26 (m, 12H), 1.17 (s, 6H), 0.98 (m, 5H), 0.71 (m, 2H), 0.66 (m, 2H). MS: 604.3 (M+1).
Example 11/1 to 11/7 The following Examples were prepared similar as in Example 11:
Structure Analytical data HN
0 1H-NMR (400 MHz, DMSO-d6) 6: 7.60 (t, 1H), 7.29 (t, 1H), 6.90 (s, 1H), 6.48 (s, 1H), 6.30 (s, 1H), 4.29 (t, 2H), 3.65 11/i (d, 2H), 3.27 (d, 2H), 3.56 (s, 3H), 2.47 (s, 3H), 1.84 (t, N* 2H), 1.50 (m, 3H), 1.29 (m, 12H), 1.07 (s, 6H), 0.95 (m, 0 5H), 0.88 (m, 2H), 0.67 (m, 2H). MS: 548.4 (M+1).
# Structure Analytical data o \
N
/ 0 1H-NMR (400 MHz, CDCI3) 6: 6.96 (s, 1H), 6.87 (s, 1H), 3\--1\-IN 6.43 (s, 1H), 6.14 (s, 1H), 4.32 (t, 2H), 3.63 (d, 2H), 3.52 11/2 / \ (d, 2H), 3.02 (s, 6H), 2.58 (s, 3H), 1.91 (t, 2H), 1.57 (m, N * 3H), 1.37 (m, 12H), 1.29 (s, 6H), 1.02 (m, 5H) ,0.82 (m, 0) o 2H), 0.66 (m, 2H). MS: 562.8 (M+1).
o H(N-SrFiN 0 1H-NMR (400 MHz, CDCI3) 6: 7.00 (m, 2H), 6.42 (m, 2H), 6.11 (s, 1H), 4.33 (t, 2H), 3.61 (d, 2H), 3.50 (m, 4H), 2.56 =
11/3 o / \ (m, 5H), 1.91 (t, 2H), 1.56 (m, 3H), 1.32 (m, 12H), 1.26 (s, OH N lp 6H), 1.00 (m, 5H), 0.84 (m, 2H), 0.65 (m, 2H).
MS: 606.4 0) o (M+1).
o 1H-NMR (400 MHz, DMSO-d6) 6: 7.87 (t, 1H), 7.31 (t, 1H), o HP------\HN 6.90 (s, 1H), 6.48 (s, 1H), 6.33 (s, 1H), 4.28 (t, 2H), 3.67 o,) = (d, 2H), 3.46 (m, 2H), 3.29 (m, 2H), 3.23 (m, 2H), 2.97 (s, 11/4-,s / \ 3H), 2.48 (s, 3H), 1.86 (t, 2H), 1.84(m, 3H), 1.27 (m, o' N p0 12H), 1.03 (s, 6H), 0.98 (m, 5H), 0.87 (m, 2H), 0.66 (m, 0) 2H). MS: 640.4 (M+1).
o 1H-NMR (400 MHz, DMSO-d6) 5:7.60 (t, 1H), 7.29 (t, 1H), o 73rHN 6.90 (s, 1H), 6.48 (s, 1H), 6.31 (s, 1H), 4.64 (t, 1H), 4.29 (t, 2H), 3.66 (d, 2H), 3.39 (m, 2H), 3.33 (m, 2H), 3.11 (m, 11/5 HO / \ 2H), 2.47 (s, 3H), 1.84 (t, 2H), 1.50 (m, 3H), 1.26 (m, 0 12H), 1.02 (s, 6H), 0.94 (m, 5H), 0.87 (m, 2H), 0.67 (m, CI) 2H). MS: 578.4 (M+1).
H\I--rN 1H-NMR (400 MHz, DMSO-d6) 6: 7.66 (t, 1H), 7.30 (t, 1H), o 6.90 (s, 1H), 6.48 (s, 1H), 6.30 (s, 1H), 4.42 (t, 1H), 4.28 If (t, 2H), 3.66 (d, 2H), 3.37 (m, 2H), 3.29 (d, 2H), 3.09 (m, 11/6 / \ 2H), 2.48 (s, 3H), 1.84 (t, 2H), 1.52 (m, 5H), 1.29 (m, OH N p0 12H), 1.06 (s, 6H), 0.98 (m, 5H), 0.88 (m, 2H), 0.67 (m, 0) 2H). MS: 592.5 (M+1).
o Fir\--Sv7iN 1H-NMR (400 MHz, DMSO-d6) 5:7.66 (t, 1H), 7.29 (t, 1H), o 6.90 (s, 1H), 6.48 (s, 1H), 6.29 (s, 1H), 4.36 (t, 1H), 4.28 1/ (t, 2H), 3.67 (d, 2H), 3.29 (m, 4H), 3.03 (m, 2H), 2.48 (s, 11/7 / \ 3H), 1.86 (t, 2H), 1.51 (m, 3H), 1.41 (m, 16H), 0.99 (s, HO 0) 1104 0 6H), 0.89 (m, 5H), 0.88 (m, 2H), 0.66 (m, 2H).
MS: 606.5 (M+1).
Example 12 o H2N \ .
I
N
d12 Step 1: Ethyl 5-(3-bromo-5-(tert-butyl)pheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (12a) To a solution of compound P18a (643 mg, 1.71 mmol) in 1,4-dioxane/H20 (3 mU0.8 mL) 1,3-dibromo-5-(tert-butyl)benzene (595 mg, 2.05 mmol), Cs2CO3 (1.11 g, 3.42 mmol) and Pd(PPh3)4 (66 mg, 0.17 mmol) were added under N2. The mixture was stirred under microwave at about 110 C for 2.5 h. Removal of the solvents and purification by prep. TLC
(PE/EA = 20/1) yielded compound 12a (275 mg, 35%) as yellow solid.
Step 2: Ethyl 5-(3-(tert-buty1)-5-cyclopropylpheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (12b) To a solution of compound 12a (275 mg, 0.60 mmol) in toluene/H20 (2 mU0.1 mL) cyclopropylboronic acid (154 mg, 1.80 mmol), tricyclohexylphosphine (17 mg, 0.06 mmol), K3PO4 (505 mg, 2.11 mmol) and Pd(OAc)2 (7 mg, 0.03 mmol) were added under N2.
The mixture was stirred at 100 C for 3 h, then concentrated and purified by prep.
TLC (PE/EA =
20/1) to yield compound 12b (150 mg, 60%) as a colorless solid.
Step 3: 5-(3-(tert-Buty1)-5-cyclopropylpheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylic acid (12c) To a solution of 10% NaOH in water/Me0H (10 mL, 1:1) was added compound 12b (150 mg, 0.36 mmol) and the mixture was stirred at 70 C for 3 h. Then 2M HCI was added to adjust the pH to 4. The mixture was extracted with EA and removal of the organic solvents gave the crude compound 12c (100 mg, 90%).
Step 4: 5434 tert-Buty1)-5-cyclopropylpheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxamide (12) To a solution of compound 12c (50 mg, 0.125 mmol) in DCM (5 mL) was added (C0C1)2 (160 mg, 1.25 mmol) dropwise and then a drop of DMF under N2. The mixture was stirred at rt for 1 h and then concentrated. Then NH3 in THF was added and the mixture was stirred for 1 min, concentrated and purified by prep. HPLC to afford compound 12 (15 mg, 35%) as a colorless solid. 1H-NMR (500 MHz, CDCI3) 6: 0.63-0.66 (m, 4H), 0.91-1.00 (m, 5H), 1.34-1.38 (m, 12H), 1.54 (m, 3H), 1.93 (m, 1H), 2.62 (s, 3H), 3.72 (d, 2H), 5.44 (br s, 2H), 6.19 (s, 1H),6.75 (s, 1H), 7.11-7.14 (m, 2H). MS (m/z): 393 (M+1).
Example 13 to Example 15 y_ 03 o , 0 0 0\ 0 OH 0 03N
H I \ H I \ * H I \
dCF3 CF3 13 0) 14 0) 15 Step 1: Methyl 3-(1-(cyclohexylmethyl)-5-methy1-4-(oxetan-3-vIcarbamov1)-1H-pyrrol-2-v1)-5-(trifluoromethyl)benzoate (13) A mixture of 5-bromo-1-(cyclohexylmethyl)-2-methyl-N-(oxetan-3-y1)-1H-pyrrole-carboxamide (1.54 g, 4.66 mmol), compound P68 (1.50 g, 4.24 mmol), K2CO3 (1.46 g, 10.6 mmol) and TBAB (60 mg, 0.18 mmol) in 1,4-dioxane/H20(10 mL/5 mL) was added Ph(PPh3)2Cl2 (300 mg) under N2. The solution was heated under microwave conditions at 100 C for 1.5 h. Water was added and the solution was extracted with EA. The organic layer was washed with brine, dried over NaSO4, filtered, concentrated and purified by CC (PE/EA
= 5/1) to give compound 13 (1.12 g, 63%) as a colorless solid.
Step 2: 3-(1-(CyclohexvImethyl)-5-methy1-4-(oxetan-3-vIcarbamov1)-1H-pyrrol-2-y1)-5-(trifluoromethypbenzoic acid (14) To a stirred solution of compound 13 (680 mg, 1.42 mmol) in a mixture of THF
(10 mL) and H20 (3 mL) was added Li0H.1-120 (420 mg, 10 mmol) and this mixture was stirred at 60 C for 3 h. The mixture was adjusted to pH = 2-3 with 1M HCI and then extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC
(PE/EA = 2/1) to give compound 14 (640 mg, 97%) as a colorless powder.
Step 3: 5-(3-(tert-Butylcarbamov1)-5-(trifluoromethyl)pheny1)-1-(cyclohexylmethyl)-2-methyl-N-(oxetan-3-v1)-1H-pyrrole-3-carboxamide (15) A mixture of compound 14 (160 mg, 0.34 mmol), tert-butylamine (26 mg, 0.36 mmol), HATU
(94.2 mg, 0.36 mmol) and DIPEA (97.4 mg, 0.76 mmol) in DMF (5 mL) was stirred at rt for 20 min. The mixture was diluted with EA and the organic layer was washed with brine, dried over Na2SO4, concentrated and purified by prep. TLC to give compound 15 (46 mg, 26%) as a colorless powder. 1H-NMR (CDCI3, 300 MHz) 6: 7.89 (m, 2H), 7.69 (s, 1H), 6.35 (s, 1H), 6.25 (d, 1H, J = 7.2 Hz), 5.99 (s, 1H), 5.20 (m, 1H), 4.99 (t, 2H, J = 7.2 Hz), 4.58 (t, 2H, J =
7.2 Hz), 3.77 (d, 2H, J = 6.9 Hz), 2.60 (s, 3H), 1.61 (m, 3H), 1.50 (s, 9H), 1.33-1.38 (m, 3H), 0.99-1.03 (m, 3H), 0.63 (m, 2H). MS: 520 (M+1).
Examples 15/1 to 15/9 Using similar procedures as described in Example 15 the following Examples have been prepared:
# Structure Analytical data 0 Y 1H-NMR (CDCI3, 300 MHz) 6: 7.65 (s, 1H), 7.60 (s, 1H), ov.3o N N\ 7.59 (s, 1H), 6.32 (s, 1H), 6.21 (d, 1H, J = 6.9 Hz), 5.20 15/1 H I \ . (q, 1H, J = 7.2 Hz), 4.99 (t, 2H, J = 7.2 Hz), 4.57 (t, 2H, J
N = 7.2 Hz), 3.77 (d, 2H, J = 6.9 Hz), 2.87 (s, 3H), 2.60 (s, d c,3 3H), 1.61 (m, 3H), 1.53 (s, 9H), 1.33-1.38 (m, 3H), 0.99-1.03 (m, 3H), 0.65 (m, 2H). MS: 534 (M+1).
o 1H-NMR (DMSO-d6, 300 MHz) 6: 8.56 (d, 1H, J =
7.5 Hz), oa 0 NH 8.32 (d, 1H, J = 6.9 Hz), 8.19 (d, 2H, J = 12.3 Hz), 7.87 N (s, 1H), 6.85 (s, 1H), 4.95 (q, 1H, J = 7.2 Hz), 4.72 (t, 2H, 15/2 H I \ * J = 7.2 Hz), 4.54 (t, 2H, J = 7.2 Hz), 4.14(q, 1H, J = 6.9 N Hz), 3.87 (d, 2H, J = 7.2 Hz), 2.54 (s, 3H), 1.51 (m, 3H), d 0,3 1.35-1.19(m, 9H), 1.33-1.38 (m, 3H), 0.98-0.94(m, 3H), 0.68 (m, 2H). MS: 506 (M+1).
0 y , 1H-NMR (CDCI3, 300 MHz) 6: 7.88 (s, 2H), 7.69 (s, 1H), uN 0 NH ` 6.29(s, 1H), 6.21 (d, 1H, J = 6.9 Hz), 5.20(q, 1H, J = 7.2 N
15/3 H I \ * Hz), 4.99 (t, 2H, J = 7.2 Hz), 4.59 (t, 2H, J =
7.2 Hz), 3.76 N (d, 2H, J = 6.9 Hz), 2.87 (s, 3H), 2.60 (s, 3H), 1.85 (q, 2H, C) 0,3 J = 7.5 Hz), 1.57 (m, 3H), 1.43 (s, 6H), 1.28 (m, 3H), 0.95 (t, 3H, J = 7.5 Hz), 0.68 (m, 2H). MS: 534 (M+1).
0\3N o 1H-NMR (400 MHz, DMSO-d6) 6: 8.26 (d, J = 6.8 Hz, 1H), N
. 7.45 (s, 1H), 7.32 (s, 1H), 7.14 (s, 1H), 6.68 (s, 1H), 4.98-H I \ 4.93 (m, 1H), 4.73-4.70 (t, J = 7.0 Hz, 2H), 4.56-4.53 (t, J
15/4 N/ = 6.6 Hz, 2H), 3.83 (d, J = 7.2 Hz, 2H), 2.83 (s, 3H), 2.52 C) 0 Ny (s, 3H), 1.45 (s, 12H), 1.40 (s, 9H), 1.27-1.20 (m, 3H), 0.97-0.89 (m, 3H), 0.66-0.60 (m, 2H). MS: 522 (M+1).
oao 1H-NMR (400 MHz, DMSO-d6) 6: 8.28 (d, 1H), 7.83 (s, N 1H), 7.76 (s, 1H), 7.70 (s, 1H), 7.51 (d, 1H), 6.96 (s, 1H), H I \ . 4.98-4.94 (d, 1H), 4.73-4.71 (t, 2H), 4.56-4.54 (t, 2H), 15/5 N 3.82-3.81 (d, 2H), 2.52 (s, 3H), 1.50-1.40 (m, 3H), 1.40 C) 0 NH (s, 9H), 1.34 (s, 9H), 1.29-1.15 (d, 3H), 0.96-0.93 (m, 3H), 0.66-0.61 (m, 2H). MS: 508 (M+1).
oao 1H-NMR (400 MHz, DMSO-d6) 6: 8.30-8.27 (t , 2H), 7.83 N (s, 1H), 7.72 (s, 1H), 7.53 (s, 1H), 6.70 (s,1H), 4.98-4.94 H I \ * (d, 1H), 4.73-4.71 (t, 2H), 4.56-4.54 (t, 2H), 4.15-4.11 (m, 15/6 N 1H), 3.83-3.81 (d, 2H), 2.53 (s, 3H), 1.47 (m, 3H), 1.34 (s, NH
C) 0 ,. 9H), 1.31-1.26(m, 3H), 1.19-1.18(d, 6H), 0.96-0.91 (m, 3H), 0.65-0.63 (m, 2H). MS: 494 (M+1).
OH 1H-NMR (400 MHz, DMSO-d6) 6: 7.48-7.46 (t, 2H), 7.44 NNN I\ lik 0, 1H), 7.31 (s, 1H), 7.14 (s, 1H), 6.61 (s, 1H), 3.82-3.81 C) (d, 2H), 3.17-3.16 (d, 2H), 2.82 (s, 3H), 2.53 (s, 3H), Ni 1.47-1.45 (m, 12H), 1.29-1.20 (m, 12H), 1.08 (s, 6H), 0 / 0.98-0.87 (m, 3H), 0.67-0.61 (m, 2H). MS: 538 (M+1).
# Structure Analytical data OH 0 1H-NMR (400 MHz, DMSO-d6) 6: 7.81 (s, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 7.47-7.45 (m,1H), 6.62 (s, NfiN-I 1 \ * 1H), 4.63 (s, 1H), 3.82-3.80 (d, 2H), 3.18-3.16 (d, 2H), d 15/8 N 2.54 (s, 3H), 1.50-1.48 (m, 3H), 1.39 (s, 9H), 1.34 (s, 9H), 0 N7 1.29-1.17 (m, 3H), 1.08 (s, 6H), 1.00-0.95 (m, 3H), 0.70-0.63 (m, 2H). MS: 524 (M+1).
OH 0 1H-NMR (400 MHz, DMSO-d6) 6: 8.29-8.28 (d, 1H), 7.82 NN
H I \ ip, (s, 1H), 7.71 (s, 1H), 7.52 (s, 1H), 7.49-7.47 (m, 1H), 6.62 I
(s, 1H), 4.63 (m, 1H),4.16-4.11 (m, 1H),3.82-3.81 (d, d 2H), 3.18-3.16 (d, 2H), 2.54 (s, 3H), 1.49-1.47 (m, 3H), NH
_ 1.34 (s, 12H), 1.31-1.17 (m, 6H), 1.08 (s, 6H), 0.96-0.92 O )--- (m, 3H), 0.66-0.64 (m, 2H). MS: 510 (M+1).
Example 16 MeO 0 N I \ *
N
d16 Step 1: 1-(CyclohexvImethvI)-5-(3,5-di- terf-butylphenv1)-2-methvI-1H-pwrole-3-carboxamide (16a) To a solution of 1-(cyclohexylmethyl)-5-(3,5-di-tert-butylpheny1)-2-methyl-1H-pyrrole-3-carboxylic acid (410 mg, 1.0 mmol) in DMF (25 mL) was added HATU (456 mg, 1.2 mmol) in an ice-water bath below 10 C. The mixture was stirred for 60 min and then NH4CI (81 mg, 1.5 mmol) was added to the mixture. The mixture was stirred for additional 12 h, quenched with ice water and extracted with EA. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, evaporated and purified by prep. HPLC to give compound 16a as a colorless solid.
Step 2: 1-(CyclohexvImethvI)-5-(3,5-di-terf-butylphenv1)-N-(4-methoxybutv1)-2-methvI-1 H-pv r r ol e -3- carboxami d e (16) A mixture of compound 16a (82 mg, 0.2 mmol) and 1-chloro-4-methoxybutane (27 mg, 0.22 mmol) in DMF (5 mL) was added NaH (60%, 24 mg, 0.6 mmol) at 0 C and the mixture was stirred overnight under Ar at_90 C, quenched with ice water and extracted with EA. The organic layer was separated, washed with brine, dried over Na2504, filtered, evaporated and purified by prep. HPLC to give compound 16 (16 mg, 16%) as a colorless solid.
(400 MHz, DMSO-d6) 6: 7.63-7.60 (t, J = 5.8 Hz, 1H), 7.35 (s, 1H), 7.16-7.15 (d, J = 1.6 Hz, 2H), 6.49 (s, 1H), 3.77-3.75 (d, J = 6.8 Hz, 2H), 3.34-3.31 (t, J = 5.8 Hz, 2H), 3.22 (s, 3H), 3.17-3.16 (d, J = 6.0 Hz, 3H), 2.52 (s, 3H), 1.51-1.50 (t, J = 3.0 Hz, 4H), 1.46-1.43 (d, J = 9.2 Hz, 3H), 1.31 (s, 18H), 1.27-1.21 (t, J = 11.2 Hz, 3H), 0.94-0.89 (t, J = 10.8 Hz, 3H), 0.65-0.62 (d, J = 11.2 Hz, 2H). MS: 495 (M+1).
Example 17/1 to 17/374 The following Examples were prepared similar as described above:
# Structure Analytical data 1H-NMR (CDCI3, 500 MHz) 6: 7.82 (d, 1H), 7.61 o HN (d, 1H), 7.24 (d, 1H), 6.27 (s, 1H), 5.61 (d, 1H), 4.24-4.15 (m, 3H), 3.98 (d, 2H), 3.78 (d, 2H), 3.52 17/1 / \ 110 (dd, 2H), 2.62 (s, 3H), 1.98 (dd, 2H), 1.66-1.51 (m, N 9 k 16H),1.43-1.30 (m, 12H), 1.00-0.97 (m, 3H), 0.66-CH ,-.-N
0 ) 0.60 (m, 2H). MS: 654.3 (M+1).
\
0 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 HN (d, 1H), 6.12 (s, 2H), 4.33 (t, 2H), 3.65-3.59 (m, / \ 4H), 3.17-2.82 (m, 2H), 2.64-2.60 (m, 6H), 2.12 17/2 N 10, 0 (br s, 2H), 1.90 (t, 2H), 1.58-1.56 (m, 3H), 1.45-1.28(m, 12H), 1.03-1.00 (m, 5H), 0.88-0.84 (m, O)12H), 0.72-0.66 (m, 2H). MS: 539.3 [M+1]t 0\\ 0 s--1H-NMR (400 MHz, DMSO-d6) 6: 7.58 (t, 1H), 6.97 z=
(t, 1H), 6.90 (d, 1H), 6.49 (d, 1H), 6.34 (s, 1H), HN 4.28 (t, 2H), 3.67 (d, 2H), 3.20 (q, 2H), 2.96 (q, 17/3 / \ 2H), 2.88 (s, 3H), 2.49 (s, 3H), 1.85 (t, 2H), 1.69-N .
0 1.62 (m, 2H), 1.51-1.49 (m, 3H), 1.35-1.25 (m, 12H), 0.99-0.87 (m, 7H), 0.72-0.63 (m, 2H). MS:
&570.4 [M+1]t =
\
o=s6,--\_\_\
a 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 (d, 1H), 6.06 (s, 1H), 5.77 (t, 1H), 4.33 (t, 2H), HN 3.64 (d, 2H), 3.39 (q, 2H), 3.02 (t, 2H), 2.90 (s, 17/4 /\
N * 3H), 2.59 (s, 3H), 1.94-1.86 (m, 4H), 1.69-1.50 (m, 7H), 1.46-1.35 (m, 12H), 1.03-1.00 (m, 5H), 0.87-0 0.84 (m, 2H), 0.72-0.64 (m, 2H). MS:
583.3 [M+1]+.
0) 1 Q1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 \ o "'IHN (d, 1H), 6.11 (d, 1H), 4.33 (t, 2H), 4.06-4.00 (m, 1H), 3.89-3.83 (m, 1H), 3.78-3.63 (m, 4H), 3.36-/ \ 3.31 (m, 1H), 2.59 (s, 3H), 2.01-1.89 (m, 5H), 0 1.60-1.56 (m, 4H), 1.38-1.34(m, 12H), 1.03-1.00 MS: 519.3 (M+1).
(m, 5H), 0.86-0.85 (m, 2H), 0.69-0.63 (m, 2H).
& 1 # Structure Analytical data 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 L-ci HN (d, 1H), 6.11 (d, 1H), 4.33 (t, 2H), 4.06-4.00 (m, / \ 1H), 3.89-3.83 (m, 1H), 3.78-3.63 (m, 4H), 3.36-17/6 N *
0 3.31 (m, 1H), 2.59 (s, 3H), 2.01-1.89 (m, 5H), 1.60-1.56 (m, 4H), 1.38-1.34 (m, 12H), 1.03-1.00 C(m, 5H), 0.86-0.85 (m, 2H), 0.69-0.63 (m, 2H). I) 1 MS: 519.3 (M+1) HN¨____\ 0 1H-NMR (400 MHz, CDCI3) 6: 10.04 (s, 2H), 6.97 (s, 1H), 6.44 (s, 1H), 6.17 (br s, 1H), 6.11 (s, 1H), C---0 HN 4.33 (t, 2H), 4.11-4.02 (m, 3H), 3.64 (d, 2H), 3.60-+ICI / \ 3.34 (s, 4H), 3.05-2.87 (m, 2H), 2.57 (s, 3H), 1.90 17/7 N *
0 (t, 3H), 1.56-1.52 (m, 3H), 1.38-1.35 (m, 12H), 1.04-1.02 (m, 5H), 0.86-0.85 (m, 2H), 0.672-0.65 ) 1 (m, 2H). MS: 534.4 (M¨CI)+.
HO\
1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 HN (d, 1H), 6.08-6.03 (m, 2H), 4.66 (t, 1H), 4.42 (dd, 17/8 / \
*
0 4H), 4.33 (t, 2H), 3.80-3.78 (m, 4H), 3.64 (d, 2H), N
2.57 (s, 3H), 1.90 (t, 2H), 1.56 (s, 3H), 1.42-1.35 (m, 12H) , 1.04-0.99 (m, 5H), 0.87-0.84 (m, 2H), 0.72-0.66 (m, 2H). MS: 535.3 (M+1).
0) 1 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.84 FIN (br s, 1H), 6.42 (d, 1H), 6.09 (br d, 1H), 4.33 (t, 2H), 3.86-3.84 (m, 4H), 3.63 (d, 2H), 2.99 (br s, 17/9 / \
N *
0 4H), 2.58 (s, 3H), 1.90 (t, 2H), 1.58-1.56 (m, 3H), 1.45-1.32 (m, 12H), 1.04-0.96 (m, 5H), 0.87-0.84 (m, 2H), 0.70-0.65 (m, 2H). MS: 520.1 (M+1).
0) 1 c;,s0____\ o 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 0' HN (d, 1H), 6.05 (s, 1H), 5.92 (t, 1H), 4.34 (t, 2H), / \ 3.64 (d, 2H), 3.31 (t, 2H), 3.09-3.06 (m, 2H), 2.96 17/10 N *
0 (td, 2H), 2.58 (s, 3H), 2.18 (d, 2H), 1.91-1.84 (m, 5H), 1.59-1.56 (m, 3H), 1.38-1.35 (m, 12H), 0 1.04-0.99 (m, 5H), 0.87-0.84 (m, 2H), 0.73-0.65 (m, ) 1 2H). MS: 581.4 (M+1).
oõ4 1H-NMR (400 MHz, CDCI3) 6: 6.95 (d, 1H), 6.72 (t, :? 0 1H), 6.42 (d, 1H), 6.15 (s, 1H), 4.33 (t, 2H), 4.11 HN (d, 2H), 3.95 (dd, 2H), 3.77 (td, 2H), 3.63 (d, 2H), o 17/11 / \
*
0 2.87 (s, 3H), 2.59 (s, 3H), 2.15-2.08 (m, 2H), 1.89 (t, 2H), 1.79 (d, 2H), 1.60-1.53 (m, 3H), 1.46-1.38 (m, 12H), 1.04-1.00 (m, 5H), 0.86-0.83 (m, 2H), N
0.73-0.65 (m, 2H). MS: 611.3 (M+1).
0) 1 0, 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 osa_..\ o HN (d, 1H), 6.05 (s, 1H), 5.91 (t, 1H), 4.34 (t, 2H), 3.64 (d, 2H), 3.58-3.44 (m, 2H), 3.28-3.19 (m, 2H), / \3.09-3.01 (m, 1H), 2.90-2.80 (m, 2H), 2.58 (s, 3H), 0 2.38-2.33 (m, 1H), 2.01-1.96 (m, 1H), 1.90 (t, 2H), (m, 5H), 0.87-0.64 (m, 4H). MS: 567.3 (M+1).
1.59-1.54 (m, 3H), 1.44-1.35 (m, 12H), 1.04-1.00 0) 1 # Structure Analytical data o--, 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 HN (d, 1H), 6.06 (s, 1H), 5.93 (s, 1H), 4.83 (d, 2H), / \
0 4.53 (d, 2H), 4.33 (t, 2H), 3.64 (d, 2H), 2.58 (s, 3H), 1.90 (t, 2H), 1.74 (s, 3H), 1.59 (br s, 3H), 1.38-1.35 (m, 12H), 1.04-1.00 (m, 5H), 0.87-0.84 (m, 2H), 0.69-0.66 (m, 2H). MS: 505.3 (M+1).
0) =
O-o 1H-NMR (400 MHz, CDCI3) 6: 6.95 (d, 1H), 6.89 \¨N HN (br s, 1H), 6.42 (d, 1H), 6.24 (br s, 1H), 4.33 (t, \
/ \ 2H), 4.14 (br s, 2H), 3.96-3.86 (m, 4H), 3.64-3.52 *
0 (m, 4H), 3.36 (br s, 1H), 3.01 (br s, 3H), 2.58 (s, 3H), 1.90 (t, 2H), 1.57 (br s, 3H), 1.43-1.26 (m, 12H), 1.03-1.02 (m, 5H), 0.88-0.83 (m, 2H), 0.69-) = 0.66 (m, 2H). MS: 548.4 (M+1).
o, 1H-NMR (400 MHz, CDCI3) 6: 6.88 (d, 1H), 6.35 0---'-q (d, 1H), 6.12 (d, 1H), 6.02 (s, 1H), 4.89-4-85 (m, o HN 1H), 4.26 (t, 2H), 3.57 (d, 2H), 3.38 (m, 1H), 3.20-3.15 (m, 1H), 3.10-3.02 (m, 1H), 2.97 (dd, 1H), 17/15 / \ 2.52-2.46 (m, 4H), 2.31-2.26 (m, 1H), 1.84-1.82 N *
0 (m, 2H), 1.52-1.50 (m, 3H), 1.37-1.26 (m, 12H), 0.96-0.93 (m, 5H), 0.80-0.77 (m, 2H), 0.65-0.59 0) 1 (m, 2H). MS: 553.3 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 7.98 (s, 1H), 6.95 HO-...(CLI4 HN (d, 1H), 6.82 (br s, 1H), 6.41 (d, 1H), 6.23 (s, 1H), / \ 4.63 (d, 2H), 4.30 (t, 2H), 3.61 (d, 2H), 2.56 (s, o 17/16 N * 3H), 1.86 (t, 2H), 1.56-1.51 (m, 3H), 1.42-1.36 (m, o 12H), 1.02-0.96 (m, 5H), 0.82-0.79 (m, 2H), 0.70-0.63 (m, 2H). MS: 559.3 (M), 418.2 (M-0) = C6H10N203)+.
o 6 o ---\ (d, 1H), 6.80 (br s, 1H), 6.44 (d, 1H), 6.25 (br s, H2N-..[N HN 1H-NMR (400 MHz, CDCI3) : 8.18 (s, 1H), 6.98 1H), 6.15 (s, 1H), 5.68 (br s, 1H), 4.72 (d, 2H), 17/17 o / \
N IP
0 4.34 (t, 2H), 3.65 (d, 2H), 2.60 (s, 3H), 1.90 (t, 2H), 1.58-1.55 (m, 3H), 1.38-1.35 (m, 12H), 1.04-0.99 (m, 5H), 0.87-0.84 (m, 2H), 0.73-0.66 (m, 0) = 2H). MS: 559.3 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 8.29 (s, 1H), N HN 8.01 (t, 1H), 7.87 (d, 1H), 6.91 (d, 1H), 6.48 (d, / \ 1H), 6.42 (s, 1H), 4.29-4.26 (m, 4H), 3.68 (d, 2H), 17/18 N 10, 0 2.50 (s, 3H), 1.85 (t, 2H), 1.51-1.49 (m, 3H), 1.35-1.25 (m, 12H), 0.99-0.94 (m, 5H), 0.90-0.64 (m, ) = 9H). MS: 516.3 (M+1).
HO
1H-NMR (400 MHz, DMSO-d6) 6: 12.17 (s, 1H), o (3h-1\-IN 7.53 (t, 1H), 6.91 (d, 1H), 6.49 (d, 1H), 6.42 (s, 1H), 4.28 (t, 2H), 3.67 (d, 2H), 3.12 (d, 2H), 2.49 17/19 / \
0 (s, 3H), 2.12 (d, 2H), 1.85 (t, 2H), 1.52-1.50 (m, 3H), 1.35-1.24 (m, 12H), 1.00-0.87 (m, 13H), 0.72-0.65 (m, 2H). MS: 549.1 (M+1).
0) =
# Structure Analytical data o 1H-NMR (400 MHz, DMSO-d6) 6: 7.66 (t, 1H), 7.54 -----)-T-IN (br s, 1H), 6.89 (d, 1H), 6.82 (s, 1H), 6.48 (d, 1H), / \ 6.37 (s, 1H), 4.27 (t, 2H), 3.65 (d, 2H), 3.11 (d, &
0 1H), 2.46 (s, 3H), 1.97 (s, 2H), 1.84 (t, 2H), 1.51-= 1.49 (m, 3H), 1.34-1.26 (m, 12H), 0.99-0.88 (m, 13H), 0.70-0.62 (m, 2H). MS: 548.3 (M+1).
o ,f o 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 (d, 1H), 6.08 (s, 1H), 6.00 (d, 1H), 4.64-4.60 (m, HN 1H), 4.34 (t, 2H), 3.65 (d, 2H), 3.54-3.48 (m, 2H), 17/21 / \ 3.14-3.09 (m, 2H), 2.59 (s, 3H), 1.90 (t, 2H), 1.59-1.53 (m, 3H), 1.45-1.34 (m, 12H), 1.04-1.00 (m, 5H), 0.87-0.84 (m, 2H), 0.73-0.62 (m, 2H). MS:
&
0 = 503.4 (M+1).
HO..,_, 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 o (d, 1H), 6.05 (s, 1H), 5.89 (d, 1H), 4.85-4.84 (m, HN 1H), 4.62-4.58 (m, 1H), 4.35-4.29 (m, 3H), 3.65 (d, 17/22 / \ 2H), 2.96-2.89 (m, 1H), 2.58-2.50 (m, 4H), 1.90 (t, N *
0 2H), 1.57 (m, 6H), 1.42-1.25 (m, 12H), 1.03-1.00 0) = (m, 5H), 0.88-0.84 (m, 2H), 0.72-0.66 (m, 2H).
MS: 519.3 (M+1).
HO
>____\ 0 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 F3c HN (d, 1H), 6.13 (t, 1H), 6.08 (s, 1H), 4.34 (t, 2H), / \ 4.14-4.10 (m, 1H), 3.75-3.63 (m, 4H), 2.58 (s, 3H), 17/23 N *
1.90 (t, 2H), 1.59-1.54 (m, 3H), 1.45-1.35 (m, 0 ) = 12H), 1.04-0.99 (m, 5H), 0.87-0.84 (m, 2H), 0.72-0.65 (m, 2H). MS: 547.3 (M+1).
H
0,1\10 1H-NMR (400 MHz, CDCI3) 6: 7.96 (s, 1H), 6.95 's¨( 0 HN (d, 1H), 6.45 (d, 1H), 6.41 (d, 1H), 6.14 (d, 1H), 6.11 (s, 1H), 4.34 (t, 2H), 3.64 (d, 2H), 2.58 (s, 17/24 1 \ 110, 3H), 1.90 (t, 2H), 1.57 (br s, 3H), 1.49-1.34 (m, N
0 12H), 1.04-0.99 (m, 5H), 0.87-0.85 (m, 2H), 0.72-CI) 0.65 (m, 2H). MS: 550.2 (M+1).
=
o, Ns, ¨I
`----1 0 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 (d, 1H), 6.08 (s, 1H), 6.02 (d, 1H), 4.65-4.58 (m, FIN 1H), 4.34 (t, 2H), 4.18-4.13 (m, 2H), 3.64 (d, 2H), 17/25 / \3.22-3.17 (m, 2H), 2.57 (s, 3H), 1.91 (t, 2H), 1.57 N
0 (br s, 3H), 1.37-1.34 (m, 12H), 1.03-1.00 (m, 5H), 0.88-0.85 (m, 2H), 0.72-0.64 (m, 2H). MS: 523.2 & 11 (M+1).
# Structure Analytical data o 1H-NMR (400 MHz, DMSO-d6) 5: 11.45 (s, 1H), o- ---HN o 7.59 (br s, 1H), 6.90 (d, 1H), 6.48 (d, 1H), 6.35 (s, ---TIN 1H), 4.28 (t, 2H), 3.66 (d, 2H), 3.37 (s, 2H), 3.17-17/26 /\ 3.14 (m, 3H), 2.46(s, 2H), 1.85 (t, 2H), 1.51-1.49 0 (m, 3H), 1.34-1.25 (m, 12H), 1.10 (s, 6H), 0.98-0.95 (m, 5H), 0.88-0.86 (m, 2H), 0.68-0.62 (m, 0) = 2H). MS: 612.3 (M+1).
1H-NMR (400 MHz, DMSO-d6) 5: 7.41 (br s, 1H), HN HN 6.91 (d, 1H), 6.49 (d, 1H), 6.45 (s, 1H), 4.28 (t, 2H), 3.67 (d, 2H, J = 6.8 Hz), 3.09 (d, 2H, J = 6.4 =NCI /\ Hz), 2.49 (s, 3H), 2.01-1.84 (m, 4H),1.52-1.49 (m, 17/27 N *
0 3H), 1.35-1.23 (m, 12H), 1.00-0.94 (m, 11H), 0.89-CIA
0) = 0.87 (m, 2H), 0.70-0.65 (m, 2H). MS: 506.2 [(M¨
+.
o 1H-NMR (400 MHz, DMSO-d6) 5: 7.77 (t, 1H), 7.66 HN HN (s, 1H), 6.90 (d, 1H, J = 2.0 Hz), 6.49 (d, 1H, J =
---- / \ 2.0 Hz), 6.37 (s, 1H), 4.28 (t, 2H), 3.66 (d, 2H, J =
0 *
0 6.8 Hz), 3.29 (d, 2H), 2.49 (s, 3H), 1.85 (t, 2H), CI) = 1.76 (s, 3H), 1.52-1.50 (m, 3H), 1.35-1.22 (m, 18H), 0.99-0.87 (m, 7H), 0.71-0.65 (m, 2H). MS:
548.4 (M+1).
o HO---( 1H-NMR (400 MHz, DMSO-d6) 5: 7.68-7.63(m, NH 2H), 6.91 (d, 1H, J = 2.4 Hz), 6.49 (d, 1H, J = 2.0 0 Hz), 6.39 (s, 1H), 4.28 (t, 2H), 3.68 (d, 2H, J = 6.8 7)1\-IN Hz), 3.32 (d, 2H, J = 6.0 Hz), 2.49 (s, 3H), 2.40 (t, 17/29 2H), 2.27 (t, 2H), 1.85 (t, 2H), 1.52-1.50 (m, 3H), / \
N IP1.34-1.23 (m, 12H), 1.21 (s, 6H), 0.99-0.97 (m, o 5H), 0.89-0.87 (m, 2H), 0.71-0.65 (m, 2H). MS:
0) = 606.4 (M+1).
HO¨' r-NH 1H-NMR (400 MHz, CDCI3) 5: 7.48 (s, 2H), 6.97 o (d, 1H, J = 2.0 Hz), 6.54(t, 1H), 6.43 (d, 1H,J =
V)-7-1N 2.4 Hz), 6.13 (s, 1H), 4.33 (t, 2H), 3.97 (s, 2H), / \
17/30 N lip 0 3.63 (d, 2H, J = 7.6 Hz), 3.45 (d, 2H, J =
6.8 Hz), 2.58 (s, 3H), 1.90 (t, 2H), 1.58 (br s, 3H), 1.49-0) if 1.28 (m, 18H), 1.04-1.00 (m, 5H), 0.86-0.84 (m, 2H), 0.73-0.65 (m, 2H).
HO 1H-NMR (400 MHz, CDCI3) 5: 7.32 (s, 1H), 6.97 \---)r-NH (d, 1H, J = 1.6 Hz), 6.43 (d, 1H, J = 2.0 Hz), 6.40 O
o (t, 1H), 6.12 (s, 1H), 4.34 (t, 2H), 3.88 (br s, 2H), Vrl\-1N 3.64 (d, 2H, J = 7.2 Hz), 3.42 (d, 2H, J =
6.4 Hz), 17/31 / \ 2.58 (s, 3H), 2.37 (br s, 2H), 1.90 (t, 2H), 1.57-0 1.54 (m, 3H), 1.46-1.38 (m, 18H), 1.05-1.00 (m, 0)5H), 0.87-0.84 (m, 2H), 0.73-0.68 (m, 2H). MS:
= 578.3 (M+1).
# Structure Analytical data 0S-NH 11-1-NMR (400 MHz, DMSO-d6) 6: 7.68 (t, 1H), 7.09 7ri-IN (s, 1H), 6.91 (d, 1H, J = 1.6 Hz), 6.49(d, 1H, J =
1.6 Hz), 6.38 (s, 1H), 4.28 (t, 2H), 3.68 (d, 2H, J =
o /\ 7.2 Hz), 3.62 (t, 2H), 3.25 (t, 4H), 3.17 (s, 3H), 17/32 , N *
0 2.50 (s, 3H), 1.85 (t, 2H), 1.51-1.49 (m,3H), 1.35 (s, 9H), 1.31-1.28 (m, 9H), 0.99-0.87 (m, 7H), 0) 1 0.71-0.64 (m, 2H). MS: 628.3 (M+1).
9 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H,J =
2.0 O r Hz), 6.43 (d, 1H,J = 2.0 Hz), 6.33 (t, 1H), 6.13 (s, 1H), 5.34 (br s,1H), 4.33 (t, 2H), 3.64 (d, 2H, J =
)-7-IN
7.2 Hz), 3.48 (d, 2H,J = 6.4 Hz), 2.58 (s, 3H), / \
N 110 2.47-2.42 (m, 1H), 1.90 (m, 2H), 1.58-1.54 (m, 3H), 1.46-1.33 (m, 18H), 1.21-1.17 (m, 2H), 1.04-0.94 (m, 7H), 0.86-0.84 (m, 2H), 0.73-0.65 (m, d = 2H). MS: 610.2 (M+1).
i-OH
r 0 1H-NMR (400 MHz, CDCI3) 6: 6.95 (d, 1H), 6.66 ot\NH (br t, 1H), 6.42 (d, 1H), 6.21 (m, 1H), 6.08 (s, 1H), HN 4.33 (m, 2H), 3.87-3.82 (m, 2H), 3.68-3.56 (m, o 17/34 / \ 8H), 3.46-3.44 (m, 2H), 2.56 (s, 3H), 1.99-1.95 (m, N *
0 2H), 1.90 (t, 2H), 1.70-1.57 (m, 7H), 1.43-1.32 (m, 12H), 1.03-1.00 (m, 5H), 0.87-0.84 (m, 2H), 0.71-O)1 0.65 (m, 2H). MS: 634.3 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 8.31-8.25 (m, 1H), 0 0 NH 7.87 (s, 1H), 6.97 (d, 1H, J = 2.0 Hz), 6.44 (d, 1H, 0 J = 2.0 Hz) ,6.29 (t, J = 6.6 Hz, 1H), 6.11 (s, 1H), o----s Hz), 3.35 (d, 2H, J = 6.4 Hz), 3.06 (dd, J = 4.0, J =
17/35 / \
N *16.0 Hz, 1H), 2.79 (dd, J = 6.0, J = 16.0 Hz, 1H), o)2.58 (s, 3H), 1.85 (t, 2H), 1.59-1.54 (m, 3H), 1.47-111 1.38 (m, 18H), 1.05-1.00 (m, 5H), 0.88-0.84 (m, 2H), 0.74-0.69 (m, 2H). MS: 663.1 (M+1).
OH 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 oi----\ o HN (d, 1H), 6.30 (t, 1H), 6.18 (s, 1H), 6.09 (s, 1H), 4.65 (d, 2H), 4.42 (d, 2H), 4.34 (t, 2H), 3.82 (d, /\
17/36 N 2H), 3.64 (d, 2H), 2.57 (s, 3H), 1.90 (t, 2H), 1.57 lp 0 (s, 3H), 1.38-1.34 (m, 12H), 1.04-0.99 (m, 5H), (m+1).
"311 0 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 s\_...r FIN (d, 1H), 6.08-6.05 (m, 2H), 4.33 (t, 2H), 3.64 (d, / \ 2H), 3.36 (d, 2H), 3.02 (t, 3H), 2.58 (s, 3H), 2.44 17/37 N *
(d, 2H), 1.98-1.89 (m, 4H), 1.84-1.57 (m, 4H), 1.43-1.35 (m, 12H), 1.04-0.99 (m, 5H), 0.87-0.84 (m, 2H), 0.72-0.64 (m, 2H). MS: 565.3 (M+1).
0) 11 # Structure Analytical data OH 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 o,s0L¨.
(d, 1H), 6.19 (t, 1H), 6.11 (s, 1H), 4.34 (t, 2H), 3.64 (d, 2H), 3.41 (d, 2H), 2.98-2.83 (m, 4H), 2.58 /\
17/38 N (s, 3H), 2.25 (td, 2H), 1.90 (t, 2H), 1.77-1.74 (m, *
0 2H), 1.59-1.54 (m, 3H), 1.44-1.38 (m, 12H), 1.04-0.99 (m, 5H), 0.87-0.84 (m, 2H), 0.72-0.66 (m, ) = 2H). MS: 581.3 (M+1).
002_\HN 0 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 (d, 1H), 6.08 (s, 1H), 4.33 (t, 2H), 3.85-3.77 (m, / \ 4H), 3.63 (d, 2H), 3.54 (s, 2H), 3.26 (s, 3H), 2.39 17/39 N lip, 0 (s, 3H), 1.90 (m, 2H), 1.67-1.57 (m, 7H), 1.38-1.34 (m, 12H), 1.04-1.00 (m, 5H), 0.86-0.84 (m, 2H), 0.72-0.65 (m, 2H). MS: 563.3 (M+1).
0) =
HO
cO;0 0 1H-NMR (400 MHz, DMSO-d6) 6: 12.49 (br s, 1H), N 7.46 (t, 1H), 6.90 (d, 1H), 6.48 (d, 1H), 6.36 (s, 17/40 / \
0 1H), 4.28 (t, 2H), 3.74 (dd, 2H), 3.66 (d, 2H), 3.36-N
3.27 (m, 4H), 2.47 (s, 3H), 1.86-1.84 (m, 4H), 1.51-1.45 (m, 5H), 1.35-1.23 (m, 12H), 1.00-0.87 O)1(m, 7H), 0.71-0.64 (m, 2H).
orYO 1H-NMR (400 MHz, DMSO-d6) 6: 7.28-7.24 (m, o 2H), 7.03 (br s, 1H), 6.90 (d, 1H), 6.48 (d, 1H), i\-IN
6.34 (s, 1H), 4.28 (m, 2H), 3.70-3.65 (m, 4H), \
N
0 3.32-3.30 (m, 4H), 2.48 (s, 3H), 1.93-1.84 (m, 4H), *
1.51-1.42 (m, 5H), 1.35-1.24 (m, 12H), 1.00-0.85 (m, 7H), 0.71-0.63 (m, 2H). MS: 576.1 (M+1).
CI) =
oq1H-NMR (300 MHz, CDCI3) 6: 7.22 (d, J = 7.8 Hz, o 1H), 7.01 (s, 1H), 6.23 (s, 1H), 6.19 (d, J = 5.4 Hz, HN
1H), 5.26-5.20 (m, 1H), 4.99 (t, J = 5.1 Hz, 2H), / \ 4.58 (t, J = 4.8 Hz, 2H), 3.76 (d, J = 5.4 Hz, 2H), 17/42 N lip 2.96 (d, J = 15.9 Hz, 2H), 2.60 (s, 3H), 1.57-1.51 0) F (m, 3H), 1.37--1.25 (m, 19H), 0.98-0.96 (m, 4H), 0.64-0.58 (m, 2H). MS: 483.4 (M+1).
o--\ 0 1H-NMR (400 MHz, DMSO-d6) 6: 7.78 (t, 1H), 7.35 HN (t, 1H), 7.15 (d, 2H), 6.47 (s, 1H), 4.60 (dd, 2H), / \ 4.33 (t, 2H), 3.75 (d, 2H), 3.43 (t, 2H), 3.14-3.06 17/43 N * (n, 1H), 1.52 (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.21 0) (m, 21H), 0.94-0.83 (m, 3H), 0.67-0.60 (m, 2H).
MS: 479.4 (M+1).
o 1H-NMR (400 MHz, DMSO-d6) 6: 7.74 (t, 1H), 7.36 N (s, 1H), 7.15 (d, 2H), 6.51 (s, 1H), 4.49 (t, 1H), / \ 4.40 (d, 2H), 4.30 (d, 2H), 3.75 (d, 2H), 3.55 (dd, N * 2H), 3.46 (d, 2H), 2.52 (s, 3H), 1.80 (t, 2H), 1.45 0) (d, 3H), 1.31-1.19 (m, 21H), 0.95-0.90 (m, 3H), 0.67-0.59 (m, 2H). MS: 523.4 (M+1).
# Structure Analytical data o 1H-NMR (400 MHz, DMSO-d6) 6: 7.35 (t, 1H), 7.15 (d, 2H), 6.28 (s, 1H), 4.76 (t, 1H), 4.27-4.02 (m, Ho/N / \ 3H), 3.79 (d, 2H), 3.60-3.57 (m, 1H), 3.34 (in 17/45 N . solvent signal, 1H), 2.53 (s, 3H), 1.46-1.43 (m, d 3H), 1.30-1.21 (m, 21H), 0.94-0.85 (m, 3H), 0.68-0.60 (m, 2H). MS: 465.1 (M+1).
o oiY 1H-NMR (400 MHz, DMSO-d6) 5: 8.16 (s, 1H), HN 7.49 (d, 1H), 7.36 (m, 2H), 7.15 (d, 1H), 4.66 (d, o / \ 2H), 4.54 (d, 2H), 3.76 (d, 2H), 3.57 (s, 3H), 3.14 N * (s, 2H), 2.50 (s, 3H), 1.45 (d, 3H), 1.31-1.13 (m, 21H), 0.95-0.84 (m, 3H), 0.68-0.60 (m, 2H). MS:
d 537.4 (M+1).
037\ o 1H-NMR (400 MHz, DMSO-d6) 5: 7.81 (t, 1H), 7.20 HN (t, 1H), 7.15 (s, 1H), 6.98 (s, 1H), 6.53 (s, 1H), IP
0 / \
\ ' 4.41 (d, 2H), 4.27 (d, 2H), 3.76 (d, 2H), 3.48 (s, 17/47 N * 2H), 3.41 (d, 2H), 3.32 (s, 3H), 2.52 (s, 3H), 1.46 d (br d, 3H), 1.40(s, 3H), 1.33-1.24(m, 12H), 0.96-0.61 (m, 9H). MS: 521.3 (M+1).
, oOH 1H-NMR (500 MHz, CDCI3) 5: 7.26 (d, J =
1.5 Hz, \....../ FIN 1H), 7.01 (d, J = 1.0 Hz, 1H), 6.22 (s 2H), 4.08 (br / \ s, 1H), 3.83-3.74 (m, 4H), 3.71 (d, J =
7.5 Hz, 2H), 17/48 N *
N--- 3.66 (s, 3H), 3.45 (d, J = 6.0Hz, 2H), 2.61 (s, 3H), 1.82-1.80 (m, 1H),1.66-1.53 (m, 15H), 1.41-1.36 d a MS: 564.3 (M+1).
(m, 9H), 1.03-1.01 (m, 3H), 0.70-0.64 (m, 2H).
HO 1H-NMR (500 MHz, CDCI3) 6: 7.27 (d, J =
1.5 Hz, o -IN 1H), 7.03 (d, J = 1.5 Hz, 1H), 6.40 (t, J
= 6.5 Hz, ----I\
1H), 6.20 (s, 1H), 3.70 (d, J = 7.0 Hz, 2H), 3.67 (s, 17/49 / \ 3H), 3.66 (d, J = 6.5 Hz, 2H), 2.60 (s, 3H), 1.57-d N * N ...... 1.54 (m, 12H), 1.38 (s, 9H), 1.31 (s, 6H), 1.03-1.01 (m, 3H), 0.71-0.65 (m, 2H). MS: 550.4 (M+1).
_v o 4 1H-NMR (400 MHz, DMSO-d6) 5: 12.20 (s, 1H), HOOC N 8.05 (s, 1H), 6.90 (d, 1H), 6.47 (d, 1H), 6.40 (s, H I \ * 0 1H), 4.27-4.29 (t, 2H), 3.66-3.67 (d, 2H), 2.49-2.51 N
d (m, 3H), 1.84-1.87(t, 2H), 1.50-1.52 (t, 3H), 1.25-1.35 (m, 14H), 0.96-1.03 (m, 7H) ,0.66-0.69 (d, 2H), 0.64 (d, 2H). MS: 519.2 (M+1).
o 4 1H-NMR (400 MHz, DMSO-d6) 6:12.32 (s, 1H), HOOC 7.40-7.43 (t, 1H), 6.90 (d, 1H), 6.48 (d, 1H), 6.35 2cN
H I \ * 0 (s, 1H), 4.27-4.29 (t, 2H), 3.65-3.67 (d, 2H), 3.46-17/51 N 3.47 (d, 2H), 2.48 (s, 3H), 1.83-1.86 (t, 2H) , 1.49-C) 1.51 (m, 3H), 1.25-1.35 (m, 12H) , 0.93-1.00 (m, 7H), 0.87-0.89 (m, 4H), 0.66-0.69 (m, 2H). MS:
533.3 (M+1)+.
# Structure Analytical data o 4 1H-NMR (400 MHz, DMSO-d6) 6:12.66 (s, 1H), 6.90-6.90 (d, 1H), 6.49 (d, 1H), 6.09 (s, 1H), 3.96-4.42 (m, 6H), 3.67-3.69 (d, 2H), 3.38 (s, 1H), 2.45 17/52 HOOC 4N I \ = 0 N
d (s, 3H), 1.83-1.86 (t, 2H), 1.50-1.51 (m, 3H) , 1.25-1.34 (m, 12H), 0.98-1.02 (m, 5H), 0.87 (m, 2H), 0.65-0.68 (m, 2H). MS: 519.1 (M+1).
o 4 11-1-NMR (400 MHz, DMSO-d6) 6: 12.26 (s, 1H), 6.91 (d, 1H), 6.50 (d, 1H), 5.95 (s, 1H), 4.27 (t, CN 1 \ .
0 2H 4.09-4.11 m 2H 3.68 d 2H 2.95 m 2H
), ( , ), ( , ), ( , ), 17/53 HOOC N 2.46-2.51 (m, 1H), 2.24 (s, 3H), 1.81-1.86 (m, 4H), d 1.23-1.52 (m, 17H), 0.96-1.05 (m, 5H), 0.85-0.87 (m, 2H), 0.65-0.73 (m, 2H). MS: 547.3 (M+1)+.
o 4 1H-NMR (400 MHz, DMSO-d6) 6:12.42 (s, 1H), 6.91 (d, 1H), 6.49 (d, 1H), 5.94 (s, 1H), 4.27 (t, N I \ . 0 2H), 3.84 (m, 2H), 3.67 (d, 2H), 3.13 (s, 2H), 2.24 Hooc0 d 17/54 N (s, 3H), 1.92 (d, 2H), 1.84 (t, 2H), 1.50-1.52 (m, 3H), 1.23-1.34 (m, 14H), 1.16 (m, 3H), 0.96-1.01 (m, 5H), 0.86-0.88 (m, 2H), 0.68-0.70 (m, 2H).
MS: 561.4 (M+1)+.
HOOCv:\ o 1H-NMR (400 MHz, DMSO-d6) 6:12.15 (s, 1H), 4 7.76 (d, 1H), 6.91 (d, 1H), 6.49 (d, 1H), 6.42 (s, N 1H), 4.47-4.53 (m, 1H), 4.28 (t, 2H), 3.67 (d, 2H), H I \ ill o 2.88-2.92 (d, 1H), 2.47 (s, 3H), 2.24-2.40 (m, 4H), d 1.84-1.87 (m, 2H), 1.49-1.51 (m, 3H), 1.24-1.35 (m, 12H), 0.94-0.98 (m, 5H), 0.87-0.89 (m, 2H), 0.62-0.68 (m, 2H). MS: 533.3 (M+1)+.
HOOC o 4 1H-NMR (400 MHz, DMSO-d6) 6:12.07 (s, 1H), 7.75 (d, 1H), 6.91 (d, 1H), 6.49 (d, 1H), 6.43 (s, N
H I \ . 0 1H), 4.27-4.31 (m, 3H), 3.68 (d, 2H), 2.71 (t, 1H), 17/56 N 2.48 (s, 3H), 2.38-2.41 (m, 2H), 2.34-2.37 (m, 2H), d 2.16-2.19 (m, 2H), 1.48-1.50 (m, 3H), 1.23-1.35 (m, 12H), 0.93-0.98 (m, 5H), 0.87-0.90 (m, 2H), 0.65-0.68 (m, 2H). MS: 533.3 (M+1)+.
Hooc 1H-NMR (400 MHz, DMSO-d6) 6: 12.06 (s, 1H), 0, o 4 7.28 (d, 1H), 6.90 (d, 1H), 6.47 (d, 1H), 6.38 (s, 'N 1H), 4.28 (t, 2H), 3.66 (d, 3H), 2.48 (s, 3H), 2.09-H I \ 4I 0 2.14 (m, 1H), 1.90-1.94(m, 2H), 1.84-1.86 (m, d 4H), 1.49-1.51 (m, 3H), 1.24-1.39 (m, 16H), 0.97-1.00 (m, 5H), 0.91-0.94 (m, 2H), 0.62-0.70 (m, 2H). MS: 561 (M+1)+.
HOOC
U 0 1 1H-NMR (400 MHz, CD30D) 5: 6.98 (s, 1H), 6.50 (d, 1H), 6.32 (s, 1H), 4.33 (t, 2H), 3.92 (m, 1H), N
H I \ * 0 3.73 (d, 2H), 2.58 (m, 1H), 2.52 (s, 3H), 2.09 (m, 17/58 N 2H), 1.91 (m, 2H), 1.56-1.77 (m, 9H), 1.30-1.42 d (m, 12H), 1.01-1.07 (m, 5H), 0.88-0.90 (m, 2H), 0.67-0.76 (m, 2H). MS: 561 (M+1)+.
# Structure Analytical data , o 4 1H-NMR (400 MHz, CDCI3) 6: 6.97 (s, 1H), 6.43 (d, 1H), 6.06 (s, 1H), 5.80 (s, 1H), 4.33 (m, 2H), N 3.63 (d 2H) 3.25 (m, 2H), 2.59 (s, 3H), 2.25-2.32 HOOC H I \ * 0 "
(m, 1H), 2.01-2.06 (m, 2H), 1.89-1.91 (m, 4H), N
C)1.52-1.56 (m, 4H), 1.42-1.48 (m, 2H), 1.25-1.38 (m, 12H),1.00-1.07 (m, 7H), 0.84-0.86 (m, 2H), 0.67-0.73 (m, 2H). MS: 575.5 (M+1)+.
HOOC ,..N 1H-NMR (400 MHz, DMSO-d6) 6: 12.22 (s, 1H), N 7.42 (m, 1H), 7.19 (s, 1H), 7.15 (s, 1H), 6.97 (S, H I \ = 1H), 6.49 (s, 1H), 3.76 (d, 2H), 3.36 (s, 2H), 2.50 17/60 N (s, 3H), 1.47 (d, 3H), 1.40 (s, 3H), 1.30-1.23 (m, d 12H), 1.08 (s, 6H), 0.93 (m, 3H), 0.84 (m, 2H), 0.76 (m, 2H), 0.64 (m, 2H). MS: 507.3 (M+1)+.
0 4 1H-NMR (400 MHz, DMSO-d6) 5: 12.48 (s, 1H), HOOC 7.56 (m, 1H), 7.19 (s, 1H), 7.15 (s, 1H), 6.97 (s, 0 N I \ * 1H), 6.49 (s, 1H), 3.73-3.77 (m, 4H), 3.27-3.32 (m, 4H), 2.50 (s, 3H), 1.85 (d, 2H), 1.45-1.50 (m, 5H), d 1.40 (s, 3H), 1.30-1.23 (m, 12H), 0.95 (m, 3H), 0.84 (m, 2H) 0.76 (m, 2H), 0.64 (m, 2H). MS: 549 (M+1)+
0 0 4 1H-NMR (400 MHz, DMSO-d6) 5: 7.34 (m, 1H), 7.29 (s, 1H), 7.19 (s, 1H), 7.14 (s, 1H), 7.04 (s, I N I \ = 1H), 6.97 (s, 1H), 6.47 (s, 1H), 3.76 (d, 2H), 3.65 d (m, 2H), 3.34-3.28 (m, 4H), 2.51 (s, 3H), 1.91 (d, 2H), 1.45-1.50 (m, 4H), 1.40 (s, 3H), 1.30-1.20 (m, 12H), 0.92 (m, 3H), 0.83 (m, 2H), 0.76 (m, 2H), 0.64 (m, 2H). MS: 548.3 (M+1)+
0 4 1H-NMR (400 MHz, CDCI3) 5: 7.25 (s, 1H), 7.13 (m, 1H), 7.00 (m, 1H), 6.15 (s, 1H), 5.86 (m, 1H), I:01 I \ Ilk 3.98 (m, 2H), 3.71 (d, 2H), 3.38 (m, 2H), 3.29 (m, 17/63 N 2H), 2.62 (s, 3H), 1.85 (m, 1H), 1.68 (m, 2H), 1.53 d (m, 3H), 1.40 (s, 3H), 1.38-1.33 (m, 14H), 1.00 (m, 3H), 0.87 (m, 2H), 0.75 (m, 2H), 0.64 (m, 2H). MS:
505.4 (M+1)+.
OH 0 4 1H-NMR (400 MHz, DMSO-d6) 5: 7.54 (m, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 6.98 (s, 1H), 6.53 (s, N
cca-NH I \ * 1H), 4.78 (s, 2H), 3.77 (d, 2H), 3.59 (m, 4H), 3.22 d 17/64 N (d, 2H), 2.52 (s, 3H), 1.60-1.45 (m, 4H), 1.40-1.34 (m, 5H), 1.30-1.23 (m, 12H), 0.93 (m, 3H), 0.83 (m, 2H), 0.76 (m, 2H), 0.64 (m, 2H). MS: 521.3 (M+1)+.
0 4 1H-NMR (400 MHz, CDCI3) 5: 7.25 (s, 1H), 7.12 ca 0 (s, 1H), 7.00 (s, 1H), 6.15 (s, 1H), 5.89 (d, 1H), N
H 4.69 (m, 1H), 4.00-3.90 (m, 2H), 3.82 (m, 1H), I \ .
17/65 N 3.75-3.70 (m, 3H), 2.61 (s, 3H), 2.31 (m, 1H), 1.88 d (m, 1H), 1.56 (m, 3H), 1.42 (m, 3H), 1.41-1.33 (m, 12H), 1.00 (m, 3H), 0.88 (m, 2H), 0.75 (m, 2H), 0.65 (m, 2H). MS: 477.4 (M+1)+.
# Structure Analytical data 0N 4 1H-NMR (400 MHz, CDCI3) 6: 7.25 (s, 1H), 7.12 .µ 0 (s, 1H), 7.00 (s, 1H), 6.15 (s, 1H), 5.89 (d, 1H), ' H I \ Mk 4.00-3.91 (m, 2H), 3.83 (m, 1H), 3.75-3.71 (m, 17/66 N 3H), 2.61 (s, 3H), 2.31 (m, 1H), 1.88 (m, 1H), 1.53 d (m, 3H), 1.42 (m, 3H), 1.41-1.33 (m, 12H), 1.00 (m, 3H), 0.87 (m, 2H), 0.75 (m, 2H), 0.65 (m, 2H).
MS: 477.2 (M+1)+.
O H 0 4 1H-NMR (400 MHz, CDCI3) 5: 7.26 (s, 1H), 7.13 Ni,' N
S (m, 1H), 7.01 (s, 1H), 6.30 (m, 1H), 6.22 (s, 1H), O fr-1 1 \ . 3.71 (d, 2H), 3.47 (d, 2H), 3.02 (s, 3H), 2.61 (s, 17/67 N 3H), 1.54 (m, 3H), 1.43 (s, 9H), 1.39-1.26(m, ) 12H), 0.99 (m, 3H), 0.87 (m, 2H) 0.75 (m, 2H), 0.65 (m, 2H). MS: 556.3 (M+1)+.
N 1H-NMR (400 MHz, CDCI3) 6: 7.26 (m, 1H), 7.14 (m, 1H), 7.02 (m, 1H), 6.22 (m, 1H), 6.06 (m, 1H), H I \ . 3.71 (d, 2H), 3.43 (d, 2H), 3.21 (s, 3H), 2.61 (s, d 17/68 N 3H), 1.53 (m, 3H), 1.49 (s, 3H), 1.42-1.33 (m, 12H), 1.20 (s, 6H), 0.99 (m, 3H), 0.87 (m, 2H), 0.74 (m, 2H), 0.65 (m, 2H). MS: 493.5 (M+1)+.
n 0 , 1H-NMR (400 MHz, DMSO-d6) 6: 8.20 (d, 1H, J =
8.0 Hz), 7.93 -7.90 (m, 2 H), 7.58 (d 1H, J = 8.0 N\----N \ . 1 Hz), 6.91 (s, 1H), 3.95-3.85 (m, 5H), 3.51-3.50 (m, H I \ 2H), 3.38-3.34 (m, 2H), 2.55-2.50 (m, 3H), 1.72-17/69 N 0 1.62 (m, 2 H), 1.56 (m, 4 H), 1.55-1.45 (m, 7H), d c,3 1.23 (m,9 H), 0.95-0.86 (m, 3H), 0.67-0.64 (m, 2H). MS: 624.3 (M+H)+.
,N-N
N: ...k.,...õ o 4 1H-NMR (400 MHz, DMSO-d6) 6: 7.85 (m, 1H), N 7.19 (m, 1H), 7.14 (m, 1H), 6.96 (m, 1H), 6.43 (s, H N
H I \ iir 1H), 3.76 (d, 2H), 3.52 (m, 2H), 3.07 (m, 2H), 2.50 17/70 N (s, 3H), 1.46 (m, 2H), 1.39 (s, 3H), 1.29-1.22 (m, C) 12H), 0.96-0.91 (m, 3H), 0.85-0.81 (m, 2H), 0.77-0.75 (m, 2H), 0.65-0.62 (m, 2H). MS: 503.2 (M+1)+.
0 4 1H-NMR (400 MHz, DMSO-d6) 6: 8.27 (m, 1H), N
INIµ Y--NN 7.19 (s, 1H), 7.15 (s, 1H), 6.98 (s, 1H), 6.56 (s, l'N-NH H I \ 1, 1H), 4.61 (d, 2H), 3.79 (d, 2H), 2.53 (s, 3H), 1.46 17/71 N (m, 3H), 1.40 (s, 3H), 1.30-1.22 (m, 12H), 0.96-d 0.90 (m, 3H), 0.85-0.79 (m, 2H), 0.78-0.75 (m, 2H), 0.68-0.60 (m, 2H). MS: 489.2 (M+1)+.
Oa 0 0 y_ N
\ 1H-NMR (400 MHz, DMSO-d6) 5: 8.10 (d, 1H), 7.56 (s,1H), 7.49 (d, 1H), 7.43 (d, 1H), 7.35 (s, N
H I \ .. 1H), 6.72 (s, 1H), 6.03 (s, 1H), 3.84-3.94 (m, 5H), 17/72 N 3.36 (m, 2H), 2.53 (s, 3H), 1.67-1.70 (m, 8H), 1.53 C) NH
0 (m, 2H), 1.45 (m, 3H), 1.23 (m, 3H), 1.12 (s, 9H), 0.88 (m, 3H), 0.60 (m, 2H). MS: 574.3 (M+1)+.
# Structure Analytical data HOk_N
1H-NMR (400 MHz, DMSO-d6) 6: 11.93 (s, 1H), o o HN 7.61 (d, 1H), 7.18 (t, 1H), 7.14 (d, 1H), 6.97 (s, 1H), 6.47 (s, 1H), 3.76(d, 2H), 3.17-3.12 (m, 2H), 17/73 / \
N # 2.51 (s, 3H), 1.70-1.66 (m, 2H), 1.46 (d, 3H), 1.40 (s, 3H), 1.30-1.13 (m, 12H), 0.95-0.62 (m, 9H).
MS: 521.2 (M+1).
0) 11 k o 1H-NMR (400 MHz, DMSO-d6) 5: 7.61 (t, 1H), 7.18 HN (d, 1H), 7.15 (d, 1H), 6.97 (s, 1H), 6.86 (s, 1H), / \ 6.47 (s, 1H), 3.76 (d, 2H), 3.114-3.09 (m, 2H), 17/74 N . 2.51 (s, 3H), 1.67-1.63 (m, 2H), 1.46 (d, 3H), 1.40 (s, 3H), 1.30-1.21 (m, 12H), 1.09 (s, 6H), 0.95-0.62 (m, 9H). MS: 520.4 (M+1).
0) II
a0 y 1H-NMR (CDCI3, 300 MHz) 5: 7.99 (s, 1H), 7.76 0 NH (s, 2H), 6.28 (s, 1H), 6.10 (s, 1H), 5.68 (d, 1H, J =
N 8.0 Hz), 4.16 (m, 1H), 3.98 (m, 2H), 3.79 (d, 2H, J
H I \ .
N = 7.2 Hz), 3.53 (m, 2H), 2.62 (s, 3H), 1.98 (m, 2H), 1.58-1.52 (m, 5H), 1.49 (s, 18H), 1.40-1.33 NH
01, 3H), 1.00 (m, 3H), 0.64 (m, 2H). MS: 579.2 d o 1H-NMR (400 MHz, CDCI3) 6: 8.67 (d, 1H, J = 8.8 o HO Hz), 8.33 (d, 1H, J = 7.2 Hz), 7.90 (d, 1H, J = 8.8 KN
N
H 1 \ lit Hy Hz), 7.72-7.68 (m, 1H), 7.55-7.47 (m, 2H), 6.34 (s, 1H), 6.19 (t, 1H, J = 6.0 Hz), 4.62 (s, 1H), 3.68-17/76 3.63 (m, 1H), 3.42 (d, 2H, J = 6.0 Hz), 3.31-3.26 S=0 W 8 (m, 1H), 2.676 (s, 3H), 1.48 (br s, 3H), 1.28 (s, 6H), 1.26 (s, 3H), 1.21 (s, 9H), 0.94-0.86 (m, 3H), 0.52-0.47 (m, 2H). MS: 554.3 (M+1).
H
N-N
1\,1, jchN 0 V 1H-NMR (400 MHz, CDCI3) 5: 7.27 (m, 1H), 7.09 N (m, 1H), 6.98 (m, 1H), 6.29 (m, 1H), 6.15 (s, 1H), 17/77 H I \ . 3.76 (d, 2H, J = 7.6 Hz), 3.71 (d, 2H, J =
7.2 Hz), 2.64 (s, 3H), 1.55-1.52 (m, 9H), 1.48 (s, 3H), 1.41-N
d 1.24 (m, 12H), 1.00 (m, 3H), 0.86 (m, 2H), 0.74 (m, 2H), 0.66 (m, 2 H). MS: 531.4 (M+1)+.
o3 0 1H-NMR (400 MHz, CDCI3) 6: 7.26 (t, 1H), 7.13 (t, N 1H), 7.00 (t, 1H), 6.13 (s, 1H), 4.93 (br s, 1H), HO 4.61 (d, 2H), 4.47 (d, 2H), 3.91 (s, 2H), 3.82 (d, / \
CH
17/78 N 10, 2H), 3.71 (d, 2H), 3.12 (s, 3H), 2.38 (s, 3H), 1.58-1.53 (m, 3H), 1.42 (s, 3H), 1.36-1.25 (m, 12H), 1.01-0.98 (m, 3H), 0.86 (dd, 2H), 0.74 (dd, 2H), 0.68-0.60 (m, 2H). MS: 521.3 (M+1).
\ 1H-NMR (400 MHz, CDCI3) 5: 6.97 (d, 1H), 6.43 0 (d, 1H), 6.06 (s, 1H), 5.76 (t, 1H), 4.33 (t, 2H), HN 3.64 (d, 2H), 3.39 (q, 2H), 2.75-2.65 (m, 2H), 2.59 17/79 / \ (s, 3H), 2.56 (s, 3H), 1.90(t, 2H), 1.83-1.79(m, N * 2H), 1.57-1.51 (m, 7H), 1.45-1.33 (m, 12H), 1.03-O)1o 1.00 (m, 5H), 0.87-0.84 (m, 2H), 0.71-0.65 (m, 2H). MS: 567.3 [M+1]t # Structure Analytical data o--zI s 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 n\r\¨\ 0 (d, 1H), 6.08 (s, 1H), 5.99 (t, 1H), 4.34 (t, 2H), µ-' HN 3.64 (d, 2H), 3.59-3.54 (m, 2H), 3.14 (t, 2H), 2.92 /\ (s, 3H), 2.58 (s, 3H), 2.19-2.12 (m, 2H), 1.90 (t, 0 2H), 1.57 (br s, 3H), 1.44-1.36 (m, 12H), 1.04-1.00 (m, 5H), 0.87-0.84 (m, 2H), 0.72-0.65 (m, 2H).
0) Ill MS: 555.3 [M+1r.
OH 1H-NMR (400 MHz, CDCI3) 6: 6.95 (d, 1H), 6.42 c;IsD____\ o (d, 1H), 6.13 (t, 1H), 6.08 (s, 1H), 4.34 (t, 2H), 0' HN 3.64 (d, 2H), 3.50 (dt, 2H), 3.41 (d, 2H), 2.86 (dd, / 2H), 2.58 (s, 3H), 2.14-1.99 (m, 4H), 1.90 (m, 2H), 17/81 N\ .
0 1.59-1.41 (m, 3H), 1.38-1.28 (m, 12H), 1.04-0.99 (m, 5H), 0.88-0.85 (m, 2H), 0.73-0.65 (m, 2H).
CI) I MS: 597.4 (M+1).
o 17/82 N N¨ MS: 495.3 (M+H)+.
d a 1H-NMR (400 MHz, DMSO-d6) 6: 8.23 (d, 1H, J =
HN 8.0 8.0 Hz), 7.96-7.71 (m, 3H), 7.57 (d, 1H, J = 8.0 H \
N Hz), 6.88 (s, 1H), 3.95-3.85 (m, 5H), 3.38-3.32 (m, I IF
0 2H), 2.55 (m, 3H), 1.72-1.68 (m, 2H), 1.56-1.45 d c3 (m, 7H), 1.24-1.21 (m, 3H), 1.08 (m, 6H), 0.93-0.88 (m, 3H), 0.79-0.75 (m, 3H), 0.68-0.59 (m, 2H). MS: 598.3 (M+H)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.06-8.04 (m, N 1µ1 \
1 1H), 7.89-7.88 (m, 2H), 7.57 (d, 1H, J =
8.0 Hz), H I \ . S=0 6.88 (s, 1H), 3.95-3.88 (m, 6H), 3.56-3.52 (m, 2H), 17/84 N 8 2.38-3.33 (m, 2H), 2.56 (m, 3H), 1.95-1.92 (m, C) cF, 4H), 1.72-1.69(m, 2H), 1.56-1.46 (m, 5H), 1.33 (m, 6H), 1.26-1.23 (m, 3H), 0.94-0.91 (m, 3H), 0.67-0.64 (m, 2H). MS: 610.3 (M+H)+.
1H-NMR (400 MHz, DMSO-d6) 6: 7.99 (d, 1H, J =
a 0 N 8.4 Hz), 7.90-7.88 (m, 2H), 7.56 (d, 1H, J
= 8.0 H \ .
N = Hz), 6.88 (s, 1H), 3.95-3.85 (m, 5H), 3.63-3.58 (m, 17/85 N 8 2H), 3.38-3.32 (m, 2H), 2.55 (m, 3H), 1.72-1.68 C) cF3 (m, 2H), 1.55-1.46 (m, 5H), 1.34-0.95 (m, 15H), 0.92-0.89 (m, 3H), 0.66-0.64 (m, 2H). MS: 612.3 HO 1H-NMR (300 MHz, CDCI3) 6: 6.99 (s, 1H), 6.89 1 N I \ II (s, 1H), 6.18 (s, 1H), 6.15 (m, 1H), 4.27 (s, 2H), 3.67 (d, J = 7.2 Hz, 2H), 3.39 (d, J = 5.7 Hz, 2H), N
d 2.60 (s, 3H), 1.59-1.53 (m, 3H), 1.36-1.33 (m, 18H), 1.25 (m, 8H), 1.01 (m, 3H), 0.67-0.66 (m, 2H). MS: 495.4 (M+1)+.
# Structure Analytical data 1H-NMR (400 MHz, CDCI3) 6: 0.55-0.64 (m, 2H), a , 0.83-0.89 (m, 2H), 1.02-1.10 (m, 2H), 1.26 (s, 9H), 1.35-1.44 (m, 2H), 1.53-1.61 (m, 2H), 1.75-1.84 HN
N
H .11.6 Hz, 2H), 3.85-3.88 (m, 2H), 3.98-4.01 (m, On, 3H), 1.97-2.00 (m, 2H), 2.64 (s, 3H), 3.53 (t, J
I \ * 0 F3c¨d2H), 4.12-4.21 (m, 1H), 4.74 (s, 1H), 5.65 (d, J =
7.6 Hz, 1H), 6.38 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H). MS: 652.2 [M+1].
a0 1H-NMR (400 MHz, DMSO-d6) 6: 8.10 (d, 1H), N HN¨' 7.56 (s,1H), 7.49 (d, 1H), 7.43 (d, 1H), 7.35 (s, H I \ * =-10 1H), 6.72 (s, 1H), 6.03 (s, 1H), 3.84-3.94 (m, 5H), 17/88 N ii 0 3.36 (m, 2H), 2.53 (s, 3H), 1.67-1.70 (m, 8H), 1.53 d OH (M, 2H), 1.45 (m, 3H), 1.23 (m, 3H), 1.12 (s, 9H), 0.88 (m, 3H), 0.60 (m, 2H). MS: 574.3 (M+1)4".
HN. ja 1H-NMR (400 MHz, DMSO-d6) 6: 8.13 (d, o FIN J=8.4Hz, 1H), 7.78 (s, 1H), 7.63 (d, J=8.4Hz, 1H), H II
0 N = 7.54 (m, 2H), 7.42 (m, 1H), 6.71 (s, 1H), 4.13 (m, I \ S0 17/89 N II 1H), 3.84 (m, 2H), 3.31 (m, 2H), 2.53 (s, 3H), 2.39 0 (m, 1H), 2.21 (m, 1H), 1.89 (d, 1H), 1.66 (m, 1H), d 1.55 (s, 9H), 1.45 (m, 3H) , 1.32-1.21 (m, 12H), 0.84 (m, 3H), 0.60 (m, 2H). MS: 585.3 (M+1) .
Fi2N 0 0 11-I-NMR (400 MHz, DMSO-d6) 6: 8.13 (d, J=
H I \ * C HN:< 8.4Hz, 1H), 7.76 (s, 1H), 7.53 (s, 1H), 7.43 (m, CXN
o 2H), 7.30 (s, 1H), 7.04 (s, 1H), 6.67 (s, 1H), 3.84 17/90 N 8 (m, 2H), 3.69 (m, 2H), 3.37-3.30 (m, 4H), 2.52 (s, C) 3H), 1.92 (m, 2H), 1.55-1.44 (m, 14H), 1.22-1.16 (m, 12H), 0.96-0.82 (m, 3H) , 0.62 (m, 2H). MS:
629.3 (M+1)+.
9µ
1H-NMR (400 MHz, DMSO-d6) 6: 8.29 (m, 1H), HN 8.15 (d, J=8.4Hz, 1H), 7.78 (s, 1H), 7.54 (s, 1H), N
H I \ = ,,c, 7.43 (m, 1H), 6.73 (s, 1H), 4.54-4.48 (m, 3H), 17/91 N 0 4.28-4.21 (m, 2H), 3.85 (m, 2H), 2.53 (s, 3H), 1.55 C) (s, 9H), 1.44 (m, 3H), 1.20-1.16 (m, 12H), 0.95-0.80 (m, 3H), 0.64 (m, 2H). MS: 592.3 (M+1)+.
s 0---zsa 1H-NMR (400 MHz, DMSO-d6) 6: 8.13 (d, o J=8.4Hz, 1H), 7.78 (s, 1H), 7.63 (m, 1H), 7.52 (s, N Hy 1H), 7.41 (m, 1H), 6.72 (s, 1H), 4.14 (m, 1H), 3.84 H I \ .0 s-n Tr-- (m, 2H), 3.31-3.22 (m, 1H), 3.13-3.08 (m, 2H), 17/92 N 0 d 2.53 (s, 3H), 2.11-2.00(m, 4H), 1.55 (s, 9H) , 1.45 (m, 3H) , 1.21-1.16 (m, 12H) , 0.95-0.88 (m, 3H) , 0.61 (m, 2H). MS: 620.3 (M+1)+.
# Structure Analytical data 0 j< 1H-NMR (400 MHz, DMSO-d6) 6: 8.12 (d, HN J=8.4Hz, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 7.44 (m, Hoy I \ * 4=0 1H), 6.23 (s, 1H), 4.39 (s, 1H), 3.86-3.78(m, 4H), 17/93 N 0 3.27 (m, 2H), 2.27 (s, 3H), 1.55 (s, 9H), 1.45-1.38 d (m, 7H), 1.22-1.17 (m, 12H), 1.14 (s, 3H), 0.93-0.82 (m, 3H), 0.64 (m, 2H). MS: 586.4 (M+1)+.
HNj< 1H¨NMR (400 MHz, CDCI3) 6: 8.17 (d, J=8.4Hz, HON I \ 11 =10 ii 1H), 7.57 (s, 1H), 7.22 (m, 1H), 6.24 (s, 1H), 4.70 (m, 1H), 4.55-4.48 (m, 3H), 4.12 (m, 2H), 3.77 (m, N
d 0 2H), 2.57 (s, 3H), 1.62 (s, 9H), 1.54 (m, 3H), 1.34-1.28 (m, 12H), 1.01-0.92 (m, 3H), 0.62 (m, 2H).
MS: 544.3 (M+1)+.
ao 1H-NMR (400 MHz, DMSO-d6) 6: 8.12 (d, N lit Hy J=8.8Hz, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 7.45 (m, I =_,.
1H), 6.27 (s, 1H), 4.32 (s, br, 1H), 3.95-3.80 (m, I \ S=0 17/95 N 8 4H), 3.29 (m, 2H), 2.87 (s, 3H), 2.26 (s, 3H), 1.78 d (m, 2H), 1.59-1.44(m, 14H), 1.22-1.012(m, 12H), 0.96-0.91 (m, 3H), 0.63 (m, 2H). MS: 586.4 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 8.07 (d, 1H, J = 8.8 QHz), 7.82 (d, 1H, J = 7.2 Hz), 7.10-7.05 (m, 2H), N sS 6.76 (t, 1H, J = 6.0 Hz), 6.43 (s, 1H), 5.60 (d, 1H, HjC¨I µ0 J = 7.6 Hz), 4.19-4.15 (m, 1H), 3.99-3.96 (m, 2H), 17/96 7---N N 3.55-3.50 (m, 4H), 3.01 a, 4H, J = 5.6 Hz), 2.63 d 0 (s, 3H), 2.00-1.97 (m, 2H), 1.67-1.63 (m, 4H), 1.51-1.48 (m, 4H), 1.38-1.26 (m, 6H), 0.99-0.95 (m, 3H), 0.60-0.56 (m, 2H). MS: 567.1 (M+1)+.
a 1H-NMR (400 MHz, DMSO-d6) 6: 8.23 (d, 1H, J =
o HN 8.0 Hz), 7.94-7.91 (m, 1H), 7.86 (s, 1H), 6.56 (d, N
H \ =, 1H, J = 8.0 Hz), 6.88 (s, 1H), 3.94-3.85 (m, 5H), 17/97 N 6 3.38-3.31 (m, 2H), 1.78 (m, 3H), 1.72-1.68 (m, d c,3 2H), 1.55-1.45 (m, 5H), 1.23-1.21 (m, 3H), 1.15 (m, 9H), 0.93-0.88 (m, 3H), 0.65-0.62 (m, 2H).
MS: 584.2 (M+1)+.
o 1H-NMR (400 MHz, DMSO-d6) 6: 8.13 (d, Fly J=8.4Hz, 1H), 7.74 (s, 1H), 7.67 (t, J=5.6Hz, 1H), H I= \ 11 s=o 7.53 (s, 1H), 7.42 (m, 1H), 6.65 (s, 1H), 3.84(m, d 8 2H), 3.19 (m, 2H), 2.53 (s, 3H), 1.55 (s, 9H), 1.44 (m, 3H), 1.24-1.16 (m, 12H), 1.07 (t, J= 6.8Hz, 3H), 0.97-0.82 (m, 3H), 0.63 (m, 2H). MS: 516.3 (M+1)+.
6,N o N
Hy 1H-NMR (400 MHz, DMSO-d6) 6: 8.12 (d, J=8.4Hz, 1H), 7.74 (s, 1H), 7.64 (m, 1H), 7.51 (s, H I \ * =0 1H), 7.40 (m, 1H), 6.63 (s, 1H), 3.83 (m, 2H), 2.75 17/99 N 0 (M, 1H), 2.72 (s, 3H), 1.54 (s, 9H), 1.44 (m, 3H), d 1.24-1.16 (m, 12H), 0.92-0.82 (m, 3H), 0.62 (m, 4H), 0.49 (m, 2H). MS: 528.3 (M+1)+.
# Structure Analytical data o , 1H-NMR (400 MHz, CDCI3) 6: 8.20 (d, J=8.8Hz, rN __,, ni 1H), 7.58 (s, 1H), 7.24 (m, 1H), 6.17 (s, 1H), 4.49 \ IP =() (s, br, 1H), 4.19 (m, 4H), 3.78 (m, 2H), 3.07 (m, 17/100 ' N
d 0 4H), 2.41 (s, 3H), 1.62 (s, 9H), 1.55 (m, 3H), 1.34-1.26 (m, 12H), 1.02-0.93 (m, 3H), 0.63 (m, 2H).
MS: 606.3 (M+1)+.
a CF3 1H-NMR (CDCI3, 500 MHz) 6: 8.05 (d, 1H), 7.56 0 NH (d, 1H), 7.22 (dd, 1H), 6.21 (s, 1H), 5.54 (d, 1H), N
H I \ . ,...c, 4.95 (t, 1H), 4.12-4.08 (m, 1H), 3.92 (d, 2H), 3.72-17/101 N 8 3.65 (m, 4H), 3.46 (dt, 2H), 2.56 (s, 3H), 1.94-1.90 d (m, 2H), 1.54 (s, 9H), 1.48-1.42 (m, 9H),1.31-1.23 (m, 4H), 0.94-0.90 (m, 3H), 0.57-0.52 (m, 2H).
MS: 598.2 (M+1).
a Fõ 1H NMR (CDCI3, 500 MHz) 6: 7.77 (d, 1H), 7.63 --..N--- (d, 1H), 7.27-7.25 (m, 1H), 6.26 (s, 1H), 5.60 (d, H
N \ 411 I = 1H), 4.20-4.16 (m, 1H), 4.02-3.97 (m, 3H), 3.92-17/102 N ii 3.88 (m, 1H), 3.78 (d, 2H), 3.52 (t, 2H), 2.82-2.76 C) (m, 2H), 2.63 (s, 3H), 2.13-2.11 (s, 1H), 1.98 (dd, 2H), 1.89-1.87 (d, 1H), 1.63-1.32 (m, 19H), 1.35-0.60 (m, 11H). MS: 652.2 (M+1).
0ON 0 1H-NMR (CDCI3, 400 MHz) 6: 7.97 (s, 1H), 7.72 (s, 1H), 7.56 (s, 1H), 6.25 (s, 1H), 5.65 (d, 1H, J =
N
H \ 8.0 Hz), 4.16-4.18 (m, 1H), 3.98 (d, 2H, J
= 11.2 I lio 17/103 N Hz), 3.74 (d, 2H, J = 6.8 Hz), 3.52 (t, 2H, J = 11.2 C) Hz), 2.63 (s, 6H), 1.98 (d, 2H, J = 11.6 Hz), 1.48-1.55 (m, 5H), 1.33-1.38 (m, 12H), 0.99 (br s, 3H), 0.59-0.66 (m, 2H). MS: 479.3 (M+1)+.
0 1H-NMR (CDCI3, 400 MHz) 6: 7.76 (d, 1H), 7.42 a 0 (d, 1H), 6.16 (s, 1H), 5.60 (d, 1H, J = 7.6 Hz), 4.61 N (t, 2H, J = 6.4 Hz), 4.14-4.17 (m, 1H), 3.96-3.99 H I \ lik 0 (m, 2H), 3.71 (d, 2H, J = 6.8 Hz), 3.53 (dd, 2H), d 17/104 N 2.86 (t, 2H, J = 6.4 Hz), 2.61 (s, 3H), 1.96-1.99 (m, 2H), 1.47-1.55 (m, 5H), 1.35-1.47 (m, 12H), 0.98-1.02 (m, 3H), 0.62-0.68 (m, 2H). MS: 507.3 (M+1)+.
HO 1H-NMR (CDCI3, 400 MHz) 6: 7.14 (d, 2H, J = 5.6 a 0 Hz), 6.11 (s, 1H), 5.59 (d, 1H, J = 8.0 Hz), 4.81 (d, N 1H, J = 3.2 Hz), 4.29-4.39 (m, 2H), 4.14-4.18 (m, H I \ . 0 1H), 3.97 (d, 2H, J = 11.2 Hz), 3.70 (d, 2H, J = 7.2 d 17/105 N Hz), 3.49-3.55 (m, 2H), 2.60 (s, 3H), 1.96-2.18 (m, 4H), 1.83 (d, 2H, J = 4.4 Hz), 1.37-1.58 (m, 17H), 1.03-1.05 (m, 3H), 0.67-0.70 (m, 2H). MS: 509.3 (M+1)+.
Q0 1H-NMR (DMSO-d6, 400 MHz) 6: 7.92 (d, 1H, J =
N HN 8.0 Hz), 7.57 (s, 1H), 7.55 (s, 0.25H), 7.45 (s, 1H), H I \ 41 7.41 (s, 0.50H), 7.38 (d, 1H, J = 8.0 Hz), 7.21 (s, 17/106 N12.rf 8 0.25H), 6.78 (s, 1H), 3.85-3.94 (m, 5H), 3.33-3.38 dP (m, 2H), 2.54 (s, 3H), 1.68-1.71 (m, 2H), 1.46-1.55 F2,,c (m, 5H), 1.21-1.26 (m, 3H), 1.11 (s, 9H), 0.89-0.94 (m, 3H), 0.60-0.67 (m, 2H). MS: 582.3 (M+1)+.
# Structure Analytical data oa 1H-NMR (CDCI3, 400 MHz) 6: 8.31 (d, 1H, J =
HN--<OH 11.2 Hz), 7.82 (s, 1H), 7.63 (d, 1H, J =
11.2 Hz), .
N 6.39 (s, 1H), 5.66 (d, 1H, J = 10.4 Hz), 5.10 (s, H I \ S=0 1H), 4.12-4.19 (m, 1H), 3.98-4.01 (m, 2H), 3.82 (d, d 17/107 N 8 2H), 3.49-3.57 (m, 4H), 2.63 (s, 3H), 2.31-2.34 (m, 3 1H),1.97-2.01 (m, 2H), 1.55-1.64 (m, 3H), 1.22-CF 1.34 (m, 3H), 1.17 (s, 6H), 0.56-1.03 (m, 7H). MS:
600.3 (M+1)+.
00N1H-NMR (CDCI3, 400 MHz) 6: 8.29 (d, 1H, J = 8.4 0 __I Hz), 7.79 (s, 1H), 7.60 (d, 1H, J
= 8.4 Hz), 6.39 (s, N
H I \ iii HT , OH 1H), 6.33 (s, 1H), 5.70 (d, 1H, J = 7.6 Hz), 4.14-=.=1/4, 4.21 (m, 1H), 3.98-4.01 (m, 2H), 3.90-3.93 (m, 17/108 N \W 8 2H), 3.81 (d, 2H), 3.50-3.56 (m, 2H), 2.63 (s, 3H), d 3 1.97-2.00 (m, 2H), 1.97 (br s, 1H), 1.78 (t, 2H), CF
1.50-1.60 (m, 5H), 1.24-1.37 (m, 9H), 1.00 (br s, 3H), 0.57-0.64 (m, 2H). MS: 614.4 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 8.29 (d, 1H, J = 8.4 oa 0 Hz), 7.80(d, J = 1.2 Hz, 1H), 7.61 (dd, J = 1.6 Hz, N
J - 8.4 Hz 1H) 6.36 (s 1H) 5 60-5 62 (d J = 8.0 H 1 \ = =(::0 Hz, 1H), 5.29 (s, 1H), 4.13-4.18 (m, 1H), 3.97-4.00 17/109 N 8 (m, 2H), 3.81 (d, J = 6.8 Hz, 2H), 3.49-3.56 (m, ) u3 2H), 3.27 (s, 3H), 3.17 (s, 2H), 2.63 (s, 3H), 1.97-2.00 (m, 1H), 1.48-1.57 (m, 4H), 1.31-1.38 (m, 3H), 1.23 (s, 6H), 0.97-1.00 (m, 3H), 0.57-0.64 (m, 2H). MS: 614.4 (M+1)+.
a 1H-NMR (300 MHz, CDCI3) 6: 0.60-0.68 (2H, m), 0 1.00-1.04(3H, m), 1.27-1.61 (9H, m), 1.98-2.02 HN
N (2H, m), 2.65 (3H, s), 2.74 (3H, d, J = 5.1 Hz), H I \
N W ¨() 3.54 (2H, dt), 3.83 (2H, d, J = 7.2 Hz), 3.99-4.02 17/110 0 (2H, m), 4.13-4.23 (1H, m), 4.64-4.69 (1H, m), d c3 5.63 (1H, d, J = 2.1 Hz), 6.38 (1H, s), 7.65 (1H, d, J = 8.1 Hz), 7.85 (1H, s), 8.26 (1H, d, J = 8.1 Hz).
MS: 542.2 (M+1)+.
1H-NMR (300 MHz, CDCI3) 6: 0.57-0.69 (2H, m), a0 f 0.87 (t, 3H, J = 7.5 Hz), 1.02 (3H, br s), 1.23-1.57 N I-11(10H, d), 1.96-2.02 (2H, m), 2.64 (3H, s), 3.00 (q, H I \ 41 s=0 2H, J = 6.6 Hz), 3.53 (2H, t, J = 11.1 Hz), 3.82 17/111 N 8 (2H, d, J = 7.2 Hz), 3.98-4.03 (2H, m), 4.11-4.22 d cF, (1H, m), 4.78 (1H, t, J = 5.9 Hz), 5.68 (1H, d, J =
8.1 Hz), 6.39 (1H, s), 7.64 (1H, d, J = 8.1 Hz), 7.83 (1H, s), 8.24 (1H, d, J = 8.1 Hz). MS: 570.3 [M+1]+.
1H-NMR (300 MHz, CDCI3) 6: 0.57-0.69 (2H, m), a0 I 0.98.1.01 (3H, m), 1.10 (6H, d, J = 8.1 Hz), 1.32-N HN-- 1.40 (3H, m), 1.48-1.62 (5H, m), 1.97-2.02 (2H, H I \ a .,,,, m), 2.65 (3H, s), 3.50-3.63 (3H, m), 3.82 (2H, d, J
17/112 N µmrf 8 . 7.2 Hz), 3.98-4.03 (2H, m), 4.13-4.23 (1H, m), d u3 4.53-4.55 (2H, m), 5.64 (1H, d, J =
7.8 Hz), 6.39 (1H, s), 7.64 (1H, dd, J = 8.4, 1.5 Hz), 7.84 (1H, d, J = 1.2 Hz), 8.29 (1H, d, J = 8.4 Hz). MS: 570.3 [M+1]+.
# Structure Analytical data 1H-NMR (300 MHz, CDCI3) 6: 0.65-0.69 (2H, m), a 0 Ci j< 1.03 (3H, br s), 1.26 (9H, s), 1.33-1.37 (3H, m), N HII1.48-1.61 (7H, m), 2.00 (2H, dd, J = 12.6, 2.1 Hz), H I \ * S=0 2.64 (3H, s), 3.53 (2H, dt, J
= 11.6, 1.8 Hz), 3.83 d 17/113 N 8 (2H, d, J = 7.2 Hz), 3.99-4.03 (2H, m), 4.16-4.19 3 (1H, m), 5.52 (1H, s), 5.63 (1H, d, J = 7.8 Hz), CF
6.43 (1H, s), 7.71 (1H, d, J = 1.8 Hz), 7.82 (1H, d, J = 1.5 Hz). MS: 618.3 [M+1].
1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 ,s-NH2 HN (d, 1H), 6.06 (s, 1H), 5.79 (br s, 1H), 4.88 (s, 2H), o-b / \ 4.33 (t, 2H), 3.63 (d, 2H), 3.40-3.44 (m, 2H), 3.13 17/114 N lp 0 (t, 2H), 2.58 (s, 3H), 1.99-1.89 (m, 4H), 1.63-1.56 (m, 7H), 1.45-1.32 (m, 12H), 1.04-1.00 (m, 5H), 0.87-0.84 (m, 2H), 0.72-0.65 (m, 2H). MS: 584.3 ) 111 [M+1r.
1H-NMR (400 MHz, DMSO-d6) 6: 8.03 (d, 1H), N HN 7.95 (s, 1H), 7.82-7.69 (m, 3H), 7.57-7.55 (m, 1H), H I \ 11 6.86 (s, 1H), 3.94-3.85 (m, 5H), 3.38-3.30 (m, 2H), 17/115 N 8 2.55 (s, 1H), 1.72-1.69 (m, 2H), 1.54-1.45 (m, 5H), d F F 1.24-1.20 (m, 3H), 1.10 (s, 9H), 0.93-0.87 (m, 3H), 0.66-0.59 (m, 2H). MS: 566.2 [M+1]t a0 1H-NMR (400 MHz, CDCI3) 6: 8.20 (d, 1H), 7.61 N HN (d, 1H), 7.34 (d, 1H), 7.29 (d, 1H), 6.42 (d, 1H), H I \ . S=0 5.65 (d, 1H), 4.51 (s, 1H), 4.21-4.17 (m, 1H), 4.00-17/116 N 8 3.97 (m, 1H), 3.76 (d, 2H), 3.56-3.49 (m, 2H), C) 2.01-1.98 (m, 2H), 1.62-1.44(m, 16H), 1.31 (s, 9H), 1.07-1.05 (m, 3H), 0.80-0.75 (m, 2H). MS:
558.3 [M+1].
1H-NMR (400 MHz, CDCI3) 6: 8.21 (d, J = 8.0 Hz, a0 õ 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 8.0 Hz, N
HN J = 1.6 Hz, 1H), 6.30 (s, 1H), 5.85 (d, J = 8.0 Hz, H I \ . S=0 1H), 4.73 (s, 2H), 4.58 (s, 1H), 4.21-4.14 (m, 1H), 17/117 HO N 8 4.00 (dd, J = 10.0 Hz, J = 2.0 Hz, 2H), 3.83 (d, J =
d 7.2 Hz, 2H), 3.53 (td, 2H), 2.02 (dd, J = 12.4 Hz, J
= 2.0 Hz, 2H), 1.62-1.52 (m, 14H), 1.38-1.36 (m, 12H), 1.04-0.96 (m, 3H), 0.65-0.56 (m, 2H). MS:
570.3 ([M-OH]).
1H-NMR (400 MHz, CDCI3) 6: 8.17 (d, J = 8.4 Hz, a 0 FIN_., 1H), 7.57 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.45 (s, "
N 1H), 6.35 (d, J = 7.6 Hz, 1H), 5.03 (s, 2H), 4.56 (s, H I \ a =lo 1H), 4.19-4.17 (m, 1H), 3.97 (d, J = 11.6 Hz, 2H), 3.83 (d, J = 6.8 Hz, 2H), 3.54 (t, J = 11.2 Hz, 2H), d 1.98 (d, J = 12.0 Hz, 2H), 1.62-1.49(m, 14H), 1.30-1.22 (m, 12H), 0.93-0.88 (m, 3H), 0.59-0.53 (m, 2H). MS: 570.2 ([M-F]).
# Structure Analytical data 1H-NMR (400 MHz, CDCI3) 5: 8.21 (d, J = 8.4 Hz, a 0 J 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.28-7.25 (m, 1H), N Hy 6.68 (s, 1H), 6.21 (d, J = 8.0 Hz, 1H), 4.55 (s, 1H
H I \ * s=0 ), 4.24-4.21 (m, 1H), 4.01-3.98 (m, 2H), 3.87 (d, J
17/119 CI 8 . 7.2 Hz, 2H), 3.55 (td, J = 11.6 Hz, J =
1.6 Hz, (---) 2H), 2.04-2.01 (d, 2H), 1.61-1.54 (s, 13H), 1.48-1.25 (m, 13H), 0.99 (br s, 3H), 0.69-0.64 (m, 2H).
MS: 592.3 [r\A-F1].
-.....)_\ 0 1H-NMR (400 MHz, CD30D) 5: 6.96 (d, 1H, J
=
HN HN 1.6 Hz), 6.48 (d, 1H, J = 2.0 Hz), 6.29 (s, 1H), 0 / \ 4.30 (t, 2H), 3.71(d, 2H, J = 7.6 Hz), 3.42 (s, 2H), 17/120 i-NH N 410 3.08 (q, 2H), 2.52 (s, 3H), 1.88 (t, 2H), 1.57-1.54 (m, 3H), 1.37-1.27 (m, 18H), 1.07-0.98 (m, 8H), 0.86 (dd, 2H), 0.72-0.67 (m, 2H). MS: 577.5 CI) 1 [M+1].
1H-NMR (400 MHz, CDCI3) 5: 7.57 (br s, 1H), 7.27 HN HN (d, 1H), 7.13 (t, 1H), 7.01 (t, 1H), 6.88 (t, 1H), 6.25 (s, 1H), 4.15 (q, 1H), 3.71 (d, 2H, J = 7.2 Hz), 17/121 HO---O iN \ * 3.54-3.41 (m, 2H), 2.59 (s, 3H), 1.55-1.53 (m, 3H), 1.42-1.30 (m, 24H), 1.03 (br s, 3H), 0.88-0.86 (m, 2H), 0.76-0.73 (m, 2H), 0.68-0.62 (m, 2H). MS: ) II 550.4 [M+1r.
1H-NMR (400 MHz, CDCI3) 6: 7.26 (s, 1H), 7.13 HN HN (s, 1H), 7.01-6.95 (m, 3H), 6.27 (s, 1H), 3.81 (s, y0 / \ 2H), 3.70 (d, 2H, J = 6.8 Hz), 3.59 (d, 2H, J = 6.0 17/122 oN Hz), 3.40 (s, 3H), 2.62 (s, 3H), 1.58-1.52 (m, 3H), / 0) 1.47-1.24 (m, 21H), 1.00 (br s, 3H), 0.88-0.84 (m, 2H), 0.75-0.72 (m, 2H), 0.66-0.62 (m, 2H). MS:
I 550.4 [M+1]t 1H-NMR (400 MHz, CD300) 5: 6.87 (d, 1H), 6.39 HN HN (d, 1H), 6.20 (s, 1H), 4.22 (t, 2H), 3.96-3.91 (m, 1H), 3.62 (d, 2H), 3.37 (q, 2H), 2.44 (s, 3H), 1.80 17/123 HO-- iN \ *
0 (t, 3H), 1.49-1.46 (m, 3H), 1.33-1.19 (m, 23H), 1.00-0.86 (m, 5H), 0.80-0.77 (m, 2H), 0.66-0.62 ) 11 (m, 2H). MS: 578.4 [M+1r.
0 1H-NMR (400 MHz, CD30D) 5: 6.88 (d, 1H), 6.39 HN HN (d, 1H), 6.21 (s, 1H), 4.22 (t, 2H), 3.68 (s, 2H), yo / \ 3.62 (d, 2H), 3.33 (s, 2H), 3.28 (s, 3H), 2.45 (s, 17/124 o / 0) * 0 3H), 1.79 (t, 3H), 1.48-1.46 (m, 3H), 1.32-1.19 (m, 21H), 0.97-0.90 (m, 5H), 0.80-0.77 (m, 2H), 0.66-1 0.62 (m, 2H). MS: 578.4 [M+1].
a 0 Lõ,J< 1H-NMR (400 MHz, DMSO-d6) 5: 7.92 (d, 1H), 7.81-7.78 (m, 2H), 7.59 (t, 1H, J = 55.2 Hz), 7.57 N 'i H I \ * s=o (d, 1H, J = 8.0 Hz), 6.86 (s, 1H), 3.94-3.85 (m, 17/125 N 8 5H), 3.54 (q, 2H), 3.36 (t, 2H), 2.58 (s, 3H), 1.72-d F F 1.69 (m, 2H), 1.54-1.45 (m, 5H), 1.33 (s, 9H), 1.29-1.20 (m, 6H), 0.94-0.86 (m, 3H), 0.67-0.61 (m, 2H). MS: 594.3 [M+1].
# Structure Analytical data a 0 HyJ 1H-NMR (400 MHz, DMSO-d6) 6: 8.04 (d, 1H), N 7.96 (s, 1H), 7.82-7.55 (m, 4H), 6.84 (s, 1H), 4.07 H I \ * S=0 17/126 N 8 (d, 2H), 3.94-3.84 (m, 3H), 3.35 (dd, 2H), 2.55 (s, [1? F F 3H), 2.32-2.28 (m, 1H), 1.74-1.24 (m, 10H), 1.11 (s, 9H). MS: 538.2 [M+1]t HNJ 1H-NMR (400 MHz, DMSO-d6) 6: 8.03 (d, 1H), --):11 1 \ . 0 7.93 (s, 1H), 7.82-7.53 (m, 4H), 6.83 (s, 1H), 3.89 0 OH N \mu 8 (d, 2H), 3.36 (d, 2H), 2.54 (s, 3H), 1.47-1.45 (m, d F 0.85 (m, 3H), 0.66-0.60 (m, 2H). MS: 582.2 F 3H), 1.24-1.21 (m, 3H), 1.10-1.09 (m, 15H), 0.93-[M+1]t O 1H-NMR (400 MHz, DMSO-d6) 6: 8.02 (d, 1H), --:HN 7.95 (s, 1H), 7.82-7.56 (m, 3H), 7.48 (t, 1H), 7.19 11 I \ .
=-Ici (br s, 1H), 6.85 (br s, 1H), 6.78 (s, 1H), 3.89 (d, 0 NH2 N 8 2H), 3.31 (d, 2H), 2.54 (s, 3H), 1.47-1.45 (m, 3H), d F F 1.28-1.21 (m, 3H), 1.10 (s, 9H), 1.07 (m, 6H), 0.93-0.86 (m, 3H), 0.66-0.59 (m, 2H). MS: 581.3 [M+1].
OH
HyJ 1H-NMR (400 MHz, DMSO-d6) 6: 8.03 (m, 1H), N 7.94 (s, 1H), 7.81-7.55 (m, 4H), 6.86 (s, 1H), 3.90 I \ . e=0 (d, 2H), 3.60 (dd, 4H), 3.22 (d, 2H), 2.55 (s, 3H), N
d F 8 F
17/129 1.58-1.45 (m, 5H), 1.38-1.35 (m, 2H), 1.28-1.21 (m, 3H), 1.10 (s, 9H), 0.93-0.85 (m, 3H), 0.67-0.59 (m, 2H). MS: 596.3 [M+1].
HyJ 1H-NMR (400 MHz, DMSO-d6) 6: 8.02 (d, 1H), N 7.93 (s, 1H), 7.82-7.55 (m, 4H), 6.79 (s, 1H), 3.89 c OyH I \ li S=0 HO N
d 8 F (d, 2H, J = 6.8 Hz), 3.19-3.15 (m, 2H), 2.54 (s, F
1.20 (m, 3H), 1.13 (s, 6H), 1.10 (s, 9H), 0.94-0.87 3H), 1.72-1.68 (m, 2H), 1.47-1.44 (m, 3H), 1.23-(m, 3H),0.66-0.60(m, 2H). MS: 596.3 [M+1].
a y_ 1H-NMR (CDCI3, 400 MHz) 6: 7.62 (s, 1H), 7.47-HN
O 7.53 (m, 1H), 6.23 (s, 1H), 5.61 (d, J = 7.6 Hz, N 0 1H), 5.22 (s, 1H), 4.14-4.19 (m, 1H), 3.98 (d, J =
H I \ * 10.4 Hz, 2H), 3.76 (d, J = 7.2 Hz, 2H), 3.66 (s, 17/131 N 2H), 3.52 (t, J = 10.0 Hz, 2H), 2.62 (s, 3H), 1.96-C) c3 2.00 (m, 2H), 1.47-1.59 (m, 5H), 1.31-1.43 (m, 12H), 0.96-1.03 (m, 3H), 0.61-0.67 (m, 2H). MS:
562.3 (M+1)+.
a Y 1H-NMR (CDCI3, 400 MHz) 6: 7.65-7.70 (m, 2H), o HN 7.51 (d, J = 7.6 Hz, 1H), 6.28 (s, 1H), 5.61 (d, J =
N 0 8.0 Hz, 1H), 4.74 (s, 1H), 4.15-4.19 (m, 1H),3.98 H I \ * (d, J = 12.0 Hz, 2H), 3.78 (d, J = 6.8 Hz, 2H), 3.52 17/132 N (t, J = 11.2 Hz, 2H), 2.63 (s, 3H), 1.99 (d, J = 11.2 d CF3 Hz, 1H), 1.64 (s, 6H), 1.47-1.58 (m, 5H), 1.34-1.39 (m, 3H), 1.25 (s, 9H), 0.98-1.03 (m, 3H), 0.61-0.67 (m, 3H). MS: 590.3 (M+1)+.
# Structure Analytical data Q o 11-I-NMR (CDCI3, 400 MHz) ö: 0.79-0.88 (m, 2H), HN2 1.26 (s, 9H), 1.49-1.58 (m, 2H), 1.89-2.00 (m, 4H), N
2.17-2.26 (m, 1H), 2.40-2.51 (m, 2H), 2.66 (s, 3H), ==0 N 8 3.52 (t, J = 12.0 Hz, 2H), 3.99 (d, J =
12.0 Hz, 17/133 2H), 4.13-4.15 (m, 3H), 4.71 (s, 1H), 5.62 (d, J =
cF3 8.0 Hz 1H), 6.39 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H). MS: 592.2 1?
F (M-F1)+.
0 1H-NMR (400 MHz, CDCI3) 6: 8.33 (d, 1H, J
= 8.4 N
17/134 Hy Hz), 7.80 (s, 1H), 7.63 (d, 1H, J = 8.4 Hz), 6.42 (s, oH I \ ik, -..o 1H), 6.37 (t, 1H), 4.74 (s, 1H), 3.81 (d, 2H, J = 6.8 HO N
0 Hz), 3.33 (d, 2H, J = 6.4 Hz), 2.63 (s, 3H), 2.31 (s, c 3 2H), 1.58-1.56 (m, 3H), 1.35-1.32 (m, 3H), 1.26 (s, d 9H), 1.10-1.01 (m, 9H), 0.67-0.60 (m, 2H). MS:
614.3 (M+1)+.
0 j< 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J
= 8.4 Hz), 7.79 (s, 1H), 7.61 (d, 1H, J= 8.4 Hz), 6.89 (s, 0 il 17/135 I \ . 1=0 1H), 6.39 (s, 1H), 6.30-6.24 (m, 2H), 4.72 (s, 1H), cF3 3.79 (d, 2H, J = 6.8 Hz), 3.45-3.44 (m, 2H), 2.61 (s, 3H), 1.90 (t, 2H), 1.57-1.52 (m, 3H), 1.33-1.27 H2N d (m, 18H), 0.99 (s, 3H), 0.64-0.58 (m, 2H). MS:
613.3 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.23 (d, 1H, J =
Hy 8.4 Hz), 7.91 (d, 1H, J = 8.8 Hz), 7.84 (m, 2H), N 7.66 (t, 1H), 7.51 (d, 1H), 6.81 (s, 1H), 3.90 (d, c OyH 1 \ 11 S=0 ii 21 H.4,5J(m= ,63.8HH),z1).,233.-111.2-30.0(6m73H, 2),H1).,125.5(7s,(9dH, 3),H1,.J1 d 0 HN = 4.4 Hz), 2.54 (s, 3H), 1.68-1.64 (m, 2H), 1.47-N
(s, 6H), 0.92-0.84 (m, 3H), 0.68-0.60 (m, 2H). MS:
627.3 (M+1)+.
o 11-1-NMR (400 MHz, CDCI3) 5: 8.31 (d, 1H, J = 8.4 0 j< Hz), 7.80 (s, 1H), 7.62 (d, 1H, J = 8.4 Hz), 6.29 (s, HO-kr--NN =m Hy 1H), 4.72 (s, 1H), 4.55-4.50 (m, 1H), 4.29-4.24 (m, lip -=0 1H), 4.16-4.09 (m, 2H), 3.80 (d, 2H, J =
7.2 Hz), o 3.74-3.69 (m, 1H), 3.29-3.26 (m, 2H), 2.41 (s, 3H), d CF3 1.55 (br s, 3H), 1.34-1.32 (m, 3H), 1.27 (s, 9H), 1.00 (br s, 3H), 0.65-0.61 (m, 2H). MS: 614.2 (M+1)+.
0., 0 i 1mHz-)N7M8R1(4( s001MH ) Hz,.6C2D(Cd13)1H5: 8.32J8 (d0, J6.=428(.0s, HN'-' .IN
H I \ . -=C0 1H), 6.16 (d, 1H, J = 8.8 Hz), 4.72 (s, 1H), 4.17 (br 17/138 N 8 s, 1H), 3.84-3.74 (m, 4H), 3.66-3.57 (m, 2H), 2.62 d c3 (s, 3H), 1.91-1.81 (m, 3H), 1.62-1.55 (m, 4H), 1.37-1.31 (m, 3H), 1.26 (s, 9H), 1.00 (br s, 3H), 0.64-0.58 (m, 2H). MS: 584.2 (M+1)+.
# Structure Analytical data (A o 1H-NMR (400 MHz, CDCI3) 6: 8.32 (d, 1H, J
= 8.0 HN=-C:3 Hz), 7.81 (s, 1H), 7.62 (d, 1H, J = 8.0 Hz), 6.42 (s, H \
N 1H), 6.18 (d, 1H, J = 8.8 Hz), 4.71 (s, 1H), 4.17 (br I . , 17/139 N 8 s, 1H), 3.84-3.74 (m, 4H), 3.65-3.58 (m, 2H), 2.62 C) u3 (s, 3H), 1.91-1.81 (m, 3H), 1.62-1.55 (m, 4H), 1.37-1.31 (m, 3H), 1.26 (s, 9H), 1.00-0.96 (m, 3H), 0.67-0.59 (m, 2H). MS: 584.2 (M+1)+.
oa o 1H-NMR (400 MHz, CD30D) 6: 8.25 (d, 1H, J
=
N FII(CF3 8.0 Hz), 7.94 (s, 1H), 7.83 (d, 1H, J = 8.4 Hz), H I \ 41 =-0 6.75 (s, 1H), 4.08-3.95 (m, 5H), 3.84 (dd, 2H), d 17/140 N 0 3.53 (t, 2H), 2.60 (s, 3H), 1.90-1.87 (m, 2H), 1.70-3 1.58 (m, 5H), 1.36-1.33 (m, 3H), 1.06-1.02 (m, CF
3H), 0.73-0.67 (m, 2H). MS: 610.2 (M+1)+.
a 01H-NMR (400 MHz, DMSO-d6) 6: 8.92 (d, 1H, J =
HN1CF3 8.8 Hz), 8.20 (d, 1H, J = 8.0 Hz), 7.93 (d, 1H, J =
N
H I \ = s=c1 8.4 Hz), 7.90 (s, 1H), 7.56 (d, 1H, J = 8.0 Hz), ii 6.90 (s, 1H), 4.15-4.10 (m, 1H), 3.95-3.85 (m, 5H), C) u3 3.39-3.36 (m, 2H), 2.55 (s, 3H), 1.71 (dd, 2H), 1.57-1.47 (m, 5H), 1.23-1.21 (m, 6H), 0.95-0.87 (m, 3H),0.68-0.61 (m, 2H). MS: 624.2 (M+1)+.
a 0 1H-NMR (400 MHz, DMSO-d6) 6: 8.92 (d, 1H, J =
HNCF3 8.8 Hz), 8.20 (d, 1H, J = 8.0 Hz), 7.93 (d, 1H, J =
N
H I \ II s=0 8.4 Hz), 7.90 (s, 1H), 7.56 (d, 1H, J = 8.0 Hz), ii 6.90 (s, 1H), 4.15-4.10 (m, 1H), 3.95-3.85 (m, 5H), C) u3 3.39-3.36 (m, 2H), 2.55 (s, 3H), 1.71 (dd, 2H), 1.57-1.47 (m, 5H), 1.23-1.21 (m, 6H), 0.95-0.87 (m, 3H), 0.68-0.61 (m, 2H). MS: 624.2 (M+1)+.
F3c. 1H-NMR (400 MHz, CDCI3) 6: 8.29 (d, 1H, J
= 8.4 Q0 Hz), 7.82 (s, 1H), 7.63 (d, 1H, J = 9.6 Hz), 6.38 (s, N HN'T 1H), 5.61 (d, 1H, J = 8.0 Hz), 4.89 (s, 1H), 4.19-H I \ . =-Ici 4.15 (m, 1H), 4.00-3.98 (m, 2H), 3.81 (d ,2H, J =
17/143 N 8 9.2 Hz), 3.55-3.49 (m, 2H), 2.65-2.57 (m, 5H), C) u3 1.98 (dd, 2H), 1.58-1.48 (m, 5H), 1.36-1.31 (m, 9H), 1.00-0.99 (m, 3H), 0.66-0.60 (m, 2H). MS:
652.3 (M+1)+.
a CN
0 11-1-NMR (400 MHz,DMSO-d6) 6: 9.34 (s, 1H), 8.25 N HN)7(d, 1H, J = 8.4 Hz), 7.98 (d, 1H, J = 9.2 Hz), 7.94 H I \ * 0 (s, 1H), 7.58 (d, 1H, J = 7.6 Hz), 6.92 (s, 1H), 17/144 N 8 3.97-3.85 (m, 5H), 3.36 (t, 2H), 2.56 (s, 3H), 1.72-C) u3 1.70 (m, 2H), 1.57-1.45 (m, 7H), 1.32-1.19 (m, 5H), 0.93 (br s, 3H), 0.69-0.64 (m, 2H). MS: 593.3 (M+1)+.
# Structure Analytical data 1H-NMR (400 MHz, CDCI3) 6: 8.34 (br s, 1H), 8.19 a 0 HNCo (d, 1H, J = 8.4 Hz), 7.94 (d, 1H, J = 8.8 Hz), 7.90 N (s, 1H), 7.56 (d, 1H, J = 8.0 Hz), 6.90 (s, 1H), 4.62 H I \ = :---0 (d, 2H, J = 6.0 Hz), 4.19 (d, 2H, J = 6.4 Hz), 4.20-17/145 N 0 d 3.85 (m, 5H), 3.38-3.36 (m, 2H), 2.55 (s, 3H), CF 1.72-1.69 (m, 2H), 1.56-1.42 (m, 8H), 1.235-1.22 (m, 3H), 0.98-0.86 (m, 3H), 0.69-0.61 (m, 2H).
MS: 698.3 (M+1)+. =
OH
1H-NMR (400 MHz, DMSO-d6) 6: 8.22 (d, 1H, J =
a 0 8.0 Hz), 7.92 (d, 1H, J = 8.0 Hz), 7.88 (s, 1H), N E11;1 7.55 (d, 1H, J = 7.6 Hz), 7.41 (d, 1H, J = 9.2 Hz), Hs=0 6.88 (s, 1H), 3.95-3.85 (m, 5H), 3.36 (t, 2H), 3.13-17/146 N 8 3.09 (m, 1H), 2.55 (s, 3H), 1.72-1.69 (m, 2H), d CF3 1.57-1.47 (m, 5H), 1.24-1.22 (m, 3H), 0.96-0.89 (m, 12H), 0.64-0.58 (m, 2H). MS: 614.3 (M+1)+.
0 1H-NMR (400 MHz, CDCI3) 6: 8.26 (d, 1H, J = 8.0 a c7 Hz), 7.85 (s, 1H), 7.65 (dd, 1H, J = 8.4 Hz, J = 1.2 o Hz), 6.38 (s, 1H), 5.63 (d, 1H, J = 8.0 Hz), 4.98 N Flt\r (M, 1H), 4.39-4.35 (m, 4H), 4.21-4.14 (m, 1H), H I \ . s=o 4.00-3.98 (m, 2H), 3.82 (d, 2H, J
= 7.2 Hz), 3.53 N 8 (td, 2H), 3.22 (d, 2H, J = 6.4 Hz), 2.64 (s, 3H), d cF3 2.01-1.97 (m, 2H), 1.63-1.33 (m, 8H), 1.30 (s, 3H), 1.01-0.98 (m, 3H), 0.69-0.63 (m, 2H). MS: 612.3 (M+1)+.
a0 0 1H-NMR (400 MHz, DMSO-d6) 6:7.80 (d, J =
1.2 N Hz, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.46(d, J = 8.0 H I \ * NN Hz, 1H), 6.67 (s, 1H), 3.95-3.80 (m, 5H), 3.78.3.35 17/148 N (M, 5H), 2.54 (s, 3H), 1.71-1.67 (m, 2H), 1.57-1.47 d c3 (m, 5H), 1.34-1.25 (m, 9H), 0.97-0.91 (m, 3H), 0.71-0.63 (m, 2H). MS: 546.8 (M+1)+.
OH
O''''=1H-NMR (400 MHz, CDCI3) 6:7.50 (d, J = 1.2 Hz, cL 0 0 1H), 7.31 (d, J = 1.6 Hz, 1H), 6.22 (s, 1H), 5.97 (br s, 1H), 4.76-4.78 (m, 1H), 3.71 (d, J = 7.2 Hz, 2H), ril 1 \ . N 3.46 (d, J = 2.0 Hz, 3H), 3.10-3.15 (m, 1H), 2.76-N \ 2.83 (m, 2H), 2.59 (s, 3H), 2.28-2.36 (m, 2H), d c3 1.54-1.60 (m, 3H), 1.41 (s, 6H), 1.34-1.37 (m, 3H), 0.98-1.04 (m, 3H), 0.63-0.70 (m, 2H). MS: 560.3 0 1H-NMR (400 MHz, CDCI3) 6:8.21 (d, 1H, J = 8.4 N HN1CF3 Hz), 7.82 (s, 1H), 7.63 (d, 1H, J =
8.0Hz), 6.39 (s, ____ H I \ =1:21 1H), 6.12 (br s, 1H), 5.17 (d, 1H, J =
10.0 Hz), O N Illr 8 4.14-4.06 (m, 1H), 3.80 (d, 2H, J = 7.2 Hz), 3.43 17/150 HO d c3 (br s, 1H), 2.60 (s, 3H), 1.86 (t, 2H), 1.56-1.54 (m, 3H), 1.38 (d, 3H, J = 6.4 Hz), 1.31-1.24 (m, 9H), 0.98 (s, 3H), 0.62-0.54 (m, 2H). MS: 654.2 (M+1)+.
# Structure Analytical data a 1H-NMR (400 MHz, CDCI3) 6: 8.18 (d, 1H, J =
8.0 O Hz), 7.61 (d, 1H), 7.30 (d, 1H), 6.29 (s, 1H), 5.67 N HN1CF3 (d, 1H, J = 8.0 Hz), 4.81 (d, 1H, J = 9.6 Hz), 4.19-H I \ 411 =0 4.16 (m, 1H), 4.05-3.98 (m, 3H), 3.78 (d, 2H, J =
17/151 N 8 7.2 Hz), 3.56-3.50 (m, 2H), 2.62 (s, 3H), 2.00-1.97 d (m, 2H), 1.60-1.49 (m, 14H), 1.38-1.29 (m, 6H), 0.98 (m, 3H), 0.62-0.57 (m, 2H). MS: 612.3 (M+1)+.
O 1H-NMR (400 MHz, CDCI3) 6: 8.16 (d, 1H, J
= 8.4 N HN1 Hz), 7.60 (d, 1H), 7.28 (d, 1H), 6.27 (s, 1H), 6.12 s=0 (br s, 1H), 5.25 (d, 1H, J = 16.0 Hz), 4.08-4.00 (m, O N 8 1H), 3.77 (d, 2H, J = 7.2 Hz), 3.43 (br s, 2H), 2.60 17/152 HO d (s, 3H), 1.87-1.83 (m, 2H), 1.60-1.52 (m, 12H), 1.38 (d, 3H, J = 6.8 Hz), 1.33-1.21 (m, 9H), 0.97 (s, 3H), 0.63-0.58 (m, 2H). MS: 642.3 (M-i-1).
1H-NMR (CDCI3, 400 MHz) 6: 0.60-0.67 (m, 2H), o 0.73-0.76 (m, 2H), 0.86-0.88 (m, 2H), 0.96-0.99 (m, 3H), 1.24 (s, 6H), 1.27-1.40 (m, 12H), 1.42 (s, o / \ 3H), 1.49-1.59 (m, 3H), 1.86 (t, J
= 7.2 Hz, 2H), 17/153 N 10 2.61 (s, 3H), 3.38-3.43 (m, 2H), 3.64 (s 3H), 3.71 (d, J = 7.2 Hz, 2H), 5.84-5.86 (m, 1H), 6.15 (s, ) 1 1H), 7.00 (s, 1H), 7.13 (s, 1H), 7.25 (s, 1H). MS:
535.4 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 0.58-0.67 (m, 2H), o o 0.73-0.76 (m, 2H), 0.86-0.88 (m, 2H), 0.93-0.99 )1... 0--.N
H (m, 3H), 1.29-1.38 (m, 12H), 1.42 (s, 3H), 1.49-o \ / \ 1.56 (m, 3H), 2.26-2.31 (m, 2H), 2.60 (s, 3H), 17/154 N lip 2.70-2.76 (m, 2H), 3.05-3.11 (m, 1H), 3.70-3.72 (m, 5H), 4.66-4.76 (m, 1H), 5.87 (d, J = 6.8 Hz, ) 11 1H), 6.16 (s, 1H), 7.00 (s, 1H), 7.13 (s, 1H), 7.25 (s, 1H). MS: 519.3 (M+1)+.
1H-NMR (400 MHz, CDCI3) 6: 7.39 (s, 1H), 7.20 o o (s, 1H), 7.08 (s, 1H), 6.19 (s, 1H), 5.97-6.00 (m, H 1H), 4.74-4.84 (m, 1H), 3.73 (d, 2H, J = 6.8 Hz), HO I \3.06-3.11 (m, 1H), 2.76-2.81 (m, 2H), 2.60 (s, 3H), 17/155 N ilp 2.25-2.33 (m, 2H), 1.54 (d, 2H, J = 6.4 Hz), 1.43 I(s, 3H), 1.32-1.35 (m, 3H), 0.99-1.06 (m, 3H), ) OH 0.87-0.90 (m, 2H), 0.75-0.77 (m, 2H), 0.59-0.68 (m, 2H). MS: 507.3 [M+1]+.
1H-NMR (CDCI3, 400 MHz) 6: 0.59-0.65 (2H, m), Cla o j< 0.97-0.99 (3H, m), 1.23 (9H, s), 1.29-1.33 (3H, m), N FIN 1.49-1.58 (6H, m), 1.96-1.99 (2H, m), 2.62 (3H, s), H I \ . S=0 2.69 (3H, s), 3.52 (2H, dt, J
= 9.6, J = 1.2 Hz), II
17/156 N d 0 3.80 (2H, d, J = 6.8 Hz), 3.98 (2H, d, J =
10.8 Hz), 4.11-4.21 (1H, m), 4.45 (1H, s), 5.61 (1H, d, J =
8.0 Hz), 6.27 (1H, s), 7.25 (1H, s), 8.05 (1H, d, J =
8.8 Hz). MS: 530.3 (M+1)+.
# Structure Analytical data a 1H-NMR (CDCI3, 400 MHz) 6: 0.60-0.66 (2H, m), . , 0.97-1.00 (3H, m), 1.20-1.25 (11H, s), 1.32-1.37 N FINil (rrI, 3H), 1.47-1.49 (m, 6H), 1.97 (2H, dd, J = 12.0, H I = 2.0 Hz), 2.62 (3H, s), 3.52 (2H, td, J = 10.0, 1.6 \ . so 17/157 N 8 Hz), 3.80 (2H, d, J = 6.8 Hz), 3.98 (2H, d, J = 11.2 C) Br Hz), 4.15-4.17 (m, 1H), 5.11 (1H, s), 5.61 (1H, d, J
= 8.0 Hz), 6.32 (1H, s), 7.40 (1H, dd, J = 8.4, 1.6 Hz), 7.70 (1H, d, J = 1.2 Hz), 8.17 (1H, d, J = 8.4 Hz). MS: 594.2/596.2 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 0.57-0.65 (2H, m), a 0 FIN j< 0.97-1.00 (3H, m), 1.27 (9H, s), 1.29-1.33 (3H, rrl), N 1.49-1.58 (6H, m), 1.96-2.00 (2H, m), 2.63 (3H, s), H I \ . S=0 3.53(2H, td, J = 11.6, 1.2 Hz), 3.81 (2H, d, J = 7.2 17/158 N 8 Hz), 4.00 (2H, d, J = 10.8 Hz), 4.14-4.18 (1H, m), d CN 5.13 (1H, s), 5.64 (1H, d, J = 8.0 Hz), 6.38 (1H, s), 7.65 (1H, dd, J = 8.0, 1.6 Hz), 7.79 (1H, d, J = 1.6 Hz), 8.16 (1H, d, J = 8.4 Hz). MS: 541.3 (M-1-1)+.
a1H-NMR (CDCI3, 400 MHz) 6: 6.87 (s, 1H), 6.47 0 cF3 (s, 1H), 6.32 (s, 1H), 6.60 (d, J = 8.0 Hz, 1H), 4.95 (t, J = 6.0 Hz, 1H), 4.14-4.18 (m, 1H), 3.98 (d, J =
H 1 µ \ N 11.2 Hz, 2H), 3.82 (d, J = 7.6 Hz, 2H), 3.52 (t, J =
17/159 N ' i( NH 11.2 Hz, 2H), 3.11 (d, J = 6.0 Hz, 1H), 2.61 (s, C) 3H), 1.98 (d, J = 11.2 Hz, 2H), 1.46-1.58 (m, 6H), 1.27-1.36 (m, 2H), 1.01-1.04 (m, 12H), 0.69-0.74 (m, 2H). MS: 535.3 (M+1)+.
a 1H-NMR (CDCI3, 400 MHz) 6: 0.59-0.67 (m, 2H), CF3 0 93-1 00 (m 3H) 1 26-1 37 (m 4H) 1.49 (s 6H) N i 1.52-1.65 (m, 5H), 1.99 (d, 2H, J =
13.6 Hz), 2.63 H I \ . -=1:;$ (s, 3H), 3.53 (t, 2H, J = 11.2 Hz), 3.81 (d, 2H, J =
17/160 N 0 6.8 Hz), 3.99(d, 2H, J = 11.2 Hz), 4.12-4.20 (m, d u3 1H), 5.07 (s, 1H), 5.63 (d, 1H, J = 7.6 Hz), 6.39 (s, 1H), 7.63 (d, 1H, J = 8.4 Hz), 7.83 (s, 1H), 8.25 (d, 1H, J = 8.4 Hz). MS: 638.2 (M+1)+.
JF3 1H-NMR (CDCI3, 400 MHz) 6: 0.58-0.65 (m, 2H), N HN 0.91-1.00 (m, 3H), 1.16-1.34 (m, 10H), 1.44 (s, H I \ . S=0 6H), 1.57 (d, 1H, J = 8.0 Hz), 1.88 (t, 2H, J = 10.0 O N 8 Hz), 2.63 (s, 3H), 3.41-3.48 (m, 2H), 3.81 (d, 2H, J
17/161 HO d u3 =8.8Hz), 5.14 (s, 1H), 5.99 (t, 1H, J =
7.6 Hz), 6.40 (s, 1H), 7.65 (d, 1H, J = 11.2 Hz), 7.84 (s, 1H), 8.25 (d, 1H, J = 11.2 Hz). MS: 668.3 (M+1)+.
C) _lch 0 V
N 1H-NMR (400 MHz, CDCI3) 6:7.28 (m, 1H), 7.11 H N . (m, 1H), 6.99 (m, 1H), 6.19 (m, 1H), 6.14 (s, 1H), H I \ 3.71 (d, 2H, J = 7.2 Hz), 3.58 (d, 2H, J =
7.2 Hz), 17/162 N 2.59 (s, 3H), 1.62 (m, 3H), 1.55-1.46 (m, 9H), d 1.42-1.26 (m, 12H), 1.00 (m, 3H), 0.86 (m, 2H), 0.74 (m, 2H), 0.65 (m, 2 H). MS: 547.4 (M+1)+.
# Structure Analytical data O 1H-NMR (CDCI3, 400 MHz) 6: 0.57-0.66 (m, 2H), N
-7c_ Fly'-'` 0.97-1.01 (m, 3H), 1.25 (s, 6H), 1.30 (s, 12H), H I \ 1.50-1.54 (m, 3H), 1.62 (s, 9H), 1.86 (t, J = 7.4 17/163 o N W ,= Hz, 2H), 2.61 (s, 3H), 3.41-3.46 (m, 2H), 3.77 (d, J
HO d .7.2 Hz, 2H), 4.71 (s, 1H), 5.96-5.98 (m, 1H), 6.26 (s, 1H), 7.24 (s, 1H), 7.58 (s, 1H), 8.17 (d, J
= 8.8 Hz, 1H). MS: 602.3 (M+1)+.
00, 1H-NMR (400 MHz, CDCI3) 6: 0.53-0.63 (m, 2H), 0 j< 0.96-0.98 (m, 3H), 1.15-1.19 (m, 2H), 1.25 (s, 9H), N Hy 1.28-1.33 (m, 5H), 1.47-1.54 (m, 5H), 1.97-2.00 H I \ * S=0 (M, 2H), 2.62 (s, 3H), 3.21 (s, 3H), 3.50-3.56 (m, 17/164 N 8 2H), 3.78-3.80 (m, 2H), 3.97-4.00 (m, 2H), 4.20 do . (br s, 1H), 5.62 (d, J =8.0 Hz, 1H), 5.89(s, 1H), I 6.29 (s, 1H), 7.39-7.42 (m, 2H), 8.18 (d, J = 8.0 Hz, 1H). MS: 586.4 ([M+H]).
1H-NMR (CDCI3, 400 MHz) 6: 0.58-0.70 (m, 2H), ON) 0 0.86-1.11 (m, 3H), 1.17 (s, 9H), 1.21 (s, 9H), 1.23-N Hy 1.34 (m, 5H), 1.38-1.57 (m, 3H), 1.96-2.00 (m, H I \ 411 s=o 2H), 2.62 (s, 3H), 3.48-3.56 (m, 2H), 3.79-3.81 (m, d 17/165 N 8 4H), 3.97-4.00 (m, 2H), 4.13-4.19 (m, 1H), 4.88 (s, 0 1H), 5.61 (d, J = 8.0 Hz, 1H), 6.28 (s, 1H), 6.93 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H). MS: 602.2 (M+1) .
1H-NMR (CDCI3, 400 MHz) 6: 0.58-0.67 (m, 2H), oa 0 J, 0.93-0.99 (m, 3H), 1.24 (s, 9H), 1.30-1.33 (m, 3H), N Hy 1.51-1.58 (m, 5H), 1.97-2.01 (m, 2H), 2.62 (s, 3H), H I \ II s=o 3.53 (t, J = 11.2 Hz, 2H), 3.79 (d, J = 7.2 Hz, 2H), 17/166 N 8 3.99 (d, J = 11.2 Hz, 2H), 4.11-4.21 (m, 1H), 4.69 P (s, 1H), 5.61 (d, J = 7.6 Hz, 1H), 6.34 (s, 1H), d ,30 7.33-7.34 (m, 2H), 8.06 (d, J = 8.0 Hz, 1H). MS:
600.3 (M+1)+.
I 1H-NMR (CDCI3, 400 MHz) 6: 0.58-0.66 (m, 2H), O
0.93-1.04 (m, 3H), 1.23 (s, 9H), 1.27-1.32 (s, 9H), N HN'S= 1.54-1.56 (m, 3H), 1.88 (t, J = 7.6 Hz, 2H), 2.60 =
H I \ S0 7c0 N W 8 (s, 3H), 3.43 (t, J = 6.0 Hz, 2H), 3.79 (d, J = 6.8 Hz, 2H), 4.79 (s, 1H), 5.96 (d, J = 8.0 Hz, 1H), HO d=
o0H,2 6.32 (s, 1H), 6.64 (t, J = 73.6 Hz, 1H), 7.26 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H). MS: 612.3 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 0.72-0.78 (m, 2H), o cF3 1.03-1.07 (m, 3H), 1.22-1.28 (m, 15H), 1.34-1.37 I (m, 2H), 1.49-1.59 (m, 4H), 1.89 (t, J =
7.2 Hz, c) H \ 4. ,.., 0 N 2H), 3.48-3.53 (m, 2H), 4.00 (d, J = 7.6 Hz, 2H), NC
HO d HN1< 4.77 (s, 1H), 6.31 (t, J = 5.6 Hz, 1H), 6.64 (s, 1H), 7.71 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.85 (d, J = 0.8 Hz, 1H), 8.40 (d, J = 8.0 Hz, 1H). MS: 625.2 (M+1)+.
oy\
,0 1H-NMR (CD30D, 400 MHz) 6: 0.57-0.64 (m, 2H), 0.99-1.03 (m, 3H), 1.24 (s, 6H), 1.25 (s, 9H), 1.27-HO H I \ . So 1.44 (m, 3H), 1.51-1.53 (m, 3H), 1.86 (t, J = 7.6 17/169 o N HN< Hz, 2H), 3.38 (t, J = 7.6 Hz, 2H), 4.31 (d, J = 7.6 NH2 \--0 Hz, 2H), 6.67 (s, 1H), 7.86 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.93 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H). MS:
# Structure Analytical data 643.2 (M+1)+.
o 1H-NMR (400 MHz, CDCI3) 6: 8.11 (d, 1H, J = 8.4 A F Hz), 7.81 (s, 1H), 7.55-5.53 (m, 1H), 7.42-7.39 (m, HO ts,, 0 F 1H), 6.37 (s, 1H), 6.11 (d, 1H, J = 8.4 Hz), 4.62 (s, N ,0 17/170 H I \ * 2H), 3.81 (d, 2H, J = 6.8 Hz), 2.61-2.53 (m, 5H), N HN, 2.43-2.38 (m, 2H), 1.56-1.54 (m, 3H), 1.48 (s, 3H), \--0 -\ 1.38-1.25 (m, 3H), 1.23 (s, 9H), 0.98-0.88 (m, 3H), 0.65-0.58 (m, 2H). MS: 594.2 (M+1)4.
o FloA,. o 1H-NMR (400 MHz, DMSO-d6) 5:12.14 (s, 1H), 7.79 (d, 1H, J = 8.0 Hz), 7.19 (t, 1H, J = 1.6 Hz), N 7.14(t, 1H, J = 1.6 Hz), 6.97(t, 1H, J = 2.0 Hz), HI \ * 6.55 (s, 1H), 4.47-4.42 (m, 1H), 3.76 (d, 2H, J=
17/171 N 7.2 Hz), 2.51 (s, 3H), 2.42-2.37 (m, 2H), 2.10-2.05 d 4 (m, 2H), 1.45-1.47 (m, 3H), 1.40-1.21 (m, 18H), 0.95-0.72 (m, 10H). MS: 519.3 (M+1)+.
1H-NMR (400 MHz, CD30D) 5: 0.56-0.63 (m, 2H), N Hy 17/172 0.87-0.93 (m, 3H), 1.12 (s, 9H), 1.14 (s, 6H), 1.20-H I \
7c0 N W 8S= 1.23 (m, 3H), 1.44-1.47 (m, 3H), 1.75 (br s, 2H), 2.47 (s, 3H), 3.26 (br s, 2H), 3.81 (d, J = 7.2 Hz, HO d 0 Fõ 2H), 6.51 (s, 1H), 7.36 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H). MS: 630.3 [M+1].
HN 1H-NMR (400 MHz, DMSO-d6) 5: 0.60-0.67 (m, rj:11 2H), 0.88-0.97 (m, 3H), 1.09 (s, 6H), 1.14 (s, 9H), - OH N8 1.21-1.23 (m, 3H), 1.45-1.48 (m, 3H), 2.53 (s, 3H), 17/173 3.34-3.36 (m, 2H), 3.87 (d, J = 6.8 Hz, 2H), 6.79 P
d F3c (s, 1H), 7.48-7.58 (m, 3H), 7.72 (s, 1H), 8.00 (d, J
= 8.0 Hz, 1H), 12.19 (br s, 1H). MS: 616.2 [M+1].
OH
1H-NMR (400 MHz, DMSO-d6) 5: 0.59-0.66 (m, ..., =0,,,,, o 2H), 0.90-0.94 (m, 3H), 1.13 (s, 9H), 1.19-1.22 (m, Hy 3H), 1.45-1.48 (m, 3H), 2.25-2.40 (m, 4H), 2.52 (s, N
H I \ = S=0 3H), 2.85-2.95 (m, 1H), 3.87 (d, J = 6.8 Hz, 1H), d 0 / 8 4.48-4.54 (m, 1H), 6.81 (s, 1H), 7.48 (s, 1H), 7.58 (dd, J = 8.0, J = 1.6 Hz, 1H), 7.72 (s, 1H), 7.94 (d, F3c J = 8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 12.15 (s, 1H). MS: 614.2 [M+1r.
a 1H-NMR (400 MHz, CDCI3) 5: 1.05-1.10 (m, 3H), o Hy 1.26 (s, 12H), 1.49-1.80 (m, 7H), 1.97-2.00 (m, N
H I \ . ==0. 2H), 2.65(s, 3H), 3.30 (br s, 1H), 3.53(t, J = 11.2 17/175 N 0 Hz, 2H), 3.99 (dd, J = 10.4 Hz, 1.6 Hz, 2H), 4.10-d 0F3 4.23 (m, 1H), 4.68 (s, 1H), 5.62 (d, J = 8.0 Hz, 1H), 6.42 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H). MS: 582.2 [M+1}.
# Structure Analytical data 11-1-NMR (400 MHz, CDCI3) 6: 0.64 (s, 3H), 0.99-Q0 , 1.07 (m, 4H), 1.25 (s, 9H), 1.32-1.39 (m, 2H), N HN 1.46-1.54 (m, 4H), 1.98 (dd, J = 12.4 Hz, 2.0 Hz, H I \ * .=.0 2H), 2.65 (s, 3H), 3.53 (td, J = 11.2 Hz, 2.0 Hz, 17/176 N 8 2H), 3.99 (dd, J = 11.2 Hz, 2.0 Hz, 2H), 4.04 (s, (1Y--- cF3 2H), 4.12-4.21 (m, 1H), 4.70 (s, 1H), 5.63 (d, J =
7.2 Hz, 1H), 6.38 (s, 1H), 7.25 (s, 1H), 7.62 (d, J =
8.4 Hz, 1H), 7.81 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H).
MS: 584.3 [M+1]t 1H-NMR (400 MHz, CDCI3) 6: 0.86 (d, J = 6.4 Hz, a 0 2H), 0.96-0.99 (m, 2H), 1.26 (d, J = 2.0 Hz, 9H), HIN1-< 1.49-1.55 (m, 4H), 1.96-2.01 (m, 5H), 2.62-2.64 N
H I \ * =.1D (M, 3H), 3.52 (td, J = 11.2 Hz, 2.0 Hz, 2H), 3.92 17/177 N 8 (d, J = 6.4 Hz, 1H), 3.99 (dd, J = 8.4 Hz, 2.4 Hz, )= cF3 2H), 4.04 (d, J = 7.2 Hz, 1H), 4.11-4.23 (m, 1H), 4.71 (s, 1H), 5.61 (d, J = 7.2 Hz, 1H), 6.36 (s, 1H), 7.61 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.80 (br s, 1H) , 8.32 (d, J = 8.0 Hz, 1H). MS: 570.2 [M+1]t o .1-__, 0 v 1H-NMR (400 MHz, CDCI3) 6: 7.28 (s, 1H), 7.11 N
H N (M, 1H), 6.99 (m, 1H), 6.25 (m, 1H), 6.15 (s, 1H), H 1 \ . 3.72 (m, 4H), 2.92 (m, 2H), 2.61 (s, 3H), 1.54 (m, 17/178 N 3H), 1.42 (s, 3H), 1.40-1.25 (m, 12H), 1.00 (m, d 3H), 0.86 (m, 2H), 0.75 (m, 2H), 0.65 (m, 2 H).
MS: 519 (M+1)+.
o j< 1H-NMR (CDCI3, 400 MHz) 6: 0.58-0.65 (m, 2H), C 0.98-0.99 (m, 3H), 1.26 (s, 9H), 1.29-1.32 (m, 2H), IN Hri 1 \ 411 e =o 1.55-1.56 (m, 4H), 2.59 (s, 3H), 2.73 (d, J = 7.6 o II
79 N = Hz, 1H), 2.99-3.05 (m, 1H), 3.80 (d, J =
7.6 Hz, x O OH d cF3 2H), 3.88-4.58 (m, 4H), 4.74 (s, 1H), 6.33 (s, 1H), 7.60 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.77 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H). MS: 598.2 (M+1)+.
0 1H-NMR (CDCI3, 400 MHz) 6: 0.60-0.63 (m, 2H), N Ily 0.99 (br s, 3H), 1.24 (s, 6H), 1.27 (s, 9H), 1.30-1 \ *e =o 1.36 (m, 3H), 1.54-1.56 (m, 3H), 2.58 (s, 3H), ii 17/180 N o 2.93-2.98 (m, 1H), 3.79 (d, J = 6.8 Hz, 2H), 3.88-O 0H d u3 4.48 (m, 4H), 4.84 (s, 1H), 6.35 (s, 1H), 7.61 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H). MS: 626.3 (M+1)+.
HO 1H-NMR (400 MHz, DMSO-d6) 6: 12.21 (s, 1H), ="\::\ 0 ----\ 8.23 (d, 1H, J = 8.4 Hz), 7.92 (d, 2H, J = 8.0 Hz), o N
NH 7.84 (d, 2H, J= 8.4 Hz), 6.91 (s, 1H), 4.47-4.44 H I \ . S=0 (M, 1H), 3.89 (d, 2H, J = 6.8 Hz), 2.54 (s, 3H), 17/181 N ii o 2.42-2.37 (m, 2H), 2.11-2.06 (m, 2H), 1.47-1.45 d cF3 (m, 3H), 1.36-1.32 (m, 3H), 1.23-1.20 (m, 3H), 1.15 (s, 9H), 0.93-0.85 (m, 3H), 0.66-0.61 (m, 2H).
MS: 626.3 (M+1)+.
# Structure Analytical data OH
ONa 1H-NMR (400 MHz, CDCI3) 5: 8.31 (d, 1H, J = 8.4 ---"NH Hz), 7.78 (s, 1H), 7.60 (d, 1H, J = 8.4 Hz), 6.29 (s, N \ . 1 1H), 5.44 (s, 1H), 4.71 (s, 1H), 3.79 (d, 1H, J = 7.2 17/182 H I N S=0 I I Hz), 2.60 (s, 9H), 2.06-1.94 (m, 12H), 1.56-1.54 d 0.57 (m, 2H). MS: 652.2 (M+1) cF, (m, 3H), 1.42-1.26 (m, 12H), 0.99 (br s, 3H), 0.64-+.
a1H-NMR (400 MHz, CDCI3) 5: 0.47-0.50 (m, 2H), O j< 0.85-0.90 (m, 3H), 1.20 (s, 9H), 1.24-1.30 (m, 3H), N HN 1.47-1.55 (m, 5H), 1.97-2.00 (m, 2H), 2.66 (s, 3H), H I \ . o 3.50-3.55 (m, 2H), 3.63-3.65 (m, 2H), 3.96-3.99 17/183 N 8 (m, 2H), 4.17 (s, 1H), 4.76 (s, 1H), 5.62 (s, 1H), d , s 6.34(s, 1H), 7.30 (d, J = 6.4 Hz, 1H), 7.38 (d, J =
8.0 Hz, 1H), 7.59 (d, J = 6.4 Hz, 1H), 8.01 (d, J =
8.0 Hz, 1H). MS: 572.2 (M+1)+.
OH
1H-NMR (400 MHz, CD30D) 5: 0.55-0.59 (m, 2H), 0".= 0.87-0.94 (m, 3H), 1.18-1.27 (m, 13H), 1.48-1.49 \-_-_ , 0 1-11 (m, 2H), 2.41 (q, J = 10.0 Hz, 2H), 2.62-2.65 (s, N
H I \ = S=0 5H), 3.06 (br s, 1H), 3.77 (d, J = 4.2 Hz, 2H), 4.72 17/184 N 8 (t, J = 6.8 Hz, 1H), 6.70 (s, 1H), 7.41 (d, J = 4.8 C) , S Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 7.6 Hz, 1H). MS: 586.2 (M+1)+.
a OH
O 1H-NMR (400 MHz, CDCI3) 5: 0.50-1.46 (m, 11H), 1.62 (s, 6H), 1.93 (d, J = 12.4 Hz, 2H), 2.60 (s, N
H I \ * 3H),2.41 (d, J = 7.6 Hz, 2H), 3.22 (m, 1H),3.45 C), (m, 2H), 3.59 (m, 1H), 3.92 (m, 1H, m, 4.12 (m, 1H), 5.57 (br s, 1H), 6.21 (s, 1H), 7.33-7.50 (m, 4H), 7.82 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H). MS: 489.3 (M+1)+.
a 0_ N
H I \ *
17/186 N MS: 563.3 (M+1)+.
d o A OH 1H-NMR (400 MHz, CD30D) 5: 0.45-1.39 (m, HO 'Ir:L 0 11H), 1.55-1-56 (m, 6H), 2.25-2.33 (m, 2H), 2.50 N (s, 3H), 2.52-2.56 (m, 2H), 2.91-2.96 (m, 1H), H I \ .
N 3.20-3.23 (m, 1H), 3.63-3.66 (m, 1H), 4.57-3.65 d = (m, 1H), 6.46 (s, 1H), 7.31-7.41 (m, 2H), 7.49-7.52 (m, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H). MS: 503.2 (M+1)4".
# Structure Analytical data 1H-NMR (400 MHz, CDCI3) 6: 0.45-0.54 (m, 2H), a NH 0.85-0.90 (m, 4H), 1.24-1.30 (m, 5H), 1.24-1.50 ) 0 (m, 4H), 1.53 (s, 9H), 1.98-2.04 (m, 2H), 2.68 (s, N 3H), 3.37-3.41 (m, 1H), 3.53 (td, J =
11.6, J = 2.2 H I \ ii Hz, 2H), 3.67-3.71 (m, 1H), 3.97 (d, J
= 11.6 Hz, d 17/188 N 1H), 4.18 (br s, 1H), 5.63 (d, J = 6.8 Hz, 1H), 6.06 = (s, 1H), 6.29 (s, 1H), 7.52-7.57 (m, 2H), 7.68 (d, J
= 8.0 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.97 (dd, J
= 8.0, J = 1.2 Hz, 1H), 8.27 (d, J = 1.2 Hz, 1H).
MS: 530.3 (M+1)+.
J1õ NH 1H-NMR (400 MHz, CD30D) 6:0.40-1.37 (m, 11H), 1.40 (s, 9H), 2.23-2.31 (m, 2H), 2.47-2.53 HO ) El.. 0 0 (s, 5H), 2.89-2.93 (m, 1H), 3.32-3.36 (m, 1H), N
17/189 H I \ = 3.69-3.69 (m, 1H), 4.58 (t, J = 8.0 Hz, 1H), 6.47 N (s, 1H), 7.43-7.49 (m, 2H), 7.63 (d, J =
8.4 Hz, C), 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.86 (br s, 1H), 7.93 (dd, J = 8.4, J = 1.6 Hz, 1H), 8.23 (s, 1H). MS:
544.3 (M+1)+.
a 0 \ 1H-NMR (CDCI3, 400 MHz) 6: 0.62-0.69 (m, 2H), N _N NH 1.02 (br s, 3H), 1.28 (s, 9H), 1.34-1.39 (m, 3H), H
17/190 V-1C1 ___________ 1.49-1.64 (m, 5H), 1.97-2.00 (m, 2H), 2.65 (s, 3H), "- N \ __ ' 8 3.53 (t, J = 11.4 Hz, 2H), 3.82 (d, J =
7.2 Hz, 2H), d u3 3.98-4.01 (m, 2H), 4.13-4.19 (m, 1H), 5.24 (s, 1H), 5.54 (d, J = 7.6 Hz, 1H), 6.46 (s, 1H), 8.11 (s, 1H), 8.78 (s, 1H). MS: 585.2 (M+1)+ .
HO F2HCO 1H-NMR (400 MHz, CD30D) 6: 0.50-0.77 (m, 2H), N
H I \ * 1.00-1.10 (M, 3H), 1.26 (s, 6H), 1.37 (s, 9H), 1.49 (s, 9H), 1.18-1.64 (m, 6H), 2.58 (s, 3H), 3.34-3.39 N
C)1 (m, 2H), 3.57-3.73 (m, 2H), 6.16 (t, J = 74.8 Hz, 1H), 6.56 (s, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H). MS: 547.3 [m-Fi]'.
0 1H-NMR (400 MHz, CD30D) 6: 0.63-0.65 (m, 2H), XNN
H I \ * 0.98-1.01 (m, 3H), 1.22 (s, 6H), 1.28-1.29 (m, 3H), 1.33 (s, 9H), 1.54-1.55 (m, 3H), 2.35 (s, 3H), 2.55 N (s, 3H), 3.33 (s, 2H), 3.62 (d, J = 6.8 Hz, 2H), 6.10 d 17/192 (t, J = 75.6 Hz, 1H), 6.46 (s, 1H), 7.22 (d, J = 2.8 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H). MS: 505.4 [M+1].
HO
0 F2HCO 1H-NMR (400 MHz, CD30D) 6: 0.45-0.75 (m, 2H), 0 =(\_ H 1 0.87-1.00 (m, 3H), 1.33 (s, 9H), 1.45 (s, 9H), 1.14-1.61 (m, 6H), 2.34-2.42 (m, 2H), 2.52 (s, 3H), 17/193 N 2.58-2.64 (m, 2H), 3.00-3.07 (m, 1H), 3.53-3.70 d (m, 2H), 4.84-4.69 (m, 1H), 6.10 (t, J =
75.2 Hz, 1H), 6.54 (s, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H). MS: 573.4 [M+1]+.
# Structure Analytical data HO
F2HCO 1H-NMR (400 MHz, CD30D) 6: 0.62-0.65 (m, 2H), o A-A
\----"'N it, H \ 0.96-1.01 (m, 3H), 1.28-1.31 (m, 3H), 1.33 (s, 9H), \
1.53-1.55 (m, 3H) , 2.34 (s, 3H), 2.35-2.41 (m, 17/194 N 2H), 2.53 (s, 3H), 2.58-2.63 (m, 2H), 3.01-3.05 (m, d 1H), 3.61 (d, J = 6.8 Hz, 2H), 4.66 (m, 1H), 6.08 (t, J = 75.6 Hz, 1H), 6.48 (s, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H). MS: 531.3 [M-i-1].
HO 1H-NMR (300 MHz, CDCI3) 6: 0.67-0.72 (m, 2H), 0 86-0 90 (m 1H) 0 98-1 03 (m 12H) 1 26-1 36 o n ¨ (m, 14H), 1.55-1.57 (m, 3H), 2.28-2.35 (m, 2H), 2.60 (s, 3H), 2.75-2.82 (m, 2H), 3.09 (br s, 1H), 17/195 N 3.82 (d, J = 7.5 Hz, 2H), 4.06 (s, 2H), 4.75-4.83 d (m, 1H), 5.94 (d, J = 6.9 Hz, 1H), 6.28 (s, 1H), 6.49 (d, J = 0.9 Hz, 1H), 6.79 (s, 1H). MS: 538.3 (M+1)+.
HO
L. 0 HN-x_ 1H-NMR (400 MHz, CD30D) 6: 0.80-0.89 (m, 2H), 0 'c'y 1.06-1.10 (m, 12H), 1.27-1.42 (m, 15H), 1.59-1.62 (m, 3H), 2.36-2.43 (m, 2H), 2.57-2.64 (m, 5H), 17/196 N 3.02-3.07 (m, 1H), 3.23 (s, 2H), 4.01 (d, 2H), 4.63-4.68 (m, 1H), 6.78 (s, 1H), 6.80 (s, 1H), 6.96 (s, 1H). MS: 537.4 (M+1)+.
OH
\ 1H-NMR (300 MHz, CDCI3) 6: 0.60 (br s, 2H), 0.86 (t, J = 7.5 Hz, 3H), 0.98-1.04 (m, 3H), 1.17 (s, 6H), Eiy< 1.20-1.38 (m, 4H), 1.54-1.61 (m, 6H), 2.27-2.34 N
H I \ * S=0 (m, 2H), 2.60 (s, 3H), 2.77 (s, 5H), 3.05-3.10 (m, 17/197 N 8 1H), 3.53 (br s, 2H), 4.59 (s, 1H), 4.78-4.82 (m, C) . 1H), 6.04 (d, J = 6.6 Hz, 1H) 6.24 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H). MS:
592.3 (M+1)+.
(NN HNj< 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J
= 8.4 ON I \ iip ==o Hz), 7.79 (s, 1H), 7.61 (m, 1H), 6.27 (d, 1H), 4.71 N 8 (s, 1H), 3.79 (m, 2H), 3.71 (m, 8H), 2.40 (s, 3H), cF3 1.56 (m, 3H), 1.35-1.26 (m, 12H), 1.00 (m, 3H), 0.63 (m, 2H). MS: 570.3 (M-i-1).
NN . HNj< 1H-NMR (400 MHz, CDCI3) 6: 8.32 (d, 1H, J
= 8.4 1:32s I \ It --.0 Hz), 7.79 (s, 1H), 7.61 (m, 1H), 6.26 (s, 1H), 4.73 N 8 (s, 1H), 4.17 (m, 4H), 3.80 (m, 2H), 3.07 (m, 4H), C)1.00 u3 2.41 (s, 3H), 1.57 (m, 3H), 1.34-1.27 (m, 12H), 1.00 (m, 3H), 0.64 (m, 2H). MS: 618.2 (M+1)+.
# Structure Analytical data o 1H-NMR (400 MHz, DMSO-d6) 6: 12.19 (s, 1H), K ` 8.22 (d, 1H, J = 8.4 Hz), 7.92 (d, 1H, J = 8.4 Hz), NN
H I \ . =100 7.85 (d, 2H, J = 8.8 Hz), 7.52 (t, J=6.4Hz, 1H), N
d cF30 6.86 (s, 1H), 3.90 (d, 1H, J = 6.8 Hz), 3.35 (m, 2H), 2.54 (s, 3H), 1.46 (m, 3H), 1.22 (m, 3H), 1.09 (s, 9H), 1.06 (s, 6H), 0.95-0.85 (m, 3H), 0.62 (m, 2H). MS: 600.3 (M+1)+.
HO2c HNJ 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J = 8.0 )1N I \ . _,10 Hz), 7.78 (s, 1H), 7.60 (m, 1H), 6.39 (s, 1H), 6.35 (m, 1H), 4.87 (s, 1H), 3.88 (m, 2H), 3.78 (m, 2H), N
d cF38 3.64 (m, 2H), 3.53 (m, 2H), 2.56 (s, 3H), 2.13 (m, 2H), 1.64-1.55 (m, 5H), 1.32-1.26 (m, 12H), 0.99 17/201 o (m, 3H), 0.61 (m, 2H). MS: 642.3 (M+1)+.
H2N-1CKNN o HN<
H I \ . I - 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J = 8.4 Hz), 7.79 (s, 1H), 7.61 (m, 1H), 6.59 (m, 1H), 6.39 --*C) (s, 1H), 6.12 (m, 1H), 5.40 (m, 1H), 4.74 (s, 1H), 17/202 N 0 3.79 (m, 2H), 3.53 (m, 2H), 2.62 (s, 3H), 1.55 (m, d u3 3H), 1.34-1.10 (m, 18H), 1.00 (m, 3H), 0.63 (m, 2H). MS: 599.3 (M+1)+.
0 0 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J
= 8.4 HN" '. Hz), 7.78 (s, 1H), 7.60 (m, 1H), 6.36 (m, 2H), 6.11 H2N N I \ I. =c) (s, br, 1H), 5.98 (s, br, 1H), 4.77 (s, 1H), 3.86 (m, 17/203 0 d 8 2H), 3.79 (m, 2H), 2.60 (s, 3H), 1.97 (m, 2H), 1.73 cF3 (m, 2H), 1.55 (m, 2H), 1.33-1.24(m, 12H), 1.00 (m, 3H), 0.62 (m, 2H). MS: 641.3 (M-F1)+.
0 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J
= 8.4 N
HN Hz), 7.79 (s, 1H), 7.62 (d, 1H, J = 8.4 Hz), 7.00 HNjCKNN
H 1 \ . =-0 (m, 1H), 6.44 (s, 1H), 6.09 (m, 1H), 4.71 (s, 1H), 17/204 N 8 3.77 (m, 2H), 3.49 (m, 2H), 2.82 (d, 3H, J = 4.8 d u3 Hz), 2.61 (s, 3H), 1.56 (m, 3H), 1.36-1.22 (m, 18H), 0.99 (m, 3H), 0.61 (m, 2H). MS: 613.3 (M+1)+.
0 0 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J
= 8.0 N
HN< Hz), 7.78 (s, 1H), 7.61 (m, 1H), 6.58 (m, 1H), 6.40 11N N I \ . =,0 (s, 1H), 5.98 (m, 1H), 4.72 (s, 1H), 3.82 (m, 4H), N
õ
0 3.66 (m, 4H), 2.86 (d, 3H, J = 4.8 Hz), 2.60 (s, 3H), 1.95 (m, 2H), 1.72 (m, 2H), 1.56 (m, 3H), 17/205 0 d 1.36-1.24 (m, 12H), 1.00 (m, 3H), 0.60 (m, 2H).
MS: 655.3 (M+1)+.
a0 FI 1H-NMR (400 MHz, CDCI3) 5:8.20 (d, 1H, J = 8.4 N N_,I Hz), 7.58 (s, 1H), 7.27-7.25 (m, 1H), 6.24 (s, 1H), H I \ 411P o 5.53(s, 1H), 4.48 (s, 1H), 3.78-3.68 (m, 6H), 2.59 17/206 N d o (s, 3H), 2.14 (m, 2H), 1.81-1.74 (m, 2H), 1.62 (s, 9H), 1.54 (s, 6H), 1.32 (m, 12H), 0.98 (m, 3H), 0.61 (m, 2H). MS: 586.3 (M+1)+.
# Structure Analytical data 06,N o j< 1H-NMR (400 MHz, CDCI3) 5: 8.19 (d, 1H, J
= 8.4 N Hy Hz), 7.57 (s, 1H), 7.24 (m, 1H), 6.20 (s, 1H), 5.79 H I \ . S=0 (s, 1H), 4.48 (s, 1H), 3.92 (m, 1H), 4.48-3.78 (m, d 17/207 N 8 3H), 3.73-3.66 (m,2H), 2.78-2.75 (m, 1H), 2.62 (s, 3H), 1.62-1.53 (m, 16H), 1.49-1.33(m, 12H), 0.98 (m, 3H), 0.91-0.89 (m, 1H), 0.62 (m, 2H), 0.48 (m, 1H). MS: 598.3 (M+1)+.
OacN0 I, 1H-NMR (400 MHz, DMSO-d6) 5: 8.15 (d, 1H, J =
N HN 8.4 Hz), 7.91 (s, 1H), 7.76 (s, 1H), 7.53 (s, 1H), H I \ 7.43 (d, 1H, J = 6.8 Hz), 6.77 (s, 1H), 3.85 (s, 4H), 17/208 N 8 3.61-3.55 (m, 2H), 2.54 (s, 3H), 2.30 (m, 2H), d 2.00-1.96 (m, 2H), 1.55 (s, 9H), 1.50-1.44 (m,3H), 1.23-1.19 (m, 3H), 1.16 (s, 9H), 0.90-0.85 (m, 3H), 0.63 (m, 2H). MS: 597.3 (M+1)+.
00, 0 1H-NMR (400 MHz, CDCI3) .5: 8.32 (d, 1H, J = 8.4 N HNHz), 7.80 (s, 1H), 7.62 (d, 1H, J = 6.4 Hz), 6.33 (s, H I \ . 4=0 1H), 5.50 (s, 1H), 4.71 (s, 1H), 3.81-3.67 (m, 6H), 17/209 N 6 2.61 (s, 3H), 2.14 (m, 2H), 1.81-1.74 (m, 2H), 1.56 d u3 (m, 6H), 1.33 (m, 3H), 1.23-1.19 (m, 3H), 1.26 (s, 9H), 0.99 (m, 3H), 0.62 (m, 2H). MS: 598.3 (M+1)+.
1H-NMR (400 MHz, CDCI3) 5: 8.31 (d, 1H, J = 8.4 co,6 0 Hy Hz), 7.79 (s, 1H), 7.60 (d, 1H, J = 6.4 Hz), 6.30 (s, N
H 3.80-3.78 (m, 3H), 3.73-3.70 (m, 2H), 2.77-2.74 1H), 5.75 (s, 1H), 4.71 (s, 1H), 3.93-3.88 (m, 1H), I \ = S=0 II
d 0 (m, 1H), 2.62 (s, 3H), 1.56-1.41 (m, 7H), 1.37-1.31 (m, 3H), 1.26 (s, 9H), 0.99 (m, 3H), 0.90-0.87 (m, 1H), 0.62 (m, 2H), 0.46 (m, 1H). MS: 610.3 (M+1)+.
HNk 1H-NMR (400 MHz, CDCI3) 5: 8.32 (d, 1H, J
= 8.0 ..../N Hz), 7.78 (s, 1H), 7.61(m, 1H), 6.35 (s, 1H), 4.71 cc I \ 411 SI =0 (s, 1H), 3.99 (m, 4H), 3.80 (m, 2H), 3.64 (m, 4H), N
dc38 2.60 (s, 3H), 1.82-1.80 (m, 4H), 1.56 (m, 3H), 1.31 (m, 3H), 1.27 (s, 9H), 0.99 (m, 3H), 0.63 (m, 2H).
MS: 610.3 (M+H)+.
Q0 1H-NMR (400 MHz, CDCI3) 6: 8.19 (d, J=
8.4 Hz, N HN 1H), 7.60 (s, 1H), 7.26 (m, 1H), 6.27 (s, 1H), 5.62 H I \ II 0 (d, J=7.6Hz, 1H), 4.47 (s, 1H), 4.17 (m, 1H), 3.99 17/212 N 8 (m, 2H), 3.89 (m, 2H), 3.53 (m, 2H), 2.65 (s, 3H), d 2.01-1.92 (m, 3H), 1.61 (s, 9H), 1.55-1.49 (m, 4H), 1.46-1.34 (m, 4H), 1.31 (s, 9H), 0.90 (m, 2H). MS:
558.1 (M-i-1).
ON0 1H-NMR (400 MHz, CDCI3) 5: 8.20 (d, J=8.4Hz, N HN< 1H), 7.59 (s, 1H), 7.26 (m, 1H), 6.26 (s, 1H), 5.61 H I \ * 4=0 (d, J=7.6 Hz, 1H), 4.46 (s, 1H), 4.17 (m, 1H), 4.01-17/213 N 6 3.90 (m, 4H), 3.52 (m, 2H), 2.63 (s, 3H), 2.36 (m, _) 1H), 1.98 (m, 2H), 1.86 (m, 3H), 1.69 (s, 9H), ¨ 1.66-1.37 (m, 5H), 1.29 (s, 9H). MS:
544.1 (M+1)+.
# Structure Analytical data a 0 1H-NMR (400 MHz, DMSO-d6) 6: 8.23 (d, Fly< J=8.4Hz, 1H), 7.92 (m, 1H), 7.86 (m, 1H), 7.84 (s, N
H I \ . S=0 1H), 7.55 (m, 1H), 6.87 (s, 1H), 3.99-3.85 (m, 5H), 17/214 N 6 3.34 (m, 2H), 2.57 (s, 3H), 1.87 (m, 1H), 1.71 (m, d u3 2H), 1.53 (m, 2H), 1.34-1.25 (m, 6H), 1.15 (s, 9H), 0.88 (m, 2H). MS: 570.0 (M+1)+.
a 0 1H-NMR (400 MHz, CDCI3) 5: 8.32 (d, J=8.4 Hz, HN 1H), 7.80 (s, 1H), 7.62 (m, 1H), 6.36 (s, 1H), 5.61 N
H I \ * o (d, J=8.0 Hz, 1H), 4.70 (s, 1H), 4.16 (m, 1H), 4.01-17/215 N 8 3.97 (m, 4H), 3.52 (m, 2H), 2.63 (s, 3H), 2.37 (m, CF3 1H), 1.98 (m, 2H), 1.80-1.62 (m, 4H), 1.58-1.41 (m, 4H), 1.27 (s, 9H). MS: 556.0 (M+1)+.
a 0 L., 1H-NMR (400 MHz, CDCI3) 6: 8.30 (d, J=8.4 Hz, F11( 1H), 7.81 (s, 1H), 7.62 (m, 1H), 6.37 (s, 1H), 5.62 N ' -H \
(d, J=8.4Hz, 1H), 4.61 (s, 1H), 4.16 (m, 1H), 4.01-1 . S=0 d 17/216 N 8 3.96 (m, 2H), 3.92 (m, 2H), 3.53 (m, 2H), 2.65 (s, 3H), 2.01-1.90 (m, 3H), 1.62-1.51 (m, 2H), 1.49-1.35 (m, 5H), 1.22 (m, 8H), 0.87 (m, 6H). MS:
584.0 (M+1)+.
Oa 0 1H-NMR (400 MHz, CDCI3) 5: 8.31 (d, J=8.4Hz, 1H), 7.80 (s, 1H), 7.62 (m, 1H), 6.36 (s, 1H), 5.61 N Hy,1 (d, J=7.6 Hz, 1H), 4.62 (s, 1H), 4.17 (m, 1H), 4.01-H I \ 4. S=0 3.95 (m, 4H), 3.52 (m, 2H), 2.63 (s, 3H), 2.37 (m, 0 CF3 1H), 1.97 (d, 2H), 1.89-1.65 (m, 3H), 1.63-1.50 (m, 5H), 1.49 (m, 2H), 1.41 (s, 6H), 0.85 (t, J=7.6Hz, 3H). MS: 570.1 (M+1)+.
a 0 CF3 1H-NMR (400 MHz, CDCI3) 6: 8.19-8.18 (m, 1H), N 7.90-7.86 (m, 4H), 6.92 (s, 1H), 3.96-3.86 (m, 1H), H I \ . s02 3.86-3.83 (m, 2H), 3.38-3.33 (m, 2H), 2.79 (s, 3H), 17/218 N HN ( 1.73-1.69 (m, 4H), 1.58-1.47 (m, 5H), 1.28-1.20 z4S02 (m, 4H), 1.17 (m, 9H), 1.06 (m, 2H). MS:
634.2 µ--.) (M+H)+.
a0 a 1H-NMR (400 MHz, DMSO-d6) 5: 7.99 (s, 1 H), N 7.82 (m, 2 H), 7.59 (s, 1 H), 7.50 (d, 1 H, J = 8 H I \ Hz), 6.75 (s, 1 H), 3.92 (m, 5 H), 3.35 (m, 2 H), 17/219 N . y 2.54 (s, 3 H), 1.71 (m, 2 H), 1.53 (m, 5 H), 1.48 (s, NH 9 H), 1.36 (m, 3 H), 0.98 (m, 3 H), 0.66 (m, 2 H).
d 0 MS: 514.2 (M+1)+.
HO2Cõ, i_ 1H-NMR (DMSO-d6, 500 MHz) 6:12.18 (s, 1H), HN 8.24 (m, 1H), 7.92-7.97 (m, 2H), 7.85-7.87 (m, N
H I \ lp, ,.(:;, 2H), 6.87 (s, 1H), 4.49-4.54 (m, 1H), 3.89-3.91 (m, 17/220 N 8 2H), 2.89-2.95 (m, 1H), 2.42 (s, 3H), 2.31-2.40 (m, d u3 2H), 2.24-2.29 (m, 2H), 1.45-1.47 (m, 3H), 1.20-1.23 (m,3H), 1.15 (s, 9H), 0.87-0.99 (m,3H), 0.60-0.68 (m, 2H). MS: 598.2 (M+1)+.
# Structure Analytical data HO2Cõ, 1H-NMR (CDCI3, 500 MHz) 6: 8.18-8.20 (m, 1H), 0µ 0 HN 7.58 (s, 1H), 7.24-7.25 (m, 1H), 6.28 (s, 1H), 5.99-Aa. "
N 6.01 (m, 1H), 4.76-4.82 (m, 1H), 4.56 (s, 1H), H I is w -='10 3.77-3.79 (m, 2H), 3.07-3.12 (m, 1H), 2.77-2.81 17/221 o (m, 2H), 2.76 (s, 3H), 2.27-2.35 (m, 2H), 1.62 (s, d 9H), 1.53-1.54 (m, 3H), 1.25-1.34 (m, 12H), 0.93-0.97 (m, 3H), 0.60-0.62 (m, 2H). MS: 586.1 (M+1)+.
HO2CNN HNJ 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J = 8.0 \ . 1 Hz), 7.79 (s, 1H), 7.61 (m, 1H), 6.36 (s, 1H), 6.07 H I ` S=0 8 (s, br, 1H), 4.72 (s, 1H), 3.79 (m, 2H), 3.44 (m, 2H), 2.60 (s, 3H), 1.88 (m, 2H), 1.55 (m, 3H), 1.32-1.26 (m, 18H), 0.93 (m, 3H), 0.63 (m, 2H).
d cF, MS: 614.3 (M+H)+.
Ho2c 0 1H-NMR (400 MHz, CD30D) 6: 8.31 (d, 1H, J
=
N
Hy 8.4 Hz), 7.90 (s, 1H), 7.81 (m, 1H), 6.71 (s, 1H), I-1 I \ . s=o 3.94 (m, 1H), 3.82 (m, 1H), 2.59 (s, 3H), 2.27 (m, 17/223 N 8 1H), 2.05 (s, 4H), 1.61-1.52 (m, 5H), 1.45-1.31 (m, d c,3 5H), 1.25 (s, 9H), 1.01 (m, 3H), 0.71 (m, 2H). MS:
626.3 (M+1)+.
HNJ 1H-NMR (400 MHz, CDCI3) 6: 8.29 (d, 1H, J
= 8.4 ....0 s-\ * 1 ii-cl (s, 1H), 3.79 (m, 2H), 3.25 (m, 2H), 2.37 (s, 3H), 0 2.17 (m, 2H), 1.78-1.71 (m, 5H), 1.62-1.47 (m, N
8H), 1.35-1.22 (m, 9H), 0.88 (m, 3H), 0.62 (m, 17/224 Ho2c d u3 2H). MS: 626.3 (M+1)+.
"7 õ,õ,J 1H-NMR (400 MHz, CDCI3) 6: 8.30 (d, 1H, J = 8.0 HO2C N .
b I \ e=o ii (s, 1H), 4.38 (m, 1H), 3.90 (m, 1H), 3.79 (m, 2H), N 0 Hz), 7.79 (s, 1H), 7.61 (m, 1H), 6.30 (s, 1H), 4.72 d u3 3.36 (m, 1H), 3.11 (m, 1H), 2.39 (s, 3H), 2.28 (m, 1H), 1.57-1.47 (m, 6H), 1.45-1.26 (m, 15H), 1.00 (m, 3H), 0.63 (m, 2H). MS: 626.3 (M+1)+.
a1H-NMR (CDCI3, 400 MHz) 6: 8.05 (d, J = 8.0 Hz, o 1H), 7.41 (s, 1H), 7.22 (m, 1H), 6.28 (s, 1H), 5.62 N Hy- (m, 1H), 4.38 (s, 1H), 4.23-4.12 (m, 1H), 4.02-3.95 H I \ * ¨
¨(:) (m, 2H), 3.86 (h, J = 6.8 Hz, 1H), 3.78 (m, 2H), 17/226 N 0 3.53 (m, 2H), 2.62 (s, 3H), 2.02-1.95 (m, 2H), C) 1.60-1.48 (m, 5H), 1.32 (d, J = 6.8 Hz, 6H), 1.30-1.21 (m, 12H), 1.02-0.94 (m, 3H), 0.59 (m, 2H).
MS: 558.3 (M+1)+.
1H-NMR (400 MHz, CDCI3) 6: 8.21 (d, 1H, J = 8.4 N Hy Hz), 7.59 (s, 1H), 7.30-7.26 (m, 1H), 6.29 (s, 1H), H I \ . S=0 5.64 (d, 1H, J = 8.0 Hz), 4.92 (s, 1H), 4.18-4.16 17/227 N 8 (m, 1H), 4.00-3.97 (m, 2H), 3.79 (m, 2H), 3.56-d 3.49 (m, 2H), 2.62 (s, 1H), 2.00-1.97 (m, 2H), 1.68-1.53 (m, 14H), 1.35-1.30 (m, 3H), 1.19 (s, 3H), 0.97 (m, 3H), 0.83-0.81 (m, 2H), 0.63-0.60 # Structure Analytical data (m, 2H), 0.50-0.47 (m, 2H). MS: 570.1 (M+1)+.
,H-NMR (400 MHz, DMSO-d6) 6: 8.19 (d, 1H, J =
N 1111 8.4 Hz), 7.99 (d, 1H, J = 8.0 Hz), 7.54-7.41 (m, H I \ . S=0 3H), 6.71 (s, 1H), 3.95-3.84 (m, 5H), 3.68-3.62 (m, 17/228 N 8 1H), 3.37-3.33 (m, 2H), 2.53 (s, 3H), 1.95-1.88 (m, d 4H), 1.72-1.68 (m, 2H), 1.57-1.45 (m, 16H), 1.23-1.20 (m, 3H), 0.93-0.88 (m, 3H), 0.66-0.61 (m, 2H). MS: 570.1 (M+1)+.
cQo CF3 1H-NMR (400 MHz, CDCI3) 6: 7.65 (s, 1H), 7.37 N 0 (d, 1H, J = 10.4 Hz), 6.41 (s, 1H), 5.62 (d, 1H, J =
H 1 \ = V:3$ 8.0 Hz), 5.07 (s, 1H), 4.16 (m, 1H), 3.99 (m, 2H), 17/229 N 14N--/ 3.83 (m, 2H), 3.53 (m, 2H), 2.63 (s, 3H), 1.98 (m, d F 2H), 1.58-1.49 (m, 5H), 1.38-1.26 (m, 12H), 1.02 (m, 3H), 0.67 (m, 2H). MS: 602.2 (M+H)+.
a CF3 1H-NMR (400 MHz, CDCI3) 6: 8.09 (d, 1H, J
= 9.6 N HN'. Hz), 7.79 (d, 1H, J = 6.4 Hz), 6.38 (s, 1H), 5.61 (d, H I \ 411 =ICI 1H, J = 8.0 Hz), 4.76 (s, 1H), 4.16 (m, 1H),3.98 17/230 N 8 (m, 2H), 3.66 (d, 2H, J = 6.8 Hz), 3.52 (m, 2H), C) F 2.63 (s, 3H), 1.98 (m, 2H), 1.59-1.47 (m, 5H), 1.35-1.24 (m, 12H), 1.00 (m, 3H), 0.58 (m, 2H).
MS: 602.3 (M+H)+.
Do 1H-NMR (400 MHz, CDCI3) 6: 8.18(d, 1H, J
=8.4 N
F CF3 Hz), 7.60 (m, 1H), 6.36 (s, 1H), 5.59 (d, 1H, J =
H 1 \ A g.0 8.0 Hz), 4.79 (s, 1H), 4.16 (m, 1H), 3.98 (m, 2H), 17/231 N --M HN--/ 3.64 (d, 2H, J = 6.8 Hz), 3.52 (m, 2H), 2.62 (s, d 3H), 1.97 (m, 2H), 1.55-1.47 (m, 5H), 1.34-1.28 (m, 12H), 1.01 (m, 3H), 0.62 (m, 2H). MS: 602.2 (M+H)+.
CQ0 1H-NMR (400 MHz, CDCI3) 6: 7.70 (s, 1H), 7.47 N CF3 (s, 1H), 6.35 (s, 1H), 5.61 (d, 1H, J =
8.4 Hz), 4.65 H\ 9 o ii 11 s,, (s, 1H), 4.17 (m, 1H), 3.98 (m, 2H), 3.80 (d, 2H, J
= 7.2 Hz), 3.53 (m, 2H), 2.82 (s, 3H), 2.62 (s, 3H), HN--/
d 1.99 (m, 2H), 1.77-1.63 (m, 5H), 1.58-1.20 (m, 12H), 1.00 (m, 3H), 0.64 (m, 2H). MS: 598.3 (M+H)+.
..
# Structure Analytical data CD0 1H-NMR (400 MHz, CDCI3) 6: 8.13 (s, 1H), 7.58 N cF3 (s, 1H), 6.15 (s, 1H), 5.52 (d, 1H, J =
7.6Hz), 4.65 H 1 \ 4. k,,,, (s, 1H), 4.13-4.06 (m, 1H), 3.93-3.90 (m, 2H), 3.48-3.41 (m, 4H), 2.55 (s, 3H), 2.24 (s, 3H), 1.94-d HN-.._/ 1.90 (m, 2H), 1.53-1.40 (m, 5H), 1.35-1.19 (m, 12H), 0.93 (m, 3H), 0.57-0.51 (m, 2H). MS: 598.3 (M+H)+.
D o 1H-NMR (400 MHz, CDCI3) 6: 8.06 (d, 1H, J = 8.0 Cl Hz), 7.42 (s, 1H), 7.28 (d, 1H, J = 8.4 Hz), 6.26 (s, N
H 4.
9 1H), 5.54-5.52 (m, 1H), 4.90 (s, 1H), 4.10 (m, 1H), 1 \ k.õo 17/234 N HN-.../ 3.92 (m, 2H), 3.74 (m, 2H), 3.46 (m, 2H), 2.55 (s, 8 3H), 1.91 (m, 2H), 1.50-1.32(m, 5H), 1.27-1.17 (m, 12H), 0.93 (m, 3H), 0.55 (m, 2H). MS: 550.2 (M+H)+.
D0 1H-NMR (400 MHz, CDCI3) 6: 7.44 (s, 2H), 6.36 CI
N (s, 1H), 5.59 (d, 1H, J = 6.4 Hz), 5.32 (s, 1H), 4.16 H 1 \410 9s,o (m, 1H), 3.99 (m, 2H), 3.81 (m, 2H), 3.53 (m, 2H), d 17/235 N HN--./ 2.62 (s, 3H), 1.98 (m, 2H), 1.59-1.41 (m, 5H), Cl 1.39-1.25 (m, 12H), 1.03 (m, 3H), 0.69 (m, 2H).
MS: 584.2 (M+H)+.
D 1H-NMR (400 MHz, CDCI3) 6: 8.64 (d, 1H, J = 8.4 o . n Hz), 8.35 (m, 1H), 7.77-7.67 (m, 2H), 7.58-7.48 N (m, 2H), 6.34 (s, 1H), 5.64 (d, 1H, J = 7.6 Hz), H 1 \ . s'il,,o 4.63 (s, 1H), 4.21-4.17 (m, 1H), 4.00-3.97 (m, 2H), 17/236 N HN-..../ 3.71-3.66 (m, 1H), 3.56-3.50 (m, 2H), 3.33-3.27 8 (m, 1H), 2.68 (s, 3H), 2.01-1.98 (m, 2H), 1.57-1.45 (m, 5H), 1.30-1.17 (m, 12H), 0.90-0.84 (m, 3H), 0.51-0.43 (m, 2H). MS: 566.3 (M+H)+.
ON0 1H-NMR (400 MHz, CDCI3) 6: 7.91 (d, 2H, J
= 8.4 N
fiN Hz), 7.44 (d, 2H, J = 8.4 Hz), 6.29 (s, 1H), 5.61 (d, H I \ . .=-Ci 1H, J = 7.6 Hz), 4.49 (s, 1H), 4.17 (m, 1H), 3.98 ii 17/237 N (m, 2H), 3.80 (m, 2H), 3.52 (m, 2H), 2.62 (s, 3H), d 1.98 (m, 2H), 1.59-1.47 (m, 5H), 1.36-1.25 (m, 12H), 0.96 (m, 3H), 0.65 (m, 2H). MS: 516.3 (M+H)+.
oa0 1H-NMR (400 MHz, CDCI3) 6: 7.92 (t, J=8.0 Hz, N HN 1H), 7.21 (d, 1H, J = 6.8 Hz), 7.16 (d, 1H, J =
10.0 H I \ lik =.1:3 Hz), 6.32 (s, 1H), 5.55 (d, 1H, J = 8.0 Hz), 4.74 (s, 17/238 N 8 1H), 4.16 (m, 1H), 3.98 (m, 2H), 3.81 (m, 2H), d F 3.52 (m, 2H), 2.62 (s, 3H), 1.98 (m, 2H), 1.56-1.47 (m, 5H), 1.37-1.21 (m, 12H), 0.99 (m, 3H), 0.63 (m, 2H). MS: 534.2 (M+H)+.
# Structure Analytical data 41110 1H-NMR (400 MHz, CDCI3) 6: 8.58 (d, J=8.4Hz, 1H), 8.26 (d, J=7.6Hz, 1H), 7.67-7.59 (m, 2H), 0 '11 i \ ii 9,.0 7.50-7.38 (m, 2H), 6.31-6.23 (m, 1H), 4.66 (s, 1H), 0 -- N , 3.76-3.70 (m, 3H), 3.63-3.58 (m, 1H), 3.41 (m, d 17/239 1-1N-_/ 2H), 3.25-3.19 (m, 1H), 2.59 (s, 3H), 1.60 (m, 4H), 1.42-1.41 (m, 3H), 1.37-1.35 (m, 3H), 1.31-1.10 (m, 9H), 0.87-0.81 (m, 3H), 0.44-0.38 (m, 2H).
MS: 596.3 (M+H).
HO2c1H-NMR (400 MHz, DMSO-d6) 6: 8.77 (d, LI 0 J=8.4Hz, 1H), 8.24 (d, J=7.6Hz, 1H), 7.93-7.91 N 4111 n (m, 1H), 7.85-7.80 (m, 2H), 7.75-7.68 (m, 2H), H 1 \Ak -,-;,0 7.67-7.59 (m, 1H), 6.75 (s, 1H), 4.56-4.50 (m, 1H), 17/240 N w SFisN'__./ 3.75-3.74 (m, 1H), 3.38 (m, 1H), 2.92-2.87 (m, d 1H), 2.58 (s, 3H), 2.41-2.36 (m, 2H), 2.28-2.26 (m, 2H), 1.39-1.34 (m, 3H), 1.17-1.01 (m, 9H), 0.87-0.85 (m, 3H), 0.82-0.74 (m, 3H), 0.50-0.42 (m, 2H). MS: 580.3 (M+H)+.
1H-NMR (400 MHz, CDCI3) 6: 8.57 (d, J=8.4Hz, 1H), 8.25 (d, J=7.6Hz, 1H), 7.68-7.66 (m, 1H), HO N sil 9 7.61-7.57 (m, 1H), 7.49-7.45 (m, 1H), 7.39 (d, H i \ 4100 ,c;#
J=7.6Hz, 1H), 6.26 (s, 1H), 6.11 (s, br, 1H), 4.73 17/241 N HN-1/ (s, 1H), 3.61-3.57 (m, 1H), 3.37 (m, 2H), 3.24-3.18 d (m, 1H), 2.56 (s, 3H), 1.79-1.76 (m, 2H), 1.40 (m, 3H), 1.18-1.10 (m, 18H), 0.85-0.79 (m, 3H), 0.42-0.40 (m, 2H). MS: 596.3 (M+H)+.
D 1H-NMR (400 MHz, CDCI3) 6: 8.66 (d, J=8.4Hz, 410 0 1H), 8.35 (d, J=7.6Hz, 1H), 7.77-7.67 (m, 1H), N 7.58-7.54 (m, 2H), 7.53-7.51 (m, 1H), 7.50 (d, II 41 S* J=7.6Hz, 1H), 6.32 (s, 1H), 5.65-5.63 (m, 1H), 17/242 N H,N--./ 4.69 (s, 1H), 4.21-4.17 (m, 1H), 3.99-3.96 (m, 2H), C? 3.88-3.82 (m, 1H), 3.56-3.50 (m, 3H), 2.68 (s, 3H), 2.29-2.25 (m, 1H), 2.01-1.97 (m, 2H), 1.77-1.46 (m, 6H), 1.26-1.20 (m, 12H). MS: 538.3 (M+H)+.
HO 0 1H-NMR (400 MHz, CDCI3) 6: 8.66 (d, J=8.4Hz, 1H), 8.34 (d, J=7.6Hz, 1H), 7.74-7.67 (m, 2H), eiN 1 \ 4., g,0 7.58-7.47 (m, 2H), 6.36 (s, 1H), 6.23 (m, 1H), 4.68 0 N 1-1N--/ (s, 1H), 3.87-3.76 (m, 5H), 3.53-3.46 (m, 3H), 2.67 d (s, 3H), 2.28-2.24(m, 1H), 1.72-1.58 (m, 6H), 1.48-1.45 (m, 1H), 1.24(s, 12H). MS: 568.2 (M+H)+.
a1H-NMR (400 MHz, CDCI3) 6: 8.21 (d, 1H, J = 8.0 0 / Hz), 7.39 (d, 1H, J = 8.0 Hz), 7.34 (s, 1H), 6.22 (s, N / 1H), 5.63 (d, 1H, J = 7.2 Hz) , 4.18-4.16 (m, 1H), H I \ . S 3.98 (m, 2H), 3.77 (m, 2H), 3.55-3.50 (m, 2H), d 17/244 N b 2.76-2.63 (m, 5H), 2.01-1.97 (m, 2H), 1.71-1.51 (m, 5H), 1.48 (s, 9H), 1.43-1.32 (m, 3H), 1.24 (s, 9H), 1.04-0.98 (m, 3H), 0.70-0.61 (m, 2H). MS
found: 555.0 (M+1)+.
# Structure Analytical data Q o j< 1H-NMR (CDCI3, 300 MHz) 6: 0.82-0.94 (2H, m), ____________________________ HN 1.01-1.09 (3H, m), 1.22-1.32 (12H, m), 1.44-1.65 (5H, m), 1.97-2.03 (2H, m), 2.63 (3H, s), 3.53 (2H, 17/245 N N 0 m), 3.98-4.03 (2H, m), 4.14-4.21 (1H, m), 4.43-d 0F3 4.49 (2H, m), 4.79 (1H, s), 5.63 (1H, d, J = 7.5 Hz), 6.92 (1H, m), 7.78 (1H, d, J = 9.0 Hz), 8.44 (1H, d, J = 9.0 Hz). MS: 585.2 (M+1)+.
0 H 1H-NMR (300 MHz, CD30D) 6: 0.64-0.89 (m, 9H), oyN
H I \ * 1.03-1.10 (m, 3H), 1.30 (s, 3H), 1.54-1.66 (m, 9H), 1.96-2.10 (m, 2H), 2.25-2.33 (m, 2H), 2.49-2.64 17/246 HO N (m, 4H), 2.92-3.19 (m, 1H), 3.30-3.43 (m, 2H), d 4 3.81-3.83 (m, 2H), 6.40 (s, 1H), 7.09 (s, 1H), 7.23 (s, 1H), 7.40-7.41 (m, 1H), 7.73-7.76 (m, 1H).MS:
521.3 (M+1)+.
a1H-NMR (CDCI3, 400 MHz) 6: 8.11 (d, J = 12.0 0 j< Hz, 1H), 7.56 (s, 1H), 7.47 (d, J = 12.0 Hz, 1H), N 02s6.50 (s, 1H), 6.23 (s, 1H), 5.60 (d, J = 9.6 Hz, 1H), H I \ . NH 4.14-4.20 (m, 1H), 3.97-4.01 (m, 2H), 3.73-3.76 d 17/247 N (m, 2H), 3.49-3.57 (m, 2H), 2.62 (s, 3H), 1.97-2.01 , (m, 2H), 1.50-1.59 (m, 5H), 1.46 (s, 9H), 1.26-1.39 CF
(m, 3H), 0.72-1.01 (m, 3H), 0.59-0.72 (m, 2H).
MS: 584.3 (M+1)+.
oa0 F 1H-NMR (CDCI3, 400 MHz) 6: 7.45 (s, 1H), 7.31 N 02S ( (d, J = 9.6 Hz, 1H), 6.27 (s, 1H), 5.68 (s, 1H), 5.60 H I \ . NH (d, J = 7.6 Hz, 1H), 4.13-4.18 (m, 1H), 3.98 (d, J =
17/248 N 11.6 Hz, 2H), 3.77 (d, J = 7.2 Hz, 2H), 3.52 (m, C) cF, 2H), 2.61 (s, 3H), 1.96-2.00 (m, 2H), 1.53-1.55 (m, 15H), 1.40-1.44 (m, 2H), 1.01-1.03 (m, 3H), 0.66-0.71 (m, 2H). MS: 602.2 (M+1)+.
-4 1H-NMR (400 MHz, CDCI3) 6: 7.77 (s, 1H), 7.64 00 0 NN (s, 1H), 7.61-7.55 (m, 1H), 7.38 (d, J=8.0Hz, 1H), \ I
N \ \ fa 6.35-6.30 (m, 2H), 5.64 (d, 1H, J=7.6Hz), 4.23-H , 4.05 (m, 2H), 4.02-3.96 (m, 2H), 3.83 (d, 2H, 17/249 N 0F3 J=7.2Hz), 3.58-3.48 (m, 2H), 2.64 (s, 3H), 2.03-d 1.96 (m, 2H), 1.62-1.36 (m, 14H), 1.07-1.00 (m,3H), 0.76-0.63 (m,2H). MS: 557.3 (M+H)+.
---- 1H-NMR (400 MHz, CDCI3) 6: 7.76 (s, 1H), 7.65 0 NN (S, 1H), 7.56 (d, 1H, J = 8.0 Hz), 7.35 (d, 1H, J =
..õ...-õ, \ = \ \ 7.6 Hz), 6.34-6.26 (m, 2H), 6.07 (br s, 1H), 4.15-11 I 4.08 (m, 1H), 3.82 (m, 2H), 3.48 (br s, 2H), 2.63 ."---). N
7 co2H 8 CF (s, 3H), 1.93-1.86 (m, 2H), 1.62-1.53 (m, 3H), 1.46-1.34 (m, 9H), 1.28 (m, 6H), 1.24-0.96 (m, 3H), 1.71-0.66 (m, 2H). MS: 587.3 (M+H)+.
# Structure Analytical data 00, 0 0._...-- 1H-NMR (400 MHz, DMSO-d6) 6: 7.59 (s, 1H), \ \N 7.53-7.49 (m, 2H), 7.42-7.37 (m, 1H), 6.69 (s, 1H), N k \ gik. N' 4.01-3.82 (m, 5H), 3.35 (m, 2H), 2.54 (s, 3H), 17/251 N 1.74-1.70 (m, 2H), 1.58-1.43 (m, 5H), 1.42 (s, 9H), d 1.31-1.20 (m, 12H), 1.02-0.92 (m, 3H), 0.67 (m, 2H). MS: 561.3 (M+1)+.
HO
0_......_, 11-I-NMR (400 MHz, CDCI3) 6: 7.53 (s, 1H), 7.44 o (d, 1H, J = 7.6 Hz), 7.25-7.21 (m, 1H), 6.26 (s, "N \ . 1 H), 6.05 (br s, 1H), 4.79 (br s, 1H), 3.77 (m, 1H), H \
17/252 N 3.15-3.05 (m, 1H), 2.81-2.72 (m, 2H), 2.60 (s, 3H), d 2.33-2.28 (m, 2H), 1.60-1.43 (m, 12H), 1.38-1.22 (m, 12H), 1.05-0.96 (m, 3H), 0.62 (m, 2H). MS:
574.8 (M+1)+.
a1H-NMR (400 MHz, CDCI3) 6: 0.35-0.50 (m, 1H), o ,.e 0.65-0.76 (m, 1H), 1.02-1.03 (m, 3H), 1.28 (s, 9H), N Hy- 1.47-1.53 (m, 5H), 1.58-1.65 (m, 3H), 1.68-1.83 H I \ 11 S=0 (m, 3H), 1.98 (m, 2H), 2.71 (s, 3H), 3.52 (m, 2H), e 17/253 N 8 3.80-3.84 (m, 1H), 3.97-4.00 (m, 2H), 4.11-4.20 ., , (m, 1H), 4.71 (s, 1H), 5.61 (d, J = 7.2 Hz, 1H), CF
6.27 (s, 1H), 7.52-7.57 (m, 1H), 7.74 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H). MS: 598.3 (M+1)+.
a1H-NMR (400 MHz, CDCI3) 6: 0.33-0.48 (m, 1H), o 0.66-0.75 (m, 1H), 0.98-1.06 (m, 3H), 1.28 (s, 9H), N HIV" 1.47-1.53 (m, 5H), 1.58-1.65 (m, 3H), 1.68-1.83 H I \ lik =00 (r11, 3H), 1.98 (m, 2H), 2.71 (s, 3H), 3.53 (m, 2H), 17/254 N 8 3.79-3.84 (m, 1H), 3.97-4.00 (m, 2H), 4.14-4.18 =,,õ
d (m, 1H), 4.71 (s, 1H), 5.61 (d, J = 7.2 Hz, 1H), CF
6.27 (s, 1H), 7.52-7.57 (m, 1H), 7.75 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H). MS: 598.3 (M+1)+.
a 0 1H-NMR (400 MHz, CDCI3) 6: 0.96-1.06 (m, 2H), EiN < 1.26 (s, 11H), 1.29-1.40 (m, 4H), 1.47-1.56 (m, N
H I \11 S=0 3H), 2.01-1.96 (m, 2H), 2.70 (s, 3H), 3.49-3.55 (m, 17/255 N 8 3H), 4.02-3.96 (m, 2H), 4.03 (s, 2H), 4.13-4.21 (m, dcF3 1H), 4.69 (s, 1H), 5.62 (d, J = 8.0 Hz, 1H), 6.40 (s, OH 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H). MS: 600.3 (M+1)+.
a0 ,, 1H-NMR (300 MHz, CDCI3) 6: 0.99-1.02 (m, 13H), N HN"'"- 1.26 (s, 9H), 1.28-1.47 (m, 4H), 1.48-1.57 (m, 2H), H I \ 441 =() 1.94-2.00 (m, 4H), 2.64 (s, 3H), 3.52 (m, 2.0 Hz, N 8 2H), 3.90 (m, 2H), 3.97-4.02 (m, 2H), 4.14-4.17 a c3 (m, 1H), 4.72 (s, 1H), 5.62 (d, J = 7.6 Hz, 1H), 6.39 (s, 1H), 7.62 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H).
F F MS: 620.3 (M+1)+.
, # Structure Analytical data a Hõ
11' 1H-NMR (300 MHz, CDCI3) 6: 0.68-0.77 (m, 2H), 0.88-1.30 (m, 13H), 1.35-1.48 (m, 3H), 1.51-1.58 NH
"
(m, 2H), 1.88-2.04 (m, 4H), 2.63-2.64 (m, 3H), I \ * S=0 N 8 3.52 (m, 2H), 3.83-3.88 (m, 2H), 4.02-3.96 (m, Fa u3 2H), 4.11-4.44 (m, 2H), 4.80-4.70 (m, 1H), 5.63 (d, J = 7.6 Hz, 1H), 6.39 (s, 1H), 7.60-7.63 (m, 1H), 7.79-7.80 (m, 1H), 8.32 (d, J = 8.0 Hz, 1H). MS:
602.3 (M+1)+.
0 1H-NMR (400 MHz, CDCI3) 6: 8.45(d, J = 8.4 Hz, Q
0 )L. 1H), 8.18 (s, 1H), 7.74 (s, 1H), 7.65-7.60 (m, 1H), N HN 6.33 (s, 1H), 5.57 (d, 1H, J = 8.0 Hz), 4.12-4.02 H I \ * -=.0 (M, 1H), 3.95-3.89 (m, 2H), 3.76 (d, 2H, J = 6.8 17/258 N 8 Hz), 3.49-3.43 (m, 2H), 2.56 (s, 3H), 1.94-1.90 (m, d CF 2H), 1.51-1.45 (m, 5H), 1.28-1.25 (m, 3H), 1.10 (s, 9H), 0.94-0.93 (m, 3H), 0.59 (m, 2H). MS: 612.3 (M+H)+.
Ho2ct 1H-NMR (CDCI3, 400 MHz) 6: 0.56-0.65 (m, 2H), 0 0.96-1.03 (m, 3H), 1.25 (s, 14H), 1.27-1.42 (m, HN 8H), 1.62-1.64 (m, 2H), 1.98-2.02 (m, 2H), 2.22-N
H I \ 11 o 2.24 (m, 2H), 2.62 (s, 3H), 3.80 (d, J = 7.2 Hz, 17/259 N 0 2H), 3.91-3.95 (m, 1H), 4.81 (s, 1H), 5.57 (d, J =
d u3 8.4 Hz, 1H), 6.33 (s, 1H), 7.60 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.79 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H).
MS: 640.3 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 0.59-0.67 (m, 3H), 0.94-1.03 (m, 5H), 1.14-1.37 (m, 21H), 1.60-1.62 H02cn 0 j< (m, 2H), 2.04-2.12 (m, 1H), 2.63 (s, 3H), 3.80 (d, N Hisil 2H, J = 6.6 Hz), 4.33 (m, 1H), 4.74 (s, 1H), 5.81 H I \ 411 S=0 (d, 1H, J = 8.4 Hz), 6.35 (s, 1H), 7.63 (d, 1H, J =
ii 17/260 single N 8.4 Hz), 7.80 (s, 1H), 8.30 (d, 1H, J =
8.4 Hz). MS:
enantiomer d CF
628.3 (M+1) . Chiral HPLC
(hexane/ethanol/NHEt2 = 70/30/0.2 on Chiralpak IC 5 pm 4.6 x 250 mm, 1 mUm in, T =
30 C): Fit = 7.646 min (2nd eluting enantiomer).
1H-NMR (CDCI3, 400 MHz) 6: 0.59-0.67 (m, 3H), 0.94-1.03 (m, 5H), 1.14-1.37 (m, 21H), 1.60-1.62 H02cn 0 j< (m, 2H), 2.04-2.12 (m, 1H), 2.63 (s, 3H), 3.80 (d, N FIN,' 2H, J = 6.6 Hz), 4.33 (m, 1H), 4.74 (s, 1H), 5.81 H I \ II S=0 (d, 1H, J = 8.4 Hz), 6.35 (s, 1H), 7.63 (d, 1H, J =
17/261 single N 8 8.4 Hz), 7.80 (s, 1H), 8.30 (d, 1H, J =
8.4 Hz). MS:
enantiomer d CF
628.3 (M+1)+; Chiral HPLC
(hexane/ethanol/NHEt2 = 70/30/0.2 on Chiralpak IC 5 pm 4.6 x 250 mm, 1 mUmin, T =
30 C): Fit = 6.256 min (1st eluting enantiomer).
Ho2Cµ
TI 01H-NMR (CDCI3, 400 MHz) 6: 7.04 (s, 2H), 6.29 N
(s, 1H), 6.00 (d, J = 7.6 Hz, 1H), 4.82-4.75 (m, 1H), 3.78 (d, J = 7.2 Hz, 2H), 3.11-3.06 (m, 1H), H--- / \ N
17/262 N ¨ 2.84-2.75 (M, 1H), 2.60 (s, 3H), 2.35-2.24 (m, 2H), d 1.57-1.51 (m, 2H), 1.37 (s, 18H), 1.33-1.25 (m, 4H), 1.02-0.84 (m, 3H), 0.69-0.64 (m, 2H). MS:
508.3 (M+1)+;
# Structure Analytical data OU 1H-NMR (400 MHz, CDCI3) 6: 8.64 (d, 1H, J = 8.4 410 o Hz), 8.33 (d, 1H, J = 7.6 Hz), 7.74-7.64 (m, 2H), N 7.60-7.50 (m, 2H), 6.37 (s, 1H), 5.89 (d, 1H, J =
H I \ 41 ss.., 8.0 Hz), 4.85 (s, 1H), 4.35-4.29 (m, 1H), 3.72-3.63 17/263 N 14N-../ (rn, 1H), 3.33-3.24 (m, 1H), 3.20-3.13 (m, 4H), d 2.66 (s, 3H), 2.42-2.38 (m, 2H), 2.22-2.18 (m, 2H), 1.52-1.45 (m, 3H), 1.30-1.13 (m, 12H), 0.91-0.86 (m, 3H), 0.52-0.42 (m, 2H). MS: 614.2 (M-i-1)+.
HO0 1H-NMR (400 MHz, CDCI3) 6: 8.65 (d, 1H, J
= 8.4 )-\N 4100 Hz), 8.34 (d, 1H, J = 7.6 Hz), 7.78-7.74 (m, 1H), H 1 \ 41 g*07.71-7.66 (m, 1H), 7.59-7.52 (m, 1H), 7.49 (d, J =
N
7.6 Hz, 1H), 6.38 (s, 1H), 6.24 (br s, 1H), 4.63 (s, d 17/264 1H), 3.70-3.66 (m, 1H), 3.45-3.40 (m, 2H), 3.33-3.26 (m, 1H), 2.67 (s, 3H), 1.52-1.47 (m, 3H), 1.33-1.12 (m, 18H), 0.91-0.87 (m, 3H), 0.53-0.45 (m, 2H). MS: 554.3 (M+1)+.
0 1H-NMR (400 MHz, CDCI3) 6: 8.65 (d, 1H, J
= 8.4 H \ 4110 0 Hz), 8.34 (d, 1H, J = 7.6 Hz), 7.75-7.68 (m, 2H), it o 7.58-7.52 (m, 1H), 7.48 (d, J = 7.6 Hz, 1H), 6.33 N 1 110 s . z (s, 1H), 6.04-5.98 (m, 1H), 4.64 (s, 1H), 3.70-3.66 d HN......, (m, 1H), 3.32-3.24 (m, 3H), 3.12-2.92 (m, 4H), 2.66 (s, 3H), 2.21-1.89 (m, 5H), 1.48 (m, 3H), 1.30-1.11 (m, 12H), 0.90 (m, 3H), 0.49 (m, 2H).
MS: 628.3 (M+1)+.
41100 1H-NMR (400 MHz, CDCI3) 6: 8.64 (d, 1H, J
= 8.8 Hz), 8.34 (d, 1H, J = 7.6 Hz), 7.77-7.65 (m, 2H), d HN..õ . (s, 4H), 3.73-3.56 (m, 5H), 3.29 (m, 1H), 2.65 (s, 3H), 1.80 (m, 4H), 1.78 (m, 3H), 1.28-1.18 (m, 12H), 0.88 (m, 3H), 0.47 (m, 2H). MS: 592.3 (M+1)+.
0 1H-NMR (400 MHz, DMSO-d6) 6: 8.77 (d, 1H, J =
0 8.8 Hz), 8.24 (d, 1H, J = 7.6 Hz), 7.86 (s, 1H), H2wAr\N
41100 7.81-7.59 (m, 4H), 7.45 (m, 1H), 7.30 (s, 1H), 7.02 H i \ 41 (s, 1H), 6.69 (s, 1H), 3.79-3.66 (m, 3H), 3.38-3.22 17/267 0 N 8 HN--../ (m, 5H), 2.58 (s, 3H), 1.92 (d, 2H, J =
15.6 Hz), 1.50-1.37 (m, 5H), 1.19-1.13 (m, 3H), 1.02 (s, 9H), 0.82-0.73 (m, 3H), 0.45 (m, 2H). MS: 623.3 (M+1)+.
HO 01H-NMR (400 MHz, DMSO-d6) 6: 8.65 (d, 1H, J =
)<\N 4110 0 8.8 Hz), 8.33 (d, 1H, J = 7.6 Hz), 7.69 (m, 2H), ...... ...... H 1 \ 40o 7.56 (m, 1H), 7.46 (d, 1H, J = 7.6 Hz), 6.39-6.31 S (m, 2H), 4.70 (s, 1H), 3.68-3.64 (m, 1H), 3.54-3.42 17/268 02 c N3 FIN--.../ (m, 4H), 3.30 (m, 1H), 2.87 (m, 2H), 2.66 (s, 3H), 2.18-2.00 (m, 4H), 1.48 (m, 3H), 1.25-1.21 (m, 3H), 1.17 (s, 9H), 0.89 (m, 3H), 0.54 (m, 2H).
MS:644.2 (M+1)+.
# Structure Analytical data O\
1H-NMR (400 MHz, CDCI3) 6: 8.63 (d, 1H, J = 8.4 AI\---\ Hz), 8.32( d, 1H, J = 7.6 Hz), 7.73-7.62 (m, 2H), N. (,,0 7.52 (m, 1H), 7.48-7.38 (m, 2H), 6.45 (s, 1H), 4.85 H 1 \
17/269 N S,' (s, 1H), 3.99-3.63 (m, 9H), 3.35-3.24 (m, 3H), 2.91 I-IN¨/ (m, 2H), 2.64 (s, 3H), 1.49-1.45 (m, 3H), 1.29-1.13 d (m, 12H), 0.88 (m, 3H), 0.47 (m, 2H). MS:
595.5 (M+1)+.
41010,ip 1H-NMR (400 MHz, CDCI3) 5: 8.65 (d, 1H, J = 8.4 Hz), 8.35 (d, 1H, J = 7.6 Hz), 7.69 (m, 2H), 7.58 02SON I \ 41, g- (m, 1H), 7.49 (m, 1H), 6.30 (s, 1H), 4.76 (s, 1H), 84 FIN-...../ 4.06 (m, 4H), 3.69 (m, 1H), 3.30 (m, 1H), 3.02 (m, 4H), 2.65 (s, 3H), 2.39-2.35 (m, 4H), 1.48 (m, 3H), 1.29-1.18 (m, 12H), 0.88 (m, 3H), 0.48 (m, 2H).
MS: 640.4 (M+1)+.
HO2c 1H-NMR (CDCI3, 400 MHz) 6: 8.64 (d, J =
8.4 Hz, U 0 1H), 8.30 (d, J = 7.6 Hz, 1H), 7.80 (m, 1H), 7.74 "N (m, 1H), 7.59 (m, 1H), 7.49 (d, J = 8.4 Hz, 1H), H 1 \ 4104a sH,N1, -/CF3 6.35 (s, 1H), 5.99 (m, 1H), 5.31 (m, 1H), 4.80 (m, 17/271 N W 60 1H), 3.75-3.60 (n, 3H), 3.30 (m, 1H), 3.08 (m, 1H), d 2.82-2.75 (m, 2H), 2.67 (s, 3H), 2.25 (m, 2H), 1.56-1.46 (m, 3H), 1.27-1.17 (m, 6H), 0.95-0.75 (m, 4H), 0.45 (m, 2H). MS: 606.2 (M+1)+;
HO2Cµ
n 0 1H-NMR (400 MHz, CD30D) 5: 0.50-0.58 (m, 2H), _____________ . ( N 0.88-0.92 (m, 3H), 1.08 (s, 9H), 1.19-1.26 (m, 4H), ' HN __ 1.45-1.46 (m, 3H), 2.06 (s, 3H), 2.24-2.32 (m, 2H), H 1 \ M s,, 2.44 (s, 3H), 2.48-2.52 (m, 2H), 2.53 (s, 3H), 2.93 17/272 N W- om (m, 1H), 3.20-3.25 (m, 2H), 3.50-3.61 (m, 1H), 4.58 (m, 1H), 6.33 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H). MS: 558.2 [m-Fl]t 1H-NMR (400 MHz, CDCI3) 5: 0.54-0.64 (m, 2H), 0 0.98-1.00 (m, 3H), 1.07 (s, 9H), 1.18-1.38 (m, 3H), N HN( 1.46-1.56 (m, 3H), 1.96-2.00 (m, 2H), 2.12 (s, 3H), H i \ 41 s,, 2.62 (m, 6H), 3.26 (br s, 1H), 3.49-3.63 (m, 3H), 17/273 N 60 3.96-3.99 (m, 2H), 4.14-4.18 (m, 1H), 4.47 (s, 1H), d 5.60 (d, J = 8.0 Hz, 1H), 6.12 (s, 1H), 7.18 (d, J =
8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H). MS: 544.3 [M+1]t u 0 1H-NMR (400 MHz, CDCI3) 6: 0.57-0.63 (m, 2H), CI ( 0.96-1.04 (m, 3H), 1.25 (s, 9H), 1.34-1.42 (m, 3H), N ______________________________ HN
H I 1.46-1.58 (m, 5H), 1.97-2.00 (m, 2H), 2.62 (s, 3H), \ 41 s,, 17/274 N O 2.77 (s, 3H), 3.49-3.55 (m, 3H), 3.98 (m, 2H), 6 4.11-4.18 (m, 1H), 4.51 (s, 1H), 5.60 (d, J = 7.6 Hz, 1H), 6.21 (s, 1H), 7.28 (d, J =8.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H). MS: 564.2 [M+1]+.
# Structure Analytical data Ho2CN
I o 1H-NMR (400 MHz, CDCI3) 6: 0.57-0.61 (m, 2H), Ci ( 0.98-1.00 (m, 3H), 1.25 (s, 9H), 1.33-1.35 (m, 3H), HN _______________________________ 1.51-1.59 (m, 3H), 2.26-2.33 (m, 2H), 2.60 (s, 3H), H 1 \ . gos 2.77-2.80 (m, 5H), 3.05-3.13 (m, 1H), 3.51-3.55 (m, 1H), 4.53 (s, 1H), 4.73-4.81 (m, 1H), 5.94-5.95 d (m, 1H), 6.23 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H). MS: 578.2 [M+1].
u 0 1H-NMR (400 MHz, CDCI3) 6: 0.59-0.61 (m, 2H), ci a( 0.99-1.04 (m, 3H), 1.19 (s, 9H), 1.23-1.36 (m, 5H), HN 1 \ sHN ___ 1.46-1.53 (m, 3H), 1.98 (m, 2H), 2.62 (s, 3H), 17/276 N ¨W- 60 3.47-3.55 (m, 4H), 3.96-3.99 (m, 2H), 4.15-4.18 d (m, 1H), 5.07 (s, 1H), 5.59 (d, J = 7.6 Hz, 1H), 6.26 (s, 1H), 7.37 (d , J = 8.4 Hz, 1H), 8.10 (d, J =
8.4 Hz, 1H). MS: 584.2 [M+1].
H 02C \
I 0 1H-NMR (400 MHz, CDCI3+ D20) 6: 0.58-0.60 (m, Ci ci( 2H), 0.88-0.89 (m, 3H), 1.29 (s, 9H), 1.32-1.35 (m, HN _______________________________ 3H), 1.51-1.77 (m, 2H), 2.30 (br s, 2H), 2.60 (s, H 1 \ 41 s,µ
3H), 2.73-2.78 (m, 2H), 3.07-3.10 (m, 1H), 3.47-3.54 (m, 3H), 4.73-4.76 (m, 1H), 6.28 (s, 1H), 7.36 d (d, J = 8.4 Hz, 1H), 8.10 (d , J = 8.4 Hz, 1H). MS:
598.2 [M+1].
HONA 1H-NMR (300 MHz, CDCI3) 6: 8.67 (d, J = 8.4 Hz, o ,o N
/ \ I \ * sis=o 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.77-7.45 (m, 4H), N NH 6.42 (s, 1H), 6.21 (t, J = 6.3 Hz, 1H), 4.66 (s, 1H), -A 3.82-3.74 (m, 1H), 3.46-3.34 (m, 3H), 2.68 (s, 3H), 1.93-1.82 (m, 2H), 1.48-1.18 (m, 20H), 0.90-0.80 F-a(m, 3H). MS: 590.3 [M+1].1r.
F
HO2C 1H-NMR (400 MHz, CD30D) 6: 0.63-0.68 (m, 2H), F7 o /---\ 0.95-0.99 (m, 3H), 1.14(s, 9H), 1.25-1.32 (m, 3H), 'N 0 0 ( HN _______________________________ 1.51-1.53 (m, 3H), 2.30-2.38 (m, 2H), 2.48 (s, 3H), H I \ 40, s', 2.54-2.60 (m, 2H), 2.97-3.02 (m, 1H), 3.26-3.28 17/279 N 60 (M, 3H), 3.66 (d, J = 6.8 Hz, 2H), 4.26-4.28 (m, d 2H), 4.38-4.40 (m, 2H), 4.63 (t, J = 8.0 Hz, 1H), 6.44 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 7.40 (d, J =
8.4 Hz, 1H). MS: 588.3 [M+1].
u1H-NMR (400 MHz, CDCI3) 6: 0.57-0.67 (m, 2H), o 0.86-1.00 (m, 3H), 1.24 (s, 9H), 1.25-1.43 (m, 5H), N = HN ( 1.46-1.53 (m, 3H), 1.68-1.71 (m, 2H), 1.80-1.85 H i \ g (m, 2H), 1.95-2.00 (m, 2H), 2.44-2.58 (m, 2H), . , 17/280 N 60 2.60 (s, 3H), 3.21 (m, 3H), 3.49-3.65 (m, 3H), 6 3.96-3.99 (m, 2H), 4.14-4.18 (m, 1H), 4.41 (s, 1H), 5.80 (d, J = 8.0 Hz, 1H), 6.11 (s, 1H), 7.15 (d, J =
8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H). MS: 570.3 [M+1].
# Structure Analytical data RO2Cµ
Ell 0 1H-NMR (400 MHz, CDCI3+ D20) 6: 0.57-0.67 (m, 5H), 1.19-1.31 (m, 14H), 1.57-1.70 (m, 4H), 1.8-N 11) HN ( 1.84 (m, 2H), 2.26-2.33 (m, 2H), 2.42-2.59 (m, H 1 \ 40 s,µ
2H), 2.77 (s, 3H), 3.08-3.10 (m, 2H), 3.19-3.25 (m, 4H), 3.60-3.65 (m, 2H), 6.12 (s, 1H), 7.15 (d, J =
d 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H). MS:
584.3 [M+1].
u 1H-NMR (400 MHz, CDCI3) 6: 9.10 (d, J = 8.8 Hz, NI \ 1H), 9.05-9.03 (m, 1H), 8.39 (d, J = 7.6 Hz, 1H), N HN ( 7.77 (d, J = 7.6 Hz, 1H), 7.67-7.62 (m, 1H), 6.42 H 1 \
=
g (s, 1H), 5.81-5.79 (m, 1H), 4.70 (s, 1H), 4.19-4.17 17/282 N 8b (m, 1H), 4.00-3.97 (m, 2H), 3.58-3.50 (m, 4H), d 2.64 (s, 3H), 1.99-1.95 (m, 2H), 1.57-1.48 (m, 5H), 1.27-1.22 (m, 12H), 0.94-0.89 (m, 3H), 0.45-0.43 (m, 2H). MS: 567.5 (M+H)+.
u1H-NMR (400 MHz, CDCI3) 6: 9.07-9.04 (m, 1H), o / \ N 8.47 (d, J = 7.6 Hz, 1H),8.21 (m, 1H),7.61-7.50 N HN ( (m, 2H), 6.46-6.36 (m, 2H), 5.70-5.69 (m, 1H), H I \ 41 g, 4.20-4.16 (m, 1H), 4.01-3.98 (m, 2H), 3.74-3.70 17/283 N 60 (m, 1H), 3.56-3.51 (m, 2H), 3.38-3.32 (m, 1H), d 2.67 (s, 3H), 2.20-1.95 (m, 2H), 1.58-1.48 (m, 5H), 1.30-1.18 (m, 12H), 0.89-0.84 (m, 3H), 0.50-0.47 (m, 2H). MS: 567.4(M+H)+.
o 1H-NMR (400 MHz, CDCI3) 6: 8.02 (d, J = 8.0 Hz, F2Hco 7C2i1-1 1 \ z\ sHp ( 51 H9)6 701.311(Hdi,J5=.887.0(tHjz=, 17H5),26H.2z9(si_,I)1H4)5, 76.(0s5-17/284 81 W 61so 1H), 3.62-3.58 (m, 1H), 3.44-3.40 (m, 2H), 2.66 (s, 3H), 2.60 (s, 3H), 1.87 (m, 2H), 1.57-1.53 (m, 3H), 1.30-1.20 (m, 18H), 0.98-0.96 (m, 3H), 0.57-0.54 (m, 2H). MS: 625.8 (M+H)+.
u 1H-NMR (400 MHz, CDCI3) 6: 8.03 (d, J = 8.0 Hz, o 1H), 7.32 (d, 1H, J = 8.0 Hz), 6.29 (s, 1H), 5.86 (t, N HN ( J = 75.2 Hz, 1H), 5.58 (m, 1H), 4.47 (s, 1H), 4.17-H I \ . s', 4.15 (m, 1H), 4.01-3.97 (m, 2H), 3.63-3.61 (m, 17/285 N 60 2H), 3.56-3.50 (m, 2H), 2.67 (s, 3H), 2.62 (s, 3H), d 2.01-1.98 (m, 2H), 1.53-1.49 (m, 5H),1.34-1.30 (m, 3H), 1.31 (s, 9H), 1.28-1.20 (m, 3H), 1.01-0.94 (m, 3H), 0.58-0.55 (m, 2H). MS: 595.8 (M+H)+.
Ho2c3C.\ a1H-NMR (400 MHz, CDCI3) 6: 8.26 (d, J = 8.4 Hz, F3c ( 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.14 (s, 1H), 5.98 (br HN 1 \ /\ Hp s, 1H), 4.69 (s, 1H), 3.68-3.63 (m, 1H), 3.42 (m, s, 17/286 N W "o 2H), 3.33-3.27 (m, 1H), 2.84 (s, 3H), 2.57 (s, 3H), d 1.87-1.84 (m, 2H), 1.63-1.52 (m, 3H), 1.43-1.40 (m, 18H), 1.05-0.92 (m, 3H), 0.73-0.70 (m, 1H), 0.48-0.46 (m, 1H). MS: 627.8 (M+H)+.
# Structure Analytical data cQ 1H-NMR (400 MHz, CDC)3) 5: 8.28 (d, J =
8.4 Hz, o 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.15 (s, 1H), 5.63-F3c N HN __ 5.61 (m, 1H), 4.56 (s, 1H), 4.16-4.12 (m, 1H), H i \ 41 s'\ ( 4.00-3.97 (m, 2H), 3.70-3.65 (m, 1H), 3.55-3.50 17/287 N 60 (MI, 2H), 3.34-3.28 (m, 1H), 2.85 (s, 3H), 2.59 (s, d 3H), 2.02-1.97 (m, 2H), 1.64-1.50 (m, 5H), 1.49-1.23 (m, 12H), 1.09-0.93 (m, 3H), 0.72-0.71 (m, 1H), 0.48-0.45 (m, 1H). MS: 597.8 (M+H)+.
c(.._. o N 1H-NMR (400 MHz, CDCI3) 5: 8.35 (d, J =
8.4 Hz, Cl cF3 ( 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H), 5.61-HN __ 5.60 (m, 1H), 4.86 (s, 1H), 4.21-4.13 (m, 1H), 17/288 N 6o 4.00-3.97 (m, 2H), 3.55-3.50 (m, 4H), 2.62 (s, 3H), d 2.00-1.96 (m, 2H), 1.75-1.70 (m, 5H), 1.58-1.22 (m, 12H), 1.10-0.98 (m, 3H), 0.60 (m, 2H). MS:
618.0 (M+H)+.
Ho2c-3C\ 1H-NMR (400 MHz, CDCI3) 5: 8.34 (d, J = 8.4 Hz, N CI CF3 ( HN __ 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H), 6.10 (br H I \ 41 g, s, 1H), 4.89 (s, 1H), 4.85-4.43 (br s, 1H), 3.62-17/289 N 0 3.42 (m, 4H), 2.59 (s, 3H), 1.88-1.84 (m, 2H), d 1.58-1.54 (m, 3H), 1.38-1.20 (m, 18H), 1.03-0.97 (m, 3H), 0.59 (m, 2H). MS: 648.0 (M+H)+.
HO o 1H-NMR (300 MHz, CDCI3) 5: 0.52-0.68 (m, 2H), ci (---'5\N 1 \ = Hp ( 0.92-1.10 (m, 3H), 1.24 (s, 9H), 1.30-1.42 (m, 3H), s 1.52-1.62 (m, 3H), 1.97-2.20 (m, 4H), 2.60 (s, 3H), s 60 2.76 (s, 3H), 2.82-2.93 (m, 2H), 3.40-3.58 (m, 5H), d 4.54 (s, 1H), 6.20-6.25 (m, 2H), 7.26 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H). MS: 642.2 (M+1)+.
HO\ _ 0 HN ( 1H-NMR (300 MHz, CDCI3) 5: 8.03 (d, J =
8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.25 (s, 1H), 6.20 H j\
N
(m, 1H), 4.47 (s, 1H), 3.52 (br s, 2H), 3.39 (m, d IS 2H), 2.96 (s, 1H), 2.77 (s, 3H), 3.25 (s, 3H), 1.40-1.30 (m, 4H), 1.26 (s, 6H), 1.25 (s, 9H), 1.10-0.91 (m, 4H), 0.62 (m, 2H). MS: 552.3 (M+1)+.
Ho2cµ
I 0 V 1H-NMR (CD30D, 400 MHz) 6: 7.14 (s, 2H), 6.67 ., 'N (s, 1H), 4.70 (m, 1H), 3.95 (d, J = 7.2 Hz, 2H), H 1 \ / \ N 3.06 (m, 1H), 2.68-2.59 (m, 2H), 2.58 (s, 3H), 2.41 17/292 N ¨ (m, 2H), 1.63-1.50 (m, 6H), 1.48-1.30 (m, 14H), d 1.20-0.98 (m, 3H), 0.76-0.65 (m, 4H). MS:
506.3 (M+1)+.
# Structure Analytical data o _- 1H-NMR (CDCI3, 300 MHz) 6: 0.59-0.63 (m, 2H), ,-, H HN 0.95-1.02 (m, 3H), 1.25 (s, 9H), 1.30-1.40 (m, 2H), ,-,..).õNõ.../N
I \ 11 =() 1.54-1.56 (m, 3H), 2.00 (s, 1H), 2.58 (s, 3H), 3.79 0-"j - d . (m, 2H), 3.94 (s, 3H), 4.16 (s, 2H), 4.21-4.30 (m, cF3 3H), 5.00 (s, 1H), 6.29 (s, 1H), 7.48 (br s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.76 (s, 1H), 8.30 (d, J =
8.1 Hz, 1H). MS: 625.3 (M+1)+.
o1H-NMR (CD30D, 400 MHz) 6: 0.66-0.74 (m, 2H), , H HN__ 0.95-1.03 (m, 3H), 1.24 (s, 10H), 1.30-1.38 (m, I \ *o 5H), 1.53-1.58 (m, 3H), 2.55 (s, 3H), 3.93-3.97 (m, N -..0 o 4H), 4.10-4.13 (m, 1H), 4.40-4.42 (m, 1H), 4.57-d u3 4.60 (m, 1H), 6.49 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H). MS:
638.3 (M+1)+.
1H-NMR (CDCI3, 300 MHz) 6: 0.61-0.68 (m, 2H), HN 0 0.98-1.00 (m, 3H), 1.27-1.35 (m, 14H), 1.52-1.56 o N HN (M, 2H), 1.71-1.75 (m, 2H), 1.84-1.97 (m, 2H), H I \ . s=o 2.63 (s, 3H), 3.21 (m, 1H), 3.61-3.69 (m, 1H), N 3.76-3.82 (m, 4H), 3.98-4.05 (m, 2H), 4.93-4.98 0 d cF3 (m, 1H), 5.26 (s, 1H), 5.66 (s, 1H), 6.32 (d, J =
10.2 Hz, 1H), 6.48 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H). MS:
653.3 (M+1)+.
a 0 CI 1H-NMR (400 MHz, CDCI3) 6: 7.19 (m, 1 H), 7.11 (s, 1 H), 7.06 (s, 1 H), 6.18 (s, 1 H), 5.63 (d, 1 H, J
N
H I \ . = 7.6 Hz), 4.16 (m, 1 H), 3.98 (m, 2 H), 3.74 (d, 2 17/296 N H, J = 7.2 Hz), 3.53 (m, 2 H), 2.60 (s, 3 H), 1.97 d A (m, 2 H), 1.54 (m, 5 H), 1.47 (s, 3 H), 1.36 (m, 3 H), 1.02 (m, 3 H), 0.86 (m, 2 H), 0.78 (m, 2 H), 0.66 (m,2 H). MS: 469.2 (M+1)+.
LIIN CF3 0 1H-NMR (400 MHz, CDCI3) 6: 7.46 (s, 1 H), 7.37 (m, 2 H), 6.22 (s, 1 H), 5.61 (d, 1 H, J = 8 Hz), H I \ . 4.16 (m, 1 H), 3.98 (m, 2 H), 3.74 (d, 2 H, J = 7.2 17/297 N Hz), 3.53 (m, 2 H), 2.62 (s, 3 H), 1.97 (m, 2 H), d A 1.54 (m, 5 H), 1.45 (s, 3 H), 1.37 (m, 3 H), 1.01 (m, 3 H), 0.86 (m, 2 H), 0.83 (m, 2 H), 0.66 (m, 2 H). MS: 503.3 (M+1)+.
HOOC,õ,, o CI 1H-NMR (400 MHz, DMSO-d6) 6: 7.99 (s, 1 H), N 7.89 (d, 1 H, J = 7.6 Hz), 7.82 (m, 2 H), 7.59 (s, 1 H I \ H), 6.75 (s, 1 H), 4.50 (m, 1 H), 3.86 (d, 2 H, J =
7.2 Hz), 2.88 (m, 2 H), 2.38 (m, 2 H), 2.24 (m, 2 NH H), 1.50 (m, 3 H), 1.39 (s, 9 H), 1.30(m, 3 H), C) o 0.98 (m, 3 H), 0.66 (m, 2 H). MS: 528.2 (M+1)+.
# Structure Analytical data HOOCõ,,cl o CI 1H-NMR (400 MHz, CDCI3) 6: 7.20 (s, 1 H), 7.10 (s, 1 H), 7.06 (s, 1 H), 6.20 (s, 1 H), 6.03 (d, 1 H, J
N
H I \ . = 6.8 Hz), 4.80 (m, 1 H), 3.74 (d, 2 H, J
= 7.2 Hz), 17/299 N 3.09 (m, 1 H), 2.78 (m, 2 H), 2.59 (s, 3 H), 2.30 d A (m, 2 H), 1.56 (m, 3 H), 1.41 (s, 3 H), 1.33 (m, 3 H), 1.02 (m, 3 H), 0.86 (m, 2 H), 0.78 (m, 2 H), 0.65 (m, 2 H). MS: 483.3 (M+1)+.
HOOCõ,, CL
CF3 1H-NMR (400 MHz, CDCI3) 6: 7.46 (s, 1 H), 7.36 (m, 2 H), 6.23 (s, 1 H), 5.98 (m, 1 H, J = 3.6 Hz), N
H I \ . 4.80 (m, 1 H), 3.73 (d, 2 H, J = 6.8 Hz), 3.07 (m, 1 17/300 N H), 2.78 (m, 2 H), 2.60 (s, 3 H), 2.30 (m, 2 H), d ad, 1.54 (m, 3 H), 1.46 (s, 3 H), 1.33 (m, 3 H), 1.00 (m, 3 H), 0.89 (m, 2 H), 0.83 (m, 2 H), 0.64 (m, 2 H). MS: 517.3 (M+1)+.
OH
ON(3IN
0 OH 1H-NMR (300 MHz, CD30D) 6: 0.74-1.03 (m, 8H), 1.29-1.42 (m, 9H), 1.54-1.73 (m, 11H), 1.97-2.09 N
17/301 H I \ * (M, 9H), 2.53 (s, 3H), 3.81 (d, J = 7.2 Hz, 2H), N 6.41 (s, 1H), 7.09 (s, 1H), 7.23 (s, 1H), 7.41 (s, d4 1H). MS: 547.3 (M+1)+.
OH
ONQ
0 1H-NMR (300 MHz, CDCI3) 6: 0.70-0.76 (m, 3H), OH 0.86-0.87 (m, 3H), 0.98-1.00 (m, 3H), 1.25-1.32 N (M, 3H), 1.36 (s, 3H), 1.42-1.55 (m, 3H), 1.59 (s, 17/302 H 1 \ .
6H), 1.90-2.11 (m, 12H), 2.58 (s, 3H), 3.70-3.73 N
d 4 (m, 2H), 5.45 (s, 1H), 6.10 (s, 1H), 7.06 (s, 1H), 7.18 (s, 1H), 7.38 (s, 1H). MS: 561.4 (M+1)+.
a 0 OMe 1H-NMR (CDCI3, 300 MHz): 6 7.76 (s, 1H), 7.60 (s, 1H), 7.54 (d, 1H), 6.27 (s, 1H), 6.11 (m, 1H), N 5.73 (m, 1H), 4.31 (m, 1H), 4.15 (m, 1H), 3.98 (d, H I \ . -- ___. -- 2H, J = 11.2 Hz), 3.77 (d, 2H, J = 6.8 Hz), 3.51 17/303 N (M, 2H), 3.10 (s, 3H), 2.62 (s, 3H), 1.97 (m, 2H), d 0 NH 1.87-1.80 (m, 3H), 1.57 (s, 6H), 1.55-1.49 (m, 2H), 1.40-1.35 (m, 3H), 1.29 (d, 6H, J = 6.4 Hz), 0.98 (m, 3H), 0.61 (m, 2H). MS: 538.2 (M+1)+.
HOOCõ,c o 1H-NMR (400 MHz, CDCI3) 6: 7.60 (s, 1H), 7.52 N (s, 1H), 7.40 (s, 1H), 6.24 (s, 1H), 5.96 (d, 1H, J =
H I \ * 7.2 Hz), 4.80 (m, 1H), 3.73 (d, 2H, J = 6.8 Hz), 17/304 N 3.08 (m, 1H), 2.80 (m, 2H), 2.62 (s, 3H), 2.30 (m, 0) CF 3 2H), 1.57-1.52 (m, 3H), 1.40-1.31 (m, 12H), 1.00 (m, 3H), 0.62 (m, 2H). MS: 519.2 (M+1)+.
# Structure Analytical data 1H-NMR (400 MHz, CDCI3) 6: 7.58 (s, 1H), 7.51 N
H I \ . (s, 1H), 7.39 (s, 1H), 6.21 (s, 1H), 5.89 (m, 1H), 3.72 (d, 2H, J = 7.2 Hz), 3.44 (m, 2H), 2.62 (s, d u3 3H), 1.87 (m, 2H), 1.57-1.51 (m, 3H), 1.39-1.30 (m, 12H), 1.31 (s, 6H),1.00 (m, 3H), 0.62 (m, 2H).
MS: 535.3 (M+1)+.
a HO
0 1H-NMR (400 MHz, CDCI3) 6: 7.74 (s, 1H), 7.63 N (s, 1H), 7.47(s, 1H), 6.26 (s, 1H), 5.67 (d, 1H, J =
H I \ . 7.6 Hz), 4.18 (m, 1H), 3.99 (m, 2H), 3.75 (d, 2H, J
17/306 N = 6.8 Hz), 3.52 (m, 2H), 2.60 (s, 3H), 1.99 (m, 0) CF3 2H), 1.63-1.46 (m, 11H), 1.40-1.33 (m, 3H), 1.00 (m, 3H), 0.62 (m, 2H). MS: 507.2 (M+1).
HOOC, o HO 11-1-NMR (400 MHz, CDCI3) 5: 7.73 (s, 1H), 7.63 (s, 1H), 7.46 (s, 1H), 6.27 (s, 1H), 6.04 (d, 1H, J =
N
H 1 \ 411 7.2 Hz), 4.78 (m, 1H), 3.74 (d, 2H, J = 7.2 Hz), 17/307 N 3.08 (m, 1H), 2.78 (m, 2H), 2.59 (s, 3H), 2.29 (m, d cF, 2H), 1.63 (s, 6H), 1.57-1.52 (m, 3H), 1.39-1.30 (m, 3H), 1.00 (m, 3H), 0.62 (m, 2H). MS: 521.2 HO
HOOCJ<N 0 1H-NMR (400 MHz, CDCI3) 6: 7.69 (s, 1H), 7.65 N (s, 1H), 7.45 (s, 1H), 6.18 (s, 1H), 6.02 (m, 1H), H I \ . 3.72 (d, 2H, J = 6.8 Hz), 3.36 (m, 2H), 2.56 (s, 17/308 N 3H), 1.81 (m, 2H), 1.67 (s, 6H), 1.56-1.50 (m, 3H), d u3 1.38-1.28 (m, 3H), 1.21 (s, 6H), 0.99 (m, 3H), 0.62 (m, 2H). MS: 537.3 (M+1)+.
N -, N
N' J.INF, 0 V 1H-NMR (400 MHz, DMSO-d6) 6: 7.61 (m, 1H), N 7.32 (s, 1H), 7.18 (s, 1H), 6.97 (s, 1H), 6.45 (s, H N
H I \ . 1H), 3.76 (d, 2H, J = 6.8 Hz), 3.46 (d, 2H, J = 6.0 17/309 N OH Hz), 2.46 (s, 3H), 1.47-1.31 (m, 9H), 1.30 (s, 3H), C-1 1.29 (s, 6H), 1.27-1.23 (m, 3H), 0.94 (m, 3H), 0.82(m, 2H), 0.75 (m, 2H), 0.64 (m, 2H). MS:
533.3 (M+1)+.
o ,kh 0 Ilr 1H-NMR (400 MHz, CDCI3) 5: 7.40 (m, 1H), 7.20 N (M, 1H), 7.07 (m, 1H), 6.20 (m, 1H), 6.16 (s, 1H), H N
H I \ 4110 3.72 (d, 2H, J = 7.2 Hz), 3.58 (d, 2H, J = 7.2 Hz), 17/310 N OH 2.59 (s, 3H), 1.59-1.48 (m, 9H), 1.43-1.25 (m, d 12H), 1.00 (m, 3H), 0.87 (m, 2H), 0.75 (m, 2H), 0.62 (m, 2H). MS: 549.4 (M+1)+.
# Structure Analytical data HO000 o N=y¨ 1H-NMR (400 MHz, CDCI3) 6: 7.23 (s, 1H), 6.86 N (s, 1H), 6.16 (m, 1H), 4.78 (m, 1H), 4.52 (m, 2H), H I \ / N 3.13 (m, 1H), 2.79 (m, 2H), 2.59 (s, 3H), 2.36 (m, \ d 17/311 N A 2H), 1.64-1.58 (m, 3H), 1.54 (m, 3H), 1.50-1.37 (m, 14H), 1.02 (m, 3H), 0.83 (m, 4H). MS: 507.1 (M+1)+.
HOOC o , N ' 1H-NMR (400 MHz, CDCI3) 6: 7.17 (s, 1H), 6.78 1----I'vN (s, 1H), 6.00(d, 1H J = 7.2 Hz), 4.79 (m, 1H), 4.52 I \ N
\ / (m, 2H), 3.11 (m, 1H), 2.81 (m, 2H), 2.60 (s, 3H), 17/312 N 2.35 (m, 2H), 1.63-1.53 (m, 6H), 1.44-1.35 (m, H
d ______ 14H), 1.07 (m, 3H), 0.85 (m, 4H). MS: 507.1 (M+1)+.
OH
o 11-1-NMR (400 MHz, CDCI3) 6: 7.40 (s, 1H), 7.21 H0*..N
(s, 1H), 7.08 (s, 1H), 6.22 (s, 2H), 3.73 (d, 2H, J =
N 1 \ * 7.2 Hz), 3.40 (m, 2H), 2.59 (s, 3H), 1.59-1.53 (m, d 17/313 N A 9H), 1.43-1.31 (m, 6H), 1.27 (s, 6H), 1.02-0.96 (m, 3H), 0.89-0.87 (m, 2H), 0.77-0.75 (m, 2H), 0.68-0.61 (m, 2H). MS: 481.3 (M+1)+.
OH
OH 0 1H-NMR (400 MHz, CDCI3) 6: 7.40 (s, 1H), 7.20 cONN (s, 1H), 7.07 (s, 1H), 6.20-6.18 (m, 2H), 3.81-3.72 FI I \ = (m, 6H), 3.43 (m, 2H), 2.59 (s, 3H), 1.66-1.53 (m, d 17/314 N A 13H), 1.43-1.33 (m, 6H), 1.00 (m, 3H), 0.87 (m, 2H), 0.77-0.75 (m, 2H), 0.68-0.61 (m, 2 H). MS:
523.3 (M+1)+.
0 OH i go0 'H-NMR (400 MHz, CDCI3) 6: 7.35 (s, 1H), 7.21 H2N- N----N (s, 1H), 7.06 (s, 1H), 6.55 (s, 1H), 6.21 (s, 1H), H I \ 4", 5.23 (m 2H), 3.85 (m, 2H), 3.71 (d, 2H, J = 6.8 17/315 N Hz), 3.34 (m, 2H), 2.54 (s, 3H), 1.58-1.52 (m, 9H), d A 1.42-1.31 (m, 6H), 0.99 (m, 3H), 0.86 (m, 2H), 0.80-0.74 (m, 2H), 0.67-0.60 (m, 2 H). MS: 516.2 (M+1)+.
O"' õ.....
,.N 0 OH 1H-NMR (400 MHz, CDCI3) 6: 7.38 (s, 1H), 7.26 L..N
(s, 1H), 7.19 (s, 1H), 7.07 (s, 1H), 6.31 (s, 1H), 3.96-3.93 (m, 4H), 3.80 (s, 2H), 3.72 (d, 2H, J =
H I \ * 6.8 Hz), 3.63-3.59 (m, 2H), 3.30 (s, 2H), 2.93-2.89 d 17/316 N A (m, 2H), 2.58 (s, 3H), 1.59-1.49 (m, 9H), 1.42-1.32 (m, 6H), 0.99-0.95 (m, 3H), 0.87 (t, 2H, J = 5.2 Hz), 0.78-0.73 (m, 2H), 0.67-0.59 (m, 2 H). MS:
522.3 (M+1)+.
# Structure Analytical data OH , R ,0 0 'H-NMR (400 MHz, CDCI3) 6:7.40 (s, 1H), 7.19 )S/ (s, 1H), 7.07 (s, 1H), 6.45 (s, 1H), 6.20 (s, 1H), N
H I \ . 3.92-3.88 (m, 2H), 3.73 (d, 2H, J = 6.8 Hz), 3.34 17/317 N (m, 2H), 2.97 (s, 3H), 2.60 (s, 3H), 1.59-1.53 (m, d A 9H), 1.43-1.32 (m, 6H), 1.00 (m, 3H), 0.88 (m, 2H), 0.77-0.74 (m, 2H), 0.68-0.61 (m, 2H). MS:
515.2 (M+1)+.
H 2N 0 0 OH , 'H-NMR (400 MHz, CDCI3) 6: 7.39 (s, 1H), 7.19 CC-j-N (s, 1H), 7.07 (s, 1H), 6.38-6.25 (m, 3H), 6.18 (s, NH I \ 4., 1H), 3.86-3.83 (m, 2H), 3.73-3.57 (m, 6H), 2.56 (s, 17/318 N 3H), 2.01-1.97 (m, 2H), 1.73-1.69 (m, 2H), 1.59-d A 1.53 (m, 9H), 1.43 (s, 3H), 1.40-1.32 (m, 3H), 1.00 (s, 3H), 0.87 (m, 2H), 0.77-0.75 (m, 2H), 0.65-0.63 (m, 2H). MS: 550.3 (M+1)+.
OH 0 OH 1H-NMR (400 MHz, CDCI3) 6: 7.40 (s, 1H), 7.20 ON, a-NN
H S I \ . (s, 1H), 7.07 (s, 1H), 6.22 (m, 1H), 6.20 (s, 1H), 3.74 (d, 2H, J = 6.8 Hz), 3.53-3.42 (m, 4H), 2.93-17/319 2.85 (m, 2H), 2.59 (s, 3H), 2.14-2.01 (m, 4H), d A 1.60-1.54 (m, 9H), 1.43-1.33 (m, 6H), 1.00 (m, 3H), 0.87 (m, 2H), 0.78-0.76 (m, 2H), 0.69-0.62 (m, 2H). MS: 571.3 (M+1)+.
0 OH 1H-NMR (400 MHz, CDCI3) 6: 7.39 (s, 1H), 7.21 0, ON
,S H I \ . (s, 1H), 7.07 (s, 1H), 6.17 (s, 1H), 5.97 (m, 1H), 3.73 (d, 2H, J = 6.8 Hz), 3.32 (m, 2H), 3.09-2.92 17/320 6 N (m, 4H), 2.60 (s, 3H), 2.20-2.17 (m, 2H), 2.01-1.87 d A (m, 3H), 1.59-1.53 (m, 9H), 1.43-1.33 (m, 6H), 1.00 (s, 3H), 0.87 (m, 2H), 0.77-0.75 (m, 2H), 0.68-0.61 (m, 2H). MS: 555.3 (M+1)+.
ii 0.saOH 1H-NMR (400 MHz, CDCI3) 6:7.39 (s, 1H), 7.21 0 (s, 1H), 7.07 (s, 1H), 6.17 (s, 1H), 5.69 (d, 1H, J =
N 7.6 Hz), 5.25-4.23 (m, 1H), 3.74 (d, 2H, J
= 7.2 H I \ * Hz), 3.14-3.06 (m, 4H), 2.60 (s, 3H), 2.39-2.36 (m, d A 2H), 2.21-2.15 (m, 2H), 1.59-1.54 (m, 9H), 1.43-1.33 (m, 6H), 1.00 (m, 3H), 0.87(m, 2H), 0.78-0.75 (m, 2H), 0.68-0.60 (m, 2H). MS: 541.3 (M+1)+.
1H-NMR (CDCI3, 300 MHz) 6: 7.85 (s, 1H), 7.55 a 0 OH (s, 1H), 7.53 (s, 1H), 6.24 (s, 1H), 6.00 (s, 1H), N 5.65(d, 1H, J = 7.6 Hz), 4.16 (m, 1H), 3.98 (d, 2H, H I \ . \ z J = 11.6 Hz), 3.76 (d, 2H, J
= 7.6 Hz), 3.52 (m, 17/322 N 7 2H), 2.62 (s, 3H), 1.98 (m, 2H), 1.89 (s, 1H), 1.61 d 0 NH (s, 6H), 1.58-1.51 (m, 5H), 1.49 (s, 9H), 1.36 (m, 3H), 1.00 (m, 3H), 0.63 (m, 2H). MS: 538.2 (M+1)+.
# Structure Analytical data 1H-NMR (CDCI3, 300 MHz) 6: 7.87 (s, 1H), 7.58 a 0 OH (s, 1H), 7.56 (s, 1H), 6.25 (s, 1H), 6.01 (d, 1H, J =
N 7.6 Hz), 5.65 (d, 1H, J = 8.0 Hz), 4.31 (m, 1H), H I \ . 4.16 (m, 2H), 3.98 (d, 2H, J = 11.2 Hz), 3.76 (d, 17/323 N 2H, J = 7.2 Hz), 3.52 (m, 2H), 2.62 (s, 3H), 1.98 d 0 NH (m, 2H), 1.91 (s, 1H), 1.63 (s, 6H), 1.58-1.48 (m, 5H), 1.40-1.33 (m, 3H), 1.29 (d, 6H, J = 6.4 Hz), 0.99 (m, 3H), 0.63 (m, 2H). MS: 524.2 (M+1)+.
a 0 OMe 1H-NMR (CDCI3, 300 MHz) 6: 7.74 (s, 1H), 7.53 (s, 2H), 6.26 (s, 1H), 5.99 (s, 1H), 5.66 (d, 1H, J =
N
H I \ * 7.6 Hz), 4.17(m, 1H), 3.98 (d, 2H, J =
11.2 Hz), 17/324 N y_ 3.78 (d, 2H, J = 7.2 Hz), 3.53 (m, 2H), 3.10 (s, dNH 3H), 2.62 (s, 3H), 1.97 (m, 2H), 1.57 (s, 6H), 1.51-O 1.50 (m, 5H), 1.47 (s, 9H), 1.34-1.32 (m, 3H), 0.91 (m, 3H), 0.62 (m, 2H). MS 552 (M+1)+.
0ON1H-NMR (CDCI3, 300 MHz) 6: 0.61-0.69 (2H, m), o 4 0.72-0.74 (2H, m), 0.88-0.98 (5H, m), 1.33-1.40 N (3H, m), 1.51-1.62 (7H, m), 1.89-2.01 (4H, m), H I \ * 0 2.61 (1H, s), 3.21 (3H, s), 3.53 (2H, t, J = 11.7 17/325 N Hz), 3.68 (2H, d, J = 6.3 Hz), 3.97-4.01 (2H, m), d OMe 4.14-4.19 (1H, m), 4.33-4.36 (2H, m), 5.59-5.62 (1H, m), 6.09 (1H, s), 6.50 (1H, s), 7.13 (1H, s).
MS: 535.4 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 0.60-0.67 (m, HOOCõ, o V 2H), 0.75-0.77 (m, 2H), 0.83-0.86 (m, 2H), 0.90-0.95 (m, 3H), 1.21-1.24 (m, 3H), 1.30 (s, 9H), 1.40 N
H I \ . (s, 3H), 1.45-1.47 (m, 3H), 2.27-2.32 (m, 2H), 17/326 N 2.36-2.41 (m, 2H), 2.50 (s, 3H), 2.80-2.94 (m, 1H), C) 3.76 (d, J = 6.8 Hz, 2H), 4.52 (m, 1H), 6.53 (s, 1H), 6.98 (s, 1H), 7.15 (s, 1H), 7.19 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 12.08 (br s, 1H). MS: 505.3 (M+1)+.
OH
0 1H-NMR (400 MHz, CDCI3) 6: 8.20 (d, 1H, J
= 8.8 HOOC ...
N . p Hz), 7.29 (s, 2H), 6.44 (m, 1H), 6.29 (s, 1H), 3.75 H I \ S=O (d 2H J = 7.2 Hz), 3.55 (d, 2H, J = 6.0 Hz), 2.58 17/327 N HµN ( (s, , 3H), 1.70 (s, 6 H), 1.53 (m, 3H), 1.30-1.22 (m, d 18H), 0.97 (m, 3H), 0.57 (m, 2H). MS:
590.3 (M+1)+.
OH
OH
0\oi o 1H-NMR (400 MHz, CDCI3) 6: 8.21 (d, 1H, J = 8.0 lk p Hz), 7.30 (s, 1H), 6.32 (s, 1H), 6.14 (m, 1H), 4.79 H I \ i S:=0 (s, 1H), 3.76 (d, 2H, J = 6.4 Hz), 3.10 (m, 1H), 17/328 N HN ( 2.79 (m, 2H), 2.59 (s, 3H), 2.34 (s, 2H), 1.71 (s, d 6H), 1.54 (m, 3H), 1.30-1.21 (m, 12H), 0.97 (m, 3 H), 0.59 (m, 2 H). MS: 588.3 (M+1)+.
# Structure Analytical data HOOCNh 1H-NMR (400 MHz, CD30D) 6: 7.67 (s, 1H), 7.44 N
H I \ .(m, 2H), 6.31 (s, 1H), 3.75 (d, 2H, J = 6.8 Hz), N
d 0 y 3.39 (s, 2H), 2.46 (s, 3H), 1.44 (m, 3H), 1.37 (m, NH 9H), 1.31-1.19 (m, 12H), 1.13 (m, 6H), 0.92 (m, 3H), 0.60-0.58 (m, 2H). MS: 552.4 (M+1)+.
HOOC,, 1H-NMR (400 MHz, DMSO-d6) 6: 7.88 (d, 1H, J
cL 0 =7.6 Hz), 7.83 (s, 1H), 7.75 (s, 1H), 7.69 (s, 1H), N 7.50 (s, 1H), 6.64 (s, 1H), 4.52 (m, 1H), 3.81 (d, H I \ . 2H, J = 6.8 Hz), 2.92-2.90 (m, 1H), 2.53 (s, 3H), 17/330 N 2.42-2.36 (m, 2H), 2.32-2.27 (m, 2H), 1.49-1.47 d 0 NH (m, 3H), 1.40 (s, 9H), 1.34-1.24 (m, 12H), 0.96-0.92 (m, 3H), 0.66-0.63 (m, 2H). MS: 550.3 (M+1)+.
O-N
(:) jc..... 0 11-I-NMR (400 MHz, CDCI3) 6: 11.02 (s, 1H), 8.19 N ,0 (d, 1H, J = 8.4 Hz), 7.57 (s, 1H), 7.22 (m, 1H), H N
H I \ . S'=0 6.35(m, 1H), 6.27 (s, 1H), 4.55 (s, 1H),3.76-3.70 17/331 N 'NH (m, 4H), 2.92 (m, 2H), 2.60 (s, 3H), 1.61-1.46 (m, d A 12H), 1.35-1.25 (m, 12H), 0.96 (m, 3H), 0.58 (m, 2H). MS: 600.3 (M+1)+
O-N F F
0 JIN 0 F 1H-NMR (400 MHz, CDCI3) 6: 10.82 (s, 1H), 8.33 N
H N p (d, 1H, J = 8.0 Hz), 7.78 (s, 1H), 7.61 (d, 1H, J=
H I \ * S,/=0 8.0 Hz), 6.36 (s, 1H) 6.33 (m, 1H), 4.74 (s, 1H), d 17/332 N /NH 3.83-3.72 (m, 4H), 2.93 (m, 2H), 2.61 (s, 3H), 1.56 _7\ (m, 3H), 1.32 (m, 3H), 1.24 (s, 9H), 1.00 (m, 3H), 0.62 (m, 2H). MS: 612.2 (M+1)+.
0'NI OH
N 1H-NMR (400 MHz, CDCI3) 6: 10.86 (s, 1H), 8.21 H N
\ -0 , , = , , . *
(d 1H J = 8 4 Hz) 7.28 (s 2H), , 6.30 (m 1H), S,= , 17/333 N NH 6.27 (s, 1H), 3.78-3.70 (m, 4H), 2.93 (m, 2H), 2.60 d A (s, 3H), 1.70 (s, 6H), 1.55 (m, 3H), 1.31-1.26 (m, 12H), 0.98 (m, 3H), 0.58 (m, 2H). MS: 602 (M+1)+
H
,N-N 1H-NMR (400 MHz, CDCI3) 6: 8.19 (d, 1H, J
= 8.4 Nõ _IJN 0 Hz), 7.56 (s, 1H), 7.21 (d, 1H, J = 7.6 Hz), 6.52 H
N
N \ m p (m, 1H), 6.26 (s, 1H), 4.57 (m, 1H), 3.97 (m, 2H), 17/334 N W I N e,NH
=.0 3.77 (d, 2H, J = 6.8 Hz), 3.40 (m, 2H), 2.61 (s, d , 312H1):010.589 (m s,9H3)1101;5045(9m(,m3H2),H1)..3m3-s1:.2548r4, (M+1)+
# Structure Analytical data H
,N-N F F
F0 1H-NMR (400 MHz, CD30D) 5: 8.31 (d, 1H, J =
N 8.4 Hz), 7.89 (s, 1H), 7.81 (d, 1H, J =
8.4 Hz), N , H I \ . s..0 6.63 (s, 1H), 3.94 (d, 2H, J =
6.8 Hz), 3.74 (m, d 17/335 N NH 2H), 3.24 (m, 2H), 2.58 (s, 3H), 1.56 (m, 3H), 1.32 _A (m, 3H), 1.26 (s, 9H), 1.02 (m, 3 H), 0.71 (m, 2H).
MS: 596.3 (M+1)4.
H
,NN OH
0 1H-NMR (400 MHz, CDCI3) 6: 8.21 (d, 1H, J
= 8.4 N 0 Hz), 7.24 (s, 2H), 6.49 (s, 1H), 6.28 (s, 1H), 3.97 N
HI \ it s:=0 (m, 2H), 3.76 (d, 2H, J = 7.2 Hz), 3.36 (m, 2H), 17/336 N NH 2.62 (s, 3H), 1.69 (s, 6H), 1.54 (m, 3H), 1.30-1.24 d A (m, 12H), 0.96 (m, 3H), 0.59 (m, 2H).
MS: 586.3 (M+1)+
a O 1H-NMR (400 MHz, CDCI3) 5: 7.61 (m, 1H), 7.39 V (m, 1H), 7.32 (m, 1H), 6.21 (s, 1H), 5.92 (s, 1H), N 5.62 (d, 1H, J = 8.0 Hz), 4.16 (m, 1H), 3.98 (m, H I \ .., 2H), 3.75 (d, 2H, J = 7.2 Hz), 3.52 (m, 2H), 2.62 17/337 N (s, 3H), 1.99 (m, 2H), 1.57-1.46 (m, 3H), 1.44-1.42 d 0 NH (M, 15H), 1.40 (m, 3H), 1.26 (m, 3H), 1.01 (m, 3H), 0.89 (m, 2H), 0.79 (m, 2H), 0.62 (m, 2H). MS:
534.3 (M-F1)+.
0 V 1H-NMR (400 MHz, CDCI3) 5: 7.62 (s, 1H), 7.38 HOOCNFN N
(s, 1H), 7.31 (s, 1H), 6.34 (m, 1H), 6.22 (s, 1H), H I \ * 5.95 (s, 1H), 3.72 (d, 2H, J = 7.2 Hz), 3.53 (d, 2H, N
d y J = 6.0 Hz), 2.60 (s, 3H), 1.55 (m, 3H), 1.48 (S, NH 9H), 1.43 (s, 3H), 1.30 (m, 9H), 1.00 (m, 3H), 0.89 (m, 2H), 0.78 (m, 2H), 0.62 (m, 2H). MS: 550.3 (M+1)+.
HOOC-3 o V 1H-NMR (400 MHz, CDCI3) 6: 7.61 (m, 1H), 7.39 (m, 1H), 7.32 (m, 1H), 6.23 (s, 1H), 6.00 (m. 1H), N
H I \ . 5.96 (s, 1H), 4.78 (m, 1H), 3.74 (d, 2H, J
= 7.2 17/339 N y Hz), 3.10 (m, 1H), 2.80 (m, 2H), 2.59 (s, 3H), 2.32 dNH (M, 2H), 1.58-1.53 (m, 3H), 1.49 (s, 9H), 1.44 (s, ID 3H), 1.38 (m, 3H), 1.01 (m, 3H), 0.89 (m, 2H), 0.79 (m, 2H), 0.62 (m, 2H). MS: 548.3 (M+1)+.
0 V 1H-NMR (400 MHz, CDCI3) 6: 7.62 (s, 1H), 7.42 N (S, 1H), 7.30 (s, 1H), 6.23 (s, 1H), 6.16 (s, 1H), cH
I \ IIP 6.02 (m, 1H), 3.72 (d, 2H, J = 7.2 Hz), 3.39 (m, N y_. 2H), 2.59 (s, 3H), 1.82 (m, 2H), 1.57-1.52 (m, 3H), 17/340 HO d NH 1.49 (s, 9H), 1.43 (s, 3H), 1.32 (m, 3H), 1.22 (s, 0 6H), 1.00 (m, 3H), 0.89 (m, 2H), 0.78 (m, 2H), 0.62 (m, 2H). MS: 564.3 (M+1)+.
# Structure Analytical data OH 0 V 1H-NMR (400 MHz, CDCI3) 6: 7.61 (m, 1H), 7.40 N (m, 1H), 7.31 (m, 1H), 6.23 (s, 1H), 6.21 (m, 1H), ,CH I \ 41", 5.98 (s, 1H), 3.74-3.73 (m, 6H), 3.44 (d, 2H, J =
N
d 0 y 6.0 Hz), 2.61 (s, 3H), 1.69-1.53 (m, 6H), 1.49 (s, NH 9H), 1.43 (s, 3H), 1.32 (m, 3H), 1.00 (m, 3H), 0.89 (m, 2H), 0.78 (m, 2H), 0.62 (m, 2H). MS: 564.3 (M+1)+.
a OH 1H-NMR (CDCI3, 400 MHz) 6: 0.63-0.66 (m, 2H), 0.76-0.77 (m, 2H), 0.86-0.89 (m, 2H), 0.98-0.99 N (m, 3H), 1.33-1.43 (m, 3H), 1.47 (s, 3H), 1.52-1.56 H I \ = (m, 5H), 1.58 (s, 6H), 1.73 (s, 2H), 2.61 (s, 3H), d 17/342 N 3.52 (t, 2H, J = 12.0 Hz), 3.73 (d, 2H, J
= 8.0 Hz), 3.96-3.99 (m, 2H), 4.15-4.17 (m, 1 H), 5.61 (d, 1H, A
J = 8.0 Hz), 6.17 (s, 1H), 7.07 (s, 1H), 7.20 (s, 1H), 7.39 (s, 1H). MS: 493.2 (M+1)+.
OMe 1H-NMR (CDCI3, 400 MHz) 6: 0.61-0.64 (m, 2H), a 0 0.75-0.77 (m, 2H), 0.86-0.89 (m, 2H), 0.98-0.99 N (m, 3H), 1.32-1.37 (m, 3H), 1.43 (s, 3H), 1.47-1.53 H I \ . (m, 11H), 1.96-2.00 (m, 2H), 2.61 (s, 3H), 3.08 (s, d 17/343 N 1H), 3.53 (t, 2H, J = 12.0 Hz), 3.74 (d, 2H, J = 8.0 Hz), 3.96-3.99 (m, 2H), 4.15-4.17 (m, 1 H), 5.61 A
(d, 1H, J = 8.0 Hz), 6.18 (s, 1H), 7.08 (s, 1H), 7.16 (s, 1H), 7.26 (s, 1H). MS 507.2 (M+1).
0 v 1H-NMR (CDCI3, 400 MHz) 6: 0.62-0.68 (m, 2H), N
(NNZ
I \ 11 0.73-0.75 (m, 2H), 0.85-0.88 (m, 2H), 0.99 (m, 3H), 1.26-1.28 (m, 1H), 1.33 (s, 9H), 1.37-1.39 (m, N
d 2H), 1.42 (s, 3H), 1.52-1.54 (m, 3H), 2.39 (m, 4H), 17/344 0.,..) 2.57 (s, 3H), 3.14-3.19 (m, 1H), 3.70-3.74 (m, 6H), 3.98-4.32 (m, 4H), 6.17 (s, 1H), 7.00 (m, 1H), 7.12 (m, 1H), 7.25 (m, 1H). MS: 532.4 (M+1)+.
0 v 1H-NMR (CDCI3, 400 MHz) 6: 0.63-0.66 (m, 2H), 0.73-0.76 (m, 2H), 0.85-0.88 (m, 2H), 0.99 (m, 0,9,isiHN I \ . 3H), 1.33 (s, 9H), 1.36-1.39 (m, 4H), 1.42 (s, 3H), `S 1.53-1.55 (m, 4H), 1.70-1.80 (m, 1H), 1.88 (d, J =
d 17/345 I N 13.2 Hz, 2H), 2.61 (s, 3H), 2.66 (m, 2H), 2.76 (s, 3H), 3.30 (m, 2H), 3.71 (d, J = 7.2 Hz, 2H), 3.80 (m, 2H), 5.89 (m, 1H), 6.15 (s, 1H), 7.00 (m, 1H), 7.12 (m, 1H), 7.25 (m, 1H). MS: 582.4 (M+1)+.
NNTh cN
N.---NN 0 V 1H-NMR (CDCI3, 400 MHz) 6: 0.64-0.67 (m, 2H), 0.73-0.75 (m, 2H), 0.86-0.88 (m, 2H), 1.00 (m, H I \ .0 3H), 1.33 (s, 9H), 1.34-1.38 (m, 2H), 1.42 (s, 3H), 17/346 N 1.61-1.63 (m, 5H), 2.53 (s, 3H), 2.57 (s, 3H), 2.60-d 3.00 (m, 3H), 3.10-3.30 (m, 5H), 3.67-3.68 (m, 2H), 3.71-3.73 (m, 2H), 6.28 (s, 1H), 7.00 (m, 1H), 7.12 (m, 1H), 7.27 (m, 1H). MS: 533.4 (M+1)+.
# Structure Analytical data (31, ,0 ;K 1H-NMR (CDCI3, 400 MHz) 6: 0.62-0.68 (m, 2H), NTh C-"NN...---NN 0 V 0.75-0.77 (m, 2H), 0.85-0.87 (m, 2H), 1.00 (m, 3H), 1.33 (s, 9H), 1.35-1.38 (m, 2H), 1.43 (s, 3H), 17/347 H I \ . 1.53-1.56 (m, 4H), 2.58-2.64 (m, 9H), 2.77 (s, 3H), N 3.24 (m, 4H), 3.50-3.52 (m, 2H), 3.70 (d, J = 7.2 C) Hz, 2H), 6.17 (s, 1H), 7.02 (m, 1H), 7.14 (m, 1H), 7.28 (m, 1H). MS: 597.4 (M+1)+.
OH 0 OCF3 1H-NMR (400 MHz, CD30D) 5: 0.65-0.74 (m, 2H), Nri 1 \ . 0.82-0.86 (m, 2H), 0.88-0.82 (m, 2H), 0.99-1.04 (m, 3H), 1.21 (s, 6H), 1.28-1.39 (m, 3H), 1.43 (s, N 3H), 1.53-1.56 (m, 3H), 2.56 (s, 3H), 3.32 (s, 2H), d 17/348 A 3.84 (d, J = 7.2 Hz, 2H), 6.51 (s, 1H), 7.07 (m, 1H), 7.11 (m, 1H), 7.23 (m, 1H). MS: 507.3 (M+1)+.
OH 0 OCF3 1H-NMR (400 MHz, CD30D) 5: 0.70-0.73 (m, 2H), N 1 \ ., w 1.01-1.05 (m, 3H), 1.22 (s, 6H), 1.33-1.36 (m, 3H), N i 1.46 (s, 9H), 1.55-1.58 (m, 3H), 2.58 (s, 3H), 3.33 d 17/349 0 NH (s, 2H), 3.90 (d, J = 7.6 Hz, 2H), 6.60 (s, 1H), 7.45 (s, 1H), 7.64 (s, 1H), 7.77 (m, 1H). MS: 552.3 (M+1)+.
HOOCcii3 o OCF3 1H-NMR (400 MHz, CD30D) 5: 0.71-0.74 (m, 2H), N 0.86-0.89 (m, 2H), 0.93-0.95 (m, 2H), 1.02-1.07 H I \ .0 (m, 3H), 1.33-1.36 (m, 3H), 1.47 (s, 3H), 1.57-1.60 17/350 N (m, 3H), 2.37-2.47 (m, 2H), 2.58 (s, 3H), 2.61-2.67 d A (m, 2H), 3.05-3.07 (m, 1H), 3.87 (d, J =
6.8 Hz, 2H), 4.66-4.73 (m, 1H), 6.57 (s, 1H), 7.10 (s, 1H), 7.14(s, 1H), 7.27(s, 1H). MS: 533.2 (M+1)+.
, HOOC o OCF3 1H-NMR (400 MHz, CD30D) 6: 0.69-0.72 (m, 2H), 0.99-1.04 (m, 3H), 1.28-1.35 (m, 3H), 1.46 (s, 9H), N
H I \ . 1.55-1.57 (m, 3H), 2.33-2.41 (m, 2H), 2.55 (s, 3H), 17/351 N y 2.57-2.64 (m, 2H), 3.00-3.05 (m, 1H), 3.89 (d, J =
d 0 NH 7.2 Hz, 2H), 4.64-4.68 (m, 1H), 6.61 (s, 1H), 7.44 (s, 1H), 7.63 (s, 1H), 7.76 (s, 1H). MS: 578.3 (M+1)+.
a0 y 1H-NMR (400 MHz, CDCI3) 5: 0.58-0.60 (m, 2H), N 0.63-1.02 (m, 4H), 1.23-1.68 (m, 12H), 1.94-1.98 H I \ .0 (m, 2H), 2.62 (s, 3H), 3.48 (t, J = 7.2 Hz, 2H), 3.76 17/352 N r--cF3 (d, J = 8.0 Hz, 2H), 3.98 (d, J = 12.4 Hz, 2H), d 0 NH 4.09-4.16 (m, 3H), 5.64-5.66 (m, 1H), 6.24 (s, 1H), 6.69 (s, 1H), 7.40 (s, 1H), 7.57 (s, 1H), 7.70 (s, 1H). MS: 560.3 (M+1)+.
# Structure Analytical data HOOCNI--"NN N,--- 1H-NMR (400 MHz, CDCI3) 5: 7.20 (s, 1H), 6.77 (s, 1H), 6.36 (m, 1H), 4.57 (m, 2H), 3.56 (d, 2H, J
17/353 dN ' = 6.4 Hz), 2.60 (s, 3H), 1.59 (m, 3H), 1.54-1.20 (m, 27H), 1.01 (m, 3H), 0.81 (m, 2H). MS: 511.3 (M+1)+.
HOOCõ, n 0 1H-NMR (400 MHz, CDCI3) 6: 7.21 (s, 1H), 6.79 N=r (s, 1H), 6.03 (d, 1H, J = 6.8 Hz), 4.82 (m, 1H), H I \ \ iN 4.58 (s, 2H), 3.11 (m, 1H), 2.81 (m, 2H), 2.61 (s, 17/354 N 3H), 2.36 (m, 2H), 1.60 (m, 3H), 1.55-1.37 (m, d 21H), 1.05 (m, 3H), 0.83 (m, 2 H). MS:
509.3 (M+1)+.
Nt---Nri 1 \ N=?/¨ 1H-NMR (400 MHz, CDCI3) 5: 7.22 (s, 1H), 6.84 NI (s, 1H), 6.22 (m, 1H), 4.59m, 2H), 3.42 (d, 2H, J =
\ / 6.0 Hz), 2.62 (s, 3H), 1.61 (m, 3H), 1.53-1.42 (m, d N A 8H), 1.36 (s, 9H), 1.28 (s, 6H), 1.04 (m, 3H), 0.87-0.79 (m, 4H). MS: 481.4 (M+1)+.
OH J7¨7-1H-NMR (400 MHz, CDCI3) 6: 7.17 (s, 1H), 6.83 _______________________ r;--,N (s, 1H), 6.24 (m, 1H), 4.54 (m, 2H), 3.42 (d, 2H, J
d 17/356 .5.6 Hz), 2.61 (s, 3H), 1.63-1.54 (m, 6H), 1.45-1.34 (m, 14H), 1.29 (s, 6H), 1.07 (m, 3H), 0.88-0.84 (m, 4H). MS: 481.3 (M+1)+.
OH
--I 1H-NMR (400 MHz, CD30D) 6: 0.59-0.65 (m, 2H), 0.78 (s, 2H), 0.89-0.96 (m, 5H), 1.22-1.29 (m, 5H), N
H \ 1.41 (s, 3H), 1.45-1.48 (m, 2H), 2.30-2.32 (m, 2H), I *
17/357 N 2.49 (s, 3H), 2.54-2.56 (m, 2H), 2.96-2.99 (m, 2H), 3.80 (d, J = 6.8 Hz, 2H), 4.04 (dd, J = 14.4, 7.2 d HN Hz, 2H), 4.60 (br s, 1H), 6.48 (s, 1H), 7.41 (s, 1H), ) 7.60 (s, 1H), 7.69 (s, 1H). MS: 574.3 (M+1)+.
OH
--I 1H-NMR (400 MHz, CD30D) 6: 0.57-0.61 (m, 2H), o'''= V 0.72-0.75 (m, 2H), 0.84-0.86 (m, 2H), 0.92-0.97 ciL 0 N (m, 3H), 1.20-1.28 (m, 3H), 1.33-1.37 (m, 6H), H I \ * 144-1.47 (m, 3H), 2.12-2.19 (m, 2H), 2.44 (s, 3H), 17/358 N 2.45-2.54 (m, 2H), 2.84-2.88 (m, 1H), 3.76 (d, J =
0 6.8 Hz, 2H), 4.46-4.50 (m, 1H), 4.78-4.84 (m, 1H), C) HN 6.45 (s, 1H), 7.37 (s, 1H), 7.56 (s, 1H), 7.63 (s, 1H). MS: 588.4 (M+1)+.
# Structure Analytical data OH
1H-NMR (400 MHz, CD30D) 6: 0.57-0.61 (m, 2H), 0 V 0.72-0.75 (m, 2H), 0.84-0.86 (m, 2H), 0.92-0.97 N (m, 3H), 1.20-1.28 (m, 3H), 1.33-1.37 (m, 6H), H I \ * 144-1.47 (m, 3H), 2.12-2.19 (m, 2H), 2.44 (s, 3H), 17/359 N 2.45-2.54 (m, 2H), 2.84-2.88 (m, 1H), 3.76 (d, J =
0 6.8 Hz, 2H), 4.46-4.50 (m, 1H), 4.78-4.84 (m, 1H), C) HN 6.45 (s, 1H), 7.37 (s, 1H), 7.56 (s, 1H), 7.63 (s, F30 1H). MS: 588.3 (M+1)+.
OH 1H-NMR (400 MHz, CD30D) 6: 0.58-0.61 (m, 2H), o V 0.71-0.74 (m, 2H), 0.83-0.85 (m, 2H), 0.92 (s, 3H), 1.23-1.30 (m, 3H), 1.37 (d, J = 7.2 Hz, 3H), 1.45-1.47 (m, 3H), 1.59 (s, 6H), 2.12-2.20 (m, 2H), 2.44 H I= \ *
17/360 N (d, J = 5.6 Hz, 3H), 2.48-2.55 (m, 2H), 2.86-2.88 0 (M, 1H), 3.75 (d, J = 6.8 Hz, 2H), 4.48 (t, J = 7.6 d HN Hz, 1H), 6.44 (s, 1H), 7.34 (t, J = 1.6 Hz, 1H), 7.43 K (t, J = 1.6 Hz, 1H), 7.50 (t, J = 1.6 Hz, 1H). MS:
F3c 602.4 (M+1)+.
N ,0 \11 17/361 HO S:=-0 O N NH MS: 623.3 (M+1)+.
d=
NC-7, OH
C)".0, 0 N,0 17/362 H I \ li S:=0 MS: 607.2 (M+1)+.
N NH
C) NC-Lc, ON ,0 HI \ 411 S:=0 17/363 N NH MS: 584.3 (M+1)+.
d -A
OH
AI F
N ,0 H I \ . S:=0 MS: 598.3 (M+1)+.
N NH
d A
# Structure Analytical data HO
*
?\----NN 0 H I \ S,:=0 17/365 dNH MS: 572.3 (M+1)+.
¨A
4111. 1H-NMR (400 MHz, CDCI3) 5: 8.68 (s, 1H), 8.08 HO- (d, 1H, J = 8.8 Hz), 7.95 (d, 1H, J = 5.6 Hz), 7.78 -NN
H I \ \ /N (t, 1H, J = 7.6 Hz), 7.58 (s, 1H), 6.75 (d, 1H, J =
17/366 N ' 6.8 Hz), 6.54-6.46 (m, 1H), 3.75 (s, 2H), 3.44 (d, (ii 2H, J = 4.4 Hz), 2.72 (s, 3H), 1.63 (s, 9H), 1.52 (d, 3H, J = 6.8 Hz), 1.33-1.28 (m, 9H), 0.98-0.89 (m, 3H), 0.54-0.48 (m, 2H). MS: 476.3 (M+1)+.
HO N 1H-NMR (400 MHz, CDCI3) 6: 8.08 (s, 1H), 7.47 (t, 7\---N
H I \ . 1H, J = 6.0 Hz), 7.38 (d, 1H, J = 2.4 Hz), 7.29 (d, 1H, J = 2.4 Hz), 6.99 (s, 1H), 3.16 (d, 2H, J = 6.0 Hz), 2.52 (s, 3H), 1.52-1.51 (m, 3H), 1.36-1.25 (m, ci HN 21H), 1.07 (s, 6H), 1.01-0.94 (m, 3H), 0.62-0.58 17/367 d )\ (m, 2H). MS: 558.3 (M+1)+.
OH
1H-NMR (400 MHz, DMSO-d6) 5: 7.59 (d, 1H, J =
2.4 Hz), 7.37 (d, 1H, J = 2.4 Hz), 6.19 (s, 1H), N6.05 (d, 1H, J = 7.2 Hz), 5.86 (s, 1H), 4.77 (t, 1H, H I \ * J = 5.2 Hz), 3.49 (s, 2H), 3.06 (t, 1H, J = 7.2 Hz), 17/368 N 2.77 (t, 2H, J = 9.2 Hz), 2.59 (s, 3H), 2.30 (t, 2H, J
d ci o = 8.8 Hz), 1.57-1.25 (m, 24H), 1.01 (s, 3H), 0.65-HN
?\ 0.60 (m, 2H). MS: 584.3 (M+1)+.
OaN 1H-NMR (400 MHz, CDCI3) 5: 10.17 (s, 1H), 8,67 O / \ (d, J = 6.0 Hz, 1H), 8.41 (d, J = 7.6 Hz, 1H), 7.73-N p 7.68 (m, 2H), 6.38 (s, 1H), 5.63 (d, J =
8.0 Hz, H I \ * S,=0 1H), 5.21 (s, 1H), 4.19 (m, 1H), 4.02-3.95 (m, 2H), 17/369 N NH 3.77-3.70 (m, 1H), 3.54 (m, 2H), 3.37-3.30 (m, d A 1H), 2.69 (s, 3H), 2.03-1.97(m, 2H), 1.59-1.42 (m, 5H), 1.29-1.19 (m, 12H), 0.95-0.85 (m, 3H), 0.55-0.46 (m, 2H). MS: 567.3 (M+H)+.
4111H-NMR (300 MHz, CDCI3) 5: 8.66 (d, J = 8.4 Hz, 1H), 8.34 (d, J = 8.4Hz, 1H), 7.80-7.45 (m, 4H), HO)(NN
I \ H I \ * si:?-.0 6.39 (s, 1H), 6.20 (t, J =
6.4 Hz, 1H), 4.70-4.52 17/370 N /1F1 (171, 1H), 3.75-3.60 (m, 1H), 3.41 (m, 2H), 3.36-3.27 (m, 1H), 2.66 (s, 3H), 1.86-1.73 (m, 2H), F--d 1.40-1.01 (m, 21H), 0.95-0.46 (m, 3H). MS:
572.3 [M+1r.
NH2 a 1H-NMR (300 MHz, CDCI3) 5: 0.87-0.68 (m, 2H), ENI 1 \ a 1.30-1.20 (m, 3H), 1.47 (s, 9H), 1.49 (s, 6H), 1.85-=p s,=0 1.50 (m, 6H), 2.79 (s, 3H), 2.95 (s, 3H), 3.80-3.60 17/371 N NH (al, 4H), 4.98 (s, 1H), 5.75 (br s, 1H), 6.44 (s, 1H), d A 6.49 (br s, 1H) ,6.70 (t, J = 6.3Hz, 1H), 7.47 (d, J =
8.4 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H). MS: 579.3 [M+1r.
# Structure Analytical data OH
O'''= 1H-NMR (400 MHz, CDCI3) 6: 8.08 (s, 1H), 7.20 (s, 1H), 6.22 (m, 1H), 4.75-4.69 (m, 1H), 4.51-4.47 (M, 2H), 3.23-3.18 (m, 1H), 2.83-2.81 (m, 2H), 17/372 N 2.61 (s, 3H), 2.43-2.36 (m, 2H), 1.70-1.60 (m, 6H), d o 1.54 (s, 9H), 1.44-1.25 (m, 5H), 1.10-0.81 (m, 7H).
HN MS: 550.3 (M+1)+.
?\---, ---1- 1H-NMR (400 MHz, CDCI3) 6: 8.04 (s, 1H), 7.96 HO)(NN
' \ Hj-4µi iN (S, 1H), 7.05 (s, 1H), 6.29 (m, 1H), 4.51 (m, 1H), 17/373 N \ 3.41 (m, 2H), 2.61 (s, 3H), 1.70-1.60 (m, 6H), 1.56 (s, 9H), 1.54-1.34 (m, 5H), 1.28-1.22 (m, 6H), d HN 1.09-0.80 (m, 7H). MS: 524.3 (M+1)+.
o HO. 1H-NMR (300 MHz, CDCI3) 6: 8.67 (d, J =
8.4 Hz, A 1)1 I \ 4", e:o 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.78-7.40 (m, 4H), N NH 6.42 (s, 1H), 6.32 (br s, 1H), 4.71 (br s, 1H), 4.30-a A 4.11 (m, 1H), 3.78-3.72 (m, 1H), 3.50-3.28 (m, 3H), 2.68 (s, 3H), 1.50-1.10 (m, 23H), 1.95-1.70 (m, 2H). MS: 572.3 [M+1]+.
F
Example 18/1 to 18/5 The following Preparative Examples were prepared similar as described in according the depicted experimental number.
# Structure educt Analytical data Oa HON 1H-NMR (CDCI3, 300 MHz) 6: 7.66 (t, 1H), 7.50 o (s, 1H), 7.36 (t, 2H), 6.21 (s, 1H), 5.63 (d, 1H, J
N
H I \ 411 17/103 = 7.8 Hz), 4.14-4.19 (m, 1H), 3.98 (d, 2H, J =
18/1 N 12.6 Hz), 3.74 (d, 2H, J = 7.2 Hz), 3.53 (t, 2H, J
d Ex.# 6 . 9.9 Hz), 2.62 (s, 3H), 2.31 (s, 3H), 1.96-2.00 (m, 2H),1.30-1.58 (m, 12H), 0.97-1.00 (m, 3H), 0.61-0.66 (m, 2H). MS: 494.3 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 8.29 (d, 1H, J =
a 0 8.4 Hz), 7.81 (s, 1H), 7.62 (dd, 1H, J
= 8.4, J =
HNj<7/10 1.6 Hz), 6.38 (s, 1H), 5.62 (d, 1H), 4.94 (br S, H I \ * S=0 F 8 1H), 4.69 (t, 1H), 4.57 (t, 1H), 4.13-4.20 (m, 1H), 18/2 N 0 Ex.# 3.98-4.00 (m, 2H), 3.81 (d, 2H), 3.53 (td, 2H), d u3 21/1 2.63 (s, 3H), 2.07 (7, 1H), 1.97-2.01 (m, 3H), 1.48-1.57 (m, 5H), 1.28-1.38 (m, 3H), 1.25 (s, 6H), 1.00-1.24 (m, 3H), 0.61-0.67 (m, 2H). MS:
616.3 (M+1)+.
# Structure educt Analytical data oa 0 HON /H-NMR (CDCI3, 400 MHz) ö: 7.70 (d, 1H), 7.41 (s, 1H), 7.20 (d, 1H), 6.15 (s, 1H), 5.62 (d, 1H, J
17/104 = 8.0 Hz), 4.27 (t, 2H, J = 6.0 Hz), 4.13-4.19 (m, N 1 \ . 0 1H), 3.96-3.99 (m, 2H), 3.72 (d, 2H, J = 7.6 Hz), 18/3 N EX.# 3.50-3.55 (m, 2H), 3.02 (t, 2H, J =
6.0 Hz), 2.61 d 6/1 (s, 3H), 1.96-1.99 (m, 2H),1.47-1.58 (m, 5H), 1.32-1.38 (m, 12H), 0.98-1.02 (m, 3H), 0.64-0.72 (m, 2H). MS: 522.3 (M+1)+.
O 0 F 1H-NMR (CDCI3, 400 MHz) 6: 7.21 (s, 1H), 7.15 (s, 1H), 6.13 (s, 1H), 5.44-5.61 (m, 2H), 4.41-17/105 4.44 (m, 1H), 4.14-4.27 (m, 2H), 3.97 (d, 2H, J =
N 1 \ * 0 12.0 Hz), 3.64-3.75 (m, 2H), 3.49-3.55 (m, 2H), 18/4 N Ex.# 2.61 (s, 3H), 2.27-2.31 (m, 2H),1.96-2.00 (m, d 26 2H), 1.38-1.57 (m, 17H), 1.02-1.04 (m, 3H), 0.65-0.72 (m, 2H). 19F-NMR (CDCI3, 376 MHz) 5:
-149.97 (s). MS: 511.4 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 5: 8.20 (d, 1H, J =
Oa 0 HNj<F 8.0 Hz), 7.84 (s, 1H), 7.63 (d, 1H, J = 8.0 Hz), 6.37 (s, 1H), 5.63 (d, 1H, J = 8.0 Hz), 5.04 (t, J =
H I \ * =-Os 6.0 Hz, 1H), 4.13-4.19 (m, 1H), 3.98-4.01 (m, 18/5 N 0 Ex .# 2H), 3.81 (d, J = 7.2 Hz, 2H), 3.49-3.56 (m, 2H), d u3 3.12-3.18 (m 2H) 2.64 (s 3H) 1.97-2.00 (m, Q
' ' ' ' ' 2H), 1.49-1.67 (m, 5H), 1.40 (s, 3H), 1.34 (s, 6H), 0.99-1.12 (m, 3H), 0.62-0.65 (m, 2H). MS:
602.3 (M+1).
Example 19 a 0 H I \ . s=o cF3 d 19 1-(CyclohexvImethyl)-2-methyl-5-(4-sulfamov1-3-(trifluoromethvI)Dtenv1)-N-(tetrahydro-2 H-pyran-4-v1)-1H-pyrrole-3-carboxamide (19) To a solution of compound 17/97 (150 mg, 0.26 mmol) in DCM (5 mL) was added TFA (5 mL) and the solution was stirred at 30 C for 5 h, concentrated and purified by prep. HPLC to give compound 19 (108 mg, 82%) as a colorless solid. 1H-NMR (400 MHz, CDCI3) 6: 0.62-0.66 (2H, m), 1.00-1.04 (3H, m), 1.26-1.57 (8H, m), 1.97-2.01 (2H, m), 2.63 (3H, s), 3.50-3.55 (2H, m), 3.81 (2H, d, J = 7.6 Hz), 3.98-4.00 (2H, m), 4.14-4.17 (2H, m), 5.05-5.07 (2H, m), 5.60 (1H, d, J = 8.0 Hz), 6.35 (1H, s), 7.64 (1H, dd, J = 8.4, 1.6 Hz), 7.82 (1H, s), 8.30 (1H, d, J = 8.0 Hz). MS: 528.2 [M+1]+.
Example 19/1 Using a procedure similar as described in Example 19, the following compound was prepared.
Structure Analytical data n 0ci 1H-NMR (300 MHz, CDCI3) 6: 0.66-0.77(2H, m), 1.05-1.11 (3H, m), 1.27-1.60 (8H, m), 1.98-2.03 (2H, m), 2.64 (3H, s), H I \
s=o 3.55 (2H, dt, J = 1.5, J = 11.4 Hz), 3.83 (2H, d, J = 7.2 Hz), 4.00 (2H, dd, J = 2.4, J = 10.2 Hz), 4.15-4.20 (1H, m), 5.53 (2H, d, J = 7.5 Hz), 5.63 (1H, d, J = 7.5 Hz), 6.41 (1H, s), 7.73 (1H, d, J = 1.8 Hz), 7.79 (1H, s). MS: 562.2 [M+1r.
Example 20 HN-<
H
d20 5434 tert-Buty1)-4-(N-(tert-butypsulfamovOphenv1)-1-(cyclohexylmethyl)-2-fluoro-N-(tetrahvdro-2H-pyran-4-v1)-1H-pwrole-3-carboxam ide (20) To a solution of compound 17/116 (100 mg, 0.18 mmol) in MeCN (30 mL) at rt under N2 was added Selecffluor (83 mg, 234 pmol) and the resulting solution was stirred at 55 C overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The combined organic layer was concentrated and purified by prep. HPLC to give compound 20 (45 mg, 43%) as a colorless solid. 1H-NMR (400 MHz, CDCI3) 6: 8.19 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 1.2 Hz, 1H), 7.27 (t, 1H), 6.51 (d, J = 5.6 Hz, 1H), 5.70 (br s, 1H), 4.48 (5, 1H), 4.02-3.95 (m, 1H), 4.00-3.97 (d, 2H), 3.75 (d, 2H), 3.54 (dd, J = 10.0 Hz, 11.6 Hz, 2H), 2.02-1.99 (m, 2H), 1.61-1.38 (m, 17H), 1.31(s, 9H), 1.05 (br s, 3H), 0.79-0.74 (m, 2H). MS: 576.3 [M+1]+.
Example 20/1 to Example 20/9 Using a procedure similar as described in Example 20, the following compounds were prepared (and optionally subsequently saponified).
# Structure Analytical data a1H-NMR (CDCI3, 400 MHz) 6: 0.73-0.81 (m, 2H), 1.06-1.10 o (m, 3H), 1.27 (s, 9H), 1.41-1.44 (m, 3H), 1.52-1.60 (m, 5H), H 2.01 (d, J = 12.8 Hz, 2H), 3.54 (t, J = 11.2 Hz, 2H), 3.78 (d, S0 I= \ =J = 6.8 Hz, 2H), 3.99(d, J = 11.2 Hz, 2H), 4.15-4.25 (m, 20/1 F N 8 1H), 4.72 (s, 1H), 5.70 (br s, 1H), 6.62 (d, J =
5.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H) 8.32 (d, J = 8.4 Hz, d 1H). 19F-NMR (CDCI3, 376 MHz) 5: -57.70 (s), -127.80. MS:
588.2 (M+1)+.
) 1H-NMR (DMSO-d6, 400 MHz) 6: 0.72-0.78 (m, 4H), 0.86-'---/ n o 0.88 (m, 2H), 0.97-1.02 (m, 3H), 1.30(s, 12H), 1.35 (s, 3H), H 1 \ 1.50-1.55 (m, 3H), 2.30-2.47 (m, 4H), 3.01-3.06 (m, 1H), 3.65 (s, 3H), 3.73 (d, J = 6.4 Hz, 2H), 4.48-4.54 (m, 1H), (--.) 1 6.47 (d, J = 5.2 Hz, 1H), 7.02 (s, 1H), 7.19 (s, 1H), 7.22 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H). MS: 523.3 (M+1)+.
o A, 1H-NMR (DMSO-d6, 400 MHz) 6: 0.76-0.78 (m, 4H), 0.86-HO .0µ 10 0.88 (m, 2H), 0.98-1.03 (m, 3H), 1.30 (s, 12H), 1.40 (s, 3H), N 1.50-1.55(m, 3H), 2.28-2.42(m, 4H), 2.91 (br s, 1H), 3.73 H I \ = (d, J = 6.8 Hz, 2H), 4.47-4.53 (m, 1H), 6.48 (d, J = 5.6 Hz, 1H), 7.02, (s, 1H), 7.20 (d, J = 12.0 Hz, 2H), 7.91 (d, J = 8.0 U 4 Hz, 1H). 19F-NMR (DMSO-d6, 376 MHz) 5: -129.55. MS:
509.3 (M+1)+.
o 1H-NMR (DMSO-d6, 400 MHz) 5: 0.75-0.78 (m, 4H), 0.84--7c N 0.87 (m, 2H), 1.00-1.04 (m, 3H), 1.16 (s, 6H), 1.30 (s, 12H), 20/4 0 F N 3.12-3.15 (m, 2H), 3.59 (s, 1H), 3.73 (d, J = 7.2 Hz, 2H), 1.40 (s, 3H), 1.50-1.55 (m, 3H), 1.72 (t, J = 8.0 Hz, 2H), 0 d 4 \ 6.42 (d, J = 5.2 Hz, 1H), 7.01 (s, 1H), 7.20 (d, J = 12.8 Hz, 2H), 7.63 (t, J = 5.2 Hz, 1H). MS: 539.4 (M+1)+.
O 1H-NMR (DMSO-d6, 400 MHz) 5: 0.74-0.78 (m, 4H), 0.84-0.87 (m, 2H), 0.97-1.03 (m, 3H), 1.13 (s, 6H), 1.24-1.35 (m, -7c il I \ /I 12H), 1.42 (s, 3H), 1.50-1.55 (m, 3H), 1.67-1.71 (m, 2H), 0 F N 3.13-3.19 (m, 2H), 3.73 (d, J = 7.2 Hz, 2H), 6.44 (d, J = 5.2 20/5 HO d 4 Hz, 1H), 7.01 (s, 1H), 7.19 (d, J = 11.6 Hz, 2H), 7.65 (t, J =
5.2 Hz, 1H), 12.17 (br s, 1H). 19F-NMR (DMSO-d6, 376 MHz) 5: -130.03. MS:525.3 (M+1)+.
o 1H-NMR (CD30D, 400 MHz) 5:0.77-0.83 (m, 2H), 1.03-1.08 N 9 (m, 3H), 1.24 (s, 15H), 1.38 (d, J = 10.8 Hz, 3H), 1.56-1.61 H I \ sli s=0 (m, 3H), 1.85 (t, J = 8.0 Hz, 2H), 3.37 (t, J = 8.0 Hz, 2H), N HI* 3.90 (d, J = 6.8 Hz, 2H), 6.62 (d, J = 5.6 Hz, 1H), 7.83 (dd, J
20/6 7Hcc0 F d = 8.4 Hz, 1.6 Hz, 1H), 7.91 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H).
19F-NMR (CD30D, 376 MHz) 5: -57.70, -127.92. MS: 618.3 (M+1)+.
OH
O'''= 1H-NMR (CD30D, 400 MHz) 6: 0.76-0.85 (m, 2H), 1.03-1.08 ,c: 0 CF30 (m, 3H), 1.24 (s, 9H), 1.38 (d, J = 10.0 Hz, 3H), 1.56-1.62 N
H I \ . S=0 (m, 3H), 2.35-2.43 (m, 2H), 2.58-2.64 (m, 2H), 3.02-3.07 (m, 20R 41 1H), 3.91 (d, J = 6.8 Hz, 2H), 4.64-4.68 (m, 1H), 6.69 (d, J =
F,....) C--) 6.0 Hz, 1H), 7.84 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.92 (s, 1H) 8.32 (d, J = 8.4 Hz, 1H). MS: 602.2 (M+1)+.
Structure Analytical data OH 11-1-NMR (CDCI3, 400 MHz) 6: 0.58-0.63 (m, 2H), 0.93-0.96 (m, 3H), 1.19 (s, 9H), 1.26-1.29 (m, 3H), 1.52 (br s, 3H), o 410 o 2.33-2.41 (m, 2H), 2.80-2.85 (m, 2H), 3.12-3.17 (m, 1H), H I \ g.0 3.35 (br s, 1H), 3.55 (br s, 1H), 4.72-4.73 (m, 1H), 4.79-4.85 20/8F N W OM 1H), 6.09-6.10 (m, 1H), 6.55 (d, J = 5.2 Hz, 1H), 7.48 (d, isi J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.69 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.66 (d, J = 8.8 Hz, 1H). MS: 584.3 (M+1)+.
o 4110 9 1H-NMR (CDCI3, 400 MHz) 6: 0.54-0.61 (m, 2H), 0.91-0.94 (m, 3H), 1.19 (s, 9H), 1.21-1.25 (m, 3H), 1.29 (s, 6H), 1.51 N \ =0 (br s, 3H), 1.92 (t, J = 7.6 Hz, 1H), 3.30-3.65 (m, 4H), 4.69-0 F N 4.70 (m 1H) 6 03-6 04 (m 1H) 6.52 (d J = 5.6 Hz 1H) 20/9 HO 7.48 (d, J = 7.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.68 (t, J =
7.6 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 7.6 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H). MS: 600.3 (M+1)+.
Example 21 and Example 22 oC
HN
0 H HNH \ HO \ *
cF3cF3 d21 d 22 Step 1: Methyl 4-(5-(4-(N-(tert-butyl)sulfamoyI)-3-(trifluoromethyl)pheny1)-2-chloro-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxamido)-2,2-dimethylbutanoate (21) To a solution of methyl 4-(5-(4-(N-(tert-butyl)sulfamoy1)-3-(trifluoromethyl)pheny1)-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxamido)-2,2-dimethylbutanoate (100 mg, 0.16 mmol) in dry THF (2 mL) was added a solution of NCS (21.6 mg, 0.16 mmol) in dry THF
(1 mL) at ¨
78 C and the solution was stirred at ¨55 C for 8 h, quenched with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 2/1) and then prep. TLC to give compound 21(75 mg, 72%) as a colorless solid.
Step 2: 4-(5-(4-(N-(tert-Butypsulfamoy1)-3-(trifluoromethyl)pheny1)-2-chloro-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxamido)-2,2-dimethylbutanoic acid (22) To a solution of compound 21(70 mg, 0.10 mmol) in a mixture of Me0H (4 mL) and H20 (0.5 mL) was added KOH (56 mg, 1.0 mmol) and the solution was stirred at 80 C for 1 h, concentrated and adjusted with 1M HCI to pH = 6. The aqueous phase was extracted with EA twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by prep. TLC to give compound 22 (41 mg, 60%) as a colorless solid. 1H-NMR (CDCI3, 400 MHz) 5: 0.60-0.69 (m, 2H), 0.99-1.04 (m, 3H), 1.27 (s, 9H), 1.28-1.34 (s, 8H), 1.40-1.47 (m, 1H), 1.56 (br s, 3H), 1.91 (d, J = 7.2 Hz, 2H), 3.47-3.53 (m, 2H), 3.89 (d, J = 7.2 Hz, 2H), 4.75 (s, 1H), 6.39-6.41 (m, 1H), 6.76 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H). MS: 634.2 (M+1)+.
Example 22/1 to Example 22/2 Using a procedure similar as described in Example 21, the following compound was prepared (and optionally subsequently saponified).
Structure Analytical data 1H-NMR (CDCI3, 400 MHz) 6: 0.49-0.55 (m, 2H), 0.90-0.95 (m, 3H), 1.19 (s, 9H), 1.22 (s, 3H), 1.25-1.40 (m, 3H), Hie< 1.46-1.65 (m, 4H), 2.03-2.06 (m, 2H), 3.35-3.41 (m, 1H), H s=o 3.54 (td, J = 11.2 Hz, 1.6 Hz, 2H), 3.77-3.82 (m, 1H), 3.99-4.01 (m, 2H), 4.23-4.26 (m, 1H), 4.61 (s, 1H), 6.23 (d, J -22/1 cdN 0 7.2 Hz, 1H), 6.74 (s, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.66 (d, J = 8.0 Hz, 1H).
MS: 586.2 (M+1)+.
OH 1H-NMR (CDCI3, 400 MHz) 5: 0.51-0.55 (m, 2H), 0.90-0 0.91 (m, 3H), 1.14 (s, 9H), 1.19-1.37 (m, 3H), 1.49-1.50 HN (m, 3H), 2.34-2.44 (m, 2H), 2.81-2.84 (m, 2H), 3.15-3.17 H \ OM 1H), 3.36-3.42 (m, 1H), 3.77-3.82 (m, 1H), 4.64 (s, 22/2N " 1H), 4.79-4.82 (m, 1H), 6.55 (d, J = 6.8 Hz, 1H), 6.75 (s, dik ci 0 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 8.35 (d, J =
8.0 Hz, 1H), 8.66 (d, J = 8.4 Hz, 1H). MS: 600.2 (M+1)+.
Example 23 Hre<
H
Cid 0 5-(4-(N-( tert-ButypsulfamovI)naphthalen-1-v1)-2,4-dichloro-1-(cyclohexvImethyl)-N-(tetrahydro-2H-ovran-4-v1)-1H-qvrrole-3-carboxamide (23) To a solution of compound 21/1 (100 mg, 0.17 mmol) in THF (3 mL) was added NCS
(46 mg, 0.34 mmol) at rt and the solution was stirred overnight at 50 C, diluted with water and extracted with EA twice. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to give compound 23 (50 mg, 48%) as a colorless solid. 1H-NMR (CDCI3, 400 MHz) 6: 0.55-0.58 (m, 2H), 0.87-0.92 (m, 3H), 1.19 (s, 9H), 1.25 (s, 3H), 1.47-1.52 (m, 2H), 1.58-1.62 (m, 2H), 2.03-2.06 (m, 2H), 3.34-3.40 (m, 1H), 3.56 (td, J = 11.6 Hz, 2.0 Hz, 2H), 3.73-3.78 (m, 1H), 3.97-4.00 (m, 2H), 4.20-4.35 (m, 1H), 4.63 (s, 1H), 6.42 (d, J = 7.2 Hz, 1H), 7.53 (d, J =
7.6 Hz, 1H), 7.59-7.60 (m, 2H), 7.70-7.75 (m, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.69 (d, J = 8.4 Hz, 1H). MS: 620.2 (M+1)+.
Example 24 n0 NNNI N )1'` Nk H I \ -11H
d 24 Step 1: Ethyl 5-(2-bromoacety1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (24a) To a suspension of AlC13 (12.0 g, 90.0 mmol) in dry DCM (100 mL) was added ethyl 1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (prepared according to Example 1d, 10 g, 40.2 mmol) and 2-bromoacetyl bromide (16.0 g, 79.3 mmol) and the solution was stirred at rt for 2 h, poured into ice water and extracted with DCM (3x). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA =
10:1) to afford intermediate 24a (7.0 g, 47%) as a yellow oil.
Step 2: Ethyl 1-(cyclohexylmethyl)-5-(2-(diethoxyphosphorypacety1)-2-methyl-1H-pyrrole-3-carboxylate (24b) A solution of intermediate 24a (7.0 g, 19 mmol) in triethyl phosphite (60 mL) was refluxed for 1h and concentrated to afford crude intermediate 24b (10.1 g) as a yellow oil.
Step 3: Ethyl 5-(2-cyclohexylideneacety1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (24c) To a solution of crude intermediate 24b (10.1 g, 18.97 mmol) in dry THF (70 mL) at 0 C was added NaH (1.86 g, 46.5 mmol). After stirring for 15 min, cyclohexanone (2.3 g, 23 mmol) was added and the solution was stirred overnight at rt, quenched with aq.
NH4CI and extracted with EA twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 10/1) to give intermediate 24c (3.6 g, 51% in two steps) as yellow powder.
Step 4: Ethyl 1-(cyclohexylmethyl)-2-methyl-5-(1,2-diazaspiror4.51dec-2-en-3-y1)-1H-pyrrole-3-carboxylate (24d) To a solution of intermediate 24c (3.6 g, 9.7 mmol) in a mixture of DMSO (20 mL) and water (ten drops) was added KO'Bu (1.86 g, 19.4 mmol) and the solution was heated overnight at 85 C, cooled to rt, poured into water, adjusted to pH-3 with 1N HCI and then extracted with EA (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 1/1) to give intermediate 24d (3.0 g, 90%) as a pale yellow powder.
Step 5: 1-(CyclohexvImethvI)-2-methvI-5-(1,2-diazaspiro[4.51dec-2-en-3-v1)-1H-pwrole-3-carboxylic acid (24e) To a solution of intermediate 24d (1.0 g, 2.9 mmol) in Me0H (15 mL) was added hydrazine monohydrate (290 mg, 5.8 mmol) and the solution was stirred at ref lux overnight, cooled to rt, concentrated and purified by CC (DCM/Me0H = 10:1) to afford intermediate 24e (490 mg, 48%) as a colorless oil.
Step 6: 1-(CyclohexvImethvI)-2-methvI-5-(1,2-diazaspirof4.51dec-2-en-3-v1)-N-(tetrahvdro-2H-pyran-4-yI)-1H-pyrrole-3-carboxamide (24f) A mixture of intermediate 24e (1.00 g, 2.8 mmol), tetrahydro-2H-pyran-4-amine (283 mg, 5.60 mmol), HATU (2.21 g, 5.60 mmol) and DIPEA (1.44 g, 11.2 mmol) in DMF (15 mL) was stirred at rt for 25 min, diluted with H20 and extracted with EA (3x). The combined organic layers were washed with H20 (3x) and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (DCM/Me0H = 80/1) to afford intermediate 24f (881 mg, 71%) as a yellow solid.
Step 7: N-(tert-Butv1)-3-(1-(cyclohexvImethvI)-5-methvl-4-((tetrahvdro-2H-pvran-4-v1)carbamov1)-1H-pwrol-2-v1)-1,2-diazaspirof4.51dec-2-ene-1-carboxamide (24) To a solution of intermediate 24f (150 mg, 0.34 mmol) in dry DCM (3 mL) was added tert-butyl isocyanate (67 mg, 0.68 mmol) at 0 C under N2 and the solution was stirred overnight at rt, washed with 1M HCI and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by prep. TLC (PE/EA = 1/5) to give example 24 (54 mg, 29%) as a colorless solid. 1H-NMR (CDCI3, 400 MHz) 6: 6.42 (s, 1H), 5.80 (s, 1H), 5.57 (d, 1H, J =
7.2 Hz), 4.10-4.17 (m, 3H), 3.99 (dd, 1H, J = 1.6, 11.2 Hz), 3.53 (dt, 1H, J = 1.6, 11.2 Hz), 3.07 (s, 2H), 2.61-2.68 (m, 2H), 2.59 (s, 3H), 1.98 (dd, 1H, J = 2.0, 12.0 Hz), 1.52-1.81 (m, 13H), 1.39 (s, 9H), 1.15-1.20 (m, 3H), 0.98-1.04 (m, 2H). MS: 540.2 (M+1)+.
Example 24/1 to 24/2 Using a procedure similar as described in Example 24, the following compounds were prepared.
# Structure Analytical data a , 0, 4 1H-NMR (CDCI3, 400 MHz) 6: 7.98-8.00 (m, 2H), 7.47-7.56 (m, 3H), 6.40 (s, 1H), 5.52 (d, 1H, J =
N N ,,,Sµ
H I \ / --.. No 8.0 Hz), 4.05-4.15 (m, 3H), 3.98 (m, 2H), 3.51 (m, 02H), 3.08 (s, 2H), 2.54 (s, 3H), 2.43-2.48 (m, 2H), d1.97 (m, 2H), 1.74-1.84 (m, 4H), 1.62-1.68 (m, 5H), 1.50-1.57 (m, 2H), 1.40-1.43 (m, 2H), 1.31-1.35 (m, 3H), 0.82-0.88 (m, 2H). MS: 581.2 (M+1)+.
ici_3N 0 N-(2 1H-NMR (CDCI3, 400 MHz) 6: 6.54 (s, 1H), 6.17 (d, 1H, J = 7.6 Hz), 5.21 (m, 1H), 5.00 (m, 1H), 4.59 N I \ i NIC' (m, 1H), 4.22 (m, 1H), 3.10 (s, 3H), 2.72-2.79 (m, 24/2 2H), 2.58 (s, 3H), 1.76-1.81 (m, 7H), 1.63-1.70 (m, N
W 5H), 1.43-1.51 (m, 5H), 1.26-1.32 (m, 7H), 1.11-d 1.16 (m, 3H), 0.97-1.02 (m, 2H). MS:
523 (M+1)+.
Example 25 n0 I
u3 K
NN µ * HN
H \
d25 5-(4-(14 tert-Butvlam ino)-2,2,2-trifluoroethvI)-3-(trifl uoromethvflphenv1)-1-(cyclohexvImethvI)-2-methyl- N-(tetrahvdro-2H-pyran-4-0-1H-qvrrole-3-carboxam ide (25) To a mixture of crude compound 32 (1.34 mmol) and KHF2 (105 mg, 1.34 mmol) in dry MeCN (5 mL) was added dry CF3CO2H at 0 C and the suspension was stirred for 5 min.
Me3SiCF3 (382 mg, 2.7 mmol) was added, the cooling bath was removed and the mixture was stirred for 20 h at rt, diluted with sat. aq. Na2CO3 (0.5 mL) and stirred for an additional two min, diluted with water and extracted with EA (3x). The combined organic phases were dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 1/1) to afford example 25 (45 mg, 6%) as a colorless solid. 1H-NMR (CDCI3, 300 MHz) 6: 7.82 (d, J =
7.5 Hz, 1H), 7.66 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 6.30 (s,1H), 5.63 (d, J = 7.5 Hz, 1H), 4.83 (q, J = 6.6 Hz, 1H), 4.20 (m, 1H), 3.99 (m, 2H), 3.78 (m, 2H), 3.54 (m, 2H), 2.63 (s, 3H), 2.00 (m, 2H), 1.59-1.48 (m, 5H), 1.34-1.29 (m, 3H), 1.04 (s, 9H), 1.00-0.98 (m, 3H), 0.65-0.61 (m, 2H).
MS: 602.4 (M+1)+.
Example 26 r) 0 NNN
H
N Isr ----"c d 26 Step 1: 4-Bromo-2-(tert-butvl)phenol (26a) To a solution of 2-(tert-butyl)phenol (5 g, 33 mmol) in DCM (200 mL) was added tetrabutyl-ammonium tribromide (16.5 mg, 33 mmol) and the mixture was stirred at rt for 12 h, diltued with H20 (50 mL) and extracted with DCM (150 mL). The organic layer was washed with brine and dried over Na2504, concentrated and purified by CC (PE/EA =5/1) to afford compound 26a (6.8 g, 89%) as a clear oil.
Step 2: 2-(tert-Butyl)-4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)phenol (26h) To a solution of compound 26a (162 mg, 0.71 mmol) in 1,4-dioxane (20 mL) was added B2Pin2 (541 mg, 2.13 mmol) and KOAc (278 mg, 2.84 mmol), followed by Pd(dppf)Cl2 (52 mg, 71 pmol) under Ar and the suspension was heated to 100 C overnight, cooled, concentrated and purified by CC (PE/EA = 50/1 to 10/1) to afford compound 26b (109 mg, 56%) as a colorless solid.
Step 3: 5-(3-(tert-Butyl)-4-hydroxvphenv1)-1-(cyclohexvImethvI)-2-methyl-N-(tetrahvdro-2H-pvran-4-vI)-1H-pvrrole-3-carboxamide (26c) A solution of 5-bromo-1-(cyclohexylmethyl)-2-methyl-N-(tetrahydro-2H-pyran-4-y1)-1H-pyrrole-3-carboxamide (382 mg, 1.0 mmol, prepared similar as described for intermediate 9b), compound 26b (331 mg, 1.2 mmol), Cs2CO3 (487 mg, 1.5 mmol) and Pd(dppf)Cl2 (30 pmol) in 1,4-dioxane and water (10 mL; 20:1) was heated to 90 C overnight, cooled to rt, evaporated, diluted with water and extracted with DCM. The organic layer was dried over MgSO4, filtered, evaporated and purified by CC (hexane/EA = 5/1) to give compound 26c (253 mg, 56%).
Step 4: 2-(tert-Butyl)-4-(1-(cyclohexvImethvI)-5-methvI-4-((tetrahvdro-2H-pvran-4-v1)carb-amov1)-1H-pyrrol-2-v1)phenvl trifluoromethanesulfonate (26d) To a solution of compound 26c (100 mg, 0.22 mmol) in DCM (20 mL) was added TEA
(44 mg, 0.44 mmol) and catalytic amounts of DMAP, followed by Tf20 (74 mg, 0.26 mmol) and the resulting mixture was stirred at rt for 12 h, concentrated and purified by CC (PE/EA =3/1) to afford compound 26d (56 mg, 43%) as a brown solid.
Step 5: 5-(3-(tert-Butv1)-4-(1-isopropv1-1H-pvrazol-5-v1)Phenv1)-1-(cvclohexvImethvI)-2-methyl- N-(tetrahvdro-2H-pvran-4-0-1H-pyrrole-3-carboxam ide (26) A 20-ml microwave vial was charged with compound 26d (100 mg, 0.17 mmol), 1-isopropyl-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole (0.2 mmol, 1.2 eq) and Cs2CO3 (167 mg, 0.51 mmol) dissolved in 1,4-dioxane and water (10 mL, 20:1), followed by Pd(dppf)Cl2 (0.03 eq) under N2. The mixture was heated to 90 C overnight, evaporated, diluted with water and extracted with DCM. The organic layer was separated, dried over Na2SO4, filtered, evaporated and purified by CC (hexane/EA = 5/1) to give compound 26. 1H-NMR (400 MHz, CDCI3) 6: 7.62 (s, 1H), 7.45 (s, 1H), 7.13 (m, 1H), 7.00 (m, 1H), 6.24-6.18 (m, 1H), 5.60 (br d, 1H, J = 6.4 Hz), 4.20-4.15 (m, 1H), 4.01-3.89 (m, 3H), 3.73 (m, 2H), 3.46 (m, 2H), 2.55 (s, 3H), 1.94-1.91 (m, 2H), 1.50-1.43 (m, 8H), 1.39-1.30 (m, 6H), 1.15 (m, 9H), 1.05-0.90 (m, 3H), 0.70-0.57 (m, 2H). MS: 545.4 (M+H).
Example 26/1 to 26/6 Using a procedure similar as described in Example 26, the following compounds were prepared.
# Structure Analytical data a 0 1H-NMR (400 MHz, CDCI3) 6: 7.43-7.38 (m, 2H), 7.06 (m, 1H), 6.94-6.90 (m, 2H), 6.16 (s, 1H), N
H I\ 'W'/ YE1 5.58 (m, 1H), 4.15-4.04 (m, 1H), 3.95-3.88 (m, 26/1 N -- N 2H), 3.72 (m, 2H), 3.46 (m, 2H), 2.56 (s, 3H), d 2.04 (s, 3H), 1.93-1.90 (m, 2H), 1.49-1.47 (m, 5H), 1.32-1.29 (m, 3H), 1.18 (s, 9H), 0.95 (m, 3H), 0.61 (m, 2H). MS: 517.3 (M+H)+.
a 0 1H-NMR (400 MHz, CDCI3) 6: 7.47 (s, 1H), 7.40 k (s, 1H), 7.36 (s, 1H), 7.02 (s, 1H), 6.11 (s, 1H), il I \ . / Nil 5.57 (d, 2H, J = 6.4 Hz), 4.13 (m, 1H), 3.92-3.89 26/2 N -N (m, 2H), 3.71 (m, 2H), 3.46 (m, 2H), 2.55 (s, 3H), d 1.94-1.90 (m, 2H), 1.58 (s, 9H), 1.51-1.50 (m, 5H), 1.34 (m, 3H), 1.91 (m, 9H), 0.97 (m, 3H), 0.61 (m, 2H). MS: 559.4 (M+H)+.
a 0 1H-NMR (400 MHz, CDCI3) 6: 7.40 (s, 1H), 7.36 ) (s, 1H), 7.29 (s, 1H), 7.19 (s, 1H), 7.01 (s, 2H), 11 I \ * / " 6.12 (s, 1H), 5.56 (d, 2H, J
= 6.4 Hz), 4.18-4.16 26/3 N -N (m, 3H), 3.92 (m, 2H), 3.71 (m, 2H), 3.46-3.45 d (m, 2H), 2.56 (s, 3H), 1.93-1.90 (m, 2H), 1.56-1.48 (m, 8H), 1.46 (m, 3H), 1.20 (s, 9H), 0.97 (m, 3H), 0.64 (m, 2H). MS: 531.4 (M+H)+.
1H-NMR (400 MHz, CDCI3) 6: 8.13 (s, 2H), 7.41 cON 0 \ (s, 1H), 7. 15 (m, 1H), 6.94 (d, 1H, J = 7.6 Hz), N -NI ? 6.14 (s, 1H), 5.54 (d, 1H, J = 7.6 Hz), 5.02 (m, H I \ \ /)¨NH 1H), 4.13-4.11 (m, 2H), 3.85 (m, 2H), 3.72 (m, 26/4 N 11 1 N 2H), 3.46 (m, 2H), 2.56 (s, 1H), 1.96-1.91 (m, d 2H), 1.51-1.48 (m, 5H), 1.33-1.32 (m, 3H), 1.23 (d, 6H, J = 6.4 Hz), 1.19 (s, 9H), 0.97 (m, 3H), 0.62 (m, 2H). MS: 572.4 (M+H)+.
Structure Analytical data 1H-NMR (400 MHz, CDCI3) 5: 7.66 (s, 1H), 7.52 o N¨N (s, 1H), 7.19-7.17 (m, 1H), 7.07-7.05 (m, 1H), HO 'ILO , 6.28 (s, 2H), 6.01 (m, 1H), 4.84-4.78 (m, 1H), ."N \ 4.15-3.98 (m, 1H), 3.80 (m, 2H), 3.14-3.05 (m, H
26/5 N 1H), 2.83-2.78 (m, 2H), 2.62 (s, 3H), 2.34-2.26 (m, 2H), 1.57-1.50 (m, 6H), 1.42-1.36 (m, 6H), 1.25 (s, 9H), 1.07-1.02 (m, 3H), 0.72-0.67 (m, 2H). MS: 559.3 (M+H)+.
1H-NMR (400 MHz, CDCI3) 5: 7.69 (s, 1H), 7.46 0 NN (s, 1H), 7.13-7.10 (m,1H), 6.98-6.96 (m,1H), HO2C ' 6.23-6.20 (m, 1H), 6.07 (br s, 1H), 4.03-4.00 (m, 26/6 H N 1H), 3.72 (m, 2H), 3.42-3.38 (m, 2H), 2.53 (s, 3H), 1.83-1.80 (m, 2H), 1.52-1.41 (m, 6H), 1.36-1.29 (m, 6H), 1.20 (s, 6H), 1.15 (s, 9H), 0.98-0.90 (m, 3H), 0.68-0.57 (m, 2H). MS: 575.3 (M-i-H)+.
Example 27 OH
1=1 Fll *
d27 Step 1: 1-(2-Flvdroxv-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-AphenvI)ethanone (27a) To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (152 mg, 0.71 mmol) in 1,4-dioxane (20 mL) was added B2Pin2 (541 mg, 2.13 mmol) and KOAc (278 mg, 2.84 mmol), followed by Pd(dppf)Cl2 (52 mg, 71 pmol) under Ar and the resulting suspension was heated to 100 C
overnight, concentrated and purified by CC (PE/EA =50/1 to 10/1) to afford compound 27a (109 mg, 59%) as a colorless solid.
Step 2: Ethyl 5-(3-acetv1-4-hydroxvphenv1)-1-(cyclohexvImethvI)-2-methyl-1H-pvrrole-3-carboxvlate (27b) A solution of ethyl 5-bromo-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (328 mg, 1.0 mmol, prepared similar as described for compound le), compound 27a (314 mg, 1.2 mmol), Cs2CO3 (487 mg, 1.5 mmol) and Pd(dppf)C12 (30 pmol) in 1,4-dioxane and water (10 mL, 20:1) was heated to 90 C overnight, cooled to rt, evaporated, diluted with water and extracted with DCM. The organic layer was dried over MgSO4, filtered, evaporated and purified by CC (hexane/EA = 5/1) to give compound 27b (250 mg, 65%) Step 3: Ethyl 5-(3-acetv1-4-(((trifluoromethvI)sulfonvI)oxv)phenv1)-1-(cyclohexvImethvI)-2-methyl-1H-pwrole-3-carboxvlate (27c) To a solution of compound 27b (84 mg, 0.22 mmol) in DCM (20 mL) was added TEA
(44 mg, 0.44 mmol) and DMAP, followed by Tf20 (75 mg, 0.26 mmol) and the resulting mixture was stirred at rt for 12 h, concentrated to dryness and purified by CC (PE/EA =
3/1) to afford compound 27c (52 mg, 46%) as a brown solid.
Step 4: Ethyl 5-(3-acety1-4-(1-isopropy1-1H-pyrazol-5-y1)0henv1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (27d) A 20-ml microwave vial was charged with compound 27c (93 mg, 0.18 mmol), 1-isopropy1-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole (47 mg, 0.20 mmol) and Cs2CO3 (167 mg, 0.51 mmol) dissolved in 1,4-dioxane and water (10 mL, 20:1), followed by Pd(dppf)C12 (0.03 eq) under N2. The mixture was heated to 90 C overnight, concentrated, diluted with water and extracted with DCM. The organic layer was dried over Na2SO4, filtered, concentrated and purified by CC (hexane/EA = 5/1) to give compound 27d (62 mg, 73%).
Step 5: 5-(3-Acetyl-4-(1-isopropy1-1H-pyrazol-5-yl)phenv1)-1-(cyclohexylmethyl)-2-methyl-1 H-pyrrole-3-carboxylic acid (27e) To a solution of compound 27d (95 mg, 0.20 mmol) in Et0H was added 1M aq. KOH
(8 mL) at rt. The mixture was stirred for 4 h at rt, concentrated, diluted with water (30 mL) and extracted with EA (150 mL). The organic layer was washed with brine, dried over Na2504, filtered, concentrated and purified by CC (hexane/EA = 1/3) to give compound 27e (80 mg, 89%).
Step 6: 5-(3-Acetyl-4-(1 -isopropy1-1H-pyrazol-5-yl)phenv1)-1-(cyclohexylmethyl)-2-methyl-N-(tetrahydro-2H-pyran-4-y1)-1H-pyrrole-3-carboxamide (27f) To a solution of 27e (94 mg, 0.21 mmol) in DMF (2 mL) was added HATU (167 mg, 0.44 mmol), D1PEA (224 mg, 1.74 mmol) and tetrahydro-2H-pyran-4-amine (48 mg, 0.48 mmol).
The mixture was stirred at rt overnight, then 5 mL H20 and 10 mL EA was added into the reaction. The organic layer was separated and the aq. layer was extracted with EA (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to give product 27f (70 mg, 63%).
Step 7: 1-(Cyclohexylmethyl)-5-(3-(2-hyd roxypropan-2-y1)-4-(1-isopropy1-1H-pyrazol-5-yl)pheny1)-2-methyl-N-(tetrahydro-2H-pyran-4-y1)-1H-pyrrole-3-carboxamide (27) A solution of 27f (70 mg, 132 pmol) in THF (4 mL) was cooled to 0 C and treated dropwise with MeMgBr (1M in Et20, 1 mmol). Upon completion of addition, the resulting suspension was allowed to warm to rt and was stirred for 5 h. Sat. aq. NH4C1 (20 mL) was added slowly and the mixture was diluted with EA (20 mL). The layers were separated and the aq. layer was extracted with EA (3x 25 mL). The combined organic layers were dried over MgSO4, filtered, concentrated and purified by prep. HPLC to afford 27 (20 mg, 28%).
1H-NMR (400 MHz, CDCI3) 6: 7.61 (s, 1H), 7.26 (s, 1H), 7.15-7.09 (m, 1H), 6.29-6.22 (m, 2H), 5.65-5.58 (m, 1H), 4.30-4.11 (m, 2H), 4.01-3.92 (m, 2H), 3.84-3.79 (m, 2H), 3.60-3.59 (m, 2H), 2.63 (s, 3H), 2.02-1.95 (m, 2H), 1.59-1.54 (m, 8H), 1.53-1.48 (m, 6H),1.46-1.39 (m, 3H), 1.06-1.00 (m, 3H), 0.72-0.67 (m, 2H). MS: 547.3 (M+H)+.
Example 28 n0 H I \=
N
5-(4-(N-( tert-Butyl)sulfamoy1)-3-(trifluoromethyl)ohenv1)-14(141 uorocyclohexyl)-methyl)-2-methyl- N-(tetrahydro-2H-pyran-4-yI)-1H-oyrrole-3-carboxam ide (28) To a solution of compound 17/255 (200 mg, 0.33 mmol) in DCM (10 mL) was added diethylaminosulfur trifluoride (0.13 mL, 0.65 mmol) in one portion at rt and the mixture was stirred at rt for 1 h, poured into water and extracted with DCM. The organic layer was concentrated and purified by prep. HPLC to give compound 28 (25 mg, 13%) as a colorless solid. 1H-NMR (300 MHz, CDCI3) 6: 0.85-1.10 (m, 2H), 1.25 (s, 11H), 1.39-1.59 (m, 8H), 1.99 (m, 2H), 2.65 (s, 3H), 3.49-3.56 (m, 3H), 3.99 (m, 2H), 4.09-4.24 (m, 3H), 4.71 (s, 1H), 5.64 (d, J = 7.5 Hz, 1H), 6.40 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H). MS: 602.2 (M+1)+.
Example 29 HO o H I \
d 29 Step 1: Methyl 5-(3-(tert-buty1)-5-(1-methylcycloorooyl)oheny1)-4-chloro-1-(cyclohexylmethyl)-2-methyl-1H-oyrrole-3-carboxylate (29a) To a solution of methyl 5-(3-(tert-buty1)-5-(1-methylcyclopropyl)pheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (368 mg, 0.85 mmol) in ACN (20 mL) was added NCS
(113 mg, 0.85 mmol) and the mixture was stirred at rt for overnight, concentrated and purified by prep. TLC (PE/EA = 50/1) to afford compound 29a (319 mg, 80%) as a pale yellow oil. 11-1-NMR (400 MHz, CDCI3) 6: 0.56-0.70 (2H, m), 0.73-0.76 (2H, m), 0.86-0.89 (2H, m), 0.97-1.03 (3H, m), 1.33 (12H, br s), 1.38 (3H, t, J = 6.8 Hz ), 1.42 (3H, s), 1.53-1.55 (3H, m), 2.55 (3H, s), 3.64 (2H, d, J = 7.2 Hz), 4.33 (2H, q, J = 6.8 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.13 (1H, t, J = 1.6 Hz), 7.29 (1H, t, J = 1.6 Hz).
Step 2: (trans)-3-(5-(3-(tert-Butyl)-5-(1-methvIcvclopropvl)phenv1)-4-chloro-1-(cyclohexvImethvI)-2-methyl-1H-pwrole-3-carboxamido)cyclobutanecarboxvlic acid (29) Compound 29a was saponified and coupled with the amino acid methyl ester and then finally saponified to obtain target compound 29 similar as described above. 11-I-NMR
(300 MHz, CDCI3) 6: 0.53-0.67 (2H, m), 0.74-0.77 (2H, m), 0.86-0.90 (2H, m), 0.94-1.04 (3H, m), 1.26-1.34 (13H, m), 1.43 (3H, s), 1.54 (3H, d, J = 6.3 Hz), 2.27-2.38 (2H, m), 2.60 (3H, s), 2.77-2.84 (2H, m), 3.06-3.17 (1H, m), 3.62 (2H, d, J = 7.2 Hz), 4.75-4.88 (1H, m), 6.97 (1H, s), 7.02 (1H, d, J = 7.8 Hz), 7.11 (1H, s), 7.31 (1H, s). MS: 539.3 [M+1]+.
Example 29/1 to 29/2 Using a procedure similar as described in Example 29, the following compounds were prepared.
Structure Analytical data 1H-NMR (300 MHz, CDCI3) 6: 0.58-0.73 (2H, m), 0.75-HO ciL 0 CI 4 0.81 (2H, m), 0.84-0.89 (2H, m), 0.95-1.04 (3H, m), 1.27-1.36 (5H, m), 1.43 (3H, s), 1.54 (7H, br s), 2.32-29/1 H I \
2.41 (2H, m), 2.43 (3H, s), 2.60-2.69 (2H, m), 3.05-3.09 (1H, m), 3.73 (2H, d, J = 7.2 Hz), 4.61-4.72 (1H, m), 0H 7.06 (1H, d, J = 1.8 Hz), 7.20 (1H, d, J = 1.8 Hz), 7.48 (1H, d, J = 1.8 Hz). MS: 541.3 [m-Fi]t JIõ. 1H-NMR (300 MHz, CDCI3) 6: 0.58-0.66 (2H, m), 0.77-HO 0 CI 4 0.83 (2H, m), 0.85-0.91 (2H, m), 0.94-0.99 (3H, m), 1.25-1.36 (4H, m), 1.44 (3H, s), 1.52 (8H, s), 2.27-2.37 29/2 H I \ *
(2H, m), 2.60 (3H, s), 2.77-2.85 (2H, m), 3.07-3.15 (4H, / m), 3.64 (2H, d, J = 7.2 Hz), 4.76-4.88 (1H, m), 7.00 0 (1H, d, J = 7.2 Hz), 7.04 (1H, t, J =
1.5 Hz), 7.15 (1H, t, J = 1.5 Hz), 7.31 (1H, t, J = 1.5 Hz). MS: 555.3 [M+1]+.
Example 30 and Example 31 0 ca y H \ = 0 H I \ 0 OH
d 30 d 31 Step 1: 1-(CyclohexvImethvI)-2-methvI-5-(8-(proo-1-en-2-vpspirofchroman-4,11-cyclopropar11-6-v1)-N-(tetrahvdro-2H-pvran-4-v0-1H-pwrole-3-carboxamide (30) To a solution of compound P97 (128 mg, 0.39 mmol) 5-bromo-1-(cyclohexylmethyl)-methyl-N-(tetrahydro-2H-pyran-4-y1)-1H-pyrrole-3-carboxamide (180 mg, 471 pmol), K2CO3 (135 mg, 981 pmol) and TBAB (10 mg) in a mixture of 1,4-dioxane (3 mL) and water (1.5 mL) was added Pd(PPh3)2C12 (20 mg) under N2. Under microwave conditions (120 W), the solution was heated at 105 C for 1 h, cooled, poured into a mixture of water and EA and extracted with EA twice. The combined organic layers were washed with water and brine, concentrated and purified by CC (PE/EA = 5/1) and then prep. HPLC to give compound 30 (109 mg, 56%) as a colorless solid.
Step 2: 1-(CyclohexvImethvI)-5-(8-(2-hydroxvpropan-2-vOspirorchroman-4,11-cvclooropanl-6-0-2-methvl-N-(tetrahvdro-2H-pvran-4-v1)-1H-pwrole-3-carboxamide (31) To a stirred mixture of compound 30 (109 mg, 0.22 mmol) and 0s04 (4 mg) in 1,4-dioxane (5 mL) was added a solution of Na104 (200 mg, 0.94 mmol) in water (2 mL). The solution was stirred at 30 C for 2 h, quenched with water and extracted with EA twice. The combined organic layers were washed with brine, concentrated and purified by CC (PE/EA
= 5/1) to give an intermediate as a colorless solid. To a stirred solution of this intermediate in dry THF
(3 mL) was added CH3MgBr (3M, 70 pL, 0.21 mmol) and the mixture was stirred at rt for 2 h, quenched with aq. NH4C1 at 0 C and extracted with EA. The organic layer was concentrated and purified by CC (PE/EA = 3/1) to give compound 31(61 mg, 53%). 111-NMR
(CDCI3 +
D20, 300 MHz) 6: 0.61-0.63 (2H, m), 0.72-0.75 (2H, m), 0.88-0.98 (5H, m), 1.32-1.35 (3H, m), 1.54-1.62 (7H, m), 1.94-1.99 (3H, m), 1.99-2.00 (1H, m), 2.63 (3H, s), 3.53 (2H, t, J =
11.7 Hz), 3.65 (2H, d, J = 7.2 Hz), 3.98 (2H, d, J = 10.8 Hz), 4.13-4.21 (1H, m), 4.44-4.47 (2H, m), 4.86 (3H, m), 5.61 (1H, d, J = 7.5 Hz), 6.08 (1H, s), 6.50 (1H, s), 6.99 (1H, s). MS:
521.4 (M+1)+.
Example 32 and Example 33 a 0 00 0,3 0,3 f., rsi Fl I \ * I *
d32 d33 0 Step 1: 1-(CyclohexvImethyl)-5-(4-formv1-3-(trifluoromethvI)ohenv1)-2-methvl-N-(tetrahvdro-2H-pvran-4-vI)-1H-ovrrole-3-carboxamide (32) A solution of 5-bromo-1-(cyclohexylmethyl)-2-methyl-N-(tetrahydro-2H-pyran-4-y1)-1H-pyrrole-3-carboxamide (2.1 g, 5.5 mmol), (4-formy1-3-(trifluoromethyl)phenyl)boronic acid (1.0 g, 4.6 mmol), K2CO3 (1.0 g, 7.2 mmol), TBAB (50 mg) and Pd(PPh3)2C12 (200 mg) in a mixture of 1,4-dioxane (10 mL) and water (5 mL) in a sealed tube was irradiated in a microwave at 100 C for 2 h, concentrated and purified by CC (PE/EA = 3/2) to give compound 32 (690 mg, 32%) as a yellow solid.
Step 2: 1-(CyclohexvImethvI)-2-methvI-5-(4-(morpholinomethyl)-3-(trifluoromethvl)phenv1)-N-(tetrahvdro-2H-pvran-4-v1)-1H-pwrole-3-carboxamide (33) To a solution of compound 32 (200 mg, 0.42 mmol) and morpholine (87 mg, 1.0 mmol) in DCM (3 mL) was added AcOH (one drop) and NaBH(OAc)3 (212 mg, 1.0 mmol) and the solution was stirred overnight at rt and quenched with sat. NaHCO3. The organic layer was washed with sat. NaHCO3, water and brine, dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to afford compound 33 (33 mg, 14%) as a colorless solid. 1H-NMR
(CDC13, 400 MHz) 6: 7.83 (d, J = 7.6 Hz, 1H), 7.59 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 6.22 (s, 1H), 5.60 (d, J = 8.0 Hz, 1H), 4.12-4.18 (m, 1H), 3.97-4.00 (m, 2H), 3.74-3.77 (m, 6H), 3.70 (s, 2H), 3.52 (m, 2H), 2.62 (s, 3H), 2.50-2.56 (m, 4H), 1.96-2.05 (m, 2H), 1.47-1.51 (m, 3H), 1.32-1.42 (m, 4H), 1.24-1.28 (m, 1H), 0.97-1.02 (m, 3H), 0.58-0.70 (m, 2H).
MS: 548.3 (M+1)+.
Example 34 cia 0 N
N N
o d 34 1-(CyclohexvImethvI)-5-(44(3,3-dimethvImorpholino)methvI)-3-(trifluoromethvflphenv1)-2-methyl-N-(tetrahvdro-2H-pyran-4-v1)-1H-pwrole-3-carboxamide (34) Using similar procedures as described in Example 33 compound 34 was prepared.
(CDCI3, 400 MHz) 6: 7.97 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.21 (s, 1H), 5.60 (d, J = 7.6 Hz, 1H), 4.11-4.18 (m, 1H), 3.98 (d, J = 11.2 Hz, 2H), 3.69-3.77 (m, 6H), 3.52 (m, 2H), 3.42 (s, 2H), 2.62 (s, 3H), 2.46 (m, 2H), 1.98 (m, 2H), 1.47-1.56 (m, 6H), 1.34-1.43 (m, 3H), 1.13 (s, 6H), 0.96-1.05 (m, 3H), 0.61-0.68 (m, 2H). MS: 576.4 (M+1)+.
Additional Examples If one were to use the appropriate building blocks as described in the Examples above, one would obtain the following compounds:
HOOCõ.
CL --(2/
-jH OH i7 OH 0 H I \ __ e _________ Nrri-'n em NhN 1 \ II OCF3 N
d d d , HOOC,,, HOOC"
Oc\ 0 '\3 0 V
H I \ 411 OCF3 CLN
( N N -H I \ \ N
N Vi."-N) Nj5A N
, HOOCõ.CL o V y ot, 0 y N
N
HO H I \ \ ,N H I \ * H I \ *
N NI/ N N
d d d CHF2 cHF2 , HOOCõ. HOOC,,, . a 0 oõ 0 HNj<
N N N
H I \ . H I \ 4. H
N N N
d d HN)\
d F F
OH
Oa 0 0:=3 FINj< N CI
N 1 \ = =i:) C-"il /N \ ir 4i-L P H
N 0 HO si:-.0 N
HNt d F F F3C d F3cC
HN
k ICY I
f , , , OH
q )\----\N F # N F dli 7)71N N=---Ns H H
N* -=10 *
N ==-0 N 11µ4), CY HN \õ......õ
IN
CY HN \õ....._ IN
0) OH
, , , OH OH
--/
Od, 0--,, q 0 c( 0 HO
HN HN i=-'-, I N r----\N
/ \ N%\S / \ N
N
& ,s-N
0 H 0) FIN
OH
OH
O
--/
OH
0-"0 --/ q 0 `Szq ----',..
O r-- 0 HN
HN N
S\ H S\ iN \ .
s i N
-HN-sf 0) OH
OH
OH
CD.L 0 CI CI
Nrla CI CI 0 CI Cl H I \ = SOH I \ . g=0 /N
----NH I \ . g=0 d d , , , HO\__, 0 HO\ 0 HO 0 A CN
= \ HNk i N`
\ i N
Sz.-.0 cy = 1:---0 '-'0 0) =
--/
0 0 0',. F
__________ 0 0 ,p 1...i. D., 0 F F
* * N
/\ iN \ * H I \ = ==0 N HI\l<
N *
0) d OH OH
0'.. F 0',.
EL 0 F CI [D, 0 0 CI Cl N N-J.---___(N.-: N
H I \ = =-,c) H I \ \ / 0 z5/1. ''NH ''' 1 \ = g=.0 FINi< d NH
, , , o o o CI a ci a a a o o N 0 0 z.; SICIN I \ * '--(:) ciii'l I N\ * # =(:) I \ * g=o j NH HN 0/
0' (-----) ---/c d ,\
, , , cl ci ci ci 0, ci I , . Lo ,..,,, I , . ,=0 H0)---N,,,,, , , . 90 _ s-N NH Oz3S N NH N
d -7C o' d ,\
d , HOOC, , HOOC ,.n 0 n L-Ths11===----¨ 1---NIC--)L--FIC>r-NN
H I \ * 4=0 H I \ \ N H I \ \ N
N HN V--"N µ __ /K V---N µ
/( d , d d OC F3 , , , HN N,N HN
\1-1 11 d I
N
V. ---N \
?
H 006 d Hood d H 00d d , , , OH H I \ . SO2 -7c-i H I \ . SO2 --70H H I \ 1, Si 02 d N NH N NH N
NH
7c , -7(N N N rN
OH H I \ II SO2 --7CH I \= SO2 ____NN0õ) I
N NH N NH N
d d ci A
d -A
, , , OH
0 HOOC,, HOy --J
0 '''=.0 o c CI CI
H 'C) 0 [sift!
I . SO2 N , N-4 \ \
H I /N
N NH N \
d 7c d A
d OH
, , , HO\L 0-N
0 ich OH 0 0 N N
H N µ N=
h H N
NN
H I \ * H-ji (I-N
/
N N N
L
d d A
d OH
OH F OH F F
F---( ,o,,, F--( F---( 0 'Aii:L 0 0 . 0 N
H I \ = !HI I \ * Nfil N N N
d A
d d . , , , OH
---I, OH 0 OCF3 HO____EsiN
0 (21'..0,v 0 F
N I \ I. 0 N
H I \ . N
H I \ .
N N N
d, d A,= d , OH
.,, N
0 '=c% 0 OH 02S3N 0 02s N
H I \ . H I \ 4, --C) H 1 \ * SO2NH
N N NH N
d d ____( UN
d , , , OH OH
ON,c::s 0 0'"=c% 0 0N N"N
,O, Auk 0 N N
H I \ * H I \ . HO H
N N N FIN
d A
, d , d and OH
--I
(:)..cic 0 N N
\ / 0 N ii H I \ * =() N HN.<
d .
Protein Expression and Purification Protein expression and purification was done as described in W02010/049144.
TA-FRET Activity Assay This method measures the ability of putative ligands to modulate the interaction between the purified bacterial expressed RORy ligand binding domain (LBD) and synthetic N-terminally biotinylated peptides which are derived from nuclear receptor coactivator proteins such as but not limited to SRC1 (NcoA1), SRC2 (NcoA2, TIF2), SRC3 (NcoA3), PGC1a, PGC16, CBP, GRIP1, TRAP220, RIP140. The peptides used are listed in Table 1 below:
Table 1 Peptide Name (aa OS entry DB entry DNA Sequence range) Protein SRC1(676-700) NP_003734 NM_003743.4 NH2-CPSSHSSLTERHKILHRLLQEGSPS-COOH
TRAP220(631-655) NP_004765 NM_004774 3 NH2-PVSSMAGNTKNHPMLMNLLKDNPAQ-COOH
TIF2(628-651) NP 006531 NM 006540.2 NH2-GQSRLHDSKGQTKLLQLLTTKSDQ-COOH
The ligand-binding domain (LBD) of RORy was expressed as fusion protein with GST in BL-21 (BL3) cells using the vector pDEST15. Cells were lysed by lysozyme-treatment and sonication, and the fusion proteins purified over glutathione sepharose (Pharmacia) according to the manufacturers instructions. For screening of compounds for their influence on the RORy-peptide interaction, the LANCE technology (Perkin Elmer) was applied. This method relies on the binding dependent energy transfer from a donor to an acceptor fluorophor attached to the binding partner of interest. For ease of handling and reduction of background from compound fluorescence LANCE technology makes use of generic fluorophore labels and time resolved detection assays were done in a final volume of 25 pL
in a 384 well plate, in a Tris-based buffer system (20 mM Tris-HCI pH 6.8; 60 mM KCI, 1 mM
DTT; 5 mM MgC12; 35 ng/pL BSA), containing 20-60 ng/well recombinantly expressed RORy-LBD fused to GST, 200-600 nM N-terminally biotinylated peptide, 200 ng/well Streptavidin-xlAPC conjugate (Prozyme) and 6-10 ng/well Eu W1024 ¨ antiGST (Perkin Elmer).
DMSO
content of the samples was kept at 1%.
After generation of the Tris-based buffer system, the potentially RORy modulating ligands were diluted. After this step, protein, peptide and fluorescent acceptor and donor solutions were mixed in the Tris-based buffer system and have been added to the compound dilutions, after this addition of 'detection mix', the assay was equilibrated for 1 h in the dark at rt in FIA-plates black 384 well (Corning). The LANCE signal was detected by a Perkin Elmer EnVisionTM Multilabel Counter. The results were visualized by plotting the ratio between the emitted light at 665 nm and 615 nm. A basal level of RORy-peptide formation is observed in the absence of added ligand. Ligands that promote the complex formation induce a concentration-dependent increase in time-resolved fluorescent signal.
Compounds which bind equally well to both monomeric RORy and to the RORy-peptide complex would be expected to give no change in signal, whereas ligands, which bind preferentially to the monomeric receptor would be expected to induce a concentration-dependent decrease in the observed signal.
To assess the antagonistic potential of the compounds, IC50 values were determined using a Ligand Sensing Assay based on Time-resolved Fluorescence Energy Transfer (TR-FRET) as described above. The normalised TR-FRET assay values, using the following equation:
1000 * 665 nm measurement value/615 nm measurement value, were transferred to the program GraphPad Prism to generate graphs and dose response curves using the following equation:
Equation: Sigmoidal dose-response (variable slope) Y = Bottom + (Top-Bottom)/(1+10^((Log EC50-X)*HillSlope)) X is the logarithm of the concentration. Y is the response.
Y starts at Bottom and goes to Top with a sigmoidal shape.
This is identical to the "four parameter logistic equation". The IC50 values are calculated using this equation. Examples listed below do reduce the signal in the TR-FRET
assay in a dose dependent manner. The Examples of the present invention usually have an inhibition activity (IC50 FRET) ranging from below 100 nM to about 20 pM and typically, from about 150 nM to about 2 pM. The RORy modulating compounds of the invention desirably have an inhibition in the TR-FRET Activity Assay ranging from below 150 nM to about 2 pM. Table 2 lists the p1C50-value of compounds of the invention (FRET). Is is understood that the data illustrated below may have reasonable variation depending on the specific conditions and procedures used by the person conducting the test. The efficacy was determined in comparison to the RORyt inhibitor T0901317 (equals 100%) and the pIC50-value is underlined, when the efficacy of the compound is below 50% of the reference.
RORy Ga14 Reporter Gene Assay Determination of a ligand mediated Ga14 promoter driven transactivation to quantify ligand binding to RORy was performed as follows: DNA encoding three different RORy protein fragments was cloned into vector pCMV-BD (Stratagene). Expression was under control of a CMV promoter and as fusion to the DNA-binding domain of the yeast protein GAL4. The amino acid boundaries of the three proteins and the respective database entries are listed in Table 3. Other vectors used were pFR-Luc (Stratagene) as regulated reporter plasmid. pFR-Luc contains a synthetic promoter with five tandem repeats of the yeast GAL4 binding sites that control expression of the Photinus pyralis (American firefly) lucif erase gene. In order to improve experimental accuracy the plasmid pRL-CMV was cotransfected. pRL-CMV
contains the constitutive CMV promoter, controlling the expression of the Renilla reniformis lucif erase.
Table 3 construct name aa borders (RefSeq) Ref sequence ID
hRORy-LBD aa259-518 NP_005051.2 NP ¨001001523 (RORy, t hRORyt aa1-497 isoform, 497aa) mRORy-LBD aa264-516 NP_035411 All Ga14 reporter gene assays were done in 293T cells (DSMZ (German Collection of Microorganisms and Cell Cultures), Braunschweig, Germany, ACC635) grown in Minimum Essential Medium (MEM) with Phenol Red. The medium is supplemented with 10%
fetal bovine serum, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 1%
Glutamax and 100 units Penicilin/Streptavidin per mL at 37 C in 5% CO2.
For the assay, 5x105 cells were plated per well in 96we11 plates in 100 pL per well, incubated over night at 37 C in 5% CO2. The following day, medium was discarded and the cells were transiently transfected using 20 pL per well of a OptiMEM - PEI-based transfection-reagent (Sigma-Aldrich, 408727) including the three plasmids described above. About 4 h after addition of the transfection solution, fresh MEM (same composition as used for plating cells, but without serum) was added. Then compound stocks, prediluted in MEM (same composition as used for plating cells) were added (final vehicle concentration not exceeding 0.1%).
Cells were incubated for additional 16 h before firefly (FF) and renilla (REN) luciferase activities were measured sequentially in the same cell extract using a Dual-Light-Luciferase-Assay system (Dyer et al., Anal. Biochem. 2000, 282:158). All experiments were done in triplicates.
Applying the Ga14 reporter gene assay as described above, the Examples of the present invention usually have an inhibition activity (IC50 FF resp. IC50 RENnorm) ranging from below 5 nM to about 20 pM and typically, from about 10 nM to about 2 pM. The RORy modulating compounds of the invention desirably have an inhibition in the Gal4 reporter gene assay ranging from below 5 nM to about 1 pM. Table 2 list the pIC50-value of typical examples of compounds of the invention that have an RORy activity in the Ga14 reporter gene assay for firefly (FF) and renilla normalised (REN) luciferase measurements. Is is understood that the data illustrated below may have reasonable variation depending on the specific conditions and procedures used by the person conducting the test. The efficacy was determined in comparison to the RORyt inhibitor T0901317 (equals 100%) and the p1C50-value is underlined, when the efficacy of the compound is below 50% of the reference.
Table 2 Ex. # plCso (FRET/FF/REN) Ex. #
p1C50(FRET/FF/REN) Ex. # plCso (FRET/FF/REN) 1 6.5/6.8/6.9 1/1 6.6/6.6/6.7 1/2 6.9/7.5/7.4 1/3 6.4/7.6/7.5 1/4 6.5/7.5/7.6 1/5 6.0/6.3/6.2 1/6 6.2/6.7/6.7 1/7 6.3/6.8/6.8 1/8 6.5/6.4/6.3 1/9 6.5/6.6/6.7 1/10 6.3/7.5/7.5 1/11 5.7/6.1/6.1 1/12 5.9/6.4/6.5 1/13 5.9/6.2/6.1 1/14 5.7/6.5/6.6 1/15 5.5/5.5/5.5 1/16 5.2/6.1/5.8 1/17 6.7/6.3/6.4 1/18 6.2/7.1/7.0 1/19 6.0/7.0/7.1 1/22 6.0/6.9/6.9 1/24 6.2/6.5/6.5 1/26 5.0/<4.7/<4.7 1/27 4.91<4.71<4.7 1/28 6.1/6.7/6.8 1/29 6.2/7.2/7.2 1/30 5.4/6.4/6.2 1/31 5.7/6.4/6.4 1/32 5.8/6.4/6.2 1/33 6.1/6.6/6.5 1/34 5.9/6.8/6.7 1/35 6.9/6.9/6.9 1/36 6.8/6.5/6.6 1/37 6.5/6.8/6.8 1/38 6.6/7.2/7.3 1/39 6.5/6.9/7.0 1/40 6.6/7.5/7.6 1/41 6.3/6.9/7.0 1/42 6.6/7.5/7.6 1/43 6.0/7.1/7.1 1/44 6.3/7.4/7.3 1/45 6.0/5.6/5.8 1/46 6.5/6.5/6.5 1/47 5.4/<4.7/<4.7 1/48 6.2/6.4/6.4 1/49 4.5/6.2/6.6 1/50 5.8/6.0/6.1 1/51 5.6/5.9/6.1 1/52 6.8/6.4/6.5 1/53 6.8/7.3/7.4 1/54 6.4/6.3/6.4 1/55 6.6/6.8/6.9 1/56 5.5/<4.7/<4.7 1/57 5.6/5.8/5.8 1/58 6.2/6.2/6.2 1/59 6.2/6.3/6.3 1/60 6.0/6.2/6.2 1/61 6.0/6.2/6.2 1/62 6.5/6.4/6.3 1/63 6.2/6.7/6.7 1/64 6.5/6.5/6.5 1/65 6.4/6.6/6.6 1/66 6.4/6.7/6.8 1/67 6.8/7.2/7.3 1/68 5.8/6.7/6.8 1/69 5.8/6.8/6.9 1/70 6.2/6.6/6.6 1/71 5.9/5.8/5.9 1/72 6.0/7.1/7.1 1/73 5.9/7.2/7.2 1/74 5.3/<4.7/<4.7 1/75 5.3/<4.7/<4.7 1176 5.9/5.9/5.8 1/77 6.7/6.9/7.0 1/78 6.5/7.1/7.1 1/79 6.4/7.2/7.2 1/80 6.7/7.5/7.5 1/81 6.7/7.4/7.4 1/82 6.8/7.4/7.4 1/83 6.5/6.9/7.0 1/84 6.8/7.6/7.6 1/85 6.5/7.7/7.7 1/86 6.8/7.6/7.6 1/87 6.5/7.2/7.2 1/88 6.4/6.5/6.5 1/89 6.6/6.3/6.2 1/90 5.7/7.0/6.9 1/91 5.7/7.4/7.4 1/92 6.7/7.0/6.9 1/93 6.7/7.4/7.4 1/94 6.3/7.4/7.3 1/95 6.8/7.0/7.1 1/96 6.7/6.7/6.8 1/97 6.6/7.1/7.0 1/98 6.2/7.3/7.3 1/99 6.4/7.1/7.2 1/100 6.6/7.2/7.2 1/101 6.6/7.2/7.2 1/102 6.3/6.4/6.4 1/103 6.4/7.3/7.3 1/104 6.3/6.8/6.8 1/105 6.6/6.5/6.5 Ex. # p1C50(FRET/FF/REN) Ex. # pIC50(FRET/FF/REN) Ex.
# p1C50(FRET/FF/REN) 1/106 6.1/7.0/7.1 1/107 6.1/7.2/7.2 1/108 5.1/7.2/7.3 1/109 4.91<4.71<4.7 1/110 6.1/7.3/7.4 1/111 6.4/7.4/7.4 1/112 6.3/7.1/7.1 1/113 5.4/<4.7/<4.7 1/114 6.6/6.7/6.8 1/115 6.6/7.3/7.3 1/116 6.9/6.9/6.9 1/117 6.3/6.8/7.0 1/118 6.2/6.5/6.6 1/119 6.7/7.4/7.3 1/120 6.9/7.1/7.3 1/121 6.9/7.0/7.2 1/122 6.8/7.0/7.0 1/123 6.3/6.8/6.8 1/124 6.2/7.5/7.5 1/125 6.1/7.4/7.4 1/126 6.2/7.1/7.0 1/127 6.3/7.5/7.4 1/128 6.3/7.2/7.2 1/129 5.8/7.3/7.3 1/130 6.1/6.8/6.8 1/131 6.3/7.8/7.8 1/132 6.2/6.8/6.8 2 6.6/7.0/7.0 2/1 6.1/6.5/6.5 2/2 6.6/7.0/7.0 2/3 5.8/6.5/6.7 3 6.6/7.4/7.4 4 6.2/6.4/6.4 6.3/7.0/7.2 6 6.2/6.3/6.4 6/1 5.7/6.7/6.7 6/2 5.5/6.5/6A 6/3 5.1/5.9/5.7 6/4 5.0/<4.7/<4.7 6/5 5.6/6.5/6.4 6/6 6.2/6.8/6.7 6/7 6.0/6.5/6.4 6/8 5.0/6.8/7.3 6/9 5.0/6.4/6.2 7 6.5/6.8/6.9 7/1 6.5/6.7/6.8 7/2 6.6/7.0/7.0 7/3 6.6/6.6/6.7 7/4 6.7/7.1/7.1 7/5 6.5/6.3/6.4 7/6 6.4/6.6/6.5 7/7 6.4/6.5/6.6 7/8 6.3/6.0/6.2 8 5.4/7.2/7.2 8/1 5.3/6.8/6.9 8/1 5.6/6.7/6.8 9 6.1/7.1/7.2 9/1 6.3/7.5/7.5 9/2 6.2/7.4/7.5 9/3 6.5/7.1/7.1 9/4 6.2/7.1/7.2 9/5 6.5/7.2/7.2 9/6 6.6/7.7/7.8 9/7 6.3/7.5/7.5 9/8 6.2/7.0/7.1 9/9 6.3/7.2/7.3 9/10 6.5/7.7/7.2 9/11 6.3/7.7/7.8 9/12 5.8/6.3/6.5 9/13 6.0/6.0/6.1 9/14 5.1/6.3/6.2 9/15 6.5/6.5/6.5 10 5.8/6.9/6.9 10/1 4.8/6.7/6.6 11 6.6/6.5/6.5 11/1 6.6/7.3/7.3 11/2 6.6/6.9/6.9 11/3 6.0/6.5/6.5 11/4 6.4/6.9/7.0 11/5 6.5/7.3/7.4 11/6 6.6/8.0/8.2 11/7 6.6/7.1/7.2 12 6.0/6.1/6.2 6.3/6.9/6.9 15/1 5.7/6.6/6.7 15/2 6.0/6.3/6.3 15/3 6.4/7.0/7.1 15/4 5.8/7.3/7.3 15/5 6.1/7.6/7.7 15/6 5.9/7.4/7.4 15/7 5.9/7.2/7.2 15/8 6.0/7.3/7.4 15/9 6.0/6.9/7.0 16 6.8/6.4/6.5 17/1 5.9/8.0/7.9 17/2 6.0/6.6/6.5 17/3 6.4/6.9/6.9 17/4 6.2/6.7/6.7 17/5 6.5/6.4/6.4 17/6 6.6/6.4/6.5 17/7 5.5/<4.7/<4.7 17/8 6.1/7.2/7.2 17/9 6.2/6.8/6.8 17/10 6.4/7.6/7.6 17/11 6.7/7.2/7.2 17/12 6.7/7.2/7.4 17/13 6.2/6.8/6.9 17/14 5.9/5.9/5.7 17/15 6.1/7.2/7.1 17/16 5.4/6.1/6.0 17/17 6.1/6.3/6.4 17/18 6.0/6.1/6.1 17/19 6.1/7.5/7.5 17/20 6.4/7.1/7.1 17/21 6.2/7.0/6.9 17/22 6.0/6.5/6.6 17/23 5.9/6.6/6.6 17/24 5.5/5.8/5.7 17/25 6.5/6.9/7.0 17/26 5.8/7.3/7.3 17/27 5.6/6.3/6.5 17/28 6.6/7.4/7.4 17/29 5.9/6.8/6.7 17/30 6.6/7.7/7.7 17/31 6.0/7.3/7.3 17/32 6.7/7.2/7.2 17/33 6.2/7.1/7.2 Ex. # plCso (FRET/FF/REN) Ex. # plCso (FRET/FF/REN) Ex. # p1C50(FRET/FF/REN) 17/34 5.8/7.0/6.9 17/35 5.8/6.4/6.3 17/36 6.1/6.9/6.9 17/37 5.9/7.1/7.1 17/38 6.0/6.7/6.7 17/39 6.4/6.9/6.8 17/40 5.9/6.9/6.8 17/41 6.4/8.1/8.2 17/42 5.7/7.5/7.6 17/43 6.7/7.4/7.4 17/44 6.2/6.1/6.1 17/45 6.0/6.5/6.4 17/46 6.5/6.5/6.5 17/47 6.7/7.3/7.4 17/48 6.0/7.6/7.5 17/49 5.7/7.0/7.1 17/50 5.5/6.5/6.5 17/51 5.8/6.7/6.7 17/52 5.8/6.7/6.7 17/53 5.8/6.9/6.9 17/54 5.8/7.1/7.2 17/55 5.7/7.5/7.6 17/56 4.9/6.4/6.4 17/57 6.1/7.4/7.5 17/58 5.8/6.7/6.7 17/59 5.7/6.6/6.6 17/60 5.8/7.6/7.6 17/61 6.0/7.4/7.5 17/62 6.5/8.3/8.3 17/63 6.7/7.7/7.6 17/64 6.5/7.8/7.7 17/65 6.7/7.7/7.7 17/66 6.8/7.4/7.4 17/67 6.6/7.7/7.5 17/68 6.8/7.4/7.5 17/69 <4.7/7.2/7.4 17/70 5.9/7.9/7.9 17/71 5.8/6.9/6.8 17/72 5.2/6.1/6.1 17/73 6.0/7.2/7.3 17/74 6.3/7.3/7.2 17/75 5.2/5.8/5.8 17/76 5.7/6.9/6.9 17/77 6.1/8.0/8.1 17/78 6.3/7.3/7.3 17/79 5.8/6.4/6.3 17/80 6.3/6.9/7.0 17/81 6.2/7.1/7.1 17/82 6.1/6.7/6.7 17/83 6.9/8.2/8.3 17/84 <4.7/7.2/7.2 17/85 <4.7/7.4/7.5 17/86 6.5/7.1/7.1 17/87 6.3/6.9/6.9 17/88 6.2/7.7/7.7 17/89 5.8/6.9/6.9 17/90 5.8/7.9/8.0 17/91 6.2/7.1/7.0 17/92 6.0/7.3/7.1 17/93 6.0/6.8/6.9 17/94 5.9/6.8/6.7 17/95 6.2/7.8/7.7 17/96 5.5/6.9/7.0 17/97 6.9/8.0/8.0 17/98 6.5/6.8/6.9 17/99 6.6/6.9/7.0 17/100 6.1/6.9/6.9 17/101 6.1/7.7/7.7 17/102 6.6/6.8/6.9 17/103 6.1/6.7/6.8 17/104 6.3/6.5/6.7 17/105 5.7/6.1/6.3 17/106 6.3/7.3/7.3 17/107 6.0/6.9/6.9 17/108 6.0/6.9/7.1 17/109 6.2/7.2/7.3 17/110 5.7/6.3/6.5 17/111 6.5/7.2/7.3 17/112 6.5/7.4/7.5 17/113 6.3/6.8/6.8 17/114 6.2/6.5/6.4 17/115 6.5/7.9/8.0 17/116 6.2/7.3/7.3 17/117 6.0/7.6/7.7 17/118 5.0/6.3/6.5 17/119 6.3/7.6/7.7 17/120 5.6/6.1/6.0 17/121 6.5/7.6/7.7 17/122 6.4/7.6/7.5 17/123 5.5/7.0/7.0 17/124 6.1/7.4/7.5 17/125 7.1/6.4/6/ 17/126 6.5/6.7/6.9 17/127 6.5/7.1/7.2 17/128 6.7/8.0/8.0 17/129 6.7/8.0/8.0 17/130 6.6/7.5/7.6 17/131 6.3/6.8/6.9 17/132 5.4/6.3/6.2 17/133 5.9/6.3/6.3 17/134 6.4/7.4/7.7 17/135 6.2/6.7/6.7 17/136 6.1/6.6/6.7 17/137 6.3/<4.7/<4.7 17/138 6.7/7.1/7.3 17/139 6.8/7.2/7.4 17/140 6.7/8.0/8.1 17/141 6.5/8.3/8.5 17/142 6.4/7.4/7.6 17/143 6.9/8.2/8.2 17/144 6.3/7.7/7.7 17/145 6.2/7.6/7.7 17/146 6.0/7.4/7.5 17/147 6.1/6.7/6.7 17/148 6.1/7.0/7.0 17/149 5.9/6.6/6.6 17/150 6.3/8.0/8.2 17/151 6.5/8.3/8.3 17/152 6.0/8.2/8.2 17/153 6.5/6.7/6.7 17/154 6.5/7.2/7.3 17/155 6.2/7.0/7.0 17/156 6.5/7.1/7.2 17/157 6.4/7.0/7.1 17/158 6.1/6.1/6.2 17/159 5.8/6.8/6.9 17/160 6.7/7.8/8.0 17/161 6.2/7.6/7.6 17/162 6.1/7.5/7.7 Ex. # p1C50(FRET/FF/REN) Ex. # plCso (FRET/FF/REN) Ex. # p1C50(FRET/FF/REN) 17/163 5.8/7.0/7.2 17/164 5.9/6.4/6.5 17/165 5.3/6.5/6.9 17/166 6.8/7.8/8.0 17/167 6.1/6.6/6.8 17/168 6.0/6.4/6.4 17/169 6.1/6.7/6.7 17/170 6.5/6.8/7.0 17/171 6.1/6.9/6.9 17/172 6.4/7.5/7.5 17/173 6.5/7.3/7.3 17/174 6.7/7.1/7.1 17/175 6.1/6.6/6.7 17/176 6.6/7.1/7.0 17/177 6.8/7.3/7.4 17/178 6.1/7.9/7.9 17/179 6.4/6.1/6.1 17/180 6.2/7.1/7.2 17/181 6.4/7.0/6.9 17/182 6.3/7.8/7.9 17/183 6.7/7.9/8.1 17/184 6.1/6.9/7.1 17/185 6.3/6.4/6.2 17/186 6.4/6.9/7.1 17/187 4.8/<4.7/<4.7 17/188 6.1/6.8/6.9 17/189 5.3/6.3/6.3 17/190 5.8/6.5/6.6 17/191 5.9/7.0/6.9 17/192 5.8/6.5/6.4 17/193 5.6/6.9/7.0 17/194 4.9/6.4/6.5 17/195 6.2/7.6/7.6 17/196 5.4/7.0/7.0 17/197 6.1/7.9/7.7 17/198 6.3/6.8/6.9 17/199 6.2/6.6/6.7 17/200 6.3/6.9/6.9 17/201 6.1/5.7/5.7 17/202 6.5/7.7/7.7 17/203 6.3/7.8/7.8 17/204 6.1/6.7/6.8 17/205 6.1/6.9/7.0 17/206 6.2/7.0/7.2 17/207 6.3/7.9/8.0 17/208 6.4/6.6/6.6 17/209 6.7/7.3/7.6 17/210 6.8/7.9/8.1 17/211 6.3/8.0/8.0 17/212 6.2/7.3/7.4 17/213 6.2/7.1/7.2 17/214 6.6/7.5/7.5 17/215 6.5/7.5/7.3 17/216 6.7/7.8/7.8 17/217 6.9/7.6/7.7 17/218 6.5/7.1/7.3 17/219 6.3/6.9/7.0 17/220 6.5/6.6/6.6 17/221 5.7/7.1/7.1 17/222 6.2/7.4/7.5 17/223 6.4/7.1/7.2 17/224 6.1 /7.1 /7.2 17/225 6.1/7.6/7.6 17/226 6.5/8.2/8.2 17/227 6.3/8.1/8.1 17/228 6.4/7.7/7.7 17/229 6.2/7.2/7.3 17/230 6.6/7.5/7.6 17/231 6.6/7.5/7.7 17/232 6.1/6.8/7.0 17/233 5.8/6.5/6.5 17/234 6.7/7.1/7.2 17/235 6.7/7.6/7.6 17/236 6.2/8.1/8.2 17/237 5.9/6.5/6.5 17/238 6.0/6.9/6.7 17/239 6.0/7.9/8.1 17/240 6.1/7.5/7.6 17/241 5.9/7.7/7.8 17/242 6.4/7.5/7.6 17/243 6.2/7.4/7.6 17/244 5.0/6.2/6.2 17/245 <4.7/5.7/5.7 17/246 5.4/6.1/6.2 17/247 5.9/6.9/7.0 17/248 5.6/6.4/7.3 17/249 6.3/6.6/6.7 17/250 5.8/6.6/6.5 17/251 6.3/6.9/6.9 17/252 5.8/6.5/6.6 17/253 6.2/7.0/7.2 17/254 6.2/6.6/6.6 17/255 5.1/<4.7/<4.7 17/256 6.2/6.8/7.0 17/257 6.3/7.4/7.6 17/258 5.1/<4.7/<4.7 17/259 6.0/7.2/7.2 17/260 5.9/7.3/7.4 17/261 5.9/7.5/7.6 17/262 6.2/7.6/7.8 17/263 6.5/7.9/8.0 17/264 6.2/7.9/7.7 17/265 6.5/7.9/8.0 17/266 6.6/8.3/8.5 17/267 6.1/7.9/8.0 17/268 6.1/7.7/7.8 17/269 6.0/6.9/7.0 17/270 6.2/7.8/8.0 17/271 6.1 /7.1 /7.1 17/272 6.3/6.8/6.9 17/273 5.8/7.2/7.3 17/274 6.6/7.9/7.9 17/275 6.2/7.0/7.0 17/276 6.8/7.9/8.0 17/277 6.4/7.2/7.2 17/278 5.6/7.0/7.0 17/279 5.5/<4.7/<4.7 17/280 6.0/8.1/8.1 17/281 6.0/7.7/7.7 17/282 5.7/6.6/6.7 17/283 6.0/6.7/6.8 17/284 5.9/7.3/7.3 17/285 6.2/7.3/7.4 17/286 5.9/7.4/7.5 17/287 6.2/7.7/7.7 17/288 6.4/7.3/7.3 17/289 5.9/7.1/7.2 17/290 6.2/7.6/7.6 17/291 6.4/7.6/7.7 Ex. # plCso (FRET/FF/REN) Ex. # plCso (FRET/FF/REN) Ex. # p1C50(FRET/FF/REN) 17/292 5.9/7.5/7.4 17/293 5.9/6.6/6.7 17/294 5.5/<4.7/<4.7 17/295 6.0/6.6/6.5 17/296 6.6/7.0/7.1 17/297 6.9/7.2/7.4 17/298 5.6/5.9/6.0 17/299 5.3/7.1/7.5 17/300 6.1/7.3/7.6 17/301 5.7/7.6/7.6 17/302 5.8/7.3/7.2 17/303 5.4/6.3/6.4 17/304 5.8/7.2/7.3 17/305 5.7/6.8/6.7 17/306 5.8/6.8/6.9 17/307 5.5/6.2/6.0 17/308 5.2/6.5/6.4 17/309 6.1/6.7/6.8 17/310 6.0/7.4/7.6 17/311 6.1/7.0/7.2 17/312 6.5/7.2/7.3 17/313 6.0/6.8/6.8 17/314 6.0/7.2/7.1 17/315 5.9/6.5/6.5 17/316 5.6/6.3/6.3 17/317 5.6/6.5/6.5 17/318 5.7/7.7/7.6 17/319 5.7/6.5/6.6 17/320 5.8/7.3/7.3 17/321 6.0/7.3/7.3 17/322 5.4/5.9/6.0 17/323 5.1/5.6/5.7 17/324 5.5/6.8/6.8 17/325 5.6/7.1/7.2 17/326 6.0/7.8/7.9 17/327 6.1/6.8/6.9 17/328 6.3/6.6/6.6 17/329 5.6/6.8/6.9 17/330 5.6/7.3/7.4 17/331 5.9/6.6/6.5 17/332 6.7/6.4/6.4 17/333 6.4/6.4/6.3 17/334 5.9/5.8/5.9 17/335 6.5/5.5/5.6 17/336 6.0/<4.7/<4. 7 17/337 6.0/7.7/7.8 17/338 5.5/7.2/7.2 17/339 5.9/7.6/7.7 17/340 5.8/7.1/7.1 17/341 6.1/7.4/7.6 17/342 6.0/7.1/7.1 17/343 6.3/7.4/7.3 17/344 6.2/7.3/7.5 17/345 6.5/7.3/7.4 17/346 5.3/<4.7/<4.7 17/347 6.4/6.5/6.5 17/348 6.5/6.9/7.0 17/349 6.2/6.8/6.8 17/350 6.0/7.7/7.7 17/351 5.7/6.8/6.9 17/352 6.2/7.5/7.5 17/353 5.7/6.8/6.8 17/354 6.0/7.0/7.0 17/355 6.5/6.6/6.6 17/356 6.4/6.7/6.7 17/357 5.7/6.7/6.8 17/358 6.0/6.3/6.2 17/359 5.5/7.4/7.4 17/360 5.2/7.3/7.4 17/361 5.7/6.4/6.4 17/362 5.9/5.9/5.8 17/363 6.0/7.4/7.5 17/364 6.0/6.9/7.0 17/365 5.9/7.0/7.0 17/366 5.3/6.6/6.3 17/367 5.3/6.4/6.1 17/368 5.1/6.4/6.2 17/369 5.9/7.5/7.5 17/370 5.7/7.2/7.3 17/371 6.2/8.0/8.0 17/372 5.5/6.3/6.2 17/373 5.3/<4.7/<4.7 17/374 5.8/7.3/7.3 18/1 6.1/7.5/7.7 18/2 6.6/8.0/8.2 18/3 5.8/6.1/6.5 18/4 6.1/6.3/6.5 18/5 6.2/7.5/7.5 19 4.9/6.6/6.4 19/1 6.3/6.8/6.8 20 6.4/7.4/7.5 20/1 6.6/7.1/7.3 20/2 6.5/7.0/7.2 20/3 6.2/7.3/7.4 20/4 6.7/6.9/6.9 20/5 6.1/7.0/7.0 20/6 6.3/6.9/6.9 20/7 6.4/6.2/6.2 20/8 6.0/7.0/7.0 20/9 5.9/7.8/7.6 22 6.4/7.5/7.6 22/1 6.8/8.4/8.4 22/2 6.4/8.1/8.0 23 6.7/8.5/8.5 24 5.5/6.4/6.4 24/1 4.9/6.3/6.4 24/2 5.2/<4.7/<4.7 25 5.8/6.3/6.2 26 6.7/7.5/7.6 26/1 6.6/7.4/7.5 26/2 6.7/7.2/7.2 26/3 6.1/6.6/6.8 26/4 5.4/6.6/6.8 26/5 6.5/7.9/8.0 26/6 6.4/7.7/7.9 27 5.7/6.4/6.5 28 5.9/6.6/6.9 29 5.4/7.2/7.2 29/1 5.5/6.8/6.8 29/2 5.6/7.3/7.1 31 5.9/6.9/6.9 33 5.5/6.2/6.3 34 6.4/6.8/7.1
R6 is selected from H, C1_6-alkyl, halo-C1_6-alkyl or halogen;
R7 is selected from C3_10-cycloalkyl and C3_10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, 0-C1_6-alkyl, 0-halo-C1.6-alkyl, C1 _6-alkyl, halo-C1_6-alkyl, cycloalkyl and heterocycloalkyl;
R8 is independently selected from H, F, C1_3-alkyl, halo-C1_3-alkyl or OH;
1:113 is C3_10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, 0-C1_6-alkyl, 0-halo-C1_6-alkyl, C1_6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1_2-alkyl, halo-C1-2-alkyl;
R11 is independently selected from H, C1_6-alkyl, C0_6-alkylene-C3_6-cycloalkyl, C0_6-alkylene-C3_6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C1_3-alkyl, halo-C1_3-alkyl, 0-C1.3-alkyl, 0-halo-C1_3-alkyl and S02-C1_3-alkyl;
R12 is independently selected from H, C1_6-alkyl and halo-C1_6-alkyl;
R31 is independently selected from H, C1_6-alkyl, C0_6-alkylene-C3_6-cycloalkyl, C0_6-alkylene-C3_6-heterocycloalkyl, a 6-membered aryl wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl and aryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C1_3-alkyl, halo-C1.3-alkyl, 0-C1_3-alkyl, 0-halo-C1_3-alkyl and S02-C1-3-alkyl;
R32 is independently selected from H, C1_6-alkyl and halo-C1_6-alkyl;
x is independently selected from 1 and 2;
y is independently selected from 0, 1 and 2;
with the proviso that R3 is not an unsubstituted or substituted ring selected from Me0 R;¨N II 0 1-\H
/H
S , OMe 0 1.1 H H Me Me and Me Me.
In a first alternative, the invention provides a compound represented by Formula (1) 11 (1) an enantiomer, diastereomer, tautomer, N-oxide, solvate, formulation and pharmaceutically acceptable salt thereof, wherein R1 is selected from H, C3_6-cycloalkyl, C3_6-heterocycloalkyl, C1.10-alkylene-C3_10-cycloalkyl, C1.10-alkylene-C3_10-heterocycloalkyl, Cm0ralkylene-(5-membered monocyclic heteroaryl), wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR11, 0-C2_6-alkylene-01=1", halo-C1_6-alkyl, halogen, CO2Ru, CONR11R12, COW, SOyR11, SO3H, SO2NRiiR12, NRilcoRil, NR11S02R11, NRii-CO-NR11R123 NR11-S02-C3_6-cycloalkyl, 0-C3_6-cycloalkyl, C3_6-heterocycloalkyl, 0-C3_6-heterocycloalkyl and NR, R12;
R2 is selected from the group consisting of H, halo-C1.6-alkyl and hydroxy-C1-6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SOyR11, SO3H, NR11s02-H11, SO2NR11.-.1 C0.6-alkylene-CO2R11, coNR, R12, C0R11, NR-CO-R, NR-1-CO_NRil R12, N.-.11-S02-NR11R12, NR11.-. M12, C1_6-alkyl, halo-C1_6-alkyl, hydroxy-C1_6-alkyl, C3-6-cycloalkyl, 0-C3_6-cycloalkyl, C3.6-heterocycloalkyl and 0-C3_6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1.3-alkyl, halo-C1.3-alkyl and oxo;
5 R3 is a 6- or 10-membered mono- or bicyclic aryl or a 6- to 10-membered mono- or bicyclic heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N, 0 and S, wherein aryl and heteroaryl is substituted with at least one group selected from C3-6-cycloalkyl, C4-heterocycloalkyl, C1_4-alkylene-C3_10-cycloalkyl, carbon atom linked 5- or 6-membered monocyclic heteroaryl, C1.4-alkylene-O-R31, 0-C3_10-cycloalkyl, C(0)R31, CO-6-1 0 alkylene-C(0)N(R31)2, S02-N(R31)2, N(R31)S02-R31, S02-C3_10-heterocycloalkyl, SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1_6-alkyl, halo-C1_6-alkyl, C3_6-cycloalkyl, C3_6-heterocycloalkyl, oxo, 15 =N-0R32, OH, 0-C1.6-alkyl and 0-halo-C1_6-alkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and the carbon atom linked 5-or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1_3-alkyl, halo-C1-3-alkyl, OH, oxo, =N-OR32, 0-C1_3-alkyl and 0-halo-C1.3-alkyl; and 20 wherein aryl and heteroaryl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1_3-alkyl, halo-C1.3-alkyl, OH, 0-C1_3-alkyl and 0-halo-C1_3-alkyl; and R4 is S02-(CIVIR8)yR7, S02-NR121R7, (CR8R8)9-R1 or C3_6-cycloalkyl, which is spirocyclic fused with C3_10-cycloalkyl;
R6 is selected from H, C1_6-alkyl, halo-C1_6-alkyl, CHO, CON(R62)2 or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of 0-C1_6-alkyl, 0-halo-C1_6-alkyl and OH;
R6 is selected from H, C1_6-alkyl, halo-C1_6-alkyl or halogen;
R7 is selected from C3.10-cycloalkyl and C3_10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, 0-C1_6-alkyl, O-halo-C1_6-alkyl, C1.6-alkyl, halo-C1.6-alkyl, cycloalkyl and heterocycloalkyl;
R8 is independently selected from H, F, C1.3-alkyl, halo-C1_3-alkyl or OH;
R1 is C3.10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, 0-C1_6-alkyl, 0-halo-C1_6-alkyl, C1_6-alkyl, halo-C1_6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1_2-alkyl, halo-C1-2-alkyl;
R11 is independently selected from H, C1_6-alkyl, C0_6-alkylene-C3_6-cycloalkyl, C0_6-alkylene-C3_6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C1.3-alkyl, halo-C1_3-alkyl, 0-C1.3-alkyl, O-halo-C1_3-alkyl and S02-C1_3-alkyl;
R12 is independently selected from H, C1_6-alkyl and halo-C1_6-alkyl;
1331 is independently selected from H, C1_6-alkyl, halo-C1_6-alkyl, C0_6-alkylene-C3.6-cycloalkyl, C0.6-alkylene-C3.6-heterocycloalkyl, 5- or 6-membered heteroaryl and 6-membered aryl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, OH, oxo, C1_3-alkyl, halo-C1.3-alkyl, 0-C1_3-alkyl, 0-halo-C1_3-alkyl and S02-C1_3-alkyl;
and optionally wherein two R31 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1_4-alkyl and halo-C1_4-alkyl;
R32 is independently selected from H, C1_6-alkyl and halo-C1_6-alkyl;
R52 is independently selected from H, C1_3-alkyl and halo-C1_3-alkyl;
x is independently selected from 1 and 2;
y is independently selected from 0, 1 and 2.
In an additionally preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from phenyl, pyridinyl, pyrimidinyl, naphthyl, benzothiophenyl and quinolinyl, wherein phenyl, pyridinyl, pyrimidinyl, naphthyl, benzothiophenyl and quinolinyl is substituted with at least one group selected from C3-4-cycloalkyl, carbon atom linked 5- or 6-membered monocyclic heteroaryl, C14-alkylene-O-R31, C(0)R31, C(0)N(R31)2, S02-N(R31)2, S02-C3_10-heterocycloalkyl, SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, C1.3-alkyl, halo-C1_3-alkyl, C3_4-cycloalkyl, C3_4-heterocycloalkyl, oxo, OH, 0-C1.3-alkyl and 0-halo-C1.3-alkyl, wherein phenyl, pyridinyl, pyrimidinyl, naphthyl, benzothiophenyl, chinolinyl, alkyl, alkylene, cycloalkyl, heterocycloalkyl and the carbon atom linked 5- or 6-membered monocyclic heteroaryl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1_3-alkyl, halo-C1_3-alkyl, OH, 0-C1.3-alkyl and 0-halo-C1-3-alkyl.
In a further preferred embodiment in combination with any of the above or below embodiments of the first alternative R1 is selected from C1_10-alkyl, C3_6-cycloalkyl, C3-6-heterocycloalkyl, C1_10-alkylene-C3_10-cycloalkyl, C1_10-alkylene-C3.10-heterocycloalkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR11, 0-C2_6-alkylene-OR11, C1.6-alkyl, halo-C1.6-alkyl, halogen, CO2R11, c0NF11R12, coRil, SOyR11, SO3H, S02NR11R12, NFilicoRli, NR11s02R11, NRil_CO_NRii R12, N.-01_ S02-NR11 R12, C3.6-cycloalkyl, 0-C3-6-cycloalkyl, C3.6-heterocycloalkyl, 0-C3.6-heterocycloalkyl and NR11R12;
R2 is selected from the group consisting of H, C1_6-alkyl and halo-C1_6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SOyR11, SO3H, NR11SO2R11, SO2NR11.-.12, C0_6-alkylene-CO2R11, CONR11R12, C0R11, NR11-CO-R11, NR11-Co_NR11.-.12, NR11-S02-NRii R12, NR11.-. h1 C1_6-alkyl, halo-C1_6-alkyl, hydroxy-C1.6-alkyl, C3-6-cycloalkyl, 0-C3.6-cycloalkyl, C3_6-heterocycloalkyl and 0-C3.6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1_3-alkyl, halo-C1_3-alkyl and oxo.
In an additionally preferred embodiment in combination with any of the above or below embodiments of the first alternative R1 is selected from C1.10-alkyl, C3_6-cycloalkyl, C3-6-heterocycloalkyl, C1.10-alkylene-C3_10-cycloalkyl, more preferably C1_3-alkylene-C3-10-cycloalkyl, C1_10-alkylene-C3_6-heterocycloalkyl, more preferably C1.3-alkylene-C3-6-heterocycloalkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR", alkylene-0R11, C1_6-alkyl, halo-C1_6-alkyl, halogen, CO2H, C0NIVR12, C0R11, SOyR11, SO3H, SO2NRU R12, NRlicoRil, NR11S02R11, NR11-CO-NR11R12, NR11-S02-NR11R12, C3-6-cycloalkyl, 0-C3_6-cycloalkyl, Cm-heterocycloalkyl, 0-C34-heterocycloalkyl and NR11R12;
R2 is selected from the group consisting of H, C1_6-alkyl and halo-C1_6-alkyl, more preferably R2 is hydrogen;
or 1:11 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 6-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SOyR11, SO3H, NRuS02R11, SO2NR111R12, CMe2CO2H, CONR11 R12, C0R11, NR11-CO-R11, NR11-CO-NR11R12, NR11 SO2NRU R12, NR11R12, C1.6-alkyl, halo-Cwalkyl, hydroxy-C1.6-alkyl, C3_6-cycloalkyl, 0-C36-cycloalkyl, C3.6-heterocycloalkyl and 0-C3_6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1_3-alkyl, halo-C1_3-alkyl and oxo.
In an additionally preferred embodiment in combination with any of the above or below embodiments of the first alternative R1 contains 1(OH,J\I N 1\1- \
N , 0 or N , H H , more preferred R1 contains a carboxylic acid moiety and even more preferred R1 contains a secondary or tertiary carboxylic acid moiety.
In a preferred embodiment in combination with any of the above or below embodiments of the first alternative NR1R2 is selected from NH2, NHMe, NHEt, NH'Pr, NH1Bu, NHCH2CONH2, NHCH2CONMe2, NHCH2CH2OH, NHCH2CH(CF3)0H, NHCH2C(CF3)20H, NHCH2CH20Me, NHCH2CH2S02Me, NHCH2CH2S02NH2, NH(CH2)30H, NH(CH2)30Me, NH(CH2)40H, NH(CH2)40Me, NH(CH2)50H, NH(CH2)2CO2H, NH(CH2)3CO2H, NH(CH2)4CO2H, NH(CH2)5CO2H, NHCH2CMe2OH, NHCH(Me)CMe2OH, NHCH2CMe20Me, NHCH2CMe2CO2H, NHCH2CMe2CONH2, NHCH2CMe2CONHMe, NHCH2CMe2CONMe2, NHCH2CMe2NHSO2Me, NH(CH2)3SOMe, NH(CH2)5S02Me, NH(CH2)5S02NH2, NH(CH2)3NHSO2Me, NH(CH2)20(CH2)20H, NHCH2CHMe0H, NH(CH2)5SOMe, NC
HN--\
NH(CH2)3S02Me, HN-<, HN¨K HN-0 HN¨CN¨ HN¨C]
, HN
HN-)>. HN-\.:,H HN-\ /--\
\---\___Nr-\0 i\--NO
\ -- N 0 \ I NH
, HN- HN- HN OH HN OH
1---\
\ __I
HN-0 HN--\00 X
HN-CS HN-CS=0 HN-0=0 HN--<XH HN HN-CN-4-CS:C) O
HN-CNN N-H /-\
--/K
0 HN-X \50 HN-N 0 HN-----( \O
\ / `0 \/ ( \O N
, , , , HN-b 0 0HNo HN) HNI-C ) HN-K-\0 HNNCX 0 NH
HN---D, \H HN OH
HN-bo HN OH1,11--\_:))H HN OH
Q\
S,,.., \\*-1/4.) , S , \O , 0 , OH HN--JO
HN HN -K
p O
(JJ
HN ' 0 HN-õ. HN-b) HN--- -) r9 ----\_g_.
FIN' 03 HN.--03 II
H(N--?, 0 , , , X', , NH
HN--___ HN-3r1Ril \
NH2 \.1;) 0 , 0 , 0 , HN---) HN--) HN-\ c \----) \SC) ,4:0 -.0H --NH2 OH
, , , -)43 HN-X c HN-\ HN-\ c HN) __________________________________________________________________________ 0 OH NH2 N/ HN H HN-g%0 0 0 0 0 \
, , , , , HN N- N N"' 0 I
N'-.--)-LOH
HN -0 0-.<1 \r0 HO , OH, HO , OH , OH , HN,,, HN,,, HN,, HN HN,,,,,,N .
10<r0 0 Or0 OH, OH, OH, OH, OH, HN,,K---.1 , HN HN
HN'44.'"0 )(cf0 i'',/e OH, OH, OH, OH, HN- Nv'') --)-HN'a,,r0 HN'ON r 1 N,s/, HN-\ /<0 OH
OH, , HN --)A
HN--1 0 HN--__11 0 0 H
N
->H
5 OH, OH ,.....-OH , HN-)H0 HN--) e HN-b HN ________________________ \ _J) t)H 1 N-\ HN-\
14 \IDH
n -0 , \-0H, , 0 , 0, ,P FIND e FIN-3z, HNI\s,0 FIN --/ HN--\
HN-\
i t3 \--OH
N , , , , HN -\ HN---\ HN-\
.17-0 HN-)._____\ HN--) HN-\ NIIN) 1\1, I \ 1 N-NH
HN\____ , N\µ= No 0 HO 0 H2 0, N
, NN- , , N-NH \:)-CL N-0 HN HN
N-NH HN HN-----)N0 NO<OH
---\._ --)1\1-- N
N H , H , , , , N- N
0 I __ N
I 03na i'll-- T1 Nõ.3,,./L
OH
b , cy 10 OH, N") OH NTh S=0 and b .
, In a further preferred embodiment in combination with any of the above or below embodiments of the first alternative NI:111R2 is selected from NH2, NHMe, NHEt, NH'Pr, NHtBu, NHCH2CONH2, NHCH2CONMe2, NHCH2CH2OH, NHCH2CH(CF3)0H, NHCH2C(CF3)20H, NHCH2CH20Me, NHCH2CH2S02Me, NHCH2CH2S02NH2, NH(CH2)30H, NH(CH2)30Me, NH(CH2)40H, NH(CH2)40Me, NH(CH2)50H, NH(CH2)2CO2H, NH(CH2)3CO2H, NH(CH2)4CO2H, NH(CH2)5CO2H, NHCH2CMe2OH, NHCH(Me)CMe2OH, NHCH2CMe20Me, NHCH2CMe2CO2H, NHCH2CMe2CONH2, NHCH2CMe2CONHMe, NHCH2CMe2CONMe2, NHCH2CMe2NHSO2Me, NH(CH2)3SOMe, NH(CH2)5S02Me, NC
NH(CH2)3NHSO2Me, NH(CH2)20(CH2)20H, NHCH2CHMe0H, HN-<1, HNJ HN--<>, , HN->. HNH HN
-NO HN-\
CF3 ---N/---\0 HN- N- HN-\_____/ , HN
\----\_Nr-\0 n-N\ C /__\ HN-I...._.7 HN-y7 HN OH
/--- 0 \-N 0 \/ NH NH 0 , 0 , 14 , , , , HN---\,c-OH
LC) , HN-00 HN--\CO HN-CS HN-CS:=0 HN--<>=0 , , , , , ,0 HN HN-N-4 x 0 HN-CN-1(...._o -OCH , FIN-C% , 0 HN-CN ---\
, HN
HN-- HN ___Ng Nii_vE___I\
/--, HN-N 0 HN-( / \O --6 .__/ ___________ / / __ C__2, , Q, \
HN-Dt\I 0 OH HN-- JO
Q, HN ..-0 0 HN0 \0 , 0 P
, , , , HN-)._ , HN
--b1 HN HNI.=C
HNJ, , , , N, , HN-\ 1<0 0 0 1 HN-\ 9 HN HN->AI
\-- --).--NH H
0 , ..0 HN NH HN--Il HN--) HN--) HN--\ c \---- \S
0 HO \O /----OH
0 , --NH2 OH
, , , , HN-- e HN___\ 7 HN-) 0 HN I
C) i< 0 HN
-NH2 HN-g%0 ---0 10-1 \r 0, \ , HO , OH, HO
,, N NarHNõ HNõ HNõ, 0 0 '10,r0 ' OH OH , OH OH , OH, , , HN-\ e , HN--111 0 HNõ l HN '0 0 0 1 HN --\ 4) rOH , OH , OH , OH , HN--)r0 OH
HN
" lil HN-1:1, FIN---)A 0 \r HN--)_40 ....-- -\___ _.-OH ---"'"µc) , 0\ 0, OH , , HN-)0 HN -- 0, P HN-) HN--)ZHN-\ HN--\
Q--(-) OH lc---.. ---\--OH
\
, , 0 , 0 , HN1 HN --/ HN--)_\ HN HN-- HN-)._ \ , 0 oe-NH2 /
HN--\ HN--\ HN--\
HN---\ 1\le N f\le ),--0 N NN
I q Nx NO 0 HO 0 H2N 0 (:) H -OH , 0-- , N OH N N
i _______ / 1 S=0 , and b .
In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative NR1R2 is selected from HN---\..., HN¨v_ HN OH
HN--\___ HN-00 HN--\CO HN¨S.,---0 /OH , L-0, q , LC-) , , , HN---t:_)I)-1 HNI) HNZ
HN¨CS; HN--( \ s: HN---00 µ0 / , 0 , 0 , , , , HN--, HN OH \ HN-Ii, HN--C HNII-G
HNI C) r- 0 , HN NH2 HN) HN -\ ---)_>/_ HN
\ c HN, OH, NH2 OH
0 , \ OH
HN---\ / HN---\ c N N HNõ, 00 OH , OH
OH, , , , õ....\ HNõ, r HN,, 0 HNõ
HN , HN
0 0<0 0 0<r0 \---'y )',,, OH, OH , OH , OH , OH , HN
HN HN --b_ HN--bso N-NH
HN
,,--0 --------(N--N
OH, OH, 0 N-NI
HN
--).----NO N Q
OH 1-0 :--- =C) u , 0 ,o , I (:) and b .
, In an even more preferred embodiment in combination with any of the above or below embodiments of the first alternative NR1R2 is selected from HN-%
,0 HN-0 HN¨CS.--0 HN
\¨CS; HN¨( \SC' HN 0 HN OH
HNIDF_I HN OH HN NH2 HN-) /0 S. <
\\-0 0 , 0 0 , , 0 , OH
, HN---\ ( HN---\
\ c NH2 N HNõ, HN,, OH
.00 .<ro µ0õro 00 OH OH , OH
, , , , HN
N-NH HN-)___N-I N
0 0<r0 .--------(N,,N NO OH
N¨
I
I\l' Qz-0 NI S=0 b , and b .
In a most preferred embodiment in combination with any of the above or below embodiments of the first alternative NR1R2 is selected from HN OH HN--\ c 0 Nar OH HN
OH OH
HNõ 'O HNõ'1 HN
HN N-NH r0 00 10<r0 ------c OH OH OH
and , , , HN--)N-0 µ._ NO
H .
In another preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from 1 41 R-A -K=(N 4\ __ ( 93 /(\
R34 , R34 R34 , R34 R35 R33 R33 !NJ0,R36 "R36 R33 R33 , R33 , , , on i = R34 and , wherein R33 is independently selected from H, halogen, CN, C1_6-alkyl, fluoro-C1_6-alkyl, C1_4-alkylene-OH, C1-4-alkylene-O-C1_3-alkyl, C1.4-alkylene-0-fluoro-C1_3-alkyl, 0-C1_6-alkyl, 0-fluoro-C1-6-alkyl, NH-C1_6-alkyl, NH-fluoro-C1_6-alkyl, C3.10-cycloalkyl, C(0)N(R37)2, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C1_3-alkyl and fluoro-C1_3-alkyl;
R34 is independently selected from C14-alkylene-OH, C1.4-alkylene-O-C1_3-alkyl, C1-4-5 alkylene-0-fluoro-C1.3-alkyl, C3.10-cycloalkyl, C(0)N(R37)2, SO2N(R37)2, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C1_3-alkyl and fluoro-C1_3-alkyl;
R35 is C1.6-alkyl or fluoro-C1_6-alkyl;
10 R36 is independently selected from C1_6-alkyl, fluoro-C1_6-alkyl, C(0)N(R37)2 and SO2N(R37)2;
R37 is independently selected from H, C1_6-alkyl, halo-C1_6-alkyl, C0_4-alkylene-C3.6-cycloalkyl, C0.4-alkylene-C3.6-heterocycloalkyl, wherein alkyl and alkylene is unsubtituted or substituted with a substituent selected from halogen, OH, 0-C1_3-alkyl, CN; and cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently 15 selected from F, CN, OH, oxo, C1.3-alkyl and fluoro-C1_3-alkyl;
or wherein two R37 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1_4-alkyl and halo-C1_4-alkyl;
20 R38 is independently selected from H, C1_3-alkyl and fluoro-C1.3-alkyl;
R39 is H, F, OH, 0-C1.3-alkyl, 0-halo-C1.3-alkyl;
W is an annelated C5_8-cycloalkyl, an annelated 6-membered aryl or an annelated 5- to 6-membered heteroaryl, wherein cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 2 25 substituents selected from halogen, methyl and CF3, more preferably, W is an annelated aryl, unsubstituted or substituted with 1 to 2 substituents selected from fluoro, methyl and CF3;
X is an annelated saturated heterocycle selected from the group consisting of c.1-0 sss' ,rri- 0 õppsss'0 A-0 38 s&N-R38 sr\..A...\
ON(R37), (R4 (R37) (R37) ( n n 1:137) n ,0 tR37)n ) 1 9 µ
0 , cs5 0 .priss-[
ssss \ I
_38 (R37)n N and (R37)n =
, Y is an annelated 5- or 6-membered carbocycle, an annelated 6-membered aryl or an annelated 6-membered heteroaryl containing 1 to 2 nitrogen atoms, wherein the carbocycle, aryl or heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C1_3-alkyl and fluoro-C1_3-alkyl;
Z is an annelated 6-membered cycle forming a heteroaryl containing 1 to 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C1_3-alkyl and fluoro-C1_3-alkyl;
n is independently selected from 1 to 4.
In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from > ¨( 5 ¨ R33 / WR36 ------rR36 1 . R39 i¨( /NI ¨(___ 0 1¨</ I
1\1 411 R34 CI
N
R34 R34 , R35 9 9 9 *Ail VP
and , wherein R33 is selected from C1_6-alkyl, fluoro-C1_6-alkyl, C1.4-alkylene-OH, C1_4-alkylene-O-C1-3-alkyl, C1.4-alkylene-O-fluoro-C1.3-alkyl, 0-C1_6-alkyl, 0-fluoro-C1.6-alkyl, C3.10-cycloalkyl, C(0)N(R37)2, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C1_3-alkyl and fluoro-C1_3-alkyl, more preferably R33 is selected from fluoro, chloro, CF3, CHF2, OCF3, OCHF2, methyl, tbutyl and CMe2OH, 1-methylcyclopropyl;
R34 is selected from C1_4-alkylene-OH, C1_4-alkylene-O-C1_3-alkyl, C1_4-alkylene-O-fluoro-C1-3-alkyl, C3_10-cycloalkyl, C(0)N(R37)2, S(02)N(R37)2, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C1.3-alkyl and fluoro-C1-3-alkyl;
R35 is selected from C1_6-alkyl and fluoro-C1_6-alkyl;
R36 is selected from C1_6-alkyl, fluoro-C1_6-alkyl, C(0)N(R37)2, S(02)N(R37)2;
R37 is indenpedently selected from H, C1_6-alkyl, halo-C1_6-alkyl, C1_6-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C1_3-alkyl and fluoro-C1.3-alkyl, or wherein two R37 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, oxo, C1.4-alkyl and halo-C14-alkyl;
R35 is selected from H, C1.3-alkyl and fluoro-C1_3-alkyl;
R33 is selected from H, F or OH;
X is an annelated saturated heterocycle selected from the group consisting of sss' spr- 0 15-0 I¨N'R38 sPr N' R38 0 se\AJ
R37)n ss3 0 (R37)n Y-Lo R37)n f\lµ
(R37)n (R37)n (R37)n <5 0 sr, s R38 and (R37)n Y is an annelated 5- or 6-membered carbocycle, an annelated 6-membered aryl or an annelated 6-membered heteroaryl containing 1 to 2 nitrogen atoms, wherein the carbocycle, aryl or heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C1_3-alkyl and fluoro-C1_3-alkyl;
Z is an annelated 6-membered cycle forming a heteroaryl containing 1 to 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C1_3-alkyl and fluoro-C1_3-alkyl; and n is selected from 1 to 4.
In an equally more preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from 411, N(R37)2 N(R37)2 µN(R37)2 µN(R37)2 R33 , R33 and N(R37,2 , wherein R33 is independently selected from H, halogen, C1_6-alkyl, fluoro-C1_6-alkyl, C1_4-alkylene-OH, C1_4-alkylene-O-C1.3-alkyl, 0-C1_6-alkyl, 0-fluoro-C1_6-alkyl and C3_10-cycloalkyl, more preferably R33 is independently selected from fluoro, chloro, CF3, CHF2, OCF3, OCHF2, methyl, tbutyl and CMe2OH, 1-methylcyclopropyl;
one R37 is selected from H, C1.6-alkyl, halo-C1.6-alkyl and the other R37 is selected from C1_6-alkyl, halo-C1_6-alkyl, C0_4-alkylene-C3_6-cycloalkyl, C0_4-alkylene-C3_6-heterocycloalkyl, wherein, wherein alkyl and alkylene is unsubtituted or substituted with a substituent selected from halogen, OH, 0-C1_3-alkyl, CN; and cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, CN, OH, oxo, C1_3-alkyl and fluoro-C1_3-alkyl;
or wherein two R37 when taken together with the nitrogen to which they are attached may complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1_4-alkyl and halo-C1_4-alkyl;
W is selected from an annelated C5_8-cycloakyl, an annelated 6-membered aryl or an annelated 5- to 6-membered heteroaryl, wherein cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 2 substituents selected from halogen, methyl and CF3, more preferably, W is an annelated aryl, unsubstituted or substituted with 1 to 2 substituents selected from fluoro, methyl and CF3.
In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from OH
If g SF
g?0 10 0 1 li o i . s:::0 1 41 0 1\i(R37)2 , N(R37)2 , N(R37)2 , µN(R37)2 , CHF2 OCF3 OCHF2 .
1µ0_o II g:.-.0 'I, N(R37)2 IN(R37)2 , 1N(R37)2 , a P = CF3 a CF3 Cl Cl N(R37)2 F , 1 . gµNi--3(OR37)2 ' 1 II 4N9(C)R37)2 F2HC01. 4N( R37)2 ' = 0 CI
p N(R37)2 , N(R37)2 , µN(R37)2 , µN(R37)2 , iii N
/ \ . F
P 1 go = s,/?0 II s,-.0 .
N(R37)2 , N(R37)2 and µN(R37)2 , wherein N(R37)2 is selected from H H H H H l H
f\l< N H
I
N CF3 N1CF3 NCF3 N u3 NF N, , , , , NI NI f < 4 I ) < Ni 0 H Ni 0 NI I
N
OH and F, more preferably N(R37)2 is selected from H H H H H H
N N H N CF3 N CF3 N u3 NI<CF3 I
, , NCF3 , 1 X and , and most preferred N(R37)2 is NFII3u.
In an equally more preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from 5 ¨( N_=-( i __¨( /r\I ¨i /N N
( N--1( R34 , R34 , R34 , R34 , wherein R33 is selected from fluoro, chloro, CHMe2, CMe3, cyclopropyl, 1-methylcyclopropyl, CF3, CHF2, CMe2OH, CMe20Me, 0-CH2CMe3, 0-CH2CHMe3, OCF3 and OCHF2;
R34 is selected from C1_4-alkylene-OH, C1_4-alkylene-O-C1_3-alkyl, C3_10-cycloalkyl, 5 C(0)N(R37)2, SO2N(R37)2, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, methyl and CF3; and R37 is independently selected from H, C1_6-alkyl, halo-C1_6-alkyl.
10 In an equally more preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from V \ CF3 , , ¨0 0 HON
4 cF3 N
NH OH o o \ , cF3 41/ H I_Cro \ ir=___ y 1--( /11 y_ 1 \ /N1 %I 1 \ iNI
CI
411 V 141V ilk 14, i'll N NH N NH
15 o \ , o , o \ , o , 4 , 4 , OCF3 a O\
1 y 411 y CI NH . _iiky_111 /¨cF3 NH NH NH NH
0 0 0y 0 0 , cF3 cF3 .--cF 1 . _cF 1.y Iliky NH NH NH N NH
0 0 0 0 \ 0 , , , , , o ;- 1 . N 1 lik o i lik o NH NH
0 0 I $ CF3 , 111 , , OH OH 0...õ 0õ
411 ill 4,0 stko . 0 1.0 1.0 1.0 ,O
411 , Al , 4111 , , , , , 1.01,1101.01.014.01.=0 HN,õ<
411 , , , , iikg=0 = =,c) 1 . -,-0 i 11 :11= i * g' FIN f- , F3c ,, N---r -< 1 CF3, , o o i = -,c) i . s',0 1 * si-,0 ,c) i *$o Ny 1-114,,,6 4 41õ,z /
HN -....)CF3 , =
Br CI CI F CN
,0 9 si.-.0 i * 0 1 . si_-_-0 .
41,4 HN.,/..._ FIN , HIV 41 CI -\ ,,4... 1 HN,/__ /
V
i . . g=o ilk g'--.0 1 * go * $i=so HIVõ)z.... 41< FIN.< 141õ
rNi.< N
HN,..x..õ.
9 p 9 p 9 1 . =-,-,D 1 1, '----0 = ,----0 1 *Hto 1 = o HN/...._ , , HN..... 41 FFCIS.
HO\_1---HO-/ F--/ \O-Y----, $
, CF3 CF31 . gi?...0 ,0 CF3 ., f o .zo HN /5) CF3 HN,7 HN,,,p) HO--- FINNci 1 * (2/
NC , NH2 , -- $ , , CF3 0 CF3 9 CF3 1 * $0,z.0 p * s-,:o 1 = g%
1 * f-zo i * ',.--o 1 i HNyu3 HN
N , HN1 $ I , FIN rp ,,. 3 ' ,o o ,o ,o CF
1 . 7/--zo 1 * ,1-.-=o 1 * s,.-0 CF3 lik 7/--,-o . 9 Si =H
N
HN,,,CF3 HNNCF3 HN HN 1 I
CI
*$o 1 = s'--:o i *o 1 * sf FINI
1 '0 HINI FIN\ 1-k 1-k .< r,N1 F F i <
I
I
CHF2 0' F3C CI CI
0 p p ,0 ,5) 1 *3 *$o 1 *$o 1 Mk s0 *SNi z---y_.../0 HN HNN4 HN ..,. z Fkiz... H
, /
F2HC, F3C
CI c, CI CF3 0 b p o o p o o 1 . $i--=o * 4/--=o . o 1 = $i---,o * gi--.o 1 = e---=o Niz.... 1 FINN/..._ Hy FIN, FIN i/..._ HNiz FIN
i/_.
1 * Y 1 *
N,ssF1µ / 1 = / 1 N-N
NH
-----c o , C--0 , F 0' b \ , 0' b \
OH
1 . M / 1N / NH
/ N) N-N1 Wi N- 1 *
---c ----c --N i . /<
--N 1 * ---N
OH 0¨
/
1, ,0 N ¨ 1 * /NiNi- = 4= 1 . 7=9 * 7,0 i * , ,¨NH 0 HN - HNõ.<
¨N
N/ " / \ N N
/ \
"S
,0 s p * '-,o 1 * g'-=-o 1 * e---,o i * 10 i . $izzo i , FIN HNN4 Hti=IN4... FINiz._.. 1-IN
HisV...., / , . F
0 =
i . f.-zo 1 = y 1 * s--0 4. N"0 . NH 0 , i = 1\1/
FINiz....
NH
0 *, , 0 *0 i . HN-b = 0 1 * 0 ¨\ =
HN¨\ HN¨C) /
N-CF3, /
, , , o o i . o \---o * N 1 \ , /
0O 0µ 0 0 0 k "s-s-,s-NO N
No N 0 * 14-S___\
/--\ N U N H N
, \ i \ / /
and ' , .
In a further preferred embodiment in combination with any of the above or below embodiments of the first alternative R3 is selected from 41 .4 .4 411 A A
i 11 i . i . i 4. * 1 11 Y 1 4.
, CF3, , \, o \ , o , V , NH OH
0 \, 0 0 ...Ø..õõ,, .S'N,,,-\ ( , , / )<
i----/N1 y ¨NH N N NH N NH
0 0 \ 0 \ 0 0 \ 0 O , , , , ilik y 141 y_ . ________________________________ lik Ili P 1. 0 N NH NH NH
0 \0 0 0 N.,y,,, , , , , I , , ilk() ilko 1.0 1.110 1.0 1.0 1.0 1 , 411 , ' ' , , , (3.
o O o o / II o 1 . o 1 . ,_0 i li, .,c) / 11 ..--rN---, 1 V
O cF3 cF3 cF3 cHF2 I, i sik ro 1 11 g.0 1 41 si.-.0 1 . g,-o 1 . g',0 i =
, 1 rõN,,,,..-r- --- HIV.,< HN., HN, HN.,<
I --' , , , , 1 . g=0 =1 II
11 =-C) 1 . S 1 lik N i . NH
H..<
L.< 0 0 ' 0 i . 0 4.
1 HNb 0 1 .
HN-\ i * 1 *
CF3 , H 0 \1.---) N-/
, 1 * 0 \-0 = 0 0 HN /- . 0 0 \ / 7_ -) i N ( , , , 0, 0 0 0 0 0 k ;s,--0 / i NO N
N N N
NO .
/
and \
\__/ , , .
More preferably, R3 is selected from i 411 . 1 lik II y 11 OH NH OH
CF3 , , 0 N--z--1 . '1 _CF3 1 * -CF3 1 .
NH NH NH NH
0411 , 0 0 0 , , , , cF3 V
lik y 11V 11, g=0 1..g=0 i 1 *;=o 1 = g.c, NH
HN.,,..
41.., 1 HIV.,<
0 , Al , cF3, , 1 . '-==c) 1 . p 1 * siz--o 1 * $1=0 FINI HN 1 =$o HicCF3 HN rp 1 N.,....... 3 ,CHF2 i * Si:L.-0 1 . ===10 CF3 * Siz=0 i * i *
'---:0 I-114NCF3 Hy 1 HN 41,1Z) "\ HNV._ , HNN jz_ H/V._ Hyy HNN/__ HNV__ CI CF3 '0 7 S
o 9 111 ,o ,o ilk IlL'.o 41 g=o ..
, 4V_ HIL< HrV HNV__ , N
/ \ * F
1 4I Hg'--o , - 1 = szo Firi,z 5 Z----- and Most preferred, R3 is selected from cF3 i li 1 lik y 1 ilk 0 1 * V.0 i . Lo 9 141 41, NH
41N<
CF3 110 CI CI CI a p 9 p p 9 *$o 1 *o * s',--o 1 = szo , HN., HNN/.._ HIV HNy_s/ 4V
-9 / 9 and / ¨.
10 In a preferred embodiment in combination with any of the above or below embodiments of the first alternative R5 is selected from H, C1_6-alkyl, halo-C1.6-alkyl or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of 0-C1_6-alkyl, 0-halo-C1_6-alkyl and OH; and R6 is selected from H or halogen.
More preferably, R5 is selected from H, C1.3-alkyl, fluoro or chloro, even more preferred R5 is 15 selected from H, methyl, fluoro or chloro. Most preferably, R5 is methyl.
In a preferred embodiment in combination with any of the above or below embodiments of the first alternative R6 is selected from H, fluoro or chloro, more preferably R6 is hydrogen.
In a further preferred embodiment in combination with any of the above or below embodiments of the first alternative R4 is CR8R8-R10 ; R- is independently selected from H, F, C1_3-alkyl or halo-C1.3-alkyl; R1 is C3_10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1.6-alkyl, halo-C1--alkyl6 and cycloalkyl.
In a preferred embodiment in combination with any of the above or below embodiments of the first alternative R4 is selected from 1>0 .Andv .01.Nv F
and HO.
In an equally preferred embodiment in combination with any of the above or below embodiments of the first alternative R4 is CH2-(C4.7-cycloalkyl), wherein C4.7-cycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from fluoro or methyl.
In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative R4 is 011V,, aVvV VVVy =An.n.f OW" aVtiv Ho '0 'c and Even more preferred, R4 is *NW
~AI
ayvy I:a H07 VVVV
F F
F F and HO, and most preferred, R4 is CH2-cyclohexyl.
In another preferred embodiment in combination with any of the above or below embodiments of the first alternative the compound of Formula (1) is selected from the group consisting of o Q
3 \-1 \-1 N 0 HO
)--7-IN
111"
/ \ /\ / \
N *
0 OH N *
0 N *
CI) 0) &
0, Q 0 ,s,....7 0 0 "----1 HN ------1\-1N HN
11, if N * HN /* N *
& t CI) 0) , , , \_f HN001\-iN
/ \
N * I-IN k / \
/ \
N *
O) Szo CY
CH
LI
A 0 HOT-IN )-1\-1N 0 k HN
11, lir /\ /\ N /\
N * N * H
CY , CF3 , o LI LI
o o 0 HN AT-IN HN
if / \ / \/ \
N *N 0 N * Firk- N *
CI) I
ci .0 (a 0 0 (Q
Hbn HN HN HN
11, k *
HN*
N *
0 N * HN
N
& g-& 0) CF36 --C) , , , CLq co_0_\H HO
HN HN
0 i \
N * ck N N *
N
\ C
11'0 ICH I ) O
005,0.__, o 0 HN HN
lir 0' HN iv 0,.HNt\iN
llr / \ /
-Si, 0 \
N .
0 / '0 N *
OH)/ = 0 L\) al CH
n Q (Q
HN HN HN
CF3 if / \
i i \ * "N
\ ( N 10 N*
N . N k s-0) ,s,-.0 cf , CY 0/
, OH , ((....) HN
lir k /\ / \ N I\ N
H \
N 10 N pN 110 0) OH
& 4 CD) 4 , , , V\nN HN HN
I\
N * 0 N * Fir-- N *
0) CI) CF36' 0 &
4 , HO-.(:7 0 HO
V)-7-IN FIN HN HN
11, N * N o0 / \
' I
*
10) 4 , 0) , 0) 4 , Q (a HN HN
if HO / \ / \ /\
N IP
0 N *
Sr---f- HN*
0) 0) b 0) 4 d , (a / -Th HO \____ 0 -( szNi___µ0 HN _________________ 0 7)-7-IN 0 Q HN
N
N N
V N'N[0N / b N \
N
Q0 H02cõ,0 o 0 N
/ \ H I \ * sc-O >CH I \ .
N 0 Htl* N NH CO2H N
NH
0) po , d -7( , d ---7c , (()0,,,, = p N ill ._.,õ 0 N p H 1 \ . sr H ( _) N H 1 \ a sr N NI-1 iN 'NH N d 1---- NH
o -7( --7c , , , Ho2cµ
a i __ , 0 u3 0 cF3 a , N 0 0 'N
H 1 H I \ * g: 0 ,:--0 N
\ M. g,:: 0 H I \ gi-, N NH N ' NH
N) M NH
---7( a -7( o -7( ,a I- F F
/
)-\N
H i \ Ake g_o \_---\ H I \ 410, g,i,o o2sON . 1 \ a c) ) m 'NH NI) NH N) NH
0 -7c 0 -7c 0 -7( CQ HO2C,k F\
i MO
o Fl o N
\---<
, N ,0 0 Cl Cl CI CI 0 CI N
H 1 \ Ai sµ,..:0 H j\ M 0 H 1 \ M si:õ.,_0 N M. NH NI) 1114-11F NH N M NH
c3 --7c HO2C,1/4_ H 02Ck L o v O, o E o . , 'N 'NI
H 1 \ / \ N N
H I \ * /1 H I\
d ----c , , , 00N 0 cõ H I \ * 0 4 a 0 4 0 0 i N,......N,....õ...-,N
N N
H I \ * g',:-0 H I \ . ID
N NH N N
d d dF
5 , , , 0 1 N:
HO000., 0 ,N,N
1 k.,..,,N 0 4 HOOC N
'N H N
H I \ * 0 0 Ill I \ * H I \ *
N N N
d d d H
N, _iiii...õ_., 0 V 0 , jc 0 V 0 jk....f.õ, V
V
I N N
N H N N
H I \ = H H I \ * H I \ .
N N N
d d d , , , HOOCõ \:\ _0-N
a 0 CI o cF3 0=\/Nici..,...N 0 V
N H N
H I \ H I \ H I
N \ *
OH
N I* N
y_ N I/
d 0 NH
d A
d , , , HO000o HO000 o H2N 0 0 OH
N N1=-Y
H I \ \,N h,--.i._._ Nzi\ 1 \
=
N \
N N
d A
d d A
OH
HOOC,.cl o V 0 OH Ao. 0 OH
N
N ,0 H I \ = \ = gs?õ, H I \ . 8:=0 N 0 OH N HN ( N NH
d d d A
O 0 0 v _,--;Nri 1 \ . bi 1 \ * =-b' 1 \ .
O v OH N y_ 0 OH N y 0 OH N
d 0 d NH
d 0 NH
---i o HOOC) V HOOC :\ o OCF3 1,..1-1 1----' "NN N-Y¨
N H I \ . H I
\ N
\ /
H I . y N N
d d d 0 NH A A
y y y Ni----N--1 (1-: i</i HN 1 \ * 1:1<0 HO
0 / \
N =
d d F F
0) lir OH ' OH
O -NH . 0 \ OSIN 0 ----7cOl I \ . N , --m-- i, NH
H I \ w S N
NH
H I \ * S,I
N
,o 011 N (r0 N Cr HO d 0 d u3 F3c d F3d , , , OH
HO"L 0 .0, 0 ONia 0 OH
N N NH N
H I \ *
N 0" '0 N
FdN
d d a , , , OH OH
..---1--J,,, OH
(21'''.0 o V 'CI 0 V ,..]
O" ".c.-1 0 N
H I \ . N
H HN j<
N N H I \ == =() d0 0 ldN 8 HN d HN
)-F3 , F3 C)<
, C * , A, ca0ci 4 HO
HN ==ci N N
H I \ ==o H I \ .
ad * 0 N
d , , and an enantiomer, diastereomer, tautomer, N-oxide, solvate and pharmaceutically acceptable salt thereof.
In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative the compound of Formula (1) is selected from the group consisting of (a HO
) HN
1 ----\-----1\-IN 0 -----11 110"
/\ so /\ \ / \
N
0 OH N *
0 0) *
0) , CH , , 0, Q
HO
HN ---.\--T-IN HN
1r ir / \
N * "N* / \
N .
0 /\
0)0:--(:) , CH 0) , , _,OH 0 0 oi HNel\-1N lir 0 (1\-1N
lir N * H1,1* N *C 0 N * ) OS' CH
?..4 0 0 SITiN )-7-IN 0 ir /\ /\ Nk HN i \
N * N ,H
N$
, , ' 0 HN -S Oq rl\-IN HN
11, i \ i \ i \
* N * FIN* N *
0) I
0) 0) = , , , a Q
o ( 0 0 Hbn HN H HN
lir i \ /N \ * HN* ICI / \
0)N * 7*
N *
0 d-CF 31 ....
o oq cot_\ 0 OH HO
HN HN
i \ * \ 0 i\
0 c-k--N N 'PN
0) 8'o , CI) N\
, '..k 0 OST-M__-\ 0 0 HN HN
ir 0,FIN-ti\lN
ir /\ `S, 0 0)N 110 N
*0 OHNI *0 0) , , , Q()......) Q
HN HN HN
CF3 111, / \ s (N* /
N N * N * "Nk s-0) 0 CI) 0/ 0) 0 Q HO HO
HN kl\-IN k V)-71N
if k / \ "N" * N / \ N
N *H N IP \
CI) OH
CI) A & A
n 0 HO
7)-7-IN HN HN
/ \ I\ I\
* 0 N *
N ET ----- N$
CI) 0) CF36 -C) 13) A , HO
HO
0 --/.3 I-IN HN HN
ir / " / \0 0 /\
'1 N * N *
0 N .
CY A , CD) 0) A , , Q Q
IF HN HN
HO / \ / \ / \
*
N * FIN*
d 6 & A d' , z 0 b 0 CI) ____________________________________________________________ /
N *
and an enantiomer, diastereomer, tautomer, solvate and pharmaceutically acceptable salt thereof.
5 In a second alternative, the present invention provides a compound of Formula (1) R4 (i) an enantiomer, diastereomer, tautomer, N-oxide, solvate, formulation and pharmaceutically 10 acceptable salt thereof, wherein R1 is selected from a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0 and S, or 15 C1.10-alkyl substituted with a group selected from halogen, CN, OR11, SOyR11, SO3H, NRiis02-11, S02NR11R12, co2R11, COW, CONR11R12, NR-CO-R, NRUCONRhlRl2, S02-NRiiR12, NR11R12 and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, 0 and S, or C0_1-alkylene-C3_10-cycloalkyl substituted with a group selected from halogen, CN, SOyR11, NR11s02-11, S02NR11R12; c02.-.m11;
CONR11R12, CO-R11, NR11-CO-NR11 R12, NR, -S02_ H and NR11R12, or C2.10-alkylene-C3_10-cycloalkyl, C2_10-alkylene-O-C3_10-cycloalkyl, C2.10-alkylene-C6-10-heterocycloalkyl and C2_10-alkylene-O-05_10-heterocycloalkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, CN, 0-C1_6-alkyl, 0-halo-C1.6-alkyl, halo-C1.6-alkyl, halogen, CO2R11, CONIT1R12, SO2R11, S02NR1 R12, NR11coRil, NR11S021111, C3.6-cycloalkyl, 0-C3_6-cycloalkyl, C36-heterocycloalkyl, 0-C3_6-heterocycloalkyl, 0-C2_6-alkylene-0R11 and NR11R12;
R2 is selected from the group consisting of H, C1_6-alkyl, halo-C1_6-alkyl and hydroxy-C1-6-alkyl;
or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR", SOyR1'1, SO3H, h SO2NR11.-. m1 C0_6-alkylene-0O2R11, coNRil R12, C0R11, NR11-c0_Rii, Co_NRii NR11-S02-NR,,R12, NR11 R12, C1_6-alkyl, halo-C1_6-alkyl, hydroxy-C1_6-alkyl, cycloalkyl, 0-C3_6-cycloalkyl, C3_6-heterocycloalkyl and 0-C3.6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1_3-alkyl, halo-C1_3-alkyl and oxo;
R3 is a 6- or 10-membered mono- or bicyclic aryl or a 6- to 10-membered mono-or bicyclic heteroaryl containing 1 or 2 heteroatom selected from the group consisting of N, 0 and S, wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, CN, C1_6-alkyl, C3_10-cycloalkyl, C0.6-alkylene-C3-10-heterocycloalkyl, C0.6-alkylene-0-R31, C0_6-alkylene-000R31, C0_6-alkylene-C(0)R31, CO-6-alkylene-C(0)N(R31)2, Co_calkylene-N(R31)C(0)R31, C0.6-alkylene-S02-N(R31)2, Co_6-alkylene-N(R31)S02-R31, C0_6-alkylene-S02-R31, C0_6-alkylene-S0-R31 and C0_6-alkylene-N(R31)2, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1_3-alkyl, C3_6-cycloalkyl, C3.6-heterocycloalkyl, OH, 0-C1_3-alkyl, 0-halo-C1_3-alkyl, 0-C3.6-cycloalkyl, 0-C3_6-heterocycloalkyl, oxo, N(R32)2, COOH, CON(R32)2, CN and NR32-COR32, and wherein optionally two adjacent substituents complete a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1_6-alkyl, halo-C1_6-alkyl, C3-6-cycloalkyl, C3.6-heterocycloalkyl, oxo, OH, 0-C1..6-alkyl and 0-halo-C1.6-alkyl;
R4 is S02-(CR8R8)yR7, S02-NR12R7, (CR8R8),-R1 or C3.6-cycloalkyl, which is spirocyclic fused with C3_10-cycloalkyl;
R6 is selected from H, halo-C1_6-alkyl, CHO, CON(R62)2 or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of 0-C1_6-alkyl, 0-halo-C1_6-alkyl and OH;
R6 is selected from H, C1_6-alkyl, halo-C1_6-alkyl or halogen;
R7 is selected from C3_10-cycloalkyl and C3_10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, 0-halo-C1..6-alkyl, C1_6-alkyl, halo-C1_6-alkyl, cycloalkyl and heterocycloalkyl;
R8 is independently selected from H, F, C1_3-alkyl, halo-C1_3-alkyl or OH;
R1 is C3_10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, 0-C1_6-alkyl, 0-halo-C1_6-alkyl, C1_6-alkyl, halo-C1_6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1_2-alkyl, halo-C1-2-alkyl;
R11 is independently selected from H, C0.6-alkylene-C3_6-cycloalkyl, C0_6-alkylene-C3_6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C1_3-alkyl, halo-C1_3-alkyl, 0-halo-C1_3-alkyl and S02-C1_3-alkyl;
R12 is independently selected from H, C1_6-alkyl and halo-C1_6-alkyl;
R31 is independently selected from H, C1_6-alkyl, C0_6-alkylene-C3_6-cycloalkyl, C0_6-alkylene-C3.6-heterocycloalkyl, 5- or 6-membered heteroaryl and 6-membered aryl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, OH, oxo, C1_3-alkyl, halo-C1_3-alkyl, 0-C1_3-alkyl, 0-halo-C1_3-alkyl and S02-C1_3-alkyl;
' 53 and optionally wherein two R31 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1.4-alkyl and halo-C1_4-alkyl;
R32 is independently selected from H, C1.6-alkyl and halo-C1.6-alkyl;
R52 is independently selected from H, C1.3-alkyl and halo-C1_3-alkyl;
x is independently selected from 1 and 2;
y is independently selected from 0, 1 and 2.
In a further preferred embodiment in combination with any one of the above or below embodiments of the second alternative NR1R2 is selected from NHCH2CONH2, NHCH2CONMe2, NHCH2CH2OH, NHCH2CH(CF3)0H, NHCH2C(CF3)20H, NHCH2CH20Me, NHCH2CH2S02Me, NHCH2CH2S02NH2, NH(CH2)30H, NH(CH2)30Me, NH(CH2)40H, NH(CH2)40Me, NH(CH2)50H, NH(CH2)2CO2H, NH(CH2)3CO2H, NH(CH2)4CO2H, NH(CH2)5CO2H, NHCH2CMe2OH, NHCH(Me)CMe2OH, NHCH2CMe20Me, NHCH2CMe2CO2H, NHCH2CMe2CONH2, NHCH2CMe2CONHMe, NHCH2CMe2CONMe2, NHCH2CMe2NHSO2Me, NH(CH2)3SOMe, NH(CH2)5S02Me, NH(CH2)5S02NH2, NH(CH2)3NHSO2Me, NH(CH2)20(CH2)20H, NHCH2CHMe0H, NH(CH2)5SOMe, NCNN--\
NH(CH2)3S02Me, HN-3<, HN--(rF HN-CN- CF3, \--N 0 C
HN HN-V/H \--N7-\0 C\--N
NH
, ,0 HN-00 HN--\CO HN-CS HNSO HN-CS;
, HN--) HN-\4 HN->21 N
NH
\
, , HN NH\------) HN---11-4 o HN--- HN- HN--\ /
\S
/)/---OH )rNH 2 -OH
, , , HN--( / HN----\ / HN--\ _.._ HN--) /<
ICIHN--) 0 --) g JP
00 0 0 , \, HN
, , , HN--.< Nil- N'-'= N 0 HN -0 0 \r0 /<r(3 N)-LOH
HO, HO OH OH L./
, , , , CD.,,r0 HN, HN,, ...\ HN,,, HN HN,,, OH, OH, OH, OH, OH, HN,,,,i HNo HN
Helk.0 )(r0 OH, OH, OH, OH, HN---) /<0 HN HNHNON / HNN7"--) HN--\ p 7N,s/, \
OH, 0/0 o'0 OH
HN-->_1;11 0 HN->_r\il 0 HN-)A HN--->_111 0 r z 0\ , OH, OH, OH, HN ---)A 0 HN-.) 0 HN--rrHN-- 4D
1 HN--\ \OH
0 , \-OH HN-\
CDI , , , HN-\_80 1 1-1\1--\N Nil-- N3 I
\--OH, OH 1 Nrc OH 0 OH
0, N- N
LCZ.-0 1\1Th I__(.--No 0H NI N'N) S=0 b ._.--c) o--/ Ni / and NO .
, In a more preferred embodiment in combination with any one of the above or below 5 embodiments of the second alternative NR1R2 is selected from NHCH2CONH2, NHCH2CONMe2, NHCH2CH2OH, NHCH2CH(CF3)0H, NHCH2C(CF3)20H, NHCH2CH20Me, NHCH2CH2S02Me, NHCH2CH2S02NH2, NH(CH2)30H, NH(CH2)30Me, NH(CH2)40H, NH(CH2)40Me, NH(CH2)50H, NH(CH2)2CO2H, NH(CH2)3CO2H, NH(CH2)4CO2H, NH(CH2)5CO2H, NHCH2CMe2OH, NHCH(Me)CMe2OH, NHCH2CMe20Me, 10 NHCH2CMe2CO2H, NHCH2CMe2CONH2, NHCH2CMe2CONHMe, NHCH2CMe2CONMe2, NHCH2CMe2NHSO2Me, NH(CH2)3SOMe, NH(CH2)5S02Me, NH(CH2)3NHSO2Me, F
NC HN--\
NH(CH2)20(CH2)20H, NHCH2CHMe0H, HN-\<1, HN-<r , HN-CN-, CF3, HN-r-\0 HN \---\_NrTho C-- \--NO r \--- NCO
HN-\____ \___/ \
HN-- HN-v...O_H HN---\L---OH
HN-CO HN-\CO HN-CS HN-CS-,---0 ,NO H -CN -4 x 0 -N-1(___ HN-CS; 0 HN-CN HN
HN--) \
HN- 0 qH HN-- JO HN--\-S- 9 HN
\ --)--NH2 HN----)1 Nr0 P 8 , HN OH HN NH2 HN NH HN--)___[\11 HN--)._>/_ \-----) µS"\C' zr34 o HO 0 HN) 4:) HN-- HN--\ / HN--\ / HN--\ p c__N-/ ( >--OH --NH2 HN-S:=0 - I tNH2 0 0 0 , \
, , , , HN--<, Nil- N Na HN,,, HN- 0 (j4 0 'Or10 0 0 \r rr HO OH HO OH OH OH
, , , , , HN,,, HN,,, i HNr0 0 OH , OH, OH , OH , 0 HN-)._1,71, HN--) HN-11 0 HN---...11 IN \r0 HN-\ 1 < r ...o--OH , OH , OH, HN->111 0 HN 0 0. P
---)Z
HN HN
)4) (C --IN--\
\
HN-\ \
0 , \--OH, OH, , HN--)ip 4c HN-).
HN-\
d>r-NH\--cm 1--( 1-1\ N pH OH, 0 2 , , H .
O 0', i) , , S=0 0 and \ib .
More preferably, NR1R2 is selected from HN---)(7,H ,0 HN-00 HN-CS--:--0 HN-CS
--\ ' \ c HN -\
c \ Nar HNõ, HN /<0 0 , HN
HNõ,or HN N-O 0<r0 N34 OH LO Le10 N
OH, OH, 0, 6 , 0 and N
S='-0 0;
and most preferred NR1R2 is HN OH HN-\ c 0 N
-4 N3)\A 0 OH HN C)H , OH
HNõ HN,,,Oro HN
.0,r0 101<r0 OH, OH and OH.
In another preferred embodiment in combination with any one of the above or below embodiments of the second alternative R3 is , --R33 R33 R33 ( 1 . R39 h (N i----K\ N
R34 , R34 , R34 and R34, wherein R33 is independently selected from C1_6-alkyl and fluoro-C1_6-alkyl;
R34 is independently selected from halogen, C1_6-alkyl, fluoro-C1.6-alkyl, 0-C1.6-alkyl, 0-fluoro-C1_6-alkyl, NH-C1_6-alkyl and NH-fluoro-C1_6-alkyl;
R39 is selected from H, F and OH.
In yet another preferred embodiment in combination with any one of the above or below embodiments of the second alternative R3 is selected from F 1 * OH 1 411 1 . OH
F
-( N _c=-( 1 \ N
3 , 5/ ( F2HCO 0N-x_ --( ----- . 3 /
y_ 7-HN-/ , HN , and .
More preferably, R3 is 4. 1 lik F =
1 * OH 1 11 -)<
1 'OH 1 \ '/NI i . F
, , , , 9 , CF3 1 i-( 0- -(CF3 --(.
\ 0-x (0 3 - -)\--\ /N i---=( 41%1 CF3,,CF3 and , , .
Even more preferably, R3 is N=?<
5 /N 1-= /N L- ?, and ?
5/¨
.
In a further preferred embodiment in combination with any one of the above or below embodiments of the second alternative R5 is selected from H, C1.6-alkyl, halo-C1_6-alkyl or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of 0-C1_6-alkyl, 0-halo-C1.6-alkyl and OH.
More preferably, R5 is selected from H, C1_3-alkyl, fluoro or chloro, even more preferred R5 is selected from H, methyl, fluoro or chloro. Most preferably, R5 is methyl.
In a preferred embodiment in combination with any of the above or below embodiments of the second alternative R6 is selected from H, fluoro or chloro, more preferably R6 is hydrogen.
In another preferred embodiment in combination with any one of the above or below embodiments of the second alternative R4 is S02-R7, S02-NR12R7, CHR8-R1 and (CH)2R10;
R7 is independently selected from C3_10-cycloalkyl and C3_10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, OH, alkyl, halo-C1_6-alkyl and cycloalkyl;
R8 is H, F, C1.3-alkyl or halo-C13-alkyl;
R1 is C3_10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C16-alkyl, halo-C1_6-alkyl and cycloalkyl.
In a further preferred embodiment in combination with any one of the above or below embodiments of the second alternative R4 is selected from vw vw 11140, vw 0-vvvb 0-s, y 0_1 0vw ' NI
N ob,00 0' N
or More preferably, R4 is CH2-C4.7-cycloalkyl, most preferably, R4 is CH2-cyclohexyl.
In yet another preferred embodiment in combination with any of the above or below embodiments of the second alternative, the compound of Formula (1) is selected from the group consisting of oq o ol--\
HN, HN HN F3C.,..\ HN
, 0' /S --O / \
N * N \ N
= N 1104 0) CY 0) 0 0 0 0 -1\-1N
)I-T-IN
H2N----1\1N
N * ---N \ N
z N CH * CI) 0) , OL.q HO
_________________________________________________________________ 9Th HN H.20 7)-7-iN
/\
N * N * N \ N
=
0) 0) , 0) , , , 0 0\
0," \S
SI___q i --7 L... 0 HN HO--N HN
/\ /\ /\
N * N 1110 N .
CI) 0) OL..q 0 0/-"\ 0 0 HN HN -------5F?N
0 /\
N \ N N * N *
0) oq (2.4 o o 0 HN HN )----\ --1\-IN
/ \ / \ 0 / \
*
ICI) CI) 0) , , , oL..q0 0 0 HN F HN HN
I\ / \ / \
N10 rij IP
0) Sr:--0 Cril b 0 1_ 4 1 . . ...q 0q 0 HN HN / \
/ \
\ CF3 *
N$
Olt oq L...q o o clq / \
10 / \ HN
Y
N
0, b )criN *
, OqOz_q (Lq HN HN HN
/\ CF3 /\ / \
NP N * N *
0) 0) F
C) HO2Ck El 0 HOOC, 0 H
--r I \ * ljCn ____ N-N
N
, d c3 , d , HOOCõ.0N ::01,,,.0, H I = \ /NI N
H \ \ \ /N
7---N ________________ N
d d and an enantiomer, diastereomer, tautomer, N-oxide, solvate and pharmaceutically acceptable salt thereof.
More preferred are compounds of Formula (1) selected from the group consisting of oq o ol--\
HN, HN HN F3C...._1 HN
O'70 / \ /\
N * N \ z N N 110 0) CI) Crj \i HN
/ \
N *
CI) 0) 0) 01..qHO
9""Th HN HSCN
kl\-IN
N 110 N * 0) \ z N
CY CI) 0 0, 0."
"-Si.q HN HO-C HN
/\ / \ / \
N * N 110, N *
Cf) 0) '/ OLq 0 HN HN
/\ 0 / \
0) 0) 0) OL..q01....q )Th 0"---\ 0 HN HN HN
/ \ \ 0 /\
*
or , , , 0 I:4 0 CL:14 HN F HN HN
N * 0 , 0 b ,s--0 , 0 b , , 0 OLq HN HN / \
/ \ / \ CF3 Ni 104 Y 10 N \ N ,S=0 Olt 0) / 9=1 lb, , , , cLq 0 ci_q HN HN (1..q / \
E / \ HN
Y * N . / \
,S=0 N *
b oq o oq o zq HN HN HN
/ \ CF3 0) N * ,0) N * Fande N #
.
The invention also provides the compound of the invention for use as a medicament.
Also provided is the compound of the invention for use in treating RORy mediated inflammatory and autoimmune diseases.
Preferably, the disease is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, psoriatic arthritis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, asthma, mucosal leishmaniasis, multiple sclerosis, systemic sclerosis, type 1 diabetes, Kawasaki disease, Hashimoto's thyroiditis, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thromobotic purpura, myasthenia gravis, Sjorgren's syndrome, scleroderma, ulcerative colitis, epidermal hyperplasia, glomerulonephritis, chronic obstructive pulmonary disease and amyotrophic lateral sclerosis. More preferably, the disease is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, psoriatic arthritis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, asthma, multiple sclerosis, type 1 diabetes, chronic obstructive pulmonary disease and amyotrophic lateral sclerosis. Most preferred, the disease is rheumatoid arthritis or psoriasis.
Also provided is a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier.
In the context of the present invention C1_12-alkyl means a saturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, which may be straight chained or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
The term "halo-C1.12-alkyl" means that one or more hydrogen atoms in the alkyl chain are replaced by a halogen. A subset of this term is "fluoro-C1_4-alkyl", wherein one or more hydrogen atoms in the alkyl chain are replaced by a fluorine atom. Preferred examples thereof are CF3, CH2CF3 and CH2CH2F.
C2-12-alkenyl means a hydrocarbon chain having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, which may be straight chained or branched, containing at least one carbon to carbon double bond. Examples thereof include ethenyl, propenyl, dodecenyl, 2-methylenehexyl and (2E,4E)-hexa-2,4-dienyl.
C2-12-alkynyl means a hydrocarbon chain having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, which may be straight chained or branched, containing at least one carbon to carbon triple bond. Examples thereof include ethynyl, propynyl and dodecynyl.
A "C0_6-alkylene" means that the respective group is divalent and connects the attached residue with the remaining part of the molecule. Moreover, in the context of the present invention, "Co-alkylene" is meant to represent a bond.
A C3_10-cycloalkyl group means a saturated mono-, bi- or multicyclic ring system comprising 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, pentacyclo[4.2Ø02=5.03'8.04Ioctyl and adamantyl.
A C3_10-heterocycloalkyl group means a saturated or partially unsaturated 3, 4, 5, 6, 7, 8, 9 or 10-membered carbon mono-, bi- or multicyclic ring wherein 1, 2 or 3 carbon atoms are replaced by 1, 2 or 3 heteroatoms, respectively, wherein the heteroatoms are independently selected from N, 0 and S. Examples thereof include epoxidyl, oxetanyl, pyrrolidinyl, 5 tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl, 4-quinuclidinyl, 1,4-dihydropyridinyl and 3,6-dihydro-2H-thiopyranyl. The C3_10-heterocycloalkyl group can be connected via a carbon or nitrogen atom, if not stated otherwise.
A 5- to 10-membered mono- or bicyclic heteroaryl system containing up to 4 heteroatoms means a monocyclic heteroaromatic ring such as pyrrolyl, imidazolyl, furanyl, thiophenyl, 10 pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and thiadiazolyl. It further means a bicyclic ring system wherein the heteroatom(s) may be present in one or both rings including the bridgehead atoms. Examples thereof include quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzisoxazolyl, benzodioxanyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl and pyrazolo[1,5-a]pyrimidinyl. The nitrogen 15 or sulphur atom of the heteroaryl system may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. If not stated otherwise, the heteroaryl system can be connected via a carbon or nitrogen atom. Examples for N-linked heterocycles are s, se, SN
1_/
and .
A 6- to 10-membered mono- or bicyclic aryl system means an aromatic carbon cycle such as 20 phenyl or naphthalenyl.
The term "N-oxide" denotes compounds, there the nitrogen in the heteroaromatic system (preferably pyridinyl) is oxidized. Such compounds can be obtained in a known manner by reacting a compound of the present invention (such as in a pyridinyl group) with H202 or a peracid in an inert solvent.
25 Halogen is selected from fluorine, chlorine, bromine and iodine. The preferred halogen is fluorine.
Furthermore, the compounds of the present invention are partly subject to tautomerism. For example, if a heteroaromatic group containing a nitrogen atom in the ring is substituted with a hydroxy group on the carbon atom adjacent to the nitrogen atom, the following 30 tautomerism can appear:
) When a substitution of a residue with cycloalkyl or heterocycloalkyl is described, it is understood that the substitution can be connected straight and, when the connecting carbon atom is sp3-hybridized, in addition spirocyclic. For example, when cyclohexan is substitued with the heterocycloalkyl group oxetan-3-yl, the following structures are possible:
aCj and It will be appreciated by the skilled person that when lists of alternative substituents include members which, because of their valency requirements or other reasons, cannot be used to substitute a particular group, the list is intended to be read with the knowledge of the skilled person to include only those members of the list which are suitable for substituting the particular group.
The compounds used in the present invention can be in the form of a pharmaceutically acceptable salt or a solvate. The term "pharmaceutically acceptable salts"
refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. In case the compounds of the present invention contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the present invention which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the present invention which contain one or more basic groups, i.e. groups which can be protonated, can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids known to the person skilled in the art. If the compounds of the present invention simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
The present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
In practical use, the compounds used in the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.
The tablets, pills, capsules and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
The compounds used in the present invention may also be administered parenterally.
Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral (including intravenous), ocular, pulmonary, nasal and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. Preferably compounds of the present invention are administered orally.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
When treating or preventing RORy-mediated conditions for which compounds of Formula (1) are indicated, generally satisfactory results are obtained when the compounds are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of mammal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligram to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
The present invention describes modulators, in the following also referred to as ligands, which bind to the RORy receptor. Surprisingly, it has been found that compounds of Formula (1) act as modulators of the RORy receptor.
The RORy receptor is considered to be involved in thymocyte development, thus the modulators described herein may be useful in the treatment of inflammatory skin diseases such as atopic eczema and psoriasis. It is further suggested that down-modulation of RORy transcriptional activity with a ligand could result in a shift of the immune response towards a Th2 type response which could be beneficial in the treatment of certain allergic inflammatory conditions such as rheumatoid arthritis, systemic lupus erythomatosis, inflammatory bowel disease (Crohn's Disease) and multiple sclerosis (Tesmer et. al., lmmunol.
Rev. 2008, 223:97).
The compounds of Formula (1) show antagonistic activity, with respect to the dose dependent modulation of the constitutive interaction of the RORy ligand binding domain with peptides derived from the co-activators such as SRC-1, TRAP 220 or TIF-2.
It has been surprisingly found that the interaction between RORy ligand binding domain and the peptides can be determined by a homogenous FRET based ligand-sensing assays. Even more surprising was the identification of compounds of Formula (1) as ligands for RORy.
The identification of high affinity ligands for RORy with agonistic and antagonistic properties is the basis to enable experts knowledgeable in the field to establish assays for the identification of novel agonistic and antagonistic RORy ligands from libraries of small molecules. The identification of ligands which bind to and modulate the activity of RORy1 and RORyt is the first mandatory step to develop new small molecule based medicines with a potential to be developed for the treatment of diseases which are directly or indirectly controlled by the activity of RORy1 or RORyt. Such diseases include but are not restricted to inflammatory diseases, asthma, rheumatoid arthritis, autoimmune diseases or diseases with an autoimmune component such as systemic lupus erythomatosis, inflammatory bowel disease (Crohn's disease), ulcerative colitis, inflammatory skin diseases such as atopic eczema or psoriasis, multiple sclerosis or similar diseases.
The compounds of the present invention can be prepared by a combination of methods known in the art including the procedures described in Schemes I to Ill below.
Pyrrole-3-esters of general structure A (Scheme I) can be N-derivatized by alkylation with alkyl halides, by reaction with sulfonyl chlorides or sulfamoyl chlorides in the presence of appropriate bases in appropriate solvents. The introduction of an aromatic or heteroaromatic substituents in the 5-position of intermediates B (Scheme I) can be achieved either by bromination with N-bromosuccinimide (NBS) and subsequent Suzuki cross coupling with boronic esters or boronic acids or by an Ir-catalyzed direct borylation (as described in J. Am.
Chem. Soc.
2007, 129:15434) of intermediate B (Scheme l), followed by boronic ester hydrolysis and Suzuki cross coupling with halo-aromatics or halo-heteroaromatics. The order of alkylation and bromination to prepare intermediates C can be inverted as depicted in Scheme I. The common intermediate E (Scheme I) can be further transformed into carboxamides by ester hydrolysis and amide formation using methods known to those skilled in the art.
Scheme I
0Alk 0Alk o R6 NBS oR6 ______________________ 1 Alk = alkyl RN ---1-1 R5 N Br ili A ill 1 xR4 I XR4 base, solvent base, solvent 0Alk 0Alk NBS
R5 Br ,....-0, 1. direct borylation" B¨R3 2. boronic ester hydrolysis -7-0 Suzuki coupling 0Alk 0Alk HNR1R2 Oi_.R...6 XR 0 _ . ....R 6 ester OH amide 3 .. hydrolysis 0 R6 formation 0 / \ ___________________ ... i \ ' R4 D Suzuki coupling 11 R4 E R5 R' ri R4 R' ri Alternatively, for purposes of tailored late stage derivatization, the formation of the amide can be performed first, followed by bromination and Suzuki cross-coupling as final step, as depicted in Scheme II.
Scheme II
0Alk OHNR1R2 0 o R6 6 ester hydrolysis R amide coupling 0 _ R:
R H R ''--H ________ .... / \
11 il N H
Alk = alkyl0 1 NBS
_.r.-' B¨R
NR1R2 0' NR1R2 0 _ _ R6 Suzuki coupling / \ , 11 \
IR' 11 R' R- Br In alternative to Pd-catalyzed cross coupling reactions the 2-position of pyrrole A (Scheme III) can be acylated and the resulting ketone intermediate B (Scheme III) can be further transformed into heteroaromatics containing analogues of the general formula C
in Scheme III, using methods described in Org. Lett. 2008, 10:2897. Again, intermediate C (Scheme III) can be further transformed into carboxamides by ester hydrolysis and amide formation using methods known to those skilled in the art.
Scheme III
0Alk 0Alk 0Alk R6 acylation / \
a ...
' / \ R6 R steps for hetero-romatic ring formation R r, R- N H R5 Ki R4 R4 0 R4 "
Alk = alkyl I
R' R, R', R", R"' = additional substituents 1. ester hydrolysis 2. amide formation R r, S¨
Y
D µ /
I
R' Abbreviations Ac acetyl ACN acetonitrile aq. aqueous B2Pin2 4,4,4',4',5,5,5',5'-octamethy1-2,2'-bi-1,3,2-dioxaborolane CC flash chromatography on silica gel COD cyclooctadiene Cy cyclohexyl dba dibenzylideneacetone DCE 1,2-dichlroroethane DCM dichloromethane DIPEA diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-dimethylformamide dppf 1,1'-bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane dtbpy 4,4'-di-tert-buty1-2,2'-bipyridine EA ethyl acetate HATU 0-(7-azabenzotriazole-1-y1)-N,N,N',N4etramethyluronium hexafluorophosphate MOM methoxymethyl MTBE tert-butylmethylether NBS N-bromosuccinimide NCS N-chlorosuccinimide Pin pinacolato (0CMe2CMe20) PE petroleum ether prep. preparative rt room temperature TBAB tertabutylammonium bromide Tf trifluoromethanesulfonyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Experimental Section Preparative Examples The synthesis of the following Preparative Examples is described in W02012/139775:
B
tk _(¨ ___________________________ ¨Y
B \ / / 76 N B¨(4N <
0' \ ,I3 \
-c,-\
P1 0 P2 0F3 , P3 0-7 , leL-'El 11 0 _______________________________________ V-NH ).- C)sB . V-N
N 0 HO' 0 cl 8 5, P6 , P10 , P11 , _________ -0 '0 02 g / NSõN - õ_,õµ CF3 ___________ :B *
L............õ kmanoi---00 (H0)2B¨Ce-0/ \
( / P13 . P14 \ ( P15 , ____________________________________________ _o\ -os 7\ V-os -=( 4 B * 0 _______________________________________________ .
)--Ci\B--C¨N/H B \ /N 0' -0 td \ rµli r--ci \
P16 P17 A, P20 P21 A , , , .4 V
_________ 13 lik ID (H0)2B 4I F __________ 'B 411 __ , ,I3 * )70,B *
-0' 1-0,/ _____________________________________________ -0 P22 0F3P24 p25 0F3 P26 0F3 P27 4 , , , , , )B * __ B B
:
-0 V-0, ['d * V-0, -T-0 411 -Os P28 4 P29 OH, P34 A , P35 A , , ________________ -0 ________________ B
: 41 -0 /--CF -0\ ? CF3 y_ _____________________________ sg 411, _.il 3 ) ,B * s-NHc-0' -0 ii 0 81 )\--P37 0 , P39 , P40 , )-Os 0 -0\
-.... ,B * g-Nb * ___)o'B II o )- B . 0 0 8 o' ) ____\-o 0 HO \-o, o c):E) ATL, :g- ,NH OH 13 11 -7 (5) B .
"-NH 0 S
P46 0F3 p47 0F3 P48 CF3 y 3 9 B cF, , . B * N 0 B * 0 P52 F , P68 0 P88 P98 OH , \ -o, o 7-o'B 11, Preparative Example P7 B . 0 \
Step 1: 4-Bromo-2-(tert-butvl)phenol (P7a) To a solution of 2-(tert-butyl)phenol (30.0 g, 200 mmol) in CHCI3 (600 mL) was added tetra-n-butyl ammonium tribromide (121 g, 250 mmol) and the solution was stirred for 2 h at rt, concentrated and the crude product was partitioned between Et20 and water. The organic layer was washed sequentially with 1M HCI twice and brine twice. The organic layer was separated and dried over MgSO4, concentrated and purified by CC (PE/EA = 7/1) to give compound P7a (39.9 g, 89%) as a colorless solid.
Step 2: 4-Bromo-2-(tert-butvI)-1-(methoxymethoxv)benzene (P7b) NaH (4.40 g, 110 mmol) and MOMCI (9.60 g, 120 mmol) were gradually added to a solution of compound P7a (22.8 g, 100 mol) in dry DMF (300 mL) while cooling on ice and the mixture was stirred at 0 C overnight, poured into ice water and extracted with EA (3x). The combined organic layer was washed with water (3x) and brine consecutively, dried over Na2SO4, concentrated and purified by CC (PE/EA = 100/1) to give compound P7b (24.9 g, 92%) as a light yellow oil.
Step 3: 2434 tert-Butv1)-4-(methoxvmethoxv)phenv1)-4,4,5,5-tetramethvI-1,3,2-dioxaborolane (P7) A solution of compound P7b (24.2 g, 89.0 mmol), B2Pin2 (24.1 g, 95.0 mmol), KOAc (9.31 g, 95.0 mmol) and Pd(dppf)Cl2 (4.00 g) in dry DMF (500 mL) was heated at 90 C
overnight under N2, concentrated and the residue was partitioned between water and EA.
The aq.
layer was extracted with EA and the combined organic layers were washed with water twice and brine consecutively. The organic layer was dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 5/1) to give compound P7 (15.4 g, 54%) as a colorless solid.
5 Preparative Example P8 )ckB /_ Step 1: 6-tert-Butv1-4-hydroxvpvridin-2(11-1)-one (P8a) A mixture of 6-tert-butyl-4-hydroxy-2H-pyran-2-one (38 g, 168 mmol) and aq.
NH4OH (150 mL, 30%) in dry toluene (200 mL) was heated at reflux for 1 h, concentrated and purified by 10 CC (PE/EA = 5/1) to give compound P8a (22.5 g, 80%) as a colorless solid.
Step 2: 4-Bromo-6-tert-butvlovridin-2(11-1)-one (P8b) To a solution of compound P8a (9.7 g, 60 mmol) in DMF (100 mL) was added POBr3 (17.2 g, 60 mmol) and the mixture was heated at 90 C for 2 h, was concentrated, diluted with water and extracted with EA. The organic layer was washed with brine (3x), concentrated and 15 purified by CC (PE/EA = 5/1) to give compound P8b (22.5 g, 80%) as a yellow solid.
Step 3: 4-Bromo-2-tert-butyl-6-(neopentvloxv)Pvridine (P8c) To a solution of compound P8b (2.0 g, 8.66 mmol) in dry DMF (20 mL) was added NaH
(0.62 g, 26.0 mmol) under N2 and the mixture was stirred at rt for 1 h. Then 1-bromo-2,2-dimethylpropane (2.37 g, 15.7 mmol) was added and the resulting mixture was heated at 20 80 C overnight, quenched with water (10 mL) and extracted with EA twice.
The combined organic layers were washed with brine (3x), concentrated and purified by CC
(PE/EA = 50/1) to give compound P8c (0.5 g, 20%) as an oil.
Step 4: 2-tert-Butyl-6-(neopentvloxv)-4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)pvridine (P8) 25 A mixture of compound P8c (2.2 g, 7.72 mmol), B2Pin2 (2.94 g, 11.6 mmol), KOAc (1.13 g, 11.6 mmol) and Pd(dppf)Cl2 (200 mg) in dry DMF (20 mL) was heated at 90 C
under N2 overnight, quenched with water and extracted with EA twice. The combined organic layers were washed with brine (3x), concentrated and purified by CC (PE/EA = 50/1) to give compound P8 (2.5 g, 97%) as an oil.
Preparative Example P9 os tB \ <¨_?/ o, /N
2,6-Di-tert-butyl-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)Pyridine (P9) Under N2 a catalyst stock solution was prepared by weighing [(COD)Ir(p-OMe)12 (104 mg, 0.312 mmol Ir), dtbpy (84 mg, 0.312 mmol) and B2Pin2 (2.64 g, 10.4 mmol) into a vial followed by the volumetric addition of degassed MTBE to make up a 25 mL
solution which upon shaking developed a deep red color. The solution was transferred to a vial and sealed with a rubber septum. Under N2, a vial was charged with 2,6-di- tert-butylpyridine (1.91 g, 10.0 mmol) followed by 25 mL of the catalyst stock solution. The reaction was heated at 80 C for 2 h, concentrated and purified by CC (PE/EA = 8/1) to give compound P9 (1.89 g, 60%) as a colorless solid.
Preparative Example P18a and Preparative Example P18 o o N \OH
dP18a d P18 Step 1: Ethyl 1-(cyclohexylmethyl)-2-methy1-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)-1H-pyrrole-3-carboxylate (P18a) To a solution of 1-(cyclohexylmethyl)-2-ethyl-1H-pyrrole-3-carboxylate (prepared according to Example 1d, 2.12 g, 8.51 mmol) in THF (20 mL) was added [(COD)Ir(p-OMe)]2 (167 mg, 0.25 mmol), dtbpy (137 mg, 0.51 mmol) and B2Pin2 (2.38 g, 9.37 mmol) and the solution was stirred overnight at 100 C under N2, concentrated and purified by CC (PE/EA =
50/1) to give compound P18a (2.24 g, 70%) as a colorless solid.
Step 2: 1-(Cyclohexylmethyl)-4-(ethoxycarbony1)-5-methyl-1H-pyrrol-2-ylboronic acid (P18) To a solution of P18a (1.50 g, 4.00 mmol) in a mixture of acetone (15 mL) and water (15 mL) was added sodium periodate (2.55 g, 12.0 mmol) and ammonium acetate (1.00 g, 13 mmol) at rt and the solution was stirred at reflux for 2 d, concentrated and extracted with EA. The organic layer was washed with 0.1M HCI and brine consecutively, dried over Na2SO4, filtered and concentrated to give intermediate P18 (1.17 g, quant.) as a colorless solid.
Preparative Example P19 -os 0 N
)10)3 41 o Step 1: 2-(tert-Butyl)-4-chlorophenol (P19a) To a mixture of 4-chlorophenol (50 g, 0.39 mol) and t-BuOH (57.6 g, 0.78 mol) was added conc. H2SO4 (40 mL) and the solution was stirred at rt for 48 h, poured into ice-water and extracted with EA twice. The combined organic layers were washed with water (3x) and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA =
40/1) to give compound P19a (48.5 g, 68%) as a colorless solid.
Step 2: 2-(tert-ButvI)-4-chlorophenvl trifluoromethanesulfonate (P19b) To a solution of compound P19a (32.0 g, 174 mmol) and pyridine (22.5 mL, 278 mmol) in dry DCM (500 mL) was added a solution of Tf20 (35.5 mL, 209 mmol) in dry DCM (150 mL) under ice cooling and the solution was stirred for 4 h at rt, poured into 1M
HCI and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 10/1) to give compound P19b (40.0 g, 82%) as a pale yellow solid.
Step 3: Methyl 2-(tert-butyI)-4-chlorobenzoate (P19c) A solution of compound P19b (40.0 g, 142 mmol), dppp (5.0 g, 12 mmol), Pd(OAc)2 (2.7 g, 12 mmol) and NEt3 (150 mL, 1.1 mol) in a mixture of Me0H (300 mL) and DMSO
(400 mL) was stirred overnight at 55 C under an atmosphere of CO. Water and EA were added and the organic layer was separated, washed with water twice and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 8/1) to give compound P19c (27.1 g, 84%) as a colorless solid.
Step 4: 2-(tert-Butyl)-4-chlorobenzoic acid (P19d) To a stirred solution of compound P19c (542 mg, 2.40 mmol) in a mixture of DMSO (6 mL) and H20 (2 drops) was added t-BuOK (538 mg, 4.8 mmol) and this mixture was stirred at 85 C for 4 h, adjusted to pH = 2-3 with 1N HCI and then extracted with EA
(3x). The combined organic layers were washed with water (3x) and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 2/1) to give compound P19d (404 mg, 80%) as a yellow solid.
Step 4: (2-(tert-Buty1)-4-chlorophenv1)(piperidin-1-yOmethanone (P19e) A solution of compound P19d (404 mg, 1.91 mmol), piperidine (244 mg, 2.87 mmol), HATU
(870 mg, 2.29 mmol) and DIPEA (616 mg, 4.78 mmol) in DMF (5 mL) was stirred at rt for 20 min, quenched with water and extracted with EA twice. The combined organic layers were washed with water (3x) and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by prep. TLC (PE/EA = 1/1) to give compound P19e (550 mg, 97%) as a yellow solid.
Step 5: (2-(tert-Butv1)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-v1)phenv1)(piperidin-1-vpmethanone (P19) A stirred solution of PCy3 (100 mg, 0.35 mmol) and Pd(dba)2 (200 mg, 0.35 mmol) in 1,4-dioxane (20 mL) was stirred at rt for 30 min, then compound P19e (550 mg, 1.97 mmol), P2Bin2 (767 mg, 2.17 mmol) and KOAc (546 mg, 1.90 mmol) was added and the solution was heated at 90 C for 3 h, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give compound P19 (159 mg, 22%) as a colorless solid.
Preparative Example P23 :B =
Step 1: 1-(3-BrOM0-5-(tert-butVOIDhenVOCyClObutan01(P23a) To an oven dried 100 mL 3-neck flask was added 1,3-dibromo-5-(tert-butyl)benzene (500 mg, 1.72 mmol) in dry THF (30 mL) under N2 and the mixture was cooled to ¨78 C. n-BuLi (2.5M, 1 mL) was added and the mixture was stirred at ¨78 C for 1 h. Then cyclobutanone (181 mg, 2.58 mmol) was added. After the reaction was complete (monitored by LC-MS) the mixture was quenched with aq. NH4CI and extracted with EA. The organic layer was dried over MgSO4, filtered and evaporated to give compound P23a (243 mg, 50%) as a yellow solid.
Step 2: 1-Bromo-3-(tert-butv1)-5-cyclobutvlbenzene (P23b) To the mixture of compound P23a (243 mg, 0.86 mmol) in DCM ( 20 mL) was added TFA (3 mL) and the mixture was stirred at rt. Triethylsilane (200 mg, 1.72 mmol) was added and the mixture was stirred overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL).
The organic layer was washed with brine, dried over Na2SO4 and concentrated to give compound P23b (150 mg, 66%) as a colorless solid.
Step 3: 2-(3-(tert-Butv1)-5-cyclobutvlphenv1)-4,4,5,5-tetramethvI-1,3,2-dioxaborolane (P23) To a mixture of compound P23b (133 mg, 0.50 mmol), B2Pin2 (152 mg, 0.60 mmol) and KOAc (98 mg, 1.00 mmol) in 1,4-dioxane (10 mL) under Ar was added Pd(dppf)Cl2 (0.03 eq) and the mixture was heated at 80 C overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (hexane/EA = 20/1) to give compound P23 (110 mg, 70%) as colorless solid.
Preparative Example P30 ___________________________________ -o :13 100 P30 ¨
Step 1: 1-Bromo-3-(tert-butv1)-5-(2-rnethoxvpropan-2-v1)benzene (P30a) To a mixture of 2-(3-Bromo-5-(tert-butyl)phenyl)propan-2-ol [synthesis described in W02012/139775] (190 mg, 0.7 mmol) in DMF (10 mL) was added NaH (60%, 20 mg, 1.2 mmol) and the mixture was stirred at rt for 10 min. Then Mel (423 mg, 3.0 mmol) was added and the mixture was stirred overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (hexane/EA = 10/1) to give compound P30a (125 mg, 64%) as a colorless solid.
Step 2: 2-(3-(tert-Butv1)-5-(2-methoxvproPan-2-Ophenv1)-4,4,5,5-tetramethvl-1,3,2-dioxaborolane (P30) To a mixture of compound P30a (128 mg, 0.45 mmol), B2Pin2 (137 mg, 0.54 mmol) and KOAc (88 mg, 0.9 mmol) in 1,4-dioxane (25 mL) was added Pd(dppf)C12 (0.03 eq) under Ar and the mixture was heated at 80 C overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (hexane/EA = 5/1) to give compound P30 (78 mg, 52%) as a colorless solid.
Preparative Example P31 :B N
Step 1: 4-(1-(3-Bromo-5-(tert-butvl)phenvI)ethvI)morpholine (P31a) A mixture of 1-(3-Bromo-5-(tert-butyl)phenyl)ethanone [synthesis as described in W02012/139775] (510 mg, 2.0 mmol) and morpholine (208 mg, 2.4 mmol) in DCE (30 mL) was stirred at 0 C for 1 h. Then NaBH(OAc)3 (845 mg, 4.0 mmol) was added at this temperature and the mixture was stirred overnight, diluted with aq. NH4C1 (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (hexane/EA = 8/1) to give compound P31a (172 mg, 26%) 5 as a colorless solid.
Step 2: 4-(1-(3-(tert-Butv1)-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)PhenvI)ethvI)morpholine (P31) To a mixture of compound P31a (163 mg, 0.5 mmol), B2Pin2 (152 mg, 0.6 mmol) and KOAc (98 mg, 1.0 mmol) in 1,4-dioxane (25 mL) under Ar was added Pd(dppf)Cl2 (0.03 eq). The 10 mixture was heated at 80 C overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (hexane/EA = 5/1) to give compound P31 (78 mg, 42%) as a colorless solid.
Preparative Example P32 4-o :13 110 15 P32 N \0 Step 1: 3-Bromo-5-(tert-butvl)benzaldehvde (P32a) To a mixture of 1,3-dibromo-5-(tert-butyl)benzene (876 mg, 3.0 mmol) in THF
(10 mL) was added tert-BuLi (2.5 M, 2.4 mL, 6.0 mmol) at ¨78 C and the mixture was stirred for 1 h at this temperature. Then DMF (222 mg, 3.0 mmol) was added at this temperature and stirred for 2 20 h., diluted with aq. NH4C1 (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC
(hexane/EA = 5/1) to give compound P32a (452 mg, 63%) as a colorless solid.
Step 2: 4-(3-Bromo-5-(tert-butvl)benzvl)morpholine (P32b) A mixture of compound P32a (450 mg, 1.87 mmol) and morpholine (194 mg, 2.24 mmol) in 25 DCE (30 mL) was stirred at 0 C for 1 h. Then NaBH(OAc)3 (561 mg, 2.66 mmol) was added at this temperature and then stirred overnight, diluted with aq. NH4CI (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by prep. TLC to give compound P32b (142 mg, 28%) as a colorless solid.
30 Step 3: 4-(3-(tert-Butv1)-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)benzyl)morpholine (P32) To a mixture of compound P32b (145 mg, 0.46 mmol) and B2Pin2 (152 mg, 0.6 mmol) and KOAc (98 mg, 1.0 mmol) in 1 ,4-dioxane (25 mL) was added Pd(dppf)C12 (0.03 eq) under Ar and the mixture was heated at 80 C overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by prep. HPLC to give P32 (80 mg, 54%) as a colorless solid.
Preparative Example P33 V
_o ____________________________________ :13 *
P33 o\
Step 1: Methyl 3-bromo-5-(prop-1-en-2-yl)benzoate (P33a) To a solution of methyl 3-bromo-5-iodobenzoate (3.40 g, 10 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh3)4 (300 mg, 0.26 mmol), prop-I-en-2-y' boronic acid (1.0 g, 12 mmol), K2CO3(2.8 g, 20 mmol) and H20 (1 mL) under N2. The mixture was stirred overnight at 90 C, concentrated and purified by CC (PE/EA = 6/1) to give compound P33a (1.9 g, 71%) as a solid.
Step 2: Methyl 3-bromo-5-(1-methylcyclopropyl)benzoate (P33b) To a solution of Et2Zn (4 mL of 1.0M solution in hexanes, 4.0 mmol) in dry DCM
(4 mL) at 0 C was added freshly distilled TFA (0.36 mL, 4.0 mmol) in DCM (4 mL) very slowly (ca. 30 min). The gray mixture was stirred at 0 C for 20 min at which time CH2I2 (0.4 mL, 4.0 mmol) dissolved in DCM (4 mL) was introduced by cannulation. The resulting slurry was stirred for 20 min before the addition of compound P33a (0.53 g, 2.0 mmol) dissolved in DCM (3 mL).
The slurry was allowed to warm to rt over 30 min, quenched by the addition of sat. aq. NH4CI
(5 mL) and the layers were separated. The aq. layer was extracted with hexane (2x) and dried over MgSO4. Evaporation and purification by CC (PE/EA = 7/1) afforded compound P33b (300 mg, 46%) as a colorless oil.
Step 3: 3-Bromo-5-(1-methylcyclopropyl)benzoic acid (P33c) Compound P33b (270 mg, 1.0 mmol) and LiOH (50 mg, 2.0 mmol) were mixed in THF
(3 mL) and H20 (3 mL). The mixture was stirred for 10 h, then the pH was adjusted to pH 3 with aq. HCI and extracted with EA (3x 10 mL). The organic layer was dried and concentrated to afford the crude product P33c (250 mg, quant.).
Step 4: 3-Bromo-N-(tert-buty1)-N-methy1-5-(1-methylcyclopropypbenzamide (P33d) To a solution of compound P33c (250 mg, 1.0 mmol) in DMF (5 mL) was added HATU
(380 mg, 1.0 mmol), MeNHtBu (174 mg, 2.0 mmol) and Et3N (202 mg, 2.0 mmol) and the mixture was stirred overnight. After removal of the solvents the crude product was purified with prep.
HPLC to afford compound P33d (300 mg, 95%).
Step 5: N-(tert-Butv1)-N-methyl-3-(1-methvIcyclopropv1)-5-(4,4,5,5-tetramethv1-1,3,2-dioxaborolan-2-yl)benzamide (P33) To a suspension of compound P33d (323 mg, 1.0 mmol), B2Pin2 (380 mg, 1.5 mmol), KOAc (290 mg, 3.0 mmol) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl2 (20 mg) under N2. The mixture was heated to 100 C for 16 h, concentrated and purified by CC (PE/EA =
4/1) to afford compound P33 (200 mg, 68%) as a colorless solid.
Preparative Example P33/1 to P33/2 Using similar procedures as described in Preparative Example P33, the following compounds were prepared:
# Structure # Structure ___\(-1) ___\6 0-.B
0 NHl< 0 H
Preparative Example P36 Br 4.
Step 1: 1-(3-Bromo-5-(trifluoromethoxv)phenvflethanone (P36a) To the solution of 1,3-dibromo-5-(trifluoromethoxy)benzene (654 mg, 2.06 mmol) in toluene (6 mL) were added tri-n-butyl-1-ethoxyvinyl tin (969 mg, 2.68 mmol) and Pd(PPh3)2Cl2 (147 mg 0.21 mmol) under N2. The mixture was stirred at 95 C for 3 h, concentrated and dissolved in 1,4-dioxane and 2M HCI. The mixture was stirred rapidly at 25 C
for 1 h and then extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC to give compound P36a (580 mg, 55%).
Step 2: 1-Bromo-3-(tert-butvI)-5-(trifluoromethoxv)benzene (P36) An oven dried flask was charged with DCM (5 mL) and TiCI4 (763 mg, 4.06 mmol), Zn(CH3)2 (1M, 4 mL) was added and the solution was cooled to ¨30 C and stirred at constant temperature for 0.5 h. Then a solution of compound P36a (572 mg, 2.03 mmol) in DCM was added dropwise and the mixture was allowed to warm to 0 C over a period of 40 min, stirred at rt for 2 h, 45 min at 45 C and 40 C overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give product P36 (180 mg, 30%) as a yellow oil.
Preparative Example P38 Step 1: 4-Bromo-2-(tert-butvl)aniline (P38a) To a solution of 2-(tert-butyl)aniline (14.9 g, 100 mmol) was added a solution of NBS (17.8 g, 100 mmol) in DMF at rt. The mixture was stirred overnight at rt, diluted with water (30 mL) and extracted with Et20 (3x 250 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC to give compound P38a (19 g, 83%).
Step 2: N-(4-Bromo-2-(tert-butvl)phenvI)-2-(hvdroxvimino)acetamide (P38b) To a solution of compound P38a (5.0 g, 21.9 mmol), hydroxylamine hydrochloride (5.48 g, 78.9 mmol) and sodium sulfate (24.9 g, 175 mmol) in H20 (150 mL) and 2M HCI
(7.4 mL) at rt under N2 was added chloral hydrate (3.88 g, 26.3 mmol). The resulting solution was stirred at 55 C for 18 h, cooled to rt, diluted with water (100 mL) and extracted with EA (3x 50 mL).
The combined organic layers were concentrated to give P38b (5 g) as a viscous oil.
Step 3: 5-Bromo-7-(tert-butvl)indoline-2,3-dione (P38c) A solution of compound P38b (5 g, 16.7 mmol) in conc. H2SO4 (30 mL) was stirred at 80 C
for 1 h, cooled to rt, poured onto crushed ice (200 mL) and allowed to stand for 30 min. The precipitate was collected by filtration, washed with water (3x) and dried under vacuum to yield compound P38c (2 g) as a yellow solid.
Step 4: 5-Bromo-7-(tert-butvl)indolin-2-one (P38d) KOH (796 mg, 14.2 mmol) was added into a mixture of compound P38c (2 g, 7.1 mmol), ethyleneglycol (20 mL) and hydrazine hydrate (0.5 g, 9.93 mmol). The mixture was stirred at 80 C for 3h, cooled to rt and poured into ice cold water. The pH of the mixture was adjusted to pH 1-2 with 12M HCI and the mixture was stirred at rt for 12 h and extracted with EA. The organic phase was evaporated to give compound P38d (1.5 g) as a yellow solid.
Step 5: 5-Bromo-7-(tert-butvI)-1,3,3-trimethvlindolin-2-one (P38e) To a solution of compound P38d (1.0 g, 3.73 mmol) in DMF (20 mL) was added a solution of CH3I (0.93 mL) in DMF at 0 C. The mixture was stirred overnight at rt, diluted with water (100 mL) and extracted with Et20 (3x 100 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC to give compound P38e (500 mg, 43% over 4 steps) as a light yellow solid.
Step 6: 7-(tert-Butv1)-1,3,3-trimethv1-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-vpindolin-2-one (P38) A solution of compound P38e (760 mg, 2.45 mmol) was treated as described for Example P33, Step 5 to give compound P38 (750 mg, 86%) as a colorless solid.
Preparative Example P45 =
,Sõ
P45 d Step 1: 4-Bromo-2-(difluoromethoxv)benzene-1-sulfonvl chloride (P45a) To a solution of 4-bromo-2-(difluoromethoxy)aniline (4.50 g, 18.9 mmol) in AcOH (20 mL) was added conc. HCI (10 mL) at rt and the solution was cooled to 5 C. Then a solution of NaNO2 (1.45 g, 21.0 mmol) in H20 (15 mL) was added and the solution was stirred at 0 C for 1 h. The resulting diazonium salt was added to a mixture of saturated solution of SO2 in AcOH (100 mL) and CuC12.2H0 (3.61 g, 21.0 mmol) in H20 (50 mL) at rt and the solution was stirred at rt for 30 min, poured into water and extracted with DCM twice.
The combined organic layers were purified by CC (PE) to give compound P45a (2.1 g, 35%) as an oil.
Step 2: 4-Bromo-N-(fert-butvI)-2-(difluoromethoxv)benzenesulfonamide (P45b) To a solution of compound P45a (2.10 g, 6.53 mmol) and pyridine (1.19 g, 15.1 mmol) in CH2Cl2 (20 mL) was added tert-butylamine (511 mg, 7.00 mmol) at rt and the mixture was stirred for 1 h, then washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 4/1) to give compound P45b (2.16 g, 92%) as a colorless solid.
Step 3: N-(tert-Butyl)-2-(difluoromethoxv)-4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-vl)benzenesulfonamide (P45) A solution of compound P45b (2.16 g, 6.03 mmol) was treated as described for Example P33, Step 5 to give compound P45 (1.25 g, 51%) as a colorless solid.
Preparative Example P45/1 to P45/17 Using similar procedures as described in Preparative Example P45, the following compounds were prepared:
# Structure # Structure F F F
F F
)-o, o P45/1 B 0 o k _____________________ P45/2 )70,B A--K l',,o -d ,== \4vH W
Br ________________________ 4.
______________________ 13 e , )-o 90 sE, * ss, P45/3 7-d \(1H P45/4 -o' \\IH
CN F F
) F
µ,-0,13 id& ,ss, \___os o P45/5 ___________________________ -0' W \vH P45/6 B 11 e X
\IH
F F
CNo F
)-(:), la .,,C) 0 P45/7 P45/8 )-0, AL g,..p -0,B g W NH ,13 F3C-1 ""0 W NH
F3C---c \_-0 1110 0 F3c b P45/9 '13 =
4. gs-P P45/10 \-0, 9 o __________________________________________________________ B 41/ µS
/ ___________________ -0' 1H [-0' \111 \--0 0 CI
________________________________ .B 41, e _os 9...o B . s\-P45/11 7--d NH P45/12 )---0' NH
7c CI a /--\
P45/13 ______________ -0µ *0 , ---(),B s\NH
A P45/14 \_-0 4.e 7--0' 0 0 s13 ,,iH
=
P45/15 _________________________ B 411 e P45/16 \_-0 0 .13 4. ko /---0' NH NH
---A 7c , N
i \
P45/17 ):_osi, AK g,0 -d W NH
---A
Preparative Example P49 cn 0 HBr P49 d Step 1: Methyl 5-bromo-1-(cyclohexylmethyl)-2-formyl-1H-pyrrole-3-carboxylate (P49a) To a solution of methyl 5-bromo-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (1.8 g, 6.0 mmol) (prepared similar as described in Example 1) and DMF (3 mL) in 1,2-dichloroethane (50 mL) was added POCI3 (1.38 g, 9.0 mmol) and the solution was stirred for 1 h, then warmed to 80 C overnight, diluted with water (50 mL), basified with 2M NaHCO3 and extracted with EA (3x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, evaporated and purified by CC (EA/PE = 1/10) to give compound P49a (1.1 g,58%).
Step 2: Methyl 5-bromo-1-(cyclohexylmethyl)-2-(hydroxymethyl)-1H-pyrrole-3-carboxylate (P49b) To a solution of P49a (1.1 g, 3.5 mmol) in Me0H (3 mL) at rt was added NaBH4 (152 mg, 4 mmol) and the resulting solution was stirred at this temperature for 20 min, diluted with water (50 mL) and extracted with EA (3x 50 mL). The combined layer was concentrated to give compound P49b (1.03 g, 89%).
Step 3: 5- Bromo-1-(cyclohexyl methyl)-2-(hyd roxymethyl)- N-(tetrahyd ro-2H-pyran-4-yI)-1 H-Pv r r ole -3-car boxamide (P49) Compound P49b (200 mg, 0.61 mmol) was saponified and then coupled with tetrahydro-2H-pyran-4-amine similar as described in Example 1 (Step 7 and 8) to give compound P49 (210 mg, 86%) as a colorless solid.
Preparative Example P50 oa 0 110-Br F N
P50 d Step 1: Methyl 5-bromo-1-(cyclohexylmethyl)-2-(fluoromethyl)-1H-pyrrole-3-carboxylate (P50a) To a solution of compound P49b (600 mg, 1.82 mmol) in CH2Cl2 at ¨70 C was added bis(2-methoxyethyl)aminosulfur trifluoride (400 mg, 1.82 mmol) and the resulting solution was stirred at this temperature for 1 h, then warmed to rt for additional 1 h, diluted with water (50 mL) and extracted with EA (3x 50 mL). The combined organic layer was concentrated and purified by CC (EA/PE = 1/10) to give compound P50a (90 mg, 15%).
Step 2: 5-Bromo-1-(cyclohexvImethvI)-2-(fluoromethvI)-N-(tetrahvdro-2H-pvran-4-v1)-1 H-p r r ol e -3- c arb oxamide (P50) Compound P50a (90 mg, 0.61 mmol) was saponified and then coupled with tetrahydro-2H-pyran-4-amine similar as described in Example 1 (Step 7 and 8) to give compound P50 (82 mg, 77%) as a colorless solid.
Preparative Example P51 a 0 11)70-Br CI N
P51 d 5-Bromo-2-chloro-1-(cyclohexvImethvI)-N-(tetrahvdro-2 H-pvran-4-vI)-1H-pvrrole-carboxamide (P51) To a solution of methyl 5-bromo-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (600 mg, 1.63 mmol) (prepared similar as described in Example 1) in dry THF (50 mL) was added NCS (250 mg, 1.87 mmol) at rt under nitrogen. The reaction was stirred at 55 C
for overnight and quenched with a cold aq. solution of NH4CI. The organic layer was separated and the aqueous layer extracted repeatedly with EA. The combined organic layer was washed with brine, dried over Na2SO4, filtered, evaporated and purified by CC (EA/PE =
1/3) to give compound P51 (510 mg, 80%).
Preparative Example P53 o cF3 "o I \ 411 N NI-I
2\
d P53 Step 1: 2-(4-lodo-2-(trifluoromethvl)phenvI)acetvl chloride (P53a) To a solution of 2-(4-iodo-2-(trifluoromethyl)phenyl)acetic acid (2.00 g, 6.06 mmol) in DCM
(20 mL) were added (C0C1)2 (1.54 g, 12.1 mmol) and DMF (1 drop) in one portion at rt and the mixture was stirred at rt for 1 h and concentrated to give compound P53a (2.00 g, 95%) as a colorless oil.
Step 2: N-(tert-Butv1)-2-(4-iodo-2-(trifluoromethvl)qhenynacetamide (P53b) To a solution of tert-butylamine (876 mg, 12.0 mmol) in DCM (10 mL) was added TEA (2.54 g, 24.0 mmol) and the mixture was stirred at rt for 30 min, then compound P53a (2.00 g, 5.85 mmol) in DCM (10 mL) was added and the mixture was stirred at rt overnight, concentrated and purified by CC (PE/EA = 1/5) to give compound P53b (1.20 g, 52%) as a yellow solid.
Step 3: Ethyl 5-(4-(2-(tert-butvlamino)-2-oxoethvI)-3-(trifluoromethvl)phenv1)-(cyclohexvImethvI)-2-methyl-1H-pwrole-3-carboxvlate (P53) A solution of compound P53b (500 mg, 1.30 mmol), compound 1218a (535 mg, 1.40 mmol) K2CO3 (450 mg, 3.38 mmol), TBAB (10 mg) and Pd(PPh3)2Cl2 (10 mg) in a mixture of 1,4-dioxane (10 mL) and water (5 mL) in a sealed tube was irradiated by microwaves at 100 C
for 100 min, concentrated and purified by CC (PE/EA = 1/10) to afford compound P53 (100 mg, 15%) as a colorless solid.
Preparative Example P54 cF3 \ 111N NH
d0 Step 1: Benzvl 2-(4-iodo-2-(trifluoromethvl)phenvpacetate (P54a) To a solution of BnOH (2.16 g, 20.0 mmol) in DCM (20 mL) was added TEA (3.54 g, 35.0 mmol) and the mixture was stirred at rt for 30 min. Then a solution of compound P53a (3.48 g, 10.0 mmol) in DCM (15 mL) was added and the mixture was stirred at rt overnight, concentrated and purified by CC (PE/EA = 1/15) to give compound P54a (2.65 g, 79%) as a yellow oil.
Step 2: Benzvl 2-(4-iodo-2-(trifluoromethvl)qhenv1)-2-methvIpropanoate (P54b) To a solution of NaH (880 mg, 22.1 mmol) in THF (30 mL) was added compound P54a (2.65 g, 6.30 mmol) and the mixture was stirred at rt for 30 min. Then Mel (3.10 g, 22.1 mmol) was added and the mixture was stirred at rt overnight, quenched with water and extracted with EA. The organic layer was dried with MgSO4, filtered, concentrated and purified by CC
(PE/EA = 1/15) to give compound P54b (900 mg, 32%) as a yellow oil.
Step 3: Ethyl 5-(4-(1-(benzyloxy)-2-methy1-1-oxopropan-2-y1)-3-(trifluoromethyl)pheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (P54c) A solution of compound P54b (900 mg, 2.00 mmol), compound 1218a (750 mg, 2.00 mmol) K2CO3 (690 mg, 5.00 mmol), TBAB (10 mg) and Pd(PPh3)2Cl2 (10 mg) in a mixture of dioxane (10 mL) and water (5 mL) in a sealed tube was irradiated with microwaves at 100 C
for 100 min, concentrated and purified by CC (PE/EA = 1/8) to afford compound P54c (400 mg, 36%) as a colorless solid.
Step 4: 2-(4-(1-(Cyclohexylmethyl)-4-(ethoxycarbony1)-5-methyl-1H-pyrrol-2-y1)-(trifluoromethyl)pheny1)-2-methylpropanoic acid (P54d) To a solution of compound P54c (400 mg, 0.75 mmol) in Et0H (10 mL) was added Pd/C
(10%, 40 mg) in one portion at rt and the mixture was stirred under H2 (50 psi) for 5 h, filtered; concentrated and purified by CC (PE/EA = 5/1) to give compound P54d (300 g, 90%) as a colorless solid.
Step 5: Ethyl 5-(4-(1-chloro-2-methy1-1-oxopropan-2-v1)-3-(trifluoromethyl)pheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pwrole-3-carboxylate (P54e) To a solution of compound P54d (300 mg, 0.63 mmol) in DCM (10 mL) were added (C0C1)2 (159 mg, 1.25 mmol) and DMF (1 drop) in one portion at rt and the mixture was stirred for 1 h and concentrated to give compound P54e (300 mg, 95%) as a colorless oil.
Step 6: Ethyl 5-(4-(1-(tert-butylamino)-2-methyl-1-oxopropan-2-y1)-3-(trifluoromethyl)pheny1)-1-(cyclohexylmethyl)-2-methy1-1H-pyrrole-3-carboxylate (P54) To a solution of tert-butylamine (91 mg, 1.25 mmol) in DCM (5 mL) was added TEA (190 mg, 1.88 mmol) and the mixture was stirred at rt for 30 min. Then a solution of compound P54e (300 mg, 0.63 mmol) in DCM (5 mL) was added and the mixture was stirred at rt overnight, concentrated and purified by CC (PE/EA = 1/5) to give compound P54 (100 mg, 30%) as a yellow solid.
Preparative Example P55 cF3 \ g=0 141, Step 1: 4-Acetyl-N-(tert-butyI)-2-(trifluoromethyl)benzenesulfonamide (P55a) To a solution of 4-bromo-N-(tert-butyl)-2-(trifluoromethyl)benzenesulfonamide (10.5 g, 29.2 mmol) in dry THF (100 mL) was added n-BuLi (2.5M in hexane, 12.0 mL, 30.0 mmol) drop-wise over 10 min at ¨78 C under N2, then the resulting solution was stirred at ¨78 C for 1 h.
N-Methoxy-N-methylacetamide (4.63 g, 45 mmol) Was added, after stirring for a further 10 min, the cooling bath was removed and the mixture was allowed to warm to rt and then stirred at rt for 2 h, quenched with 1M HCI and extracted with EA (3x 60 mL).
The combined 5 organic phase was washed with brine, dried qver Na2SO4, filtered, concentrated and purified by CC (PE/EA = 3/1) to give compound P55a (3.7 g, 39%) as a colorless solid.
Step 2: 4-(2-Bromoacetv1)-N-(tert-butv1)-2-(trifluoromethvl)benzenesulfonamide (P55b) To a solution of compound P55a (3.7 g, 11.5 mmol) in dry THF (100 mL) was added PhNMe3Br3 (4.32 g, 11.5 mmol) dropwise at 0 C and the solution was stirred for 4 h at rt, 10 partially concentrated, washed with water twice and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 2/1) to give compound P55b (2.9 g, 63%) as yellow oil.
Step 3: Benzvl 5-(4-(N-(tert-butvl)sulfamov1)-3-(trifluoromethvl)phenv1)-14(3,3-difluorocyclobutvpmethvI)-2-methvI-1H-pvrrole-3-carboxvlate (P55c) 15 A solution of 3,3-difluorocyclobutylmethylamine (0.40 g, 2.5 mmol), phenylmethyl 3-oxobutanoate (1.05 g, 5.5 mmol), DIEA (0.71g, 5.5 mmol) in DMF (5 mL) was placed in a sealed tube in a hot oil bath (150 C) and then stirred for 15 min. A solution of compound P55b (1.21 g, 3.0 mmol) in DMF (2 mL) was added to the hot resulting solution at 100 C.
The solution was heated to 180 C quickly and stirred for another 15 min at 180 C, cooled to 20 rt, diluted with water and extracted with EA. The organic layer was washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA =
5/1) to give compound P55c (140 mg, 9%) as a brown oil.
Step 4: 5-(4-(N-(tert-Butvpsulfamov1)-3-(trifluoromethAphenv1)-1-((3,3-difluorocyclobutvpmethvI)-2-methvI-1H-pwrole-3-carboxvlic acid (P55) 25 A suspension of compound P55c (130 mg, 0.22 mmol) and 10% Pd/C (50 mg) in Me0H (15 mL) was stirred under 1 atmosphere of H2 at rt for 2 h, filtered, concentrated and purified by CC (DCM/Me0H = 15/1) to give compound P55 (65 mg, 59%) as a colorless solid.
Preparative Example P55/1 to P55/3 30 Using similar procedures at those described in Preparative Example P55, the following compounds were prepared:
Structure # Structure HO
\ HO 0 I \ =
g=0 )= HN P55/2 \ = s=o P55/3 )1\I
Preparative Example P56 >%-o o B
Steg 1: N-(4-Bromo-2-(trifluoromethvl)phenvI)-2-(hvdroxvimino)acetamide (P56a) To a solution of 4-bromo-2-(trifluoromethyl)aniline (50 g, 22 mmol), hydroxylamine hydrochloride (5.48 g, 78.9 mmol) and sodium sulfate (24.9 g, 175 mmol) in H20 (150 mL) and 2M HCI (7.4 mL) at rt under N2 was added chloral hydrate (3.88 g, 26.3 mmol) and the solution was stirred at 55 C for 18 h, cooled to rt, diluted with water (100 mL) and extracted with EA (3x 50 mL). The combined layer was concentrated to give compound P56a (5.0 g) as a viscous oil.
Step 2: 5-Bromo-7-(trifluoromethvpindoline-2,3-dione (P56b) A solution of P56a (5.0 g, 16.7 mmol) in conc. H2SO4 (30 mL) was stirred at 80 C for 1 h, cooled to rt, poured into crushed ice (200 mL) and allowed to stand for 30 min. The precipitate was collected by filtration, washed with water (3x) and dried to yield compound P56b (2.0 g) as a yellow solid.
Step 3: 5-Bromo-7-(trifluoromethvpindolin-2-one (P56c) KOH (796 mg, 14.2 mmol) was added into a mixture of P56b (2.0 g, 7.09 mmol), ethyleneglycol (20 mL) and hydrazine hydrate (98%, 0.5 g, 10 mmol), stirred at 80 C for 3 h, cooled to rt and poured into ice cold water. The pH of the mixture was adjusted to pH 1-2 with 12M HCI and stirred at rt for 12 h and extracted with EA. The organic phase was collected and evaporated to give compound P56c (1.5 g) as a yellow solid.
Step 4: 5-Bromo-1,3,3-trimethvI-7-(trifluoromethAindolin-2-one (P56d) To a solution of compound P56c (1.0 g, 3.7 mmol) in DMF (20 mL) was added a solution of CH3I (0.93 mL) in DMF at 0 C. The mixture was stirred at rt overnight, diluted with water (100 mL) and extracted with Et20 (3x100 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC to give compound P56d (500 mg, 43%) as a light yellow solid.
Step 5: 1,3,3-Trimethv1-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)-7-(trifluoromethvpi ndol in-2-one (P56) A solution of compound P56d (760 mg, 2.45 mmol) was treated as described for Example P33, Step 5 to give compound P56 (750 mg, 86%) as a colorless solid.
Preparative Example P57 I
4- lodo-N-neopentv1-6-(trifluoromethvl)pvridi n-2-am i ne (P57) A solution of 2-fluoro-4-iodo-6-(trifluoromethyl)pyridine (100 mg, 0.34 mmol) and neopentyl amine (150 mg, 1.70 mmol) in MeCN (1 mL) in a sealed tube was irradiated by microwaves at 130 C for 30 min, cooled, diluted with water and extracted with EA. The organic layer was washed with brine, dried, concentrated and purified by CC (PE/EA = 20/1) to give compound P57 (100 mg, 83%) as a colorless solid.
Preparative Example P58 cF3 \ = 6'.-=-o d P58 Step 1: Neopentv1(2-arifluoromethvflphenyl)sulfane (P58a) To a solution of Na0Et in Et0H (prepared from sodium (1.29 g, 56.1 mmol) and Et0H (40 mmol)) was added 2-(trifluoromethyl)benzene-1-thiol (5.0 g, 28.1 mmol) and neopentyl 4-methylbenzenesulfonate (6.80 g, 28.1 mmol) and the solution was stirred at reflux under N2 for 20 h, cooled to rt and the formed solid was filtered off. The cake was washed with Et20 and the combined filtrate was concentrated and diluted with water and ether consecutively.
The organic phase was washed with water, dried over Na2SO4, filtered, concentrated and purified by CC (petroleum) to give compound P58a (4.55 g, 65%) as a colorless solid.
Step 2: (4-Bromo-2-(trifluoromethvl)phenv1)(neopentvpsulfane (P58b) To a solution of compound P58a (1.0 g, 4.0 mmol) in dry DCM (15 mL) was added Br2 (640 mg, 4.0 mmol) at rt and the solution was stirred for 2 h, washed with water, sat. sodium thiosulfate and brine consecutively, dried and concentrated to give compound P58b (1.27 g, 97%) as a colorless solid.
Step 3: 4-Bromo-1-(neopentvlsulfonvI)-2-(trifluoromethvl)benzene (P58c) To a solution of compound P58b (1.27 g, 3.9 mmol) in DCM (20 mL) was added 3-chloroperoxybenzoic acid (3.0 g, 11.7 mmol) at ¨10 C and the solution was stirred at rt overnight, diluted with DCM and water and the two layers were separated. The organic layer was washed with sat. NaHCO3 twice and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 25/1) to give compound P58c (700 mg, 47%) as a colorless solid.
Step 4: Ethyl 1-(cyclohexvImethvI)-2-methvI-5-(4-(neopentvlsulfonv1)-3-(trifluoromethvl)phenv1)-1H-pyrrole-3-carboxvlate (P58) Compound P58c (359 mg, 1.0 mmol) was treated similar as described in Preparative Example P54, Step 3 to give compound P58 (500 mg, 95%) as a yellow oil.
Preparative Example P59 Step 1: 2-(Dibenzvlamino)benzoic acid (P59a) To a solution of bisbenzylamine (140 g, 0.70 mol) in THF (1.0L) was added n-BuLi (2.5M, 280 mL, 0.7 mol) dropwise under N2 at ¨30 C, then the reaction solution was stirred at this temperature for 10 min. 2-Fluorobenzoic acid (50 g, 0.35 mol) in THF (500 mL) was added dropwise at ¨30 C and the solution was heated to 0 C for 2 h, quenched with water (100 mL), concentrated, treated with conc. HCI until pH 1 and extracted with DCM
(3x 500 mL).
The organic layer was concentrated and recrystallized from Et20 to give compound P59a (40 g, 36%) as colorless solid. 1H-NMR (300 MHz, CDCI3) 6: 4.16 (s, 4H), 7.15-7.61 (m, 13H), 8.15-8.18(m, 1H).
Step 2: Methyl 2-(dibenzvlamino)benzoate (P59b) The solution of compound P59a (20 g, 63 mmol), K2CO3 (26 g, 189 mmol), CH3I
(14 g, 94 mmol) and DMF (200 mL) was stirred at rt for 2 h, diluted with Et20 (1 L) and the organic phase was washed with water (3x 500 mL) and brine consecutively, dried over Na2SO4, filtered and concentrated to give compound P59b (20 g, 96%) as colorless oil.
1H-NMR (300 MHz, CDCI3) 6: 3.89 (s, 3H), 4.25 (s, 4H), 6.94-6.99 (m, 2H), 7.21-7.37 (m, 11H), 7.69-7.72 (m, 1H).
Step 3: 1-(2-(Dibenzvlamino)phenvI)cyclopropanol (P59c) To a solution of Ti(Oi-Pr)4 (99.6 g, 0.36 mol) in dry Et20 (1.0 L) was added EtMgBr (2M in THF, 540 mL, 1.08 mol) dropwise at ¨68 C under N2 and the solution was stirred at this temperature for 1.5 h. To the reaction solution was added compound P59b (60.0 g, 0.18 mol) in dry Et20 (0.5 L) at ¨68 C and then the solution was stirred overnight at rt, quenched carefully with 1M HCI (500 mL) at 0 C and separated. The aq. layer was extracted with Et20 (3x 300 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 100/1) to give compound P59c (9.0 g, 15%) as colorless oil. 1H-NMR (400 MHz, CDCI3) 6: 0.96-0.99 (m, 2H), 1.11-1.15 (m, 2H), 4.18 (s, 4H), 6.98-7.31 (m, 14H), 7.96 (s, 1H).
Step 4: N,N-Dibenzv1-2-(1-methoxycyclopropvl)aniline (P59d) To a solution of compound P59c (5.8 g, 17.6 mmol), CH3I (3.7 g, 26.4 mmol) in dry THF (20 mL) was added NaH (60%, 1.0 g, 26.4 mmol) in portions at 0 C under N2 and the solution was stirred at rt overnight, quenched with water (50 mL) and extracted with EA
(3x 150 mL).
The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 100/1) to give compound P59d (5.0 g, 83%) as colorless oil. 1H-NMR (300 MHz, CDCI3) 6: 0.95-0.99 (m, 2H), 1.22-1.26 (m, 2H), 3.24 (s, 3H), 4.32 (s, 4H), 6.96-7.45 (m, 14H).
Step 5: 2-(1-Methoxycyclopropvl)aniline (P59e) A solution of compound P59d (4.0 g, 11.6 mmol), HCO2NH4 (7.3 g, 116 mmol), Pd/C (0.5 g) in Me0H (20 mL) was heated to 45 C for 5 h, cooled to rt, filtered and the filtrate was concentrated. The residue was dissolved in EA (200 mL) and washed with water (3x 100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give crude product P59e (1.5 g, 75%) as colorless oil. 1H-NMR (300 MHz, CDCI3) 6: 0.90-0.93 (m, 2H), 1.09-1.13 (m, 2H), 3.16 (s, 3H), 6.66-6.69 (m, 2H), 7.10-7.14 (m, 2H).
Step 5: 4-Bromo-2-(1-methoxycyclopropvl)aniline (P59f) To a solution of compound P59e (2.0 g, 12.3 mmol) in MeCN (10 mL) was added NBS (2.18 g, 12.3 mmol) in three portions at 0 C under N2 and the solution was stirred at rt overnight, concentrated and purified by CC (PE/EA = 100/1) to give compound P59f (2.0 g, 70%) as yellow oil. 1H-NMR (400 MHz, CDCI3) 6: 0.87-0.90 (m, 2H), 1.07-1.11 (m, 2H), 3.14 (s, 3H), 4.32 (br s, 2H), 6.55-6.57 (d, J = 8.0 Hz, 1H), 7.16-7.20 (m, 2H).
Step 6: 4-Bromo-2-(1-methoxycyclopropvl)benzene-1-sulfonvl chloride (P59q) A solution of compound P59f (1.0 g, 4.0 mmol) in MeCN (40 mL) was cooled to 0-5 C, AcOH
(4.0 mL) and conc. HCI (2.0 mL) were added consecutively and then NaNO2 (304 mg, 4.4 mmol) in water (3 mL) over 10 min at 0-5 C. After stirring 20 min, SO2 was bubbled in over 5 40 min while keeping the temperature below 7 C. A solution of CuC12-2H20 (818 mg, 2.4 mmol) in water (3 mL) was added and the solution was allowed to warm to rt and stirred for 1 h, extracted with EA, washed with aq. NaHCO3 (2x 100 mL) and water (2x 100 mL) consecutively, dried over Na2SO4, filtered and concentrated to give product P59g (800 mg, 50%) as yellow solid.
10 Step 7: 4-Bromo-N-(tert-butv1)-2-(1-methoxycyclopropvl)benzenesulfonamide (P59h) A solution of compound P59g (800 mg, 2.46 mmol), 2-methylprop-2-ylamine (269 mg, 3.69 mmol), Et3N (497 mg, 4.92 mmol) and MeCN (5 mL) was stirred at rt overnight, concentrated and purified by CC (PE/EA = 80/1) to give compound P59h (400 mg, 46%) as yellow solid.
1H-NMR (300 MHz, CDCI3) 6:1.15-1.23 (m, 2H), 1.25 (s, 9H), 1.28-1.33 (m, 2H), 3.22 (s, 15 3H), 5.87 (s, 1H), 7.59 (s, 1H), 7.61-7.62 (m, 2H), 8.01-8.04 (d, J =
12.0 Hz, 1H).
Step 8: N-(tert-Butyl)-2-(1-methoxycyclopropv1)-4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-vnbenzenesulfonamide (P59) Compound P59h (200 mg, 0.55 mmol) was treated similar as described for Example P33, Step 5 to give compound P59 (150 mg, 67%) as colorless solid. 1H-NMR (400 MHz, CDCI3) 20 6:1.18-1.21 (m, 2H), 1.23 (s, 9H), 1.26-1.27 (m, 2H), 1.36 (s, 12H), 3.19 (s, 3H), 5.97 (s, 1H), 7.81 (s, 1H), 7.86-7.88 (d, J = 8.0 Hz, 1H), 8.12-8.14 (d, J = 8.0 Hz, 1H).
Preparative Example P60 B g=0 7"--0 25 Step 1: 4-Bromo-2-fluorobenzene-1-sulfonvl chloride (P60a) To the solution of 4-bromo-2-fluoroaniline (6.0 g, 31.6 mmol), AcOH (9 mL) and conc. HCI (5 mL) in MeCN (180 mL) was added NaNO2 (2.6 g, 37.9 mmol) over 10 min at < 5 C
and the solution was stirred for 30 min at this temperature. SO2 gas was bubbled in over 30 min.
Then a solution of CuC12+120 (6.4 g, 37.9 mmol) in H2O (5 mL) was added and the solution 30 was stirred for additional 2 h at rt, concentrated and diluted with EA.
The organic layer was washed with water and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 40/1) to give compound P60a (3.7 g, 43%) as colorless oil.
96 .
Step 2: 4-Bromo-N-(tert-butyI)-2-fluorobenzenesulfonamide (P60b) To a solution of compound P60a (3.7 g, 13.6 mmol) and pyridine (2 mL) in DCM
(40 mL) was added 2-methylprop-2-ylamine (3.0 g, 40.7 mmol) at 0 C and the solution was stirred at this temperature for 1 h, concentrated and purified by CC (PE/EA = 40/1) to give compound P60b (2.2 g, 53%) as a colorless solid.
Step 3: 4-Bromo-N-(tert-butyI)-2-(neopentyloxy)benzenesulfonamide (P60c) To a solution of 2,2-dimethylpropan-1-ol (1.14 g, 12.9 mmol) in dry DMF (15 mL) was added NaH (60% in oil, 413 mg, 10.3 mmol) at 0 C under N2 and the solution was stirred at this temperature for 40 min. Then compound P60b (800 mg, 2.58 mmol) was added and the solution was stirred at 90 C for additional 2 h, diluted with water and extracted with EA (3x).
The combined organic layers were washed with water (3x) and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 10/1) to give compound P60c (925 mg, 95%) as a colorless solid.
Step 4: N-(tert-Buty1)-2-(neopentyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (P60) A solution of compound P60c (600 mg, 1.59 mmol) was treated as described for Example P33, Step 5 to give compound P60 (380 mg, 60%) as a colorless solid.
Preparative Example P61 o cF3 I \ 441 g=0 N
NC HN, -.
d Step 1: Ethyl 2-bromo-5-(4-(N-(tert-butypsulfamoy1)-3-(trifluoromethyl)pheny1)-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (P61a) To a solution of ethyl 5-(4-(N-(tert-butyl)sulfamoy1)-3-(trifluoromethyl)pheny1)-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (2.6 g, 5.06 mmol) in dry THF (25 mL) was added a solution of NBS (0.9 g, 5.06 mmol) in dry THF (10 mL) at ¨78 C and the solution was stirred at ¨55 C for 2 h, quenched with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and carefully purified by CC (PE/EA = 5/1) to give compound P61a (1.08 g, 36%) as a colorless solid.
Step 2: Ethyl 5-(4-(N-(tert-butyl)sulfamoyI)-3-(trifluoromethyl)pheny1)-2-cyano-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (P61b) A solution of compound P61a (800 mg, 1.35 mmol), CuCN (145 mg, 1.62 mmol) and KI (10 mg) in DMF (10 mL) was stirred at 120 C overnight under N2, cooled to rt and diluted with 27% NH4OH (2 mL). The resulting solution was filtered and the filtrate was extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 3/1) to give compound P61b (496 mg, 68%) as a colorless solid.
Step 3: 5-(4-(N-(tert-Butyl)sulfamoy1)-3-(trifluoromethyl)pheny1)-2-cyano-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylic acid (P61) A mixture of compound P61b (100 mg, 0.19 mmol) and t-BuOK (38 mg, 0.40 mmol) in a mixture of DMSO and H20 (10/1, 2 mL) was stirred at 90 C for 1 h, cooled, diluted with water, acidified with 1M HCI to pH = 6 and extracted with EA. The organic layer was washed with water and brine consecutively, dried over Na2SO4, filtered and concentrated to give compound P61 (67 mg, 70%) as a colorless solid.
Preparative Example P62 cF3 HO
I \ g=0 HN N
HN
Step 1: Ethyl 5-(4-(N-(tert-Butyl)sulfamoyI)-3-(trifluoromethyl)pheny1)-2-carbamoyl-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (P62a) To a cooled (ice bath) solution of compound P61b (257 mg, 0.48 mmol) in DMSO
(5 mL) was added 30% H202 (0.07 mL) and K2CO3 (197 mg, 1.43 mmol) and the solution was stirred overnight at rt, quenched with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA =
1/1) to give compound P62a (145 mg, 54%) as a colorless solid.
Step 2: 5-(4-(N-(tert-Butyl)sulfamoy1)-3-(trifluoromethyl)pheny1)-2-carbamoy1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylic acid (P62) A mixture of compound P62a (145 mg, 0.26 mmol) and t-BuOK (89 mg, 0.79 mmol) in a mixture of DMSO and H20 (10/1, 2 mL) was stirred at 85 C for 1 h, cooled, diluted with water, acidified with 1M HCI to pH = 6 and extracted with EA. The organic layer was washed with water and brine consecutively, dried over Na2SO4, filtered and concentrated to give crude compound P62 (162 mg) as a colorless solid.
Preparative Example P63 HoJ
I \ ( N
N __ NH
d63 Step 1: 2-(Benzyloxy)-4-bromo-6-(tert-butyl)pyridine (P63a) To a mixture of 4-bromo-6-(tert-butyl)pyridin-2(1H)-one (1.15 g, 5.0 mmol) in benzene (65 mL) was added BnBr (855 mg, 5.0 mmol) and Ag2CO3 (689 mg, 2.5 mmol) successively and the mixture was stirred at 60 C overnight, cooled to rt and the solid was filtered off. The filtrate was washed with sat. NaHCO3, dried over Na2SO4, concentrated and purified by CC
(PE/EA = 10/1) to give compound P63a (1.39 g, 86%) as a colorless oil.
Step 2: 2-(Benzyloxy)-6-(tert-buty1)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine compound (P63b) A solution of compound P63a (320 mg, 1.0 mmol), 62Pin2 (508 mg, 2.0 mmol), KOAc (294 mg, 3.0 mmol) and Pd(dppf)Cl2 (73.2 mg, 0.10 mmol) in a mixture of 1,4-dioxane and DMSO
(50/1, 15 mL) was stirred at 80 C under N2 for 1 h, cooled to rt and diluted with H20 (15 mL), extracted with EA (3x). The combined organic layers were washed with brine twice, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 10/1) to give crude compound P63b (380 mg, quant.) as a colorless solid.
Step 3: Ethyl 5-(2-(benzyloxy)-6-(tert-butyl)pyridin-4-y1)-1-(cyclohexylmethy1)-2-methyl-1 H-pirr ole -3- carbon/late (P63c) A solution of compound P63b (141 mg, 0.38 mmol), ethyl 5-bromo-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (189 mg, 0.58 mmol), Cs2CO3 (375 mg, 1.15 mmol) and Pd(dppf)Cl2 (73.2 mg, 0.1 mmol) in a mixture of 1,4-dioxane and H20 (4/1, 5 mL) was stirred at 100 C under N2 for 2 h, diluted with H20 (15 mL) and extracted with EA
(3x). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 50/1) to give compound P63c (78 mg, 42%) as a colorless solid.
Step 4: Ethyl 5-(2-(tert-buty1)-6-hydroxypyridin-4-y1)-1-(cyclohexylmethyl)-2-methyl-1 H-pv r r ol e-3- carb oxv late (P63d) To a solution of compound P63c (700 mg, 1.43 mmol) in dry DCM (30 mL) at 5 C
was added anhydrous FeCl3 (1.93 g, 7.15 mmol) and the mixture was stirred at rt for 5 h under N29 diluted with water and extracted with EA twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC
(PE/EA = 10/1) to give compound P63d (470 mg, 82%) as a colorless oil.
Step 4: Ethyl 5-(2-(tert-butyl)-6-(((trifluoromethyl)sulfonyl)oxv)Ovridin-4-y1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (P63e) To a solution of compound P63d (470 mg, 1.18 mmol) and pyridine (186 mg, 2.36 mmol) in DCM (10 mL) was added Tf20 (499 mg, 1.77 mmol) and the solution was stirred at rt for 2 h under N2, diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by prep. TLC
(PE/EA = 50/1) to give compound P63e (250 mg, 41%) as a colorless oil.
Step 5: Ethyl 5-(2-(tert-buty1)-6-(neopentylamino)pyridin-4-y1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (P63f) A solution of compound P63e (250 mg, 0.48 mmol), 2,2-dimethylpropylamine (202 mg, 2.32 mmol), t-BuONa (178 mg, 1.86 mmol), Pd(OAc)2 (21 mg, 0.09 mmol) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (73 mg, 0.18 mmol) in toluene (10 mL) was stirred at 110 C under N2 for 2 h, diluted with H20 and extracted with EA (3x). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 50/1) to give compound P63f (240 mg, quant.) as a brown solid.
Step 6: 5-(2-(tert-Butyl)-6-(neopentylamino)pyridin-4-y1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylic acid (P63) To a solution of compound P63f (240 mg) in a mixture of DMSO and H20 (10/1, 11 mL) was added t-BuOK (288 mg, 2.57 mmol) and the solution was stirred at 90 C for 4 h, cooled to rt, acidified with sat. citric acid to pH = 3 and extracted with EA. The solution was dried over Na2SO4, filtered, concentrated and purified by prep. TLC to give compound P63 (200 mg, 89%) as a yellow oil.
Preparative Example P64 r S
Br 411 9-41, Step 1: 4-Bromobenzofblthiophen-7-amine (P64a) To a solution of benzo[b]thiophen-7-amine (4.65 g, 30 mmol) in DCM (100 mL) was added a solution of Br2 (4.99 g, 0.03 mL) in DCM (120 mL) at ¨78 C and the solution was stirred for 1.5 h at ¨78 C, quenched with water and extracted with DCM (3x). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 30/1) to give of compound P64a (2.38 g, 34%) as a colorless solid.
1H-NMR (400 MHz, CD30D) 6: 6.62 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.40 (d, J =
5.2 Hz, 1H), 7.62 (d, J = 6.0 Hz, 1H).
Step 2: 4-Bromobenzof blthiophene-7-sulfonyl chloride (P64b) To a solution of compound P64a (2.38 g, 10.5 mmol) in AcOH (8 mL) was added conc. HCI
(24 mL) at rt and the solution was cooled to -5 C. Then a solution of NaNO2 (1.08 g, 15.7 mmol) in H20 (8 mL) was added and the solution was stirred at 0 C for 1 h. The resulting diazonium salt was added to a premixed solution of SO2 in AcOH (sat., 30 mL) and CuC12-1120 (1.34 g, 7.86 mmol) in H20 (20 mL) at rt and the solution was stirred at rt for 2 h, poured into water and extracted with DCM twice. The combined organic layers were concentrated and purified by CC (PE/EA = 30/1) to give compound P64b (3.26 g, quant.) as a colorless oil.
Step 3: 4-Bromo-N-(tert-butyl)benzorblthiophene-7-sulfonamide (P64) The solution of compound P64b (3.26 g, 10.5 mmol), tert-butyl amine (2.5 mL) and pyridine (30 mL) in dry DCM (100 mL) was stirred for 1 h at rt, washed with water twice and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC
(PE/EA = 10/1) to give compound P64 (2.6 g, 71%) as a colorless solid. 111-NMR (400 MHz, CDCI3) 6: 1.19 (s, 9H), 7.59 (d, J = 6.4 Hz, 1H), 7.67 (d, J = 6.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.82 (d, J
= 8.0 Hz, 1H).
Preparative Example P65 OH
Os tO'B
Step 1: Ethyl 4-((arifluoromethyl)sulfonyl)oxy)-2-naphthoate (P65a) To a solution of ethyl 4-hydroxy-2-naphthoate (15.0 g, 58.1 mmol) and NEt3 (11.7 g, 116 mmol) in dry DCM (300 mL) was added a solution of Tf20 (24.5 g, 87.1 mmol) in DCM (50 mL) at 0 C and the solution was stirred for 4 h at rt, washed with H20 and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 8/1) to give compound P65a (18.0 g, 89%) as a colorless solid.
Step 2: 3-(2-Hydroxypropan-2-yl)naphthalen-1-yltrifluoromethanesulfonate (P65b) To a solution of compound P65a (13.2 g, 42.4 mmol) in dry THF (150 mL) was added MeMgBr (1M in THF, 51 mL, 51 mmol) dropwise at 0 C and the solution was stirred at 25 C
for 1 h, diluted with sat. NH4CI and extracted with DCM twice. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 2/1) to give compound P65b (16.7 g, quant.) as a yellow oil.
Step 3: 2-(4-(4,4,5,5-Tetramethv1-1,3,2-dioxaborolan-2-v1)naphthalen-2-v1)propan-2-ol (P65) A suspension of compound P65b (1.6 g, 4.8 mmol), KOAc (1.5 g, 14.4 mmol), B2Pin2 (1.5 g, 5.7 mmol) and Pd(dppf)Cl2 (176 mg, 0.24 mmol) in 1,4-dioxane (10 mL) was stirred at 80 C
under N2 overnight, concentrated and purified by CC (PE/EA = 4/1) to give compound P65 (1.2 g, 80%) as a colorless solid. 1H-NMR (400 MHz, CDCI3) 6: 1.42 (s. 3H), 1.69 (s, 6H), 1.89 (br s, 1H), 7.45-7.50 (m, 2H), 7.82 (dd, J = 8.0, 1.6 Hz, 1H), 8.02 (d, J
= 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 8.0 Hz, 1H).
Preparative Example P66 ) NH
____________________________________ -0 :E3 Step 1: N-(tert-Butyl)-4-hvdroxv-2-naphthamide (P66a) A solution of 4-hydroxy-2-naphthoic acid (2.0 g, 10.8 mmol), t-BuNH2 (1.5 g, 20.0 mmol), HATU (4.9 g, 13.0 mmol) and DIEA (1.4 g, 10.8 mmol) in DMF (10 mL) was stirred at 60 C
for 1.5 h, cooled to rt, diluted with water and extracted with EA (3x). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 1/1) to give compound P66a (2.1 g, 81%) as a colorless solid. 1H-NMR (400 MHz, CDCI3) 6: 1.56 (s, 9H), 7.26 (br s, 1H),7.62 (d, J = 1.6 Hz, 1H), 7.76-7.85 (m, 2H), 8.01 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H).
Step 2: 3-(tert-ButvIcarbamovOnaphthalen-1-vItrifluoromethanesulfonate (P66b) To a solution of compound P66a (3.80 g, 15.6 mmol) and TEA (4.73 g, 46.8 mmol) in DCM
(20 mL) was added Tf20 (6.60 g, 23.4 mmol) and the solution was stirred at rt for 2 h, diluted with DCM, washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC
(PE/EA = 4/1) to give compound P66b (5.0 g, 85%) as a colorless solid. 1H-NMR
(400 MHz, CDCI3) 6: 1.55 (s, 9H), 7.23 (br s, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.66-7.75 (m, 2H), 8.00 (d, J
= 8.2 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H).
Step 3: N-(tert-Butv1)-4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)-2-naphthamide (P66) Compound P66b (1.2 g, 3.2 mmol) was treated as described above in Example P65, Step 3 to give compound P66 (0.9 g, 80%) as a colorless solid. 1H-NMR (400 MHz, CDCI3) 6:1.42 (s, 12H), 1.53 (s, 9H), 1.88 (br s, 1H), 7.45-7.50 (m, 2H), 7.82 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 8.18 (d, J =1.6 Hz, 1H), 8.72 (d, J = 8.4 Hz, 1H).
Preparative Example P67 cF3 Step 1: 5-Bromo-3-(trifluoromethvl)pvridine-2(1H)-thione (P67a) The mixture of 5-bromo-3-(trifluoromethyl)pyridin-2-ol (2.0 g, 8.26 mmol) and Lawesson's reagent (2.3 g, 5.79 mmol) in toluene (30 mL) was refluxed overnight, concentrated and purified by CC (PE/EA = 20/1) to give compound P67a (1.5 g, 70%) as a yellow solid.
Step 2: 5-Bromo-N-(tert-butvI)-3-(trifluoromethvl)pvridine-2-sulfonamide (P67) The mixture of compound P67a (0.60 g, 2.33 mmol) and NCS (1.24 g, 9.30 mmol) in DCM
(30 mL) was stirred at 15 C for 2.5 h, washed with water, dried over Na2SO4 and filtered.
DIEA (0.60 g, 4.65 mmol) and tert-butylamine (0.20 g, 2.79 mmol) were added to the filtrate and the mixture was stirred at rt for 1 h, concentrated and purified by CC
(PE/EA = 10/1) to give compound P67 (0.10 g, 12%) as a pale brown solid.
Preparative Example P69 ____________________________________ -0 sI3 .
T ___________________________________ -0' Step 1: 2-Bromo-4-(tert-butvI)-6-methvlphenol (P69a) To a solution of 4-(tert-butyl)-2-methylphenol (10.6 g, 64.6 mmol) in dry CCI4 (100 mL) was added Br2 (10.9 g, 67.8 mmol) slowly and the solution was stirred at rt for 2 h, poured into sat. Na2S203 and extracted with MTBE twice. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (EA/PE =
1/100) to give compound P69a (15 g, 96%) as colorless oil.
Step 2: 1-Bromo-5-(tert-butyl)-2-(difluoromethoxv)-3-methvlbenzene (P69b) To a solution of compound P69a (10.0 g, 41.1 mmol) in isopropanol (120 mL) was added aq.
NaOH solution (20%, 120 mL) at -78 C, then CHCIF2 was bubbled into the solution and the solution was heated overnight at 40 C, cooled to rt, diluted with water and extracted with EA
twice. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (EA/PE = 1/50) to give compound P69b (5.1 g, 42%) as a colorless oil.
Step 3: 2-(5-(tert-Butv1)-2-(difluoromethoxv)-3-methylphenv1)-4,4,5,5-tetramethvI-1,3,2-dioxaborolane (P69) Compound P69b (4.8 g, 16.4 mmol) was treated as described above in Example P65, Step 3 to give compound P69 (3.2 g, 57%) as a colorless solid.
Preparative Example P70 F2Nco :13 2-(3,5-Di-tert-butv1-2-(difluoromethoxv)phenv1)-4,4,5,5-tetramethvI-1,3,2-dioxaborolane (P70) Compound P70 was prepared starting from 2-bromo-4,6-di-tert-butylphenol similar as described above in Example P69, Step 2 and 3.
Preparative Example P71 Br 11 NH
N-(4-Bromo-2-(trifluoromethvl)phenv1)-2-methvIpropane-2-sulfonamide (P71) To a solution of 2-methylpropane-2-sulfonamide (1.00 g, 7.30 mmol) in DMF (10 mL) was added NaH (60% w/t in mineral oil, 350 mg, 8.80 mmol) at 0 C and the solution was stirred for 30 min. Then a solution of 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (1.80 g, 7.30 mmol) in DMF (10 mL) was added and the solution was stirred at 120 C
overnight, cooled, diluted with H20 and extracted with EA (3x 20 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 8/1) to afford compound P71 (800 mg, 31%) as a colorless solid.
Preparative Example P72 Br 411 Br 11 4-1 cY
F
o- 0 P7272 N-(4-Bromo-2-fluoro-6-(trifluoromethvl)phenv1)-2-methvIpropane-2-sulfonamide (P72) To a solution of 2-methylpropane-2-sulfonamide (173 mg, 1.15 mmol) in DMF (10 mL) was added NaH (60% w/t in mineral oil, 56 mg, 1.39 mmol) at 0 C and the solution was stirred for 30 min. Then a solution of 5-bromo-1,2-difluoro-3-(trifluoromethyl)benzene (300 mg, 1.15 mmol) in DMF (5 mL) was added and the solution was stirred at 120 C for 2 h, cooled, quenched with H20 and extracted with EA (3x 20 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 10/1) to afford compound P72 (130 mg, 31%) as a colorless solid.
Preparative Example P73 cF3 __________________________________ _o -=() Step 1: 6-Chloro-3-nitro-2-(trifluoromethvl)pvridine (P73a) A mixture of 5-nitro-6-(trifluoromethyl)pyridin-2(1/-1)-one (3.54 g, 17.0 mmol), DMF (4.96 g, 68 mmol) and POCI3 (20.9 g, 136 mmol) was heated at 90 C for 16 h, evaporated, poured into ice-water (200 mL), neutralized to pH 5 with Na2CO3 and extracted with EA
(3x 100 mL).
The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC (EA/PE = 1/20) to give compound P73a (2.77 g, 72%) as a yellow solid. 1H-NMR (CDCI3, 300 MHz) 6: 7.74 (1H, d, J = 8.4 Hz), 8.22 (1H, d, J = 8.4 Hz).
Step 2: 6-Chloro-2-(trifluoromethvI)ovridin-3-amine (P73b) To a round bottom flask fitted with a centrally mounted stirrer, carrying a reflux condenser and a dropping funnel, was charged successively iron powder (2.18 g, 39 mmol) and ammonium chloride solution (65 mL, 1M, 65 mmol). A solution of compound P73a (2.95 g, 13 mmol) in Me0H (65 mL) was allowed to drop into the stirred slurry of iron powder-ammonium chloride solution over a duration of 10 min at rt. The mixture was stirred under reflux for 2h, filtrered hot followed by hot methanol wash (2x 30 mL) and the combined washings were concentrated to leave the product precipitating out from the solution. Re-crystallization from Me0H/DCM gave compound P62b (2.0 g, 79%) as yellow solid.
(CDCI3, 300 MHz) 6: 4.27 (2H, br s), 7.09 (1H, d, J = 8.4 Hz), 7.25 (1H, d, J
= 8.4 Hz).
Step 3: 6-Chloro-2-(trifluoromethvl)pvridine-3-sulfonvl chloride (P73c) Step (a): Thionyl chloride (42 mL) was added dropwise under ice cooling over 60 min to water (250 mL) maintaining the temperature of the mixture at 0-7 C. The solution was allowed to warm to 18 C and stirring was continued for 3 d. CuCI (151 mg) was added to the mixture and the resultant yellow-green solution was cooled to ¨3 C using an acetone/ice bath. Step (b): Hydrochloric acid (36% w/w, 12.2 mL) was added with agitation to compound P73b (1.65 g, 8.4 mmol), maintaining the temperature of the mixture below 30 C
with ice cooling. The mixture was cooled to ¨5 C using an ice/acetone bath and a solution of sodium nitrite (0.68 g, 9.8 mmol) in water (2.8 mL) was added dropwise over 30 min maintaining the temperature of the mixture between ¨5 to 0 C. The resultant slurry was cooled to ¨2 C and stirred for 10 min. Step (c): The slurry from step (b) was cooled to ¨5 C and added to the solution obtained from step (a) over 95 min, maintaining the temperature of the mixture between ¨3 to 0 C (the slurry from step (b) was maintained at ¨5 C throughout the addition).
As the reaction proceeded, a solid began to precipitate. When the addition was complete, the mixture was agitated at 0 C for 75 min. The solid was collected by vacuum filtration, washed with ice-cooled water (2x 25 mL) and dried under vacuum at below 25 C
to give compound P73c (1.53 g, 66%) as yellow solid. 1H-NMR (CDCI3, 300 MHz) 6: 7.81 (1H, d, J =
8.4 Hz), 8.57 (1H, d, J = 8.4 Hz).
Step 4: N-(tert-ButvI)-6-chloro-2-(trifluoromethyl)pvridine-3-sulfonamide (P73d) To a solution of 2-methylprop-2-ylamine (5 mL) in DCM (20 mL) was added a solution of compound P73c (1.53 g, 5.5 mmol) in DCM (10 mL) dropwise at 0 C and the solution was stirred at rt for 1 h, washed with water (3x 50 mL) and brine, dried over Na2504, filtered and concentrated to give compound P73d (1.2 g, 69%) as a yellow solid. 1H-NMR
(CDCI3, 300 MHz) 6:1.26 (9H, s), 4.87 (1H, s), 7.65 (1H, d, J = 8.4 Hz), 8.53 (1H, d, J =
8.4 Hz).
Step 5: N-(tert-butyl)-6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-2-(trifluoromethvl)pvridine-3-sulfonamide (P73) A solution of compound P73d (317 mg, 1.0 mmol), B2Pin2 (280 mg, 1.1 mmol), potassium acetate (294 mg, 3.0 mol) in 1,2-dimethoxyethane (5 mL) was sparged for 5 min with N2 and then Pd(dppf)Cl2 (82 mg, 0.1 mmol) was added. The mixture was heated under ref lux for 12 h, diluted with EA (20 mL) and concentrated to dryness. The residue was taken up in EA (30 mL) and water (20 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, concentrated and re-crystallized from EA/PE
= 1/8 to given compound P73 (200 mg, 46%) as a tan solid. 1H-NMR (CDCI3, 400 MHz) 6:1.24 (9H, s), 1.40 (12H, s), 4.83 (1H, s), 8.11 (1H, d, J = 8.0 Hz), 8.54 (1H, d, J = 8.0 Hz).
Preparative Example P74 cF3 -os ---,3=13 . /N-ki Step 1: 3-(4-Hydroxv-2-(trifluoromethvI)phenv1)-3-oxopropanal (P74a) Na0Me (5.4 g, 0.10 mol) was suspended in THF (100 mL) and treated at rt with ethyl formate (7.4 g, 0.10 mol) followed by dropwise addition of a solution 1-(4-hydroxy-2-(trifluoromethyl)phenyl)ethanone (16.3 g, 0.08 mol) in THF. The mixture was stirred for 2.5 h at rt, quenched with H20 (300 mL) and extracted with Et20 (100 mL). The extracts were discarded. The aqueous phase was acidified with 6M H2SO4 (18 mL) and extracted with Et20 (2x 100 mL). This extract was washed with water and brine, dried over Na2SO4, filtered and concentrated to afford compound P74a (12.5 g, 67%) as a yellow solid.
Step 2: 4-(1-lsopropv1-1H-pvrazol-5-v1)-3-(trifluoromethvl)phenol (P74b) A mixture of compound P74a (5.0 g, 22 mmol) and isopropylhydrazine hydrochloride (3.63 g, 33 mmol) in ethanol (80 mL) was stirred at 80 C for 2.5 h, concentrated and purified by CC
(PE/EA = 10/1) to afford compound P74b (4.8 g, 81%) as a pale solid.
Step 3: 4-(1-lsopropv1-1H-pvrazol-5-v1)-3-(trifluoromethvl)phenvl trifluoromethanesulfonate (P74c) To a P74b (4.0 g, 14.8 mmol) in DCM (80 mL) was added TEA (3.0 g, 29.6 mmol) and Tf20 (6.26 g, 22.2 mmol). The mixture was stirred at rt for 3.5 h and washed with water (30 mL).
The organic phase was dried over Na2SO4, concentrated and purified by CC
(PE/EA = 40/1) to afford product P74c (4.5 g, 76%) as a pale solid.
Step 4: 1-lsopropv1-5-(4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)-2-(trifluoromethvI)-phenvI)-1H-pvrazole (P74) A mixture of P74c (2.0 g, 5.00 mmol), Pd(dppf)2Cl2 (0.2g, 0.25 mmol), B2Pin2 (1.9 g, 7.50 mmol) and KOAc (1.47g, 15.0 mmol) in 1,4-dioxane (200 mL) was stirred at 90 C
under N2 for 3 h, washed with water (400 mL) and extracted with EA (3x 100 mL). The combined organic phase was dried over Na2SO4 and evaporated to obtain product P74 (1.8 g, 95%).
Preparative Example P75 \¨osB
NN
Step 1: 2-(tert-Butyl)-4-chlorophenyl trifluoromethanesulfonate (P75a) To a solution of 2-(tert-butyl)-4-chlorophenol (30 g, 0.163 mol) and pyridine (21 mL, 0.26 30 mol) in dry DCM (500 mL) was added a solution of Tf20 (33 ml, 0.19 mol) in dry DCM (150 mL) at 0 C and the solution was stirred for 4 h at rt, poured into 1M HCI and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 10/1) to give P75a (39 g, 87%) as a colorless liquid.
Step 2: Methyl 2-(tert-butyl)-4-chlorobenzoate (P75b) A solution of P75a (36 g, 0.13 mol), dppp (4.5 g, 11 mmol), Pd(OAc)2 (2.4 g, 11 mmol) and NEt3 (135 mL, 1.0 mol) in a mixture of Me0H (300 mL) and DMSO (400 mL) was stirred overnight at 55 C under an atmosphere of CO. Water and EA were added and the organic layer was separated, washed with water twice and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 8/1) to give compound P75b (25.7 g, 89%) as a colorless solid.
Step 3: 2-(tert-Butyl)-4-chlorobenzoic acid (P75c) To a solution of P75b (4.5 g, 20 mmol) in Me0H (30 mL) was added 3M NaOH (7 mL) and the mixture was ref luxed for 12 h, concentrated and poured into water (50 mL), adjusted to pH 3 by adding 3M HCI and extracted with EA (3x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to obtain crude product P75c (4.0 g, 95 /0).
Step 4: 2-(tert-Butv1)-4-chloro-1'f-pivalovlbenzohydrazide (P75d) A solution of P75c (2.1 g, 10 mmol), HATU (5.7 g, 15 mmol) and DIPEA (3.2 g, 25 mmol) in DMF (15 mL) was stirred at rt for 30 min. Then pivalohydrazide (1.7 g, 15 mmol) was added and the mixture was stirred for 12 h under rt, poured into H20 (50 mL) and extracted with EA
(3x 50 mL). The combined organic layer were dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to afford compound P75d (2.5 g, 80%).
Step 5: 2-(tert-Butyl)-5-(2-(tert-butv1)-4-chlorophenv1)-1,3,4-oxadiazole (P75e) To a slurry of compound P75d (1.2 g, 3.8 mmol) in DCM (15 mL) was added pyridine (0.6 g, 7.6 mmol). The mixture was cooled to ¨10 C and Tf20 (2.2 g, 7.6 mmol) was added dropwise. The mixture was stirred at ¨10 C for 1 h, at 0 C for 1 h and then warmed slowly to rt and stirred for 2 h, poured into H2O (50 mL) and extracted with EA (3x 50 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC
to afford compound P75e (660 mg, 60%).
Step 6: 2-(tert-Butyl)-5-(2-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-v1)phenv1)-1,3,4-oxadiazole (P75) Compound P75e was treated as described above in Example P65, Step 3 to give compound P75 as a colorless solid.
Preparative Example P76 0)t.,/c--N H2 StelD 1: Methyl 2,2-dimethy1-4-oxopentanoate (P76a) A solution of 4-methoxy-3,3-dimethy1-4-oxobutanoic acid (180 mg, 1.12mmol) in SOCl2 (6 mL) was stirred at rt for 2 h and concentrated. Cul (628 mg, 3.3 mmol) and Et20 (8 mL) in a separate flask was treated with MeLi (22 mL, 3M) and the solution was stirred for 5 min.
Then the resulting solution was cooled to ¨78 C. The acid chloride was added as a solution in Et20 (1 mL) and the solution was stirred for additional 30 min, quenched by Me0H and warmed to rt over 2 h. Aq. NHC14 was added and the mixture was extracted with EA. The organic layer was concentrated to give compound P76a (60 mg, 33%) as a colorless oil.
Step 2: 1-Benzv1-3,3,6-trimethylpiperidin-2-one (P76b) To a solution of compound P76a (100 mg, 0.63 mmol) in DCM (10 mL) was added BnNH2 (67 mg, 0.63 mmol), NaBH(Ac0)3 (186 mg, 0.88 mmol) and AcOH (0.04 mL) at 0 C.
The mixture was allowed to reach rt and stirred overnight. Aq. NaOH (1 mL, 10%) was added dropwise and the mixture was extracted with DCM. The organic layer was concentrated and purified by CC (PE/EA = 5/1) to give compound P76b (40 mg, 30%) as a colorless oil.
Step 3: 3,3,6-Trimethylpiperidin-2-one (P76c) Na (0.3 g, 13 mmol) was added to ammonia (10 mL) at ¨78 C, resulting in a dark blue solution. A solution of compound P76b (60 mg, 0.27 mmol) in THF (1 mL) was added and the solution was stirred at ¨40 C for 2 h, quenched with NHCI4 and concentrated. The residue was diluted with water (5 mL) and extracted with EA. The organic layer was concentrated and purified CC (PE/EA = 2/1) to give compound P76c (30 mg, 87%) as a colorless solid.
Step 4: Methyl 5-amino-2,2-dimethylhexanoate (P76) A mixture of compound P76c (400 mg, 3.14 mmol) in conc. HCI (10 mL) was stirred at 120 C
in a sealed tube for 48 h and concentrated. The obtained residue (300 mg, 1.63 mmol) was dissolved in Me0H (10 mL) and TMSCI (708 mg, 6.5 mmol) was added. The solution was stirred at rt for 24 h and concentrated to give compound P76 (350 mg, 57%) as an off-white solid.
Preparative Example P77 F3c _______________________________________ *
HN1<
Step 1: N-(2-Methv1-3-(trifluoromethvl)phenvpacetamide (P77a) 2-Methyl-3-(trifluoromethyl)aniline (1.95 g, 11.1 mmol) was dissolved in (Ac)20 (10 mL) and the mixture was stirred at rt overnight, partitioned between DCM (20 mL) and aq. NaHCO3 (20 mL) and the aq. phase was extracted again with DCM (3x 20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC to afford compound P77a (2.08 g, 86%).
Step 2: N-(4-Bromo-2-methv1-3-(trifluoromethvl)phenv1)acetamide (P77b) To a solution of compound P77a (2.08 g, 9.6 mmol) in HOAc (20 mL) was added under water-cooling a solution of bromine (1.8 mL) in HOAG (10 mL). The mixture was stirred at rt overnight and at 50 C for 2 h. Additional bromine (1.5 mL) was added under water-cooling and the mixture was stirred and heated to 50 C for 4 d, cooled to rt and poured into ice water. EA was added, followed by neutralization with K2CO3. The organic layer was separated, washed with aq. Na2S203 and brine, dried over Na2SO4 and concentrated to afford compound P77b (388 mg, 16%).
Step 3: 4-Bromo-2-methvI-3-(trifluoromethvpaniline (P77c) To a solution of compound P77b (338 mg, 1.33 mmol) in Et0H (20 mL) was added (1 mL). The mixture was heated to reflux overnight, cooled to rt, concentrated, adjusted to p14-4 with 4M HC1 and extracted with EA. The organic layer was washed with brine and dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to give compound P77c (186 mg, 56%) as colorless solid.
Step 4: N-(tert-Butv1)-2-methv1-4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)-3-(trifluoro-methvl)benzenesulfonamide (P77) Compound P77 was prepared from P77c similar as described for compound P45.
Preparative Example P77/1 to P77/2 Using similar procedures at that described in Preparative Example P77, the following compounds were prepared:
Structure # Structure 9,oCI F
-P77/1 -dB _\ scµNH P77/2 __ Preparative Example P78 ONfirs1H
Step 1: tert-Butvl 3-amino-3-(hydroxymethyl)azetidine-1-carboxylate (P78a) To a solution of 1-tert-butyl 3-ethyl 3-aminoazetidine-1,3-dicarboxylate (366 mg, 1.50 mmol) in THF (10 mL) was added LiBH4 (67 mg; 3 mmol) and the solution was ref luxed for 20 min, quenched with H20, acidified with 2M aq. HCI, neutralized again with 2M aq.
Na2CO3 and extracted with EA (3x). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated to give compound P78a (300 mg, 99%) as a yellow oil.
Step 2: tert- Butyl 6-oxo-8-oxa-2,5-diazaspirof3.51nonane-2-carboxylate (P78b) To a solution of compound P78a (400 mg, 1.98 mmol) and NEt3 (404 mg, 4.00 mmol) in DCM (10 mL) was added 2-chloroacetyl chloride (222 mg, 1.98 mmol) at 0 C and the solution was refluxed for 2 h, cooled to rt, washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA =5/1) to give of compound P78b (145 mg, 30%) as a colourless oil.
Step 3: 8-oxa-2,5-diazaspiro[3.51nonan-6-one (P78) A solution of compound P78b (145 mg, 0.60 mmol) and TFA (10 mL) was stirred for 6 h at rt and concentrated to give intermediate 78 (200 mg crude) as a TFA salt. 1H-NMR
(300 MHz, DMSO-d6) 6: 3.98-3.95 (m, 1H), 4.12-4.08 (m, 5H), 4.53 (s, 2H), 8.54 (m, 3H).
MS: 143 [M+1]+.
Preparative Example P79 OJNH
Step 1: 1-tert-Butyl 3-ethyl 3-(2-((tert-butoxycarbonyl)amino)acetamido)azetidine-1,3-dicarboxylate (P79a) The solution of of 1-tert-butyl 3-ethyl 3-aminoazetidine-1,3-dicarboxylate (400 mg, 1.64 mmol), 2-[(tert-butoxy)carbonylamino] acetic acid (431 mg, 2.46 mmol), HOBT
(332 mg, 2.46 mmol), EDCI (707 mg, 3.69 mmol) and DIEA (1 mL) in THF (20 mL) was stirred overnight at rt, washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC
(PE/EA = 2/1) to give compound P79a (500 mg, 76%) as a colorless solid.
Step 2: 2,5,8-Triazaspirof3.51nonane-6,9-dione (P79) A solution of compound P79a (500 mg, 1.25 mmol) and HCI in Me0H (3M, 10 mL) was stirred at rt for 1 h and then ref luxed overnight, concentrated and diluted with Et20. The formed solid was collected by filtration, washed with Et20 and dried in vacuum to give compound P79 (200 mg, 84%) as a mono HCI salt. 1H-NMR (300 MHz, D20) 6: 4.69-4.65 (m, 2H), 4.51-4.47 (m, 2H), 4.19 (s, 2H). MS: 156 [M+1]+.
Preparative Example P80 HN
Step 1: Methyl 4-acetyltetrahydro-2H-pyran-4-carboxylate (P80a) To a suspension of 2,2'-dichloroethyl ether (14.3 g, 100 mmol), K2CO3 (27.6 g, 200 mmol), KI
(1.0 g, 6.00 mmol) in DMF (60 mL) was added methyl 3-oxobutanoate (13.9 g, 120 mmol) and the solution was stirred for 8 h at 80 C, diluted with water and extracted with EA (6x).
The combined organic layers were dried over Na2SO4, filtered and the filtrate was distilled under reduced pressure (Kp 125 to 127 C, 1.3 kPa) to give compound P80a (8.0 g, 43%) as a pale yellow liquid.
Step 2: Methyl 4-(2-bromoacetyl)tetrahydro-2H-pyran-4-carboxylate (P80b) A suspension of compound P80a (8.0 g, 43 mmol) and CuBr2 (9.63 g, 43 mmol) in EA (100 mL) was stirred overnight at 40 C, filtered and the filtrate was concentrated and purified by CC (PE/EA = 20/1) to give compound P80b (2.0 g, 18%) as a colorless solid.
Step 3: 8-Oxa-2-azaspirof4.51decane-1,4-dione (P80c) A solution of compound P80b (2.0 g, 7.5 mmol) in Me0H/NH3 (10M, 100 mL) was stirred overnight at 50 C in a sealed tube, cooled to rt, concentrated and purified by CC (PE/EA =
8/1) to give compound P80c (800 mg, 63%) as a colorless solid.
Step 4: 4-amino-8-oxa-2-azaspirof4.51decan-1-one (P80) A suspension of compound P80c (800 mg, 4.7 mmol), K2CO3 (1.19 g, 8.6 mmol) and NH2OH=HCI (598 mg, 8.6 mmol) in Et0H (30 mL) was stirred for 6 h at rt and concentrated.
Et0H (15 mL) and Raney-Ni (1 g) were added consecutively and the suspension was stirred under 50 psi of H2 atmosphere for 3 h at 65 C, filtered and the filtrate was concentrated and purified by CC (PE/EA = 1/5) to give intermediate P80 (200 mg, 25%) as a colorless solid.
1H-NMR (300 MHz, DMSO-d6+ D20) 6: 3.87-3.81 (m, 1H), 3.75-3.69 (m, 1H), 3.59-3.48 (m, 2H), 3.42-3.36 (m, 1H), 3.29-3.26 (m, 1H), 2.86-2.81 (m, 1H), 1.58-1.43 (m, 4H). MS: 171 [M+1]+.
Preparative Example P81 C
N-N7 NH2.1-1C1 Step 1: tert-Butyl (2-methv1-2-(1H-tetrazol-5-v1)propvl)carbamate (P81a) To a solution of tert-butyl (2-cyano-2-methylpropyl)carbamate (915 mg, 4.62 mmol) in DMF
(25 mL) was added NaN3 (450 mg, 6.93 mmol) and NH4CI (367 mg, 6.93 mmol). The reaction mixture was stirred at 110 C for 24 h, cooled, diluted with EA (20 mL) and washed with water (100 mL). The combined organic extracts were dried over Na2SO4, evaporated and purified by prep. HPLC to give compound P81a (345 mg, 31%) as a colorless solid.
Step 2: 2-Methyl-2-(1H-tetrazol-5-v1)propan-1-amine hydrochloride (P81) A mixture of compound P81a (345 mg, 1.43 mmol) in HCl/Me0H (4M, 30 mL) was stirred at rt overnight and evaporated to give compound P81 (241 mg, 95%) as a colorless solid.
Preparative Example 82 dN.,(<NH2=HCI
Step 1: tert-Butvl (3-(hydroxvamino)-3-imino-2,2-dimethvIpropv1)carbamate (P82a) A mixture of tert-butyl (2-cyano-2-methylpropyl)carbamate (1.75 g, 8.85 mmol), NH2OH=HCI
(584 mg, 17.7 mmol) and Et0Na (1.80 g, 26.6 mmol) in Et0H (50 mL) was stirred at 60 C
overnight, poured into water and extracted with EA. The organic extracts were dried over Na2SO4 and evaporated to give compound P82a (1.53 g, 75%) as yellow oil.
Step 2: tea-Butyl (2-methvI-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-v1)propvl)carbamate (P82b) A mixture of P82a (1.53 g, 6.64 mmol), dimethyl carbonate (1.32 g, 13.3 mmol), Et0Na (903 mg, 13.3 mmol) in Et0H (50 mL) was stirred at 60 C overnight, poured into water and extracted with EA. The combined organic layers were dried and evaporated to afford compound P82b (700 mg, 41%) as yellow solid.
Step 3: 3-(1-Amino-2-methylpropan-2-y1)-1,2,4-oxadiazol-5(4H)-one hydrochloride (P82) A mixture of compound P82b (700 mg, 2.73 mmol) in HCl/Me0H (4M, 30 mL) was stirred at rt overnight and evaporated to give compound P82 (420 mg, 98%) as a colorless solid.
Preparative Example P83 NH2=HCI
Step 1: tert-Butyl (3-(hydroxyamino)-3-iminopropyl)carbamate (P83a) A mixture of tert-butyl (2-cyanoethyl)carbamate (763 mg, 4.49 mmol), NH2OH=FICI (296 mg, 8.98 mmol) and Et0Na (916 mg, 13.5 mmol) in Et0H (50 mL) was stirred at 60 C
overnight, poured into water and extracted with EA. The combined organic extracts were dried over Na2SO4 and evaporated to give compound P83a (775 mg, 85%) as yellow oil.
Step 2: tert-Butyl (2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yflethyl)carbamate (P83b) A mixture of compound P83a (772 mg, 3.80 mmol), 1,11-carbonyldiimidazole (1.23 g, 7.61 mmol), Et0Na (518 mg, 7.61 mmol) in Et0H (50 mL) was stirred at 60 C
overnight, poured into water and extracted with EA. The combined organic layers were dried and evaporated to afford compound P83b (540 mg, 62%) as yellow solid.
Step 3: 3-(2-Aminoethyl)-1,2,4-oxadiazol-5(4H)-one hydrochloride (P83) A mixture of compound P83b (540 mg, 2.36 mmol) in HCl/Me0H (4M, 30 mL) was stirred at rt overnight and evaporated to give compound P83 (301 mg, 99%) as a colorless solid.
Peparative Example P84 *NH
Ci Step 1: 3-Bromo-N-(tert-butyl)-5-chlorobenzamide (P84a) A mixture of 3-bromo-5-chlorobenzoic acid (2.3 g, 10 mmol), HATU (3.7 g, 10 mmol) and DIPEA (2 g, 15 mmol) in DMF (30 mL) was stirred at rt for 30 min. Then 2-methylbutan-2-amine (1.0 g, 10 mmol) was added and the mixture was stirred for 12 h under rt, poured into water (100 mL) and extracted with EA (3x 50 mL). The combined organic layer was dried over Na2SO4, filtered, evaporated and purified by CC to give compound P84a (2.3 g, 80%).
Step 2: N-(tert-Butv1)-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-v1)benzamide (P84) The mixture of compound P84a (2.0 g, 6.0 mmol), B2Pin2 (2.0 g, 8.5 mmol), KOAc (1.0 g, 10.5 mmol) and Pd(dppf)C12 (100 mg) in 1,4-dioxane (50 mL) was stirred at 90 C
under N2 for 12 h, concentrated, poured into water (50 mL) and extracted with EA (3x 50 mL). The combined organic layer was dried over Na2SO4, filtered, evaporated and purified by CC to give compound P84 (1.1 g, 53%).
Preparative Example P85 A
:B * P85 Compound P85 was prepared using similar procedures as described in W02012/139775, Preparative Example P28, starting with 1,3-dibromo-5-chlorobenzene.
Preparative Example P86 ocF3 _________________________________ -o V
Step 1: 3-Bromo-N-methoxv-N-methyl-5-(trifluoromethoxv)benzamide (P86a) To a solution of 3-bromo-5-(trifluoromethoxy)benzoic acid (5.00 g, 17.5 mmol), N,0-dimethylhydroxylamine=HCI (4.20 g, 43.9 mmol), HATU (14.7 g, 38.7 mmol) in DMF
(50 mL) was added TEA (9.8 mL, 70.2 mmol) in portions at 0 C and the solution was stirred overnight at rt, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2504, filtered and concentrated to give compound P86a (5.5 g, 96%) as a yellow oil. 1H-NMR (400 MHz, CDCI3) 6: 3.37 (s, 3H), 3.56 (s, 3H), 7.48 (s, 1H), 7.52 (s, 1H), 7.80 (s, 1H).
Step 2: 1-(3-Bromo-5-(trifluoromethoxv)phenvnethanone (P86b) To a solution of compound P86a (4.5 g, 13.7 mmol) in dry THF (50 mL) was added CH3MgBr (3M in Et20, 9.2 mL, 27.6 mmol) in portions at ¨15 C and the solution was stirred for 15 min at this temperature and then at rt for 1 h, diluted with 1M HCI and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give compound P86b (3.5 g, 90%) as a yellow oil. 1H-NMR (400 MHz, CDCI3) 6: 2.62 (s, 3H), 7.60 (s, 1H), 7.74 (s, 1H), 8.02 (m, 1H).
Step 3: 1-Bromo-3-(prop-1-en-2-yI)-5-(trifluoromethoxv)benzene (P86c) To a suspension of methyltriphenylphosphonium bromide (7.60 g, 21.2 mmol) in dry THF
(150 mL) was added NaHMDS (1M in THF, 10.6 mL, 10.6 mmol) at ¨15 C and the solution was stirred further for 30 min. A solution of compound P86b (3.0 g, 10.6 mmol) in THF (5 mL) was added at ¨15 C and the mixture was stirred at rt for 1 h, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE) to give compound P86c (2.4 g, 81%) as a yellow oil.
1H-NMR (400 MHz, CDCI3) 6: 2.11 (d, J = 1.6 Hz, 3H), 5.19 (s, 1H), 5.38 (s, 1H), 7.22 (s, 1H), 7.29 (s, 1H), 7.52 (m, 1H).
Step 4: 1-Bromo-3-(1-methvIcyclopropv1)-5-(trifluoromethoxv)benzene (P86d) To a suspension of Pd(OAc)2 (1.0 g, 4.45 mmol) and compound P86c (3.0 g, 10.7 mmol) was added a solution of CH2N2 in Et20 (1M, 20 mL, 20 mmol) at ¨10 C and the solution was stirred for 30 min, filtered and the filtrate was concentrated to give compound P86d (1.9 g, 60%) as a yellow oil. 1H-NMR (400 MHz, CDCI3) 6: 0.78-0.81 (m, 2H), 0.84-0.88 (m, 2H), 1.39 (s, 3H), 7.00 (s, 1H), 7.18 (s, 1H), 7.30 (m, 1H).
Step 5: 4,4,5,5-Tetramethv1-2-(3-(1-methvIcyclopropy1)-5-(trifluoromethoxv)phenv1)-1,3,2-dioxaborolane (P86) To a suspension of compound P86d (1.0 g, 3.4 mmol), KOAc (1.40 g, 13.8 mmol) and B2Pin2 (1.80 g, 7.08 mmol) in 1,4-dioxane (40 mL) was added Pd(dppf)Cl2 (250 mg, 356 pmol) at rt under N2 and the solution was heated overnight at 80 C, cooled to rt and filtered. The filtrate was concentrated and purified by CC (PE/EA = 50/1) to give compound P86 (1.0 g, 91%) as yellow oil. 1H-NMR (300 MHz, CDCI3) 6:0.73-0.76 (m, 2H), 0.86-0.90 (m, 2H), 1.34 (s, 12H), 1.41 (s, 3H), 7.17 (s, 1H), 7.43 (s, 1H), 7.60 (s, 1H).
Preparative Example P87 ocF3 y P87 NH
Compound P87 was prepared using similar procedures as described in Preparative Example P84.
Preparative Example P89:
\--0, B N/¨\N¨
Step 1: 1-(2-(tert-Butvl)phenv1)-4-methvIpiperazine (P89a) A mixture of 2-(tert-butyl)aniline (1.0 g, 6.71 mmol), Nal (3.0 g, 20.1 mmol), K2CO3 (2.78 g, 20.1 mmol) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine (1.04 g, 6.71 mmol) in diglyme (150 mL) was stirred at 170 C for 24 h, poured into water and extracted with EA.
The organic layers were dried over Na2SO4, evaporated and purified by CC
(DCM/Me0H =
19/1) to afford compound P89a (500 mg, 32%).
Step 2: 1-(4-Bromo-2-(tert-butvl)phenvI)-4-methylpiperazine (P89b) Compound P89a (200 mg, 0.86 mmol) and Na0Ac (210 mg, 2.58 mmol) were dissolved in AcOH (5 mL) and the mixture was stirred at it Bromine (165 mg, 1.03 mmol) was added dropwise and the mixture was stirred for 2 h at rt, diluted with 2M NaOH (150 mL) and extracted with EA. The combined organic phases were dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to afford compound P89b (40 mg, 15%).
Step 3: 1-(2-(tert-Butv1)-4-(4,4,5,5-tetramethv1-1,3,2-dioxaborolan-2-v1)phenv1)-4-methvIpiperazine (P89) This compound was prepared using a similar procedure as described in Preparative Example P86, Step 5.
Preparative Example P90 OH
___________________________________ :B P90 f'0 F F
Step 1: 2-(3-Bromo-5-(trifluoromethvl)phenvI)propan-2-ol (P90a) A mixture of 1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (0.5 g, 1.8 mmol) in THF (10 mL) was cooled to 0 C and treated dropwise with MeMgBr (1M in Et20, 10 mmol, 10 mL). Upon completion of addition, the resulting suspension was allowed to warm to rt and was stirred for 5 h, slowly diluted with saturated aq. NH4C1 (10 mL) and EA (10 mL). The layers were separated and the aq. layer was extracted with EA (3x 30 mL). The combined organic layers were dried over MgSO4, evaporated and purified by CC to afford compound P90a (0.47 g, 93%).
Step 2: 2-(3-(4,4,5,5-Tetramethy1-1,3,2-dioxaborolan-2-v1)-5-(trifluoromethvl)phenv1)propan-2-01 (P90) Compound P90 was prepared using a similar procedure as described in Preparative Example P86, Step 5.
Preparative Example P91 Br ¨\ P91 N),\
Step 1: 2,6-Di- tert-butvlpvrimidin-4-ol (P91a) To a mixture of pivalimidamide (586 mg, 5.86 mmol) and ethyl 4,4-dimethy1-3-oxopentanoate (1.21 g, 7.03 mmol) in Me0H (30 mL) was added Na0Me (623 mg, 11.7 mmol) under Ar.
The mixture was refluxed at 75 C overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give compound P91a (1.04 g, 85%) as colorless solid.
Step 2: 4-Bromo-2,6-di-tert-butvIrwrimidine (P91) Compound P91a (1.04 g, 4.99 mmol) and POBr3 (10 g) was stirred at 65 C for 1 h, poured into ice/water and extracted with EA. The organic layer was dried over MgSO4, filtered and concentrated to give compound P91 (1.20 g, 89%) as a yellow oil.
Preparative Example P92 Br¨CY--; P92 Step 1: 1-MethvIcyclopropanecarboximidamide (P92a) NH4C1 (129 mg, 2.43 mmol) was suspended in toluene (10 mL) and the slurry cooled to 0 C.
AlMe3 (2M in toluene, 2.43 mmol) was added at 0 C and the mixture was allowed to warm to rt and stirred until gas evolution had ceased. Methyl 1-methylcyclopropanecarboxylate (114 mg, 1.62 mmol) was added and the mixture stirred at 80 C overnight, cooled to rt, diluted with Me0H and stirred at rt for 1 h. The solution was filtered, the solids washed with Me0H
and the solvent was removed in vacuo to afford the compound P92a (100 mg, 63%).
Step 2: 6-(tert-Butyl)-2-(1-methvIcyclopropvl)pvrimidin-4-ol (P92b) To a mixture of compound P92a (63 mg, 0.64 mmol) and methyl 4,4-dimethy1-3-oxopentanoate (121 mg, 0.77 mmol) in Me0H (30 mL) was added Na0Me (86 mg, 1.61 mmol) under Ar. The mixture was refluxed at 75 C overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give compound P92b (112 mg, 85%) as a colorless solid.
Step 3: 4-Bromo-6-(tert-buty1)-2-(1-methylcyclopropyl)pyrimidine (P92) Compound P92b (105 mg, 0.51 mmol) and POBr3 (200 mg) was stirred without solvent at 65 C for 1 h, poured into ice/water and extracted with EA. The organic layer was dried over MgSO4, filtered and concentrated to give compound P92 (121 mg, 89%) as yellow oil.
Preparative Example P93 TfO¨Cr p93 Nlv.
Step 1: Methyl 3-(1-methylcyclopropyI)-3-oxopropanoate (P93a) To a solution of 1-(1-methylcyclopropyl)ethanone (328 mg, 3.35 mmol) in THF
(90 mL) was added LiHMDS (1M in THF, 2.5 mL) at ¨78 C. The cooling bath was removed and the mixture was stirred at rt for 30 min. Dimethyl carbonate (452 mg, 5.03 mmol) was added and the mixture stirred at rt overnight, evaporated, diluted with water and EA, acidified with AcOH
and extracted with EA. The organic layer was dried over MgSO4, filtered, concentrated and purified by CC (EA/PE = 1/9) to give compound P93a (68 mg, 13%) as a yellow oil.
Step 2: 2-(tert-ButyI)-6-(1-methylcyclopropyl)pyrimidin-4-ol (P93b) To a mixture of compound P93a (60 mg, 0.38 mmol) and pivalimidamide (46 mg, 0.46 mmol) in Me0H (30 mL) was added Na0Me (51 mg, 0.95 mmol) under Ar. The mixture was ref luxed at 75 C overnight, diluted with water (20 mL) and extracted with EA
(3x 20 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give compound P93b (63 mg, 80%) as a colorless solid.
Step 3: 2-(tert-Butyl)-6-(1-methylcyclopropyl)pyrimidin-4-yltrifluoromethanesulfonate (P93) To a mixture of compound P93b (57 mg, 0.28 mmol) in DCM (10 mL) was added Tf20 (118 mg, 0.42 mmol) and TEA (71 mg, 0.70 mmol) and the mixture was stirred at rt overnight, poured into water and extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated to afford compound P93 (81 mg, 86%) as a yellow oil.
Preparative Example P94 o _ \B it Nx_H
\_ 0 7'6 P94 OMe Step 1: 3-Bromo-5-(methoxvcarbonvl)benzoic acid (P94a) To a solution of dimethyl 5-bromoisophthalate (5.0 g, 18.3 mmol) in a mixture of THF (25 mL) and Me0H (25 mL) was added NaOH (740 mg, 18.4 mmol) and the mixture was stirred at rt overnight, concentrated, diluted with 2M HCI (20 mL) and extracted with EA. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was washed with a mixture of PE/EA (10:1, 10 mL) to give compound P94a (4.2 g, 88%) as a colorless solid.
Step 2: Methyl 3-bromo-5-(tert-butvIcarbamovl)benzoate (P94b) A solution of compound P94a (400 mg, 1.54 mmol) in SOCl2 (10 mL) was heated at reflux for 2 h, concentrated and coevaporated with toluene twice. The residue was dissolved in dry DCM (6 mL). TEA (0.2 mL) and tert-butylamine (0.15 mL) were added and the solution was stirred for further 40 min, concentrated and purified by CC (PE/EA = 10:1) to give compound P94b (360 mg, 76%) as a colorless oil.
Step 3: Methyl 3-(tert-butvIcarbamov1)-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)benzoate (P94) A flask was charged with compound P94b (360 mg, 1.15 mmol), B2Pin2 (1.57 g, 5.4 mmol), KOAc (0.72 g, 7.3 mmol), Pd(dppf)C12 (60 mg) and DMF (10 mL) and the mixture was stirred at 90 C for 12 h, cooled, concentrated and purified by CC (PE/EA = 10/1) to give compound P94 (315 mg, 76%) as a colorless solid.
Preparative Example P95 OH
* p95 OMe Step 1: Methyl 3-bromo-5-(methoxv(methvI)carbamovnbenzoate (P95a) A solution of compound P94a (3.8 g, 14.7 mmol) in SOCl2 (40 mL) was heated at reflux for 2 h, concentrated and diluted with dry DCM (200 mL). Then the solution was added to a stirring solution of N,0-dimethylhydroxylamine hydrochloride (1.69 g, 17.6 mmol) and NEt3 (6 mL) in dry DCM (60 mL) slowly at 0 C and the solution was stirred for 1 h at rt, poured into water. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated to give crude compound P95a (4.2 g, 94%) as a light brown oil.
Step 2: Methyl 3-acetyl-5-bromobenzoate (P95b) To a solution of compound P95a (4.2 g, 14.0 mmol) in dry THF (120 mL) was added MeMgBr (3M in Et20, 5.5 mL, 16.7 mmol) dropwise at 0 C and the solution was stirred for 4 h at rt, quenched with aq. NHCI4 and extracted with EA twice. The combined organic layers were washed with water and brine consecutively, dried over Na2SO4, filtered and concentrated to give crude compound P95b (2.5 g) which contains 15% compound P95c (based on LCMS) as a colorless oil Step 3: Methyl 3-bromo-5-(2-hydroxvpropan-2-v1)benzoate (P95c) To a solution of crude compound P95b (2.5 g, 9.7 mmol) in dry THF (50 mL) was added MeMgBr (3M in Et20, 3.7 mL, 11.1 mmol) dropwise at 0 C and the solution was stirred for 4 h at rt, quenched with aq. NHCI4 and extracted with EA twice. The combined organic layers were washed with water and brine consecutively, dried over Na2SO4, filtered and concentrated to give crude compound P95c (2.1 g, 79% over two steps) as pale yellow oil.
Step 4: Methyl 3-(2-hydroxvpropan-2-v1)-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-0benzoate (P95) A flask was charged with compound P95c (900 mg, 3.3 mmol), B2Pin2 (4.5 g, 17.8 mmol), KOAc (2.3 g, 23.1 mmol), Pd(dppf)Cl2 (100 mg) and DMF (200 mL) and the solution was stirred at 100 C for 12 h, concentrated and purified by CC (PE/EA = 10/1) to give compound P95 (650 mg, 62%) as a colorless solid.
Preparative Example P96 OMe :B P96 OMe Step 1: Methyl 3-bromo-5-(2-methoxvproPan-2-v1)benzoate (P96a) To a solution of compound P95c (1.1 g, 4.0 mmol) in dry THF (20 mL) was added NaH (195 mg, 8.0 mmol) under N2 and the suspension was stirred for 1 hat rt. Then Mel (1.72 g, 12.0 mmol) was added and the solution was stirred at 70 C in a sealed tube overnight, poured into water and extracted with Et20. The organic layer was washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE) to give compound P96a (600 mg, 52%) as a colorless oil.
Step 2: Methyl 3-(2-methoxypropan-2-y1)-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-vl)benzoate (P96) A flask was charged with compound P96a (600 mg, 2.1 mmol), B2Pin2 (1.07 g, 4.2 mmol), KOAc (1.44 g, 14.7 mmol), Pd(dppf)Cl2 (60 mg) and DMF (10 mL) and the solution was Preparative Example P97 ___________________________________ B I/ 0 P97 -(5 To a solution of 2-(spiro[chroman-4,1'-cyclopropan]-8-yl)propan-2-ol (prepared as described in W02012/139775, Preparative Example P39) (1.0 g, 4.58 mmol) in dry THF (10 mL) was added NBS (980 mg, 5.5 mmol) and the mixture was heated at reflux overnight, cooled, poured into water and extracted with EA twice. The combined organic layers were washed Step 2: 4,4,5,5-tetramethy1-2-(8-(prop-1-en-2-yl)spirorchroman-4,11-cyclopropan1-6-y1)-1,3,2-dioxaborolane (P97) (30 mg) and KOAc (150 mg, 1.52 mmol) in DMF (5 mL) under N2 atmosphere was stirred at 95 C overnight, concentrated and purified by CC (PE/EA = 10/1) to give compound P97 (128 mg, 36%) as a colorless solid.
HN
N
Step 1: 1-Cyclohexylethyl methanesulfonate (la) A solution of 1-cyclohexylethanol (1.28 g, 10 mmol) in DCM (50 mL), mesylchloride (15 mmol), Et3N (30 mmol) was added under 0 C. The mixture was stirred for additional 2 h, quenched with ice water and extracted with EA. The organic layer was separated, washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and the crude intermediate la was used in the next step.
Step 2: 1,2-Dibromoethvl acetate (1b) Under N2, vinyl acetate (86 g, 1.0 mol) was dissolved in dry CCI4 (200 mL) and bromine (160 g, 1 mol) in dry CCI4 (100 mL) was added dropwise over 2 h with vigorous stirring in an ice-water bath below 10 C. The mixture was stirred for additional 30 min and solvent was removed to give crude product lb, which was used for the next step without further purification.
Step 3: Ethyl 2-methyl-1H-pyrrole-3-carboxvlate (1c) NH3 (gas) was bubbled to a stirred solution of compound lb (24.6 g, 10 mmol) and ethyl 3-oxobutanoate (13.0 g, 0.1 mol) in dry THF for 15 min. The solid was filtered off and solvent was removed to give crude product lc.
Step 4: Ethyl 1-(1-cyclohexvIethvI)-2-methyl-1H-pvrrole-3-carboxvlate (1d) To a solution of compound lc (1.53 g, 10 mmol) in dry DMF (10 mL) was added NaH (60%
in mineral oil, 1.2 g, 0.03 mol) in an ice-water bath below 0 C. The mixture was stirred for 30 min and then compound la (3.09 g, 15 mmol) was added to the mixture. The mixture was stirred for additional 12 h, quenched with ice water and extracted with EA.
The organic layer was separated and washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by CC (EA/PE = 1/60) to give compound id (1.63 g, 62%) as a pale yellow oil.
Step 5: Ethyl 5-bromo-1-(1-cyclohexvIethvI)-2-methyl-1H-pvrrole-3-carboxvlate (le) To a solution of compound id (1.32 g, 5.0 mmol) in dry THF (25mL) was added NBS (0.89 g, 5 mmol) at ¨78 C under N2. The reaction was stirred 5 min (monitored by TLC) and quenched with cold aq. NH4CI. The organic layer was separated and the aq.
layer extracted repeatedly with EA. The combined organic layer was washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by CC
(EA/PE= 1/60) to give compound le (1.57 g, 92%).
Step 6: Ethyl 1-(1-cyclohexvIethvI)-5-(3,5-di-tert-butvlphenv1)-2-methyl-1H-pyrrole-3-carboxvlate (1f) A suspension of compound le (1.71 g, 5 mmol), Cs2CO3 (3.25 g 10 mmol), 2-(3,5-di-tert-butylpheny1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.37 g, 7.5 mmol), Pd(dppf)Cl2 (30 mg) in 1,4-dioxane/H20(10:1, 50 mL) was heated overnight under N2 at 90 C. After cooling, the mixture was concentrated and extracted with EA. The organic layer was washed with brine, dried over magnesium sulfate, filtered, concentrated and purified by CC (EA/PE
= 1/50) to give compound if (903 mg, 40%).
Step 7: 1-(1-CyclohexvIethvI)-5-(3,5-di-tert-butvlphenv1)-2-methyl-1H-pyrrole-3-carboxylic acid (1q) To a solution of compound if (902 mg, 2 mmol) in Et0H (20 mL) was added 5M KOH
(10 mL). The mixture was ref luxed overnight, the solvent was removed under reduced pressure and the residue was adjusted to pH<2 with 4M HCI. The mixture was extracted with EA three times and the combined organic layer was washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep. HPLC to give pure product 1g as a colorless solid.
Step 8: 1-(1-CyclohexvIethvI)-5-(3,5-di-tert-butvlphenv1)-2-methyl-N-(oxetan-3-v1)-1H-pyrrole-3-carboxamide (1) To a solution of compound 1g (85 mg, 0.2 mmol) in DMF (5 mL) was added HATU
(152 mg, 0.4 mmol) and DIPEA (129 mg, 1 mmol). The mixture was stirred for 60 min and then oxetan-3-amine (110 mg, 1.5 mmol) was added to the mixture. The mixture was stirred overnight and quenched with ice water and extracted with EA. The organic layer was separated washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep. HPLC to give compound 1 (40 mg, 42%) as a colorless solid. 1H-NMR (500 MHz, DMSO-d6) 6: 0.63 (m, 2H), 1.01 (m, 4H), 1.13-1.31 (m, 20H), 1.47 (m, 6H), 2.57 (s, 3H), 3.86 (m, 1H), 4.52 (m, 2H), 4.70 (m, 2H), 4.95 (m, 1H), 6.50 (s, 1H), 7.09 (s, 2H), 7.39 (s, 1H), 8.19 (d, 1H). MS: 479.4 (M+1).
Example 1/1 to 1/132 The following Examples were prepared similar as in Example 1:
Structure Analytical data 1H-NMR (400 MHz, DMSO-d6) 6: 7.88 (t, J = 5.6 o, P Hz, 1H), 7.36 (s, 1H), 7.15 (d, J =
1.6 Hz, 1H), / N41.
H I 6.46 (s, 1H), 3.77 (d, J = 7.2 Hz, 2H), 3.60-3.55 (m, 2H), 3.31 (t, J = 7.0 Hz, 2H), 3.01 (s, 3H), 2.53 (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.21 (m, 21H), 0.93-0.88 (m, 3H), 0.68-0.62 (m, 2H). MS:
515.1 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.80 (t, J = 6.0 Hz, 1H), 7.36 (t, J = 1.8 Hz, 1H), 7.16 (d, J = 1.6 ofIr\-11 = Hz, 2H), 6.53 (s, 1H), 4.47 (d, J =
5.6 Hz, 2H), 1/2 4.15 (d, J = 5.6 Hz, 2H), 3.76 (d, J =
7.2 Hz, 2H), 3.34 (d, J = 6.0 Hz, 2H), 2.52 (s, 3H), 1.46-1.44 (m, 3H), 1.34-1.23 (m, 24H), 0.95-0.89 (m, # Structure Analytical data 3H), 0.66-0.60 (m, 2H). MS: 493.4 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.36-7.31 (m, o 2H), 7.20 (s, 1H), 7.15 (d, J = 1.6 Hz, 2H), 6.84 1 /3 \ . (s, 1H), 6.42 (s, 1H), 3.75 (d, J = 7.2 Hz, 2H), H2N 081 3.29 (s, 2H), 2.51 (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.22 (m, 21H), 1.07 (s, 6H), 0.95-0.89 (m, 3H), 0.67-0.60 (m, 2H). MS: 508.2 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.65 (t, J = 6.2 H o Hz, 1H), 7.36 (s, 1H), 7.16 (d, J = 1.6 Hz, 2H), 7.CN 0 fli 7.04 (s, 1H), 6.50 (s, 1H), 3.76 (d, J = 7.2 Hz, 1/4 , 0 N 2H), 3.28 (d, J = 6.4 Hz, 2H), 2.95 (s, 3H), 2.52 d (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.15 (m, 27H), 0.95-0.87 (m, 3H), 0.68-0.59 (m, 2H). MS: 558.1 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.81 (t, J = 5.8 o Hz, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 7.17 (d, J =
H2Nr \ 1.6 Hz, 1H), 6.96 (s, 1H), 6.53 (s, 1H), 3.78 (d, J
il git 1 /5 N = 7.2 Hz, 2H), 3.72 (d, J = 5.6 Hz, 2H), 2.53 (s, O 3H), 1.46-1.43 (m, 3H), 1.31-1.15 (m, 21H), 0.93-0.86 (m, 3H), 0.69-0.61 (m, 2H). MS: 466.1 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.65 (t, 1H), I o 7.36 (s, 1H), 7.17 (d, J = 1.6 Hz, 2H), 6.51 (s, \
1H), 3.99 (d, J = 5.2 Hz, 2H), 3.77 (d, J = 7.2 -Nr 1 it 1 /6 H N Hz, 2H), 3.00 (s, 3H), 2.84 (s, 3H), 2.52 (s, 3H), O 1.46-1.43 (m, 3H), 1.35-1.23 (m, 21H), 0.94-0.85 (m, 3H), 0.67-0.61 (m, 2H). MS: 494.2 (M+1).
o 1H-NMR (400 MHz, DMSO-d6) 6: 7.35 (t, J = 2.0 C.N \
Hz, 1H), 7.15 (d, J = 2.0 Hz, 2H), 6.18 (s, 1H), 1 .
1/7 HOi N 4.47-3.68 (m, 8H), 2.46 (s, 3H), 1.46-1.43 (m, d 3H), 1.31-1.21 (m, 21H), 0.98-0.85 (m, 3H), 0.68-0.60 (m, 2H). MS: 465.1 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6:7.36 (t, J = 1.6 o Hz, 1H), 7.15 (d, J = 1.6 Hz, 2H), 6.21 (s, 1H), o'Cir\I \ = 4.43-3.69 (m, 7H), 3.21 (s, 3H), 2.47 (s, 3H), 1/8 N 1.46-1.35 (m, 3H), 1.31-1.15 (m, 21H), 1.00-0.85 (m, 3H), 0.68-0.60 (m, 2H). MS: 479.1 (M+1).
# Structure Analytical data 1H-NMR (400 MHz, DMSO-d6) 6: 7.80 (t, J = 5.8 H2N o Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 1.6 Hz, 2H), ',sõ, \ , it 6.92 (s, 2H), 6.44 (s, 1H), 3.76 (d, J = 7.2 Hz, 1/9 N 2H), 3.56 (q, 2H), 3.18 (t, J = 7.4 Hz, 2H), 2.53 d (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.21 (m, 21H), 0.94-0.88 (m, 3H), 0.68-0.60 (m, 2H). MS: 516.1 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 8.18 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), o 6.26 (s, 1H), 5.89 (m, 1H), 4.56 (s, 1H), 4.00 (m, 1/10 c(Dy[Nil 1 \ /it sp2* 2H), 3.77 (d, J = 7.2 Hz, 2H), 3.38 (m, 2H), 3.30 N
N H (111, 2H), 2.63 (s, 3H), 1.86 (m, 1H), 1.66 (m, d 11H), 1.55-1.51 (m, 3H), 1.42-1.24 (m, 14H), 1.01-0.92 (m, 3H), 0.60 (m, 2H). MS: 586.1 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.12 (d, J =
o o 8.4 Hz, 1H), 7.74 (s, 1H), 7.63 (m, 1H), 7.52 (s, 1H)' 7.40 (m, 1H), 6.62 (s, 1H), 3.84 (m, 2H), H I \ it sPN24-- 3.56 (m, 4H), 3.27 (m, 2H), 2.52 (s, 3H), 2.38 d (m, 6H), 1.54 (s, 9H), 1.43 (m, 3H), 1.22-1.12 (m, 12H), 0.99-0.82 (m, 3H), 0.59 (m, 2H). MS:
601.1 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.45 (s, 1H), A4c,NN o 7.36 (t, J = 1.6 Hz, 1H), 7.15 (d, J = 1.6 Hz, 2H), H 1 \ = 6.48 (s, 1H), 3.77 (d, J = 6.8 Hz, 2H), 2.54 (s, 1/12 N 3H), 1.50-1.43 (m, 5H), 1.30-1.14 (m, 22H), d 0.94-0.86 (m, 3H), 0.67-0.60 (m, 2H). MS:
474.1 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 8.21 (d, J = 8.4 o Hz, 1H), 7.59 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), H2N \ II SO2 /_ 6.31 (s, 1H), 5.52 (br s, 2H), 4.67 (s, 1H), 3.80 H (d, J = 6.8 Hz, 2H), 2.63 (s, 3H), 1.62 (s, 9H), d 1.53 (m, 3H), 1.35-1.29 (m, 12H), 1.02-0.95 (m, 3H), 0.61 (m, 2H). MS Found: 488.5 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 5: 8.19 (d, J =
sa o 8.0 Hz, 1H), 7.36 (s, 1H), 7.16 (d, J = 1.6 Hz, 2H), 6.53 (s, 1H), 5.22-5.16 (m, 1H), 3.76 (d, J =
11 1 \ = 6.8 Hz, 2H), 3.50 (t, J = 9.0 Hz, 2H), 3.19 (t, J =
N
d 10.4 Hz, 2H), 2.43 (s, 3H), 1.45-1.40 (m, 3H), 1.31-1.15 (m, 21H), 0.97-0.87 (m, 3H), 0.67-0.58 (m, 2H). MS: 481.1 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 8.12 (d, J =
>LolNa 0 7.2 Hz, 1H), 7.36(t, J = 1.6 Hz, 1H), 7.16(d, J =
1.6 Hz, 2H), 6.56 (s, 1H), 4.63-4.58 (m, 1H), N \
H . 4.06-4.02 (m, 2H), 3.81-3.76 (m, 4H), 2.51 (s, d 3H), 1.45-1.43 (m, 3H), 1.38 (s, 9H), 1.31 (s, 18H), 1.27-1.15 (m, 3H), 0.92-0.84 (m, 3H), 0.67-0.59 (m, 2H). MS: 564.2 (M+1).
# Structure Analytical data 1H-NMR (300 MHz, CDCI3) 6: 0.66-0.72 (m, 2H), o\_3 cF3 0.97-1.04 (m, 9H), 1.25-1.43 (m, 4H), 1.58-1.63 (m, 4H), 2.60 (s, 3H), 3.85 (d, J = 7.2 Hz, 2H), d 1/16 N 4.07 (s, 2H), 4.57 (t, J = 6.6 Hz, 2H), 4.98 (t, J = o--)c.
7.2 Hz, 2H), 5.15-5.23 (m, 1H), 6.23-6.25 (m, 1H), 6.45 (s, 1H), 6.86 (s, 1H), 7.21 (s, 1H). MS:
508 (M+1)+.
1H-NMR (300 MHz, CDCI3) 6: 0.66-0.72 (m, 2H), 0.98-1.06 (m, 3H), 1.23-1.40 (m, 12H), 1.51-oa o 1.58 (m, 3H), 2.59 (s, 3H), 3.83 (d, J = 7.2 Hz, 2H), 4.57 (t, J = 6.6 Hz, 2H), 4.82 (q, J = 8.7 Hz, d 2H), 4.99 (t, J = 7.2 Hz, 2H), 5.15-5.23 (m, 1H), -\cF, 6.19 (d, J = 7.2 Hz, 2H), 6.35 (s, 1H), 6.62 (d, J
= 0.9 Hz, 1H), 6.93 (d, J = 0.9 Hz, 1H). MS: 508 (M+1)+.
11-I-NMR (400 MHz, DMSO-d6) 6: 8.23-8.20 m o\.3 N \ . NH (2H), 7.18 (s, 1H), 7.17 (s, 1H), 6.57 (s, 1H), 4.97-4.92 (m, 1H), 4.71 (t, 2H), 4.54 (t, 2H), 3.75 1/18 N (d, 2H), 2.42 (s, 3H), 1.48-1.46 (m, 3H), 1.41 (s, d 9H), 1.36-1.24 (m, 9H), 0.97-0.92 (m, 3H), 0.73-0.64 (m, 2H). MS: 506.3 (M+1).
1H-NMR (400 MHz, CDCI3) 6:7.32 (d, 1H), 7.04 (d, 1H), 6.23 (s, 1H), 6.20 (d, J = 7.2 Hz, 2H), oa / 5.23-5.20 (m, 1H), 5.00 (t, 2H), 4.57 (t, 2H), 3.74 Hi 1 \ = N
1/19 N (d, J = 6.8 Hz, 2H), 3.29 (s, 3H), 2.60 (s, 3H), d 2.50 (br s, 2H), 1.56-1.54 (m, 3H), 1.45 (s, 9H), 1.42-1.18 (m, 9H), 1.02-1.00 (d, 3H), 0.69-0.65 (m, 2H). MS: 520.3 (M+1).
S\ 0 o -- - ----NH
H, O \--= n.d.
d sa 0 N \ =
1/21 N n.d.
d 1H-NMR (300 MHz, DMSO-d6) 6: 8.31 (d, J =
oa 0 Aiik P 6.6 Hz, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 6.78 (s, 1H), 4.98-4.92 (m, 1H), 4.73 (t, J = 6.8 Hz, 2H), 1/22 N ii 4.55 (t, J = 6.2 Hz, 2H), 3.94-3.84 (m, 3H), 3.58-d 3.51 (m, 1H), 2.53 (s, 3H), 1.54-1.44 (m, 15H), 1.31-1.20(m, 9H), 0.95-0.88 (m, 3H), 0.70-0.62 (m, 2H). MS: 556.4 (M+1).
# Structure Analytical data sn 0 0 \--I 1 \
1/23 N Nt- n.d.
d 1H-NMR (400 MHz, CDCI3,) 5: 7.26 (s, 1H), 7.22 (d, 1H, J = 2.0 Hz), 7.10 (t, 1H, J = 2.0 Hz), 6.16 oaN 0 (s, 1H), 6.15 (s, 1H), 5.28 (s, 2H), 5.18-5.23 (m, H \ 41k \--0 1H), 4.98 (t, 2H, J = 9.6 Hz), 4.57 (t, 2H, J =
8.8 N
d \
Hz), 3.70 (d, 2H, J = 7.2 Hz), 3.54 (s, 3H), 2.60 (s, 3H), 1.55-1.51 (m, 3H), 1.45-1.31 (m, 12H), 1.03-0.97 (m, 3H), 0.68-0.64 (m, 2H). MS: 469 (M+1).
(-))CN \ it, 0 1/25 N n.d.
d 4 1H-NMR (500 MHz, CDCI3) 5: 8.14 (d, J = 8.5 o o Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.36 (dd, J =
H0x,N 1 \ 41"o ----INJH 8.5, 2.0 Hz, 1H), 6.44 (s, 1H), 6.89 (s, 1H), 6.02 1/26 , , N
r3k,d 0 ic- (t, J = 6.0 Hz, 1H), 4.53 (s, 1H), 3.86 (d, J = 7.5 Hz, 2H), 3.34 (d, J = 6.0 Hz, 2H), 1.71 (m, 6H), 1.61 (s, 9H), 1.31 (s, 9H), 1.26 (m, 3H), 1.17 (s, 6H), 0.97 (m, 2H). MS: 614.2 (M+1).
1H-NMR (500 MHz, CDCI3) 5: 8.13 (d, J = 8.0 o Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.35 (dd, J =
OH 9 8.0, 2.0 Hz, 1H), 6.89 (s, 1H), 6.89 (s, 1H), 5.97 1/27 "
µi-1\____ (t, J = 6.0 Hz, 1H), 4.46 (s, 1H), 3.87 (d, J = 7.5 F3C j U Hz, 2H), 3.74 (dd, J = 7.5, 3.0 Hz, 4H), 3.38 (d, J = 6.0 Hz, 2H), 1.78 (m, 5H), 1 .6p (s, 9H), 1.57 (m, 4H), 1.47 (m, 2H), 1.33 (s, 9H), 1.29 (m, 4H), 1.00 (m, 2H). MS: 656.2 (M+1).
1H-NMR (500 MHz, CDCI3) 5: 8.21 (d, J = 8.0 o Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.29 (dd, J =
Ho.,...,,N \ . 's-NH 8.0, 2.0 Hz, 1H), 6.88 (s, 1H), 6.49 (s, 1H), 4.80 A H 1 6 i\-- (s, 2H), 4.63 (s, 1H), 3.92 (d, J = 6.0 Hz, 2H), ..õ0 d 3.46 (m, 5H), 1.62 (s, 9H), 1.56 (m, 3H), 1.29 (m, 21H), 0.98 (m, 3H), 0.65 (m, 2H). MS: 558.3 (M-OCH3)+.
1H-NMR (500 MHz, CDCI3) 5: 8.21 (d, J = 8.0 o'. o o Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.29 (d, 2.0 41" k-NH Hz, 1H), 6.53 (d, J = 8.0, 1H), 6.49 (s, 1H), 4.72 1/29 ,,C) N b iv d (s, 3H ), 4.19 (m, 1H), 4.00 (m, 2H), 3.90 (d, J =
6.0 Hz, 2H), 3.57 (t, J = 6.0 Hz, 2H), 2.03 (d, J =
12.5 Hz, 2H), 1.75 (s, 2H), 1.62 (s, 9H), 1.58 (m, 5H), 1.30 (m, 13H), 0.99 (m, 3H), 0.64 (m, 2H).
Structure= Analytical data MS: 570.3 (M¨OCH3)+.
1H-NMR (CDCI3, 300 MHz) 6: 7.40 (d, 1H, J =
1.5 Hz), 7.25 (d, 1H, J = 7.5 Hz ), 7.13 (dd, 1H, J = 7.5 Hz, 1.5 Hz), 6.19-6.16 (m, 2H), 5.57 (s, M \ 110 HN-(- 1H), 5.22-5.17 (m, 1H), 4.99 (t, 2H, J = 6.6 Hz), 4.58 (t, 2H, J = 6.6 Hz), 3.75 (d, 2H, J = 7.2 Hz), 2.59 (s, 3H), 1.55-1.51 (m, 3H), 1.50-1.47 (m, 18H), 1.43-1.33 (m, 3H), 1.02-0.93 (m, 12H), 0.68-0.64 (m, 2H). MS: 508 (M+1) 1H-NMR (CDCI3, 400 MHz) 6: 7.40 (d, 1H, J =
2.4 Hz), 7.14 (dd, 1H, J = 10.0 Hz, 2.0 Hz), 7.04 NI* (1H, d, J = 10.0 Hz), 6.22 (s, 1H), 6.20-6.18 (m, 11 0 1H), 5.23-5.19 (m, 1H), 4.99 (t, 2H, J = 6.8 Hz), 4.57 (t, 2H, J = 6.4 Hz), 3.75 (d, 2H, J = 6.0 Hz), 2.76 (s, 3H), 2.59 (s, 3H), 1.57-1.52 (m, 12 H), 1.41 (s, 9H), 1.36-1.25 (m, 3H), 1.03-0.97 (m, 3H), 0.68-0.64 (m, 2H). MS: 522 (M+1).
1H-NMR (CDCI3, 400 MHz) 6: 7.43 (d, 1H, J =
1.2 Hz), 7.29 (d, 1H, J = 8.0 Hz), 7.16 (dd, 1H, J
= 7.6 Hz, 1.6 Hz), 6.21-6.19 (m, 2H), 5.82-5.79 \(m, 1H), 5.20-5.19 (m, 1H), 4.99 (t, 2H, J = 6.8 HN--)\-- Hz), 4.58 (t, 2H, J = 6.4 Hz), 3.76 (d, 2H, J = 7.2 Hz), 3.28 (d, 2H, J = 6.4 Hz), 2.60 (s, 3H), 1.59-1.56 (m, 3H), 1.44 (s, 9H), 1.42-1.33 (m, 3H), 1.02-0.93 (m, 12H), 0.68-0.64 (m, 2H). MS: 522 (M+1) 1H-NMR (CDCI3, 400 MHz) 6: 7.43 (d, 1H, J =
1.6 Hz), 7.17-7.10 (m, 2H), 6.24-6.17 (m, 2H), N0 5.24-5.19 (m, 1H), 4.99 (t, 2H, J = 6.8 Hz), 4.57 H N (t, 2H, J = 6.4 Hz), 4.20 (d, 1H, J = 14.0 Hz), 1/33 3.75 (d, 2H, J = 6.0 Hz), 3.14 (s, 3H), 2.63 (d, 1H, J = 14.4 Hz), 2.60 (s, 3H), 1.57-1.52 (m, 3H), 1.43-1.31 (m, 12H), 1.08 (s, 9H), 1.03-0.97 (m, 3H), 0.68-0.64 (m, 2H). MS: 536 (M+1).
1H-NMR (CDCI3, 400 MHz) 6: 7.43 (s, 1H), 7.16 /Th (d, 1H, J = 8.0 Hz), 7.09 (1H, d, J = 7.6 Hz), \N--/ 6.24(s, 1H), 6.19 (d, 1H, J = 7.6 Hz), 5.23-5.19 (m, 1H), 4.99 (t, 2H, J = 6.8 Hz), 4.57 (t, 2H, J =
\
1/34 M 0 6.4 Hz), 4.12 (m, 1H), 3.75 (d, 2H, J = 6.0 Hz), 3.38-3.35 (m, 1H), 3.27-3.23 (m, 1H), 3.07-3.05 (m, 1H), 2.60 (s, 3H), 1.76-1.67 (m, 4H), 1.63-1.45 (m, 5H), 1.41 (s, 9H), 1.36-1.25 (m, 3H), 1.03-0.97 (m, 3H), 0.68-0.64 (m, 2H). MS: 520 # Structure Analytical data (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.35 (s, 1H), O 7.32-7.28 (t, J = 6.2 Hz, 1H), 7.16-7.15 (d, J=
,c5cm \ \ ik, 1.6 Hz, 2H), 6.53 (s, 1H), 3.77-3.74 (d, J =
7.2 Hz, 2H), 3.25-3.23 (d, J = 6.0 Hz, 2H), 3.13 (s, d 3H), 2.52 (s, 3H), 1.46-1.43 (d, J = 10.4 Hz, 3H), 1.31-1.22 (m, 21H), 1.08 (s, 6H), 0.99-0.86 (m, 3H), 0.68-0.60 (m, 2H). MS: 495.2 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 7.36-7.34 (t, J =
1.6 Hz, 1H), 7.15-7.14 (d, J = 2.0 Hz, 2H), 7.01-o 6.98 (d, J = 8.8 Hz, 1H), 6.50 (s, 1H), 4.37 (s, HON \ 1 N \ = 1H), 3.93-3.89 (m, 1H), 3.76-3.73 (d, J =
7.2 Hz, 1/36 N 2H), 2.51 (s, 3H), 1.46-1.44 (t, J = 4.6 Hz, 3H), d 1.31-1.23 (m, 21H), 1.09-1.07 (t, J = 3.8 Hz, 3H), 0.95-0.89 (m, 3H), 0.66-0.60 (m, 2H). MS:
495.2 (M+1).
11-I-NMR (400 MHz, DMSO-d6) 6: 7.34-7.33 (d, J
o = 1.6 Hz, 1H), 7.16-7.15 (d, J = 2.0 Hz, 2H), _Ciji 1 \ fa 6.04 (s, 1H), 3.77-3.29 (m, 7H), 2.26 (d, 3H), 1/37 N 1.46-1.40 (m, 7H), 1.30-1.22(m, 18H), 1.14(s, HO d3H), 0.94-0.88 (m, 3H), 0.66-0.63 (m, 2H). MS:
507.2 (M+1).
11-I-NMR (CDCI3, 400 MHz) 6: 0.70 (2H, m), 0.86 oiq o (2H, m), 1.02 (5H, m), 1.39 (12H, s), 1.57 (3H, HN
=m), 1.91 (2H, t, J = 4.8 Hz), 2.57 (3H, s), 3.64 (2H, d, J = 7.2 Hz), 4.34 (2H, t, J = 4.8 Hz), 4.57 /
0 (2H, t, J = 6.4 Hz), 4.98 (2H, t, J = 7.2 Hz), 5.21-5.24 (1H, m), 6.11 (1H, s), 6.15 (1H, d, J = 7.2 1/38 N" *
0) Hz), 6.43 (1H, d, J = 2.0 Hz), 6.97 (1H, d, J =
1.6 Hz). MS: 491 (M+1).
\i_OH 1H-NMR (CDCI3, 400 MHz) 6: 0.70 (2H, m), 0.85 O (2H, m), 1.01 (5H, m), 1.23 (7H, s), 1.38 (12H, = s), 1.56 (3H, m), 1.90 (2H, t, J = 5.2 Hz), 2.59 / \ (3H, s), 3.28 (1H, s), 3.38 (2H, d, J = 6.0 Hz), 1/39 N lip 6.11-6.13 (2H, m), 6.43 (1H, d, J = 1.6 Hz), 6.97 0 3.64 (2H, d, J = 7.2 Hz), 4.33 (2H, t, J =
5.2 Hz), 0) (1H, d, J = 1.6 Hz). MS: 507 (M+1).
o 4 1H-NMR (CDCI3, 400 MHz) 6: 0.64-0.72 (2H, m), HO--N.---"Nõ--NN 0.83-0.88 (2H, m), 0.98-1.03 (5H, m), 1.35-1.49 H I \ . 0 (12H, s), 1.57-1.65 (12H, m), 1.90 (2H, t, J
= 5.2 d Hz), 2.59 (3H, s), 3.39 (2H, d, J = 6.8 Hz), 3.63 (4H, d, J = 7.2 Hz), 4.33 (2H, t, J = 4.8 Hz), 5.75 (1H, t, J = 6.0 Hz), 6.06 (1H, s), 6.43 (1H, d, J =
# Structure Analytical data 2.0 Hz), 6.97 (1H, d, J = 2.0 Hz). MS: 521 (M+1).
1H-NMR (CDCI3, 400 MHz) 6: 0.68-0.70 (2H, m), o' o 4 0.84-0.87 (2H, m), 1.00-1.03 (5H, m), 1.39 (12H, s), 1.59 (9H, s), 1.90 (2H, t, J = 5.6 Hz), 2.48 N"---NN (2H, d, J = 4.0 Hz), 2.55 (2H, t, J = 6.0 Hz), 2.60 H I \ * o (3H, s), 3.48 (2H, d, J = 5.6 Hz), 3.63 (2H, d, J =
d 7.6 Hz), 3.70 (4H, t, J = 4.4 Hz), 4.34 (2H, t, J =
5.2 Hz), 6.11 (1H, s), 6.30 (1H, d, J = 3.6 Hz), 6.45 (1H, d, J = 2.0 Hz), 6.99 (1H, d, J = 2.0 Hz). MS: 548 (M+1).
11-I-NMR (CDCI3, 400 MHz) 6: 0.64-0.74 (6H, m), cLq o 0.85-0.88 (2H, m), 1.00-1.03 (5H, m), 1.33-1.42 HN
lif (6H, m), 1.56 (3H, m), 1.90-1.92 (2H, t, J =
10.0 Hz), 2.57 (3H, s), 3.64-3.66 (2H, d, J = 7.2 Hz), 1/42 / \
N *
0 4.38-4.40 (2H, t, J = 10.4 Hz), 4.55-4.58 (2H, t, J
0) 4 = 13.2 Hz), 4.96-5.00 (2H, t, J = 14.4 Hz), 5.20-5.22 (1H, m), 6.10 (1H, s), 6.13-6.15 (1H, m), 6.43 (1H, s), 6.97 (1H, s). MS: 489 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 0.63-0.66 (m, 2H), 0.76-0.77 (m, 2H), 0.86-0.89 (m, 2H), 0.98-0.99 00, 0 1 (m, 3H), 1.33-1.43 (m, 3H), 1.47 (s, 3H), 1.52-N 1.56 (m, 5H), 1.58 (s, 6H), 1.75 (s, 2H), 2.61 (s, H
1/43 N I \ .=
OH 3H), 3.49-3.55 (t, 2H, J = 12.0 Hz), 3.72-3.74 (d, d 2H, J = 8.0 Hz), 3.96-3.99 (m, 2H), 4.15-4.17 (m, 1H), 5.60-5.62 (d, 1H, J = 8.0 Hz), 6.17 (s, 1H), 7.07 (s, 1H), 7.20 (s, 1H), 7.39 (s, 1H). MS:
493 (M+1).
1H-NMR (CDCI3, 400 MHz) 6: 0.61-0.64 (m, 2H), a 0 4 0.75-0.77 (m, 2H), 0.86-0.89 (m, 2H), 0.98-0.99 (m, 3H), 1.32-1.37 (m, 3H), 1.43 (s, 3H), 1.47-N 1.53 (m, 11H), 1.96-2.00 (m, 2H), 2.61 (s, 3H), H I \ ilk 1/44 N OMe 3.08 (s, 1H), 3.49-3.55 (t, 2H, J = 12.0 Hz), d 3.73-3.75 (d, 2H, J = 8.0 Hz), 3.96-3.99 (m, 2H), 4.15-4.17 (m, 1H), 5.60-5.62 (d, 1H, J = 8.0 Hz), 6.17 (s, 1H), 7.07 (s, 1H), 7.15 (s, 1H), 7.26 (s, 1H). MS: 507 (M+1).
O
1H-NMR (DMSO-d6, 400 MHz) 6: 8.74 (s, 1H), 2 I \ * OH 7.72 (d, 2H), 7.52 (d, 2H), 7.17 (m, 1H), 6.66 (m, 1/45 N CF3 1H), 6.60 (s, 1H), 3.85 (m, 2H), 2.53 (s, 3H), d 1.55-1.40 (m, 3H), 1.35-1.20 (m, 3H), 1.00-0.80 (m, 3H), 0.70-0.55 (m, 2H). MS: 463 (M+1).
# Structure Analytical data o 1H-NMR (CDCI3, 400 MHz) 6: 7.09 (s, 2H), 6.16 ONNN (s, 1H), 6.12 (m, 1H), 5.26 (s, 1H), 3.68-3.62 (m, H I \ 4. OH 2H), 3.61-3.56 (m, 2H), 3.54-3.51 (m, 2H), 3.36 1/46 N (s, 3H), 2.61 (s, 3H), 1.65-1.50 (m, 3H), 1.45 (s, d 18H), 1.40-1.30 (m, 3H), 1.05-0.95 (m, 3H), 0.75-0.60 (m, 2H). MS: 483 (M+1).
F3c OH
CF3 1H-NMR (CDCI3, 400 MHz) 6: 7.75-7.70 (m, 2H), 1 \ lik 7.51 (m, 1H), 7.44-7.42 (m, 1H), 6.25 (s, 1H), 1/47 N 5.40 (br s, 2H), 3.74 (d, 2H), 2.60 (s, 3H), 1.60-C) 1.45 (m, 3H), 1.35-1.20 (m, 3H), 1.00-0.90 (m, 3H), 0.65-0.50 (m, 2H). MS: 463 (M+1).
F 0 1H-NMR (400 MHz, CDCI3) 6: 7.08 (s, 2H), 6.15 F,I, T -N (s, 1H), 5.88-5.92 (t, 1H), 5.28 (s, 1H), 4.01-4.08 F H I \ = OH (m, 2H), 3.65-3.67 (d, 2H, J = 8.0 Hz), 2.60 (s, d 3H), 1.52-1.56 (m, 4H), 1.45(s, 18H), 1.34-1.37 (m, 2H), 0.96-1.03 (m, 3H), 0.67-0.73 (m, 2H).
MS: 507 (M+1).
O 1H-NMR (400 MHz, CDCI3) 6: 7.57-7.59 (d, 2H, ---N J = 8.0 Hz), 7.48-7.50 (d, 1H, J = 8.0 Hz), 6.24 H2N \ * 6 1 (s, 1H), 5.39-5.43 (m, 2H), 3.74-3.76 (d, 2H, J =
d8.0 Hz), 2.56-2.63 (m, 6H), 1.54-1.57 (m, 4H), 1.25-1.39 (m, 2H), 1.28 (t, 3H), 0.83-1.05 (m, 3H), 0.58-0.64 (m, 2H). MS: 352 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 6.91-6.93 (d, 1H, O J = 8.0 Hz), 6.87-6.89 (d, 1H, J = 8.0 Hz), 6.15 H2N \ *
I 0 (s, 1H), 5.36-5.39 (m, 2H), 4.28 (s, 2H), 3.68-1/50 N 3.70 (d, 2H, J = 8.0 Hz), 2.61-2.65 (q, 2H), 2.60 d (s, 3H), 1.50-1.59 (m, 4H),1.40-1.45 (m, 2H), 1.38 (s, 6H), 1.28 (m, 3H), 0.98-1.18 (m, 3H), 0.60-0.69 (m, 2H). MS: 395 (M+1).
0õ0 0 ;SN 1H-NMR (400 MHz, CDCI3) 6: 7.90 (s, 1H), 7.40 (m, 1H), 7.10 (m, 1H), 6.18 (s, 1H), 3.70 (d, 1H), N 3.38 (s, 3H), 2.60 (s, 3H), 1.57-1.50 (m, 3H), C) 1.38-1.25 (m, 21H), 1.00-0.90 (m, 3H), 0.70-0.60 (m, 2H). MS (m/z): 487 (M+1).
o 1H-NMR (400 MHz, CDCI3) 6: 7.30 (s, 1H), 7.08 1/52 (1\1 I \ 4.
C:IN
N (n, 2H), 6.04 (s, 1H), 3.63 (m, 10H), 2.32 (s, 3H), 1.75 (m, 1H), 1.45 (m, 3H), 1.26 (s, 21H), d 0.93 (m, 3H), 0.57 (m, 2H). MS (m/z): 479.2 (M+1).
# Structure Analytical data N
1H-NMR (500 MHz, CDCI3) 6: 7.33 (s, 1H), 7.07 o3, (m, 2H), 6.16 (s, 1H), 6.13 (m, 1H), 5.15 (al, 1/53 H µ I N41 1H), 4.91 (t, J = 7.0 Hz, 2H), 4.51 (t, J =
6.5 Hz, N 2H), 3.64 (d, J = 7.0 Hz, 2H), 2.53 (s, 3H), 1.45 d (m, 3H), 1.28 (s, 21H), 0.92 (m, 3H), 0.57 (m, 2H). MS (m/z): 465.2 (M+1).
HO 1H-NMR (500 MHz, CDCI3) 6: 7.31 (s, 1H), 7.07 ..-----1µ1 1/54 H \ (m, 2H), 6.18 (m, 1H), 6.15 (s, 1H), 3.71 (m, I ilk N 2H), 3.64 (d, J = 7.0 Hz, 2H), 3.48 (m, 2H), 2.54 d (s, 3H), 1.45 (m, 3H), 1.27 (s, 21H), 0.92 (m, 3H), 0.57 (m, 2H). MS (m/z): 453.2 (M+1).
OH 0 1H-NMR (400 MHz, CDCI3) 6: 7.31 (s, 1H), 7.07 1/55 ri 1 \ 4. (m, 2H), 6.16 (m, 2H), 3.64 (d, J = 7.2 Hz, 2H), N 3.32 (d, J = 6.0 Hz, 2H), 2.54 (s, 3H), 1.45 (m, d 3H), 1.27 (s, 21H), 1.18 (s, 6H), 0.92 (m, 3H), 0.57 (m, 2H). MS (m/z): 481.2 (M+1).
O 1H-NMR (500 MHz, CDCI3) 6: 7.38 (m, 1H), 7.14 (NN (m, 2H), 6.87 (br s, 1H), 6.35 (s, 1H), 3.70 (d, J
1/56 ,N H I \ 41 N = 7.5 Hz, 2H), 3.60 (m, 2H), 3.01 (m, 2H), 2.67 d (s, 6H), 2.57 (s, 3H), 1.52 (m, 3H), 1.33 (s, 21H), 0.98 (m, 3H), 0.64 (m, 2H). MS (m/z):
480.2 (M+1).
O
1H-NMR (500 MHz, CDCI3) 6: 7.26 (s, 1H), 7.01 oN
1/57 HO H \ (m, 2H), 6.26 (br s, 1H), 6.14 (s, 1H), 4.05 (m, I ilik N 2H), 3.58 (d, J = 7.5 Hz, 2H), 2.47 (s, 3H), 1.40 d (m, 3H), 1.20 (s, 21H), 0.87 (m, 3H), 0.52 (m, 2H). MS (m/z): 467.2 (M+1).
HO
6, 0 11-1-NMR (400 MHz, CDCI3) 6: 7.32 (s, 1H), 7.05 N (m, 2H), 6.25 (br s, 1H), 6.05 (s, 1H), 5.18 (br s, 1/58 H I \ .
N 1H), 3.64 (d, J = 6.8 Hz, 4H), 2.54 (s, 3H), 1.45 d (m, 3H), 1.24 (s, 21H), 0.92 (m, 7H), 0.57 (m, 2H). MS (m/z): 479.2 (M+1).
HO 1H-NMR (400 MHz, CDCI3) 6: 7.32 (s, 1H), 7.07 1/59 I il I \ * (m, 2H), 6.15 (m, 2H), 3.64 (d, J = 6.8 Hz, 2H), N 3.28-3.48 (m, 4H), 2.54 (s, 3H), 1.45 (m, 3H), d 1.24 (m, 24H), 0.92 (m, 3H), 0.57 (m, 2H). MS
(m/z): 467.2 (M+1).
o 1H-NMR (400 MHz, CDCI3) 6: 7.31 (s, 1H), 7.07 HO,, (m, 2H), 6.20 (br s, 1H), 6.15 (s, 1H), 3.93 (m, N
1/60 H I \ . 1H), 3.64 (d, J = 7.2 Hz, 2H), 3.45 (m, 2H), 3.22 N OM 1H), 2.53 (s, 3H), 1.45 (m, 3H), 1.27 (s, d 21H), 1.14 (m, 3H), 0.91 (m, 3H), 0.55 (m, 2H).
MS (m/z): 467.2 (M+1).
Structure Analytical data 4F 1H-NMR (400 MHz, CDCI3) 6: 7.40 (m, 1H), 7.12 (m, 2H), 6.18 (s, 1H), 6.10 (br s, 1H), 3.71 (d, J
1/61 H I \ = 7.2 Hz, 2H), 3.47 (m, 1H), 2.59 (s, 3H), 1.86 (rrl, 1H), 1.52 (m, 3H), 1.30 (s, 22H), 0.98 (m, 3H), 0.64 (m, 2H). MS (m/z): 585.2 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.72-7.69 (t, J
= 5.4 Hz, 1H), 7.47 (s, 1H), 7.23 (s, 2H), 6.57 (s, o 1H), 3.85-3.83 (d, J = 6.8 Hz, 2H), 3.65-3.62 (t, J = 6.0 Hz, 1H), 3.51-3.48 (t, J = 6.0 Hz, 2H), 1/62 H I \
3.39-3.36 (t, J = 6.0 Hz, 2H), 2.60 (s, 3H), 1.54-d 1.51 (d, J = 8.8 Hz, 3H), 1.39-1.29 (m, 21H), 1.17-1,16 (d, J = 6.0 Hz, 6H), 0.99-0.96 (d, J =
12.4 Hz, 3H), 0.76-0.70 (t, J = 10.6 Hz, 2H). MS
(m/z): 495 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.65-7.62 (t, J
= 4.8 Hz, 1H), 7.34 (s, 1H), 7.15 (s, 2H), 6.49 (s, (-NN 1H), 4.61-4.59 (t, J = 5.0 Hz, 1H), 3.76-3.74 (d, 1/63 0 H I \ 411 J = 6.4 Hz, 2H), 3.51-3.43 (m, 6H), 3.34 (s, 2H), 2.52 (s, 3H), 1.44-1.42 (d, J = 4.4 Hz, 3H), 1.30 HO (s, 18H), 1.24-1.21 (d, J = 13.2 Hz, 3H), 0.93-0.87 (t, J = 10.4 Hz, 3H), 0.64-0.61 (d, J = 10.8 Hz, 2H). MS (m/z): 497 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.67-7.64 (t, J
O = 5.2 Hz, 1H), 7.35 (s, 1H), 7.16 (s, 2H), 6.51 (s, 1H), 3.77-3.76 (d, J = 6.8 Hz, 2H), 3.42-3.39 (t, 1/64 H I \ .11 J = 5.6 Hz, 2H), 3.35 (s, 2H), 3.26 (s, 3H), 2.53 (s, 3H), 1.45-1.43 (d, J = 8.8 Hz, 3H), 1.31 (s, 18H), 1.25-1.22 (d, J = 13.2 Hz, 3H), 0.94-0.89 (t, J = 10.6 Hz, 3H), 0.68-0.60 (m, 2H). MS
(m/z): 467 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.70-7.68 (d, J
O = 4.8 Hz, 1H), 7.42 (s, 1H), 7.23 (s, 2H), 6.60 (s, 1H), 4.57-4.54 (t, J = 5.0 Hz, 1H), 3.84-3.82 (d, 1/65 H I \ J = 7.2 Hz, 2H), 3.54-3.49 (m, 2H), 3.32-3.28 (m, 2H), 2.58 (s, 3H), 1.71-1.68 (t, J = 6.4 Hz, 2H), 1.53-1.51 (d, J = 9.6 Hz, 3H), 1.38-1.29 (m, 21H), 1.01-0.96 (t, J = 10.0 Hz, 3H), 0.75-0.70 (t, J = 10.4 Hz, 2H). MS (m/z): 467 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.60-7.58 (d, J
HO 0 = 5.2 Hz, 1H), 7.35 (s, 1H), 7.15 (s, 2H), 6.48 (s, 1H), 4.39-4.37 (t, J = 5.2 Hz, 1H), 3.77-3.75 (d, N
1/66 H I \ J = 7.2 Hz, 2H), 3.43-3.38 (m, 2H), 3.18-3.14 (m, 2H), 2.52 (s, 3H), 1.48-1.43 (t, J = 10.0 Hz, 7H), 1.31-1.21 (m, 21H), 0.94-0.89 (t, J = 10.4 Hz, 3H), 0.65-0.62 (d, J = 11.2 Hz, 2H). MS
(m/z): 481 (M+1).
# Structure Analytical data 11-1-NMR (400 MHz, DMSO-d6) 6: 7.58 (s, 1H), o 7.33 (s, 1H), 7.14 (s, 2H), 6.48 (s, 1H), 4.34 (s, 1H), 3.75-3.74 (d, J = 6.0 Hz, 2H), 3.39-3.38 (d, CNN \ .
OH J = 5.2 Hz, 2H), 3.12-3.14 (d, J = 6.0 Hz, 2H), N
d2.51 (s, 3H), 1.45-1.43 (d, J = 5.6 Hz, 7H), 1.30 (s, 20H), 1.24-1.21 (d, J = 12.4 Hz, 3H), 0.91-0.88 (d, J = 11.2 Hz, 3H), 0.64-0.61 (d, J = 10.4 Hz, 2H). MS (m/z): 495 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6:12.13 (s, 1H), o 7.70-7.67 (t, J = 5.2 Hz, 1H), 7.35 (s, 1H), 7.15 HO-jc---N (s, 2H), 6.47 (s, 1H), 3.77-3.75 (d, J = 6.8 Hz, 1/68 H I \ . 2H), 3.38-3.35 (t, J = 6.0 Hz, 2H), 2.52-2.45 (m, N 5H), 1.46-1.43 (d, J = 4.6 Hz, 3H), 1.31-1.21 (t, d J = 9.8 Hz, 21H), 0.94-0.89 (t, J = 5.0 Hz, 3H), 0.65-0.62 (d, J = 10.8 Hz, 2H). MS (m/z): 481 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6:12.03 (s, 1H), HO 0 7.66-7.63 (t, J = 5.2 Hz, 1H), 7.35 (s, 1H), 7.15 (s, 2H), 6.49 (s, 1H), 3.77-3.75 (d, J = 6.8 Hz, 1/69 0 H I \ . 2H), 3.20-3.15 (m, 2H), 2.52-2.50 (d, J =
6.8 Hz, N 3H), 2.26-2.23 (t, J = 7.2 Hz, 2H), 1.73-1.66 (m, d 2H), 1.46-1.44 (d, J = 4.4 Hz, 3H), 1.31-1.15 (m, 21H), 0.98-0.89 (m, 3H), 0.65-0.62 (m, 2H). MS
(m/z): 495 (M+1).
OTh c....N 0 1H-NMR (400 MHz, DMSO-d6) 6:7.60 (s, 1H), 7.35 (s, 1H), 7.15 (s, 2H), 6.46 (s, 1H), 3.77-3 .75 (d, J = 7.2 Hz, 2H), 3.60 (s, 4H), 3.32 (s, 1/70 H I \ *
N 4H), 2.52-2.40 (t, 7H), 1.46-1.44 (d, J =
9.2 Hz, d 3H), 1.31 (s, 18H), 1.24-1.21 (d, J = 13.6 Hz, 3H), 0.91-0.88 (m, 3H), 0.68-0.60 (m,2H). MS
(m/z): 522 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.68-7.66 (t, J
= 5.4 Hz, 1H), 7.35 (s, 1H), 7.15 (s, 2H), 6.46 (s, o 1H), 3.77-3.75 (d, J = 6.8 Hz, 2H), 3.58-3.57 (d, NH 1 \ = J = 4.0 Hz, 4H), 3.22-3.18 (m, 2H), 2.52-2.50 (d, N J = 6.0 Hz, 3H), 2.39-2.34 (t, J = 10.6 Hz, 6H), d 1.66-1.62 (t, J = 6.6 Hz, 2H), 1.46-1.43 (d, J =
9.2 Hz, 3H), 1.31-1.21 (m, 21H), 0.91-0.88 (d, J
= 12.0 Hz, 3H), 0.67-0.62 (t, J = 10.8 Hz, 2H).
MS (m/z): 536 (M+1).
Ori 1H-NMR (400 MHz, DMSO-d6) 6:11.97 (s, 1H), O 7.63-7.60 (t, J = 5.6 Hz, 1H), 7.37 (s,1H), 7.18-7.17 (d, J = 1.2 Hz, 2H), 6.50 (s, 1H), 3.79-3.77 1/72 N , H 1 \ * (d, J = 7.2 Hz, 2H), 3.19-3.15 (m, 2H), 2.54-2.52 N (m, 3H), 2.25-2.21 (t, J = 7.4 Hz, 2H), 1.56-1.46 d (m, 7H), 1.33-1.24 (m, 23H), 0.96-0.88 (m, 3H), 0.69-0.67 (m, 2H). MS (m/z): 523 (M+1).
# Structure Analytical data 1H-NMR (400 MHz, DMSO-d6) 6:12.01 (s, 1H), o 7.63-7.60 (t, J = 5.6 Hz, 1H), 7.35 (s, 1H), 7.16-7.15 (d, J = 1.2 Hz, 2H), 6.48 (s, 1H), 3.77-3.75 N \
1/73 0 oiXi " I N. 11 (d, J = 6.8 Hz, 2H), 3.18-3.15 (t, J = 6.2 Hz, 2H), d 2.52-2.51 (d, J = 4.8 Hz, 3H), 2.25-2.21 (t, J =
6.8 Hz, 2H), 1.50-1.43 (m, 7H), 1.31-1.25 (m, 21H), 0.94-0.85 (m, 3H), 0.63-0.60 (m, 2H). MS
(m/z): 509 (M+1).
Ncl 1H-NMR (400 MHz, DMSO-d6) 6: 7.67 (s, 1H), c Nx./ 0 7.39 (s, 1H), 7.20 (s, 2H), 6.54 (s, 1H), 3.81-1/74 N , H I = . 3.80 (d, J = 6.0 Hz, 2H), 3.62 (s, 4H), 3.23 (s, 2H), 2.57 (s, 3H), 2.45 (s, 4H), 2.39 (s, 2H), 1.52 N
d (s, 7H), 1.35-1.26 (m, 21H), 0.96 (s, 3H), 0.69-0.67 (d, J = 10.4 Hz, 2H). MS (m/z): 550 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 7.61-7.58 (t, J
= 5.8 Hz, 1H), 7.35 (s, 1H), 7.15-7.15 (d, J = 1.6 o Hz, 2H), 6.48 (s, 1H), 3.77-3.75 (d, J = 6.8 Hz, 1/75 Ci--11 I \ .
NTh N
c,0 d 2H), 3.55-3.54 (d, J = 4.4 Hz, 4H), 3.18-3.13 (m, 2H), 2.51-2.51 (d, J = 3.2 Hz, 3H), 2.33 (s, 4H), 2.28-2.24 (t, J = 7.2 Hz, 2H), 1.49-1.40 (m, 7H), 1.31-1.21 (m, 23H), 0.92-0.88 (d, J = 12.8 Hz, 3H), 0.67-0.62 (t, J = 10.4 Hz, 2H). MS (m/z):
564 (M+1).
o ' = 1H-NMR (500 MHz, CDCI3) 6: 0.59 (m, 2H), 0.80 H2N \ . (m, 3H), 1.11 (m, 14H), 1.47 (m, 3H), 1.80-2.54 N
1/76 I (m, 8H), 3.67 (d, 2H), 5.40 (br s, 2H), 6.14 (s, d 1H), 6.94 (s, 1H), 7.08 (m, 2H). MS (m/z):
(M+1).
o\.3, 0 1H-NMR (300 MHz, DMSO-d6) 6: 8.22 (d, J =
N 6.6 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H), 6.59 (s, 1/77 H I \ Mk F 1H), 4.96 (m, 1H), 4.74 (m, 2H), 4.56 (m, 2H), N 3.74 (d, J = 6.6 Hz, 2H), 2.50 (s, 3H), 1.49 (m, d 24H), 0.98 (m, 3H), 0.71 (m, 2H). MS (m/z): 483 (M+1).
0 1H-NMR (400 MHz, CDCI3) 6: 7.60 (s, 1H), 7.53 N (s, 1H), 7.41 (s, 1H), 6.28 (s, 1H), 6.17 (d, 1H), 1/78 H I \ . 5.23 (m, 1H), 4.99 (m, 2H), 4.58 (t, 2H), 3.73 (d, dN CF 3 2H), 2.61 (s, 3H), 1.56 (s, 6H), 1.32 (m, 9H), 1.00 (m, 3H), 0.63 (m, 2H). MS (m/z): 477 (M+1).
op, 0 V 1H-NMR (400 MHz, CDCI3) 6: 7.47 (s, 1H), 7.37 N (s, 2H), 6.27 (s, 1H), 6.16 (d, 1H), 5.21 (m, 1H), 1/79 H I \ . 4.99 (m, 2H), 4.58 (m, 2H), 3.73 (d, 2H), 2.60 (s, N 3H), 1.54 (m, 4H), 1.46 (s, 3H), 1.33 (m, 3H), d u3 1.01 (m, 2H), 1.00 (m, 2H), 0.84 (m, 2H), 0.66 (m, 2H). MS (m/z): 475 (M+1).
# Structure Analytical data oa o V 1H-NMR (CDCI3, 300 MHz) 5:7.07 (s, 1H), 6.92 (d, J = 1.5 Hz, 2H), 6.10 (m, 2H), 5.15 (m, 1H), N
1/80 H I \ 411 4.91 (t, 2H), 4.50 (t, 2H), 3.64 (d, J = 6.9 Hz, N
d A 2H), 2.52 (s, 3H), 1.47 (m, 3H), 1.18-1.46(m, 9H), 0.94 (m, 3H), 0.76-0.81 (m, 10H). MS
(m/z): 461 (M+1).
1H-NMR (DMSO-d6, 400 MHz) 6:8.22 (d, 1H), 7.20 (s, 1H), 7.16 (s, 1H), 6.99 (s, 1H), 6.59 (s, N \ 1H), 4.93 (m, 1H), 4.72 (t, 2H), 4.55 (t, 2H), 3.76 N (t, 2H), 2.50 (s, 3H), 1.45 (m, 3H), 1.40 (s, 3H), d 1.31 (s, 9H), 1.23 (m, 3H), 0.95 (m, 3H), 0.84 (m, 2H), 0.76 (m, 2H), 0.65 (m, 2H). MS (m/z):
463 (M+1).
o V 1H-NMR (400 MHz, DMSO-d6) 6: 7.58 (t, 1H), HO----\,..--NN 7.19 (s, 1H), 7.14 (s, 1H), 6.97 (s, 1H), 6.48 (s, 1/82 H I \ * 1H), 4.34 (t, 1H), 3.75 (d, 2H), 3.69 (m, 2H), N 3.15 (m, 2H), 2.50 (m, 3H), 1.40-1.48 (m, 10H), d 1.27 (m, 14H), 0.77-0.96 (m, 9H). MS (m/z):
(M+1).
LN o V 1H-NMR (400 MHz, DMSO-d6) 6: 7.57 (t, 1H), 1/83 H I \ Mk 7.19 (s, 1H), 7.13 (s, 1H), 6.96 (s, 1H), 6.46 (s, N 1H), 3.75 (d, 2H), 2.73 (m, 1H), 2.50 (m, 3H), d 1.21-1.47 (m, 18H), 0.74-0.95 (m, 13H). MS
(m/z): 447 (M+1).
oaN o V 1H-NMR (400 MHz, DMSO-d6) 6:7.41 (d, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 6.97 (s, 1H), 6.53 (s, N
1/84 H I \ * 1H), 3.95 (m, 1H), 3.87 (d, 2H), 3.85 (d, 2H), N 3.35 (d, 2H), 2.56 (m, 3H), 1.71 (d, 2H), 1.45-d 1.68 (m, 8H), 1.22-1.30 (m, 12H), 0.59-0.96 (m, 9H). MS (m/z): 491 (M+1).
o . -1C1.----N 0 V 1H-NMR (400 MHz, DMSO-d6) 6: 7.33 (t, 1H), 1/85 H \
7.19 (d, 2H), 7.13 (s, 1H), 6.96 (s, 1H), 6.85 (s, I .
N 1H), 6.41 (s, 1H), 3.74 (d, 2H), 3.28 (d, 2H), d 2.50 (m, 3H), 1.22-1.46 (m, 18H), 0.75-0.95 (m, 15H). MS (m/z): 506 (M+1).
o V 1H-NMR (400 MHz, DMSO-d6) 6: 7.80 (t, 1H), 1/86 oi--- hi I \ = 7.20 (d, 2H), 6.98 (s, 1H), 6.53 (s, 1H), 4.47 (d, N 2H), 4.15 (d, 2H), 3.75 (d, 2H), 3.33 (s, 2H), d 2.50 (m, 3H), 1.23-1.47 (m, 21H), 0.63-0.96 (m, 9H). MS (m/z): 491 (M+1).
OH 0 V 1H-NMR (400 MHz, DMSO-d6) 6: 7.46 (t, 1H), 1/87 NhN 1 \ * 7.19 (d, 2H), 6.98 (s, 1H), 6.53 (s, 1H), 4.66 (s, N 1H), 3.76 (d, 2H), 3.16 (d, 2H), 2.51 (m, 3H), d 1.24-1.47 (m, 18H), 0.63-1.08 (m, 15H). MS
(m/z): 479 (M+1).
# Structure Analytical data OTh 0 V 1H-NMR (400 MHz, DMSO-d6) 6: 7.56 (t, 1H), N---NN \ 7.19 (d, 2H), 6.97 (s, 1H), 6.45 (s, 1H), 3.75 (d, 1/88 H I \ * 2H), 3.57 (m, 4H), 3.28 (m, 2H), 2.50 (m, 3H), N
d 2.40 (m, 6H), 1.22-1.47 (m, 18H), 0.75-0.96 (m, 9H). MS (m/z): 520 (M+1).
o V
1H-NMR (400 MHz, DMSO-d6) 6: 7.14 (m, 3H), Fi2N , .
1/89 I \ 6.97 (s, 1H), 6.49 (d, 2H), 3.77 (d, 2H), 2.50 (m, N 3H), 1.23-1.48 (m, 18H), 0.66-0.96 (m, 9H). MS
d(m/z): 407 (M+1).
o 1 11-I-NMR (400 MHz, CDCI3) 6: 6.96 (s, 1H), 6.42 o (s, 1H), 6.32 (m, 1H), 6.07 (s, 1H), 4.34 (t, 2H), 1/90 H 1= \ 4. 0 3.67 (m, 4H), 2.72 (t, 2H), 2.58 (s, 3H), 1.91 (t, N 2H), 1.53 (m, 3H), 1.44 (m, 12H), 1.02 (m, 5H), d 0.84 (m, 2H), 0.67 (m, 2H). MS (m/z): 507 (M+1).
oo 4 11-1-NMR (400 MHz, CDCI3) 6: 6.97 (s, 1H), 6.43 1/91 HO)N (s, 1H), 6.29 (m, 1H), 6.09 (s, 1H), 4.34 (t, 2H), H I \ * 0 3.63 (d, 2H), 3.52 (d, 2H), 2.59 (s, 3H), 1.90 (t, N 2H), 1.57 (m, 3H), 1.38 (m, 12H), 1.25 (m, 6H), d 1.01 (m, 5H), 0.83 (m, 2H), 0.67 (m, 2H). MS
(m/z): 534 (M+1).
4 1H-NMR (400 MHz, CDCI3) 6: 6.96 (s, 1H), 6.42 (s, 1H), 6.00 (s, 1H), 5.83 (br s, 1H), 4.33 (t, 1/92 H I - . 0 2H), 3.64 (d, 2H), 2.81 (s, 1H), 2.60 (s, 3H), N 1.91 (t, 2H), 1.57 (m, 3H), 1.39 (m, 12H), 1.02 d (m, 5H), 0.85 (m, 4H), 0.77 (m, 2H), 0.57 (m, 2H). MS (m/z): 475 (M+1).
a 0 4 1H-NMR (400 MHz, CDCI3) 6: 6.97 (s, 1H), 6.43 (s, 1H), 6.06 (s, 1H), 5.57 (d, 1H), 4.34 (t, 2H), N
1/93 H I \ . 0 4.17 (s, 1H), 3.96 (m, 2H), 3.63 (d, 2H), 3.49 (t, N 2H), 2.59 (s, 3H), 1.99 (d, 2H), 1.95 (t, 2H), 1.52 d (m, 5H), 1.38 (m, 12H), 1.02 (m, 5H), 0.86 (m, 2H), 0.64 (m, 2H). MS (m/z): 519 (M+1).
o 4 1H-NMR (400 MHz, CDCI3) 6: 6.97 (s, 1H), 6.43 (s, 1H), 6.05 (s, 1H), 5.83 (s, 1H), 4.34 (t, 2H), N
1/94 COF1 \ I \ II 0 3.99 (d, 2H), 3.64 (d, 2H), 3.37 (t, 2H), 3.26 (t, N 2H), 2.59 (s, 3H), 1.91 (t, 3H), 1.84 (m, 2H), d 1.57 (m, 3H), 1.34 (m, 12H), 1.02 (m, 5H), 0.86 (m, 2H), 0.69 (m, 2H). MS (m/z): 533 (M+1).
# Structure Analytical data so, 4 1H-NMR (400 MHz, CDCI3) 6: 6.96 (s, 1H), 6.42 < o (s, 1H), 6.06 (s, 1H), 5.85 (d, 1H), 4.69 (s, 1H), µ
1/95 H I \ . 0 4.34 (t, 2H), 3.94 (m, 2H), 3.84 (m, 2H), 3.71 (d, N 2H), 2.58 (s, 3H), 2.31 (m, 1H), 1.90 (m, 3H), d 1.56 (m, 3H), 1.38 (m, 12H), 1.02 (m, 5H), 0.84 (m, 2H), 0.65 (m, 2H). MS (m/z): 505 (M+1).
/o¨ o 4 1H-NMR (400 MHz, CDCI3) 6: 6.96 (s, 1H), 6.43 N (s, 1H), 6.06 (s, 1H), 5.85 (d, 1H), 4.69 (s, 1H), 1/96 H I \ = 0 4.34 (t, 2H), 3.94 (m, 2H), 3.84 (m, 2H), 3.71 (d, N 2H), 2.58 (s, 3H), 2.31 (m, 1H), 1.90 (m, 3H), d 1.56 (m, 3H), 1.38 (m, 12H), 1.02 (m, 5H), 0.84 (m, 2H), 0.64 (m, 2H). MS (m/z): 505 (M+1).
OMe ID 4 1H-NMR (400 MHz, CDCI3) 6: 6.91 (s, 1H), 6.38 (s, 1H), 6.06 (s, 1H), 5.97 (d, 1H), 4.27 (t, 2H), NIH I \ . 0 3.57 (d, 2H), 3.35 (d, 2H), 3.71 (d, 2H), 3.13 (s, N 3H), 2.52 (s, 3H), 1.84 (m, 2H), 1.50 (m, 3H), d 1.36 (m, 12H), 1.19 (s, 6H), 0.95 (m, 5H), 0.78 (m, 2H), 0.63 (m, 2H). MS (m/z): 521 (M+1).
o o 4 1H-NMR (400 MHz, CDCI3) 6: 6.89 (s, 1H), 6.31 1-12NN (m, 3H), 6.03 (s, 1H), 5.19 (s, 1H), 4.26 (t, 2H), 1/98 H I \ . 0 3.55 (d, 2H), 3.45 (d, 2H), 2.51 (s, 3H), 1.84 (t, N 2H), 1.50 (m, 3H), 1.37 (m, 12H), 1.25 (s, 6H), d 0.96 (m, 5H), 0.79 (m, 2H), 0.60 (m, 2H). MS
(m/z): 534 (M+1).
OH 0 4 ' H-N MR (400 MHz, CDCI3) 6: 6.97 (s, 1H), 6.43 (s, 1H), 6.08 (d, 2H), 4.35 (t, 2H), 3.85 (m, 4H), N
v99 aNH i \ ili 0 3.77 (d, 211), 3.44 (s, 2H), 2.59 (s, 3H), 1.90 (t, N 2H), 1.63 (m, 7H), 1.44 (m, 12H), 1.02 (m, 5H), d 1.00 (m, 2H), 0.72 (m, 2H). MS (m/z): 549 (M+1).
O 4 1H-NMR (400 MHz, CDCI3) 6: 6.89 (s, 1H), 6.36 (s, 1H), 5.99 (s, 1H), 5.84 (t, 1H), 4.73 (t, 2H), 1/100 11 I \ . o 4.40 (t, 2H), 4.25 (t, 2H), 3.58 (m, 4H), 3.20 (m, N 1H), 2.51 (s, 3H), 1.83 (m, 2H), 1.51 (m, 3H), d 1.33 (m, 12H), 0.95 (m, 5H), 0.79 (m, 2H), 0.60 (m, 2H). MS (m/z): (M+1).
O 4 1H-NMR (400 MHz, CDCI3) 6: 6.97 (s, 1H), 6.43 r------NN (s, 1H), 6.10 (s, 1H), 6.00 (t, 1H), 4.54 (d, 2H), 1/101 0,/ H 1 \ 0111 0 4.38 (d, 2H), 4.32 (t, 2H), 3.63 (d, 2H), 3.55 (d, N 2H), 2.59 (s, 3H), 1.90 (m, 2H), 1.56 (m, 3H), d 1.26 (m, 15H), 1.01 (m, 5H), 0.85 (m, 2H), 0.68 (m, 2H). MS (m/z): 519 (M+1).
o 4 1H-NMR (400 MHz, CDCI3) 6: 6.98 (s, 1H), 6.44 1/102 .7Nri 1 \ ip 0 (s, 1H), 6.10 (s, 1H), 5.81 (s, 1H), 4.33 (t, 2H), N 3.63 (d, 2H), 3.24 (d, 2H), 2.59 (s, 3H), 1.91 (m, d 2H), 1.58 (m, 3H), 1.37 (m, 12H), 1.01 (m, 6H), 0.85 (m, 2H), 0.67 (m, 2H), 0.25 (m, 2H), 0.21 # Structure Analytical data (m, 2H). MS (m/z): 489 (M+1).
H 0 4 1H-NMR (400 MHz, CDCI3) 6: 6.90 (s, 1H), 6.37 sl\INNN (s, 1H), 6.21 (t, 1H), 6.06 (s, 1H), 5.56 (s, 1H), 1/103 o"o I H I \ . 0 4.25 (t, 2H), 3.56 (d, 2H), 3.38 (d, 2H), 2.94 (s, N 3H), 2.51 (s, 3H), 1.83 (m, 2H), 1.50 (m, 3H), d 1.33 (m, 18H), 0.96 (m, 5H), 0.78 (m, 2H), 0.61 (m, 2H). MS (m/z): 584 (M+1).
0,õo o 1 1H-NMR (400 MHz, CDCI3) 6: 6.89 (s, 1H), 6.35 sN (m, 2H), 6.03 (s, 1H), 4.27 (t, 2H), 3.84 (m, 2H), 1/104 H I \ . 0 3.57 (d, 2H), 3.27 (t, 2H), 2.90 (s, 3H), 2.51 (s, N 3H), 1.84 (m, 2H), 1.58 (m, 3H), 1.30 (m, 12H), d 0.97 (m, 5H), 0.78 (m, 2H), 0.61 (m, 2H). MS
(m/z): 541 (M+1).
o 4 1H-NMR (400 MHz, CDCI3) 6: 6.91 (s, 1H), 6.37 H2N = .
1/105 I o (s, 1H), 6.04 (t, 1H), 5.45 (s, 2H), 4.27 (t, 2H), \
N 3.37 (d, 2H), 2.52 (s, 3H), 1.84 (m, 2H), 1.51 (m, d 3H), 1.29 (m, 12H), 0.94 (m, 5H), 0.79 (m, 2H), 0.61 (m, 2H). MS (m/z): 435 (M+1).
cz.o, o 1H-NMR (400 MHz, DMSO-d6) 6: 8.22 (d, 1H), N \ 7.49 (s, 1H), 7.18 (d, 2H), 6.59 (s, 1H), 5.05 (s, \
1/106 H I # 1H), 4.94 (m, 1H), 4.71 (t, 2H), 4.55 (t, 2H), 3.77 N OH (d, 2H), 2.50 (s, 3H), 1.44 (s, 9H), 1.31 (s, 9H), d 1.21 (m, 3H), 0.92 (m, 3H), 0.59 (m, 2H). MS
(m/z): 467 (M+1).
ca o 1H-NMR (400 MHz, CDCI3) 6: 7.42 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 6.25 (s, 1H), 6.18 (d, 1H), N \
1/107 H I \ * 5.24 (m, 1H), 4.97 (t, 2H), 4.56 (t, 2H), 3.73 (d, N OMe 2H), 3.09 (s, 3H), 2.60 (s, 3H), 1.53 (m, 9H), d 1.37 (m, 12H), 0.97 (m, 3H), 0.61 (m, 2H).
MS
(m/z): 481 (M+1).
o 1H-NMR (400 MHz, DMSO-d6) 6: 8.22 (d, 1H), 7.26 (s, 2H), 7.13 (s, 1H), 6.61 (s, 1H), 4.98 (m, N µ
1/108 H I \ * 1H), 4.73 (t, 2H), 4.53 (t, 2H), 3.78 (d, 2H), 3.57 N r--\ (t, 3H), 3.51 (s, 2H), 2.36 (s, 4H), 1.45 (d, 3H), d N0 1.24 (m, 12H), 0.86 (m, 3H), 0.56 (m, 2H). MS
(m/z): 508 1H-NMR (400 MHz, DMSO-d6) 6: 7.48 (t, 1H), OH 7.24 (s, 2H), 7.10 (s, 1H), 6.54 (s, 1H), 4.64 (m, 1/109 I \ . 1H), 3.78 (t, 2H), 3.55 (m, 4H), 3.40 (m, 1H), N 3.16 (d, 2H), 2.52 (s, 3H), 2.29 (m, 2H), 2.26 (m, ,_\
d N 0 2H), 1.45 (m, 3H), 1.31 (m, 12H), 1.23 (m, 3H), 1.08 (s, 6H), 0.92 (m, 3H), 0.59 (m, 2H). MS
(m/z): 538 (M+1).
# Structure Analytical data OH 0 A 1H-NMR (400 MHz, DMSO-d6) 6: 7.47 (t, 1H), 1/110 NN 1\ =11 v 7.23 (s, 1H), 7.16 (s, 1H), 7.11 (s, 1H), 6.61 (s, dN 7 1H), 3.81 (d, 2H), 3.17 (d, 2H), 2.81 (s, 3H), 2.50 (s, 3H), 1.41 (m, 15H), 1.24 (m, 3H), 1.07 0N\ (s, 6H), 0.63-0.89 (m, 8H). MS (m/z): 536 (M+1).
OH 0 A 1H-NMR (400 MHz, DMSO-d6) 6: 7.82 (s, 1H), Nt---NN 7.64 (s, 1H), 7.59 (s, 1H), 7.47 (m, 1H), 7.32 (s, 1/111 H I \ = 1H), 6.62 (s, 1H), 4.64 (s, 1H), 3.82 (d, 2H), N 3.16 (d, 2H), 2.54 (s, 3H), 1.46 (m, 15H), 1.30 d NH
0 (m, 3H), 1.11 (s, 6H), 0.63-0.97 (m, 8H). MS
(m/z): 522 (M +1).
OH 0 A 1H-NMR (400 MHz, DMSO-d6) 6: 8.28 (d, 1H), 1/112 NhN 7.68 (d, 2H), 7.48 (t, 1H), 7.34 (s, 2H), 6.63 (s, H I \ . \ 1H), 4.64 (s, 1H), 4.13 (m, 1H), 3.83 (d, 2H), N )---NH 3.16 (d, 2H), 2.49 (s, 3H), 1.17-1.48 (m, 15H), d o 1.08 (s, 6H), 0.63-0.90 (m, 9H). MS (m/z):
(M+1).
1H-NMR (400 MHz, CDCI3) 6: 8.05 (s, 1H), 7.43 N (s, 1H), 7.16 (s, 2H), 6.25 (t, J = 5.6 Hz, 1H), \
1/113 F3c H I ' ID' 6.23 (s, 1H), 3.93 (d, J = 6.0 Hz, 2H), 3.74 (d, J
N = 7.2 Hz, 2H), 2.61 (s, 3H), 1.56-1.51 (m, 4H), d 1.36 (s, 18H), 1.40-1.25 (m, 4H), 1.02-0.87 (m, 3H), 0.67-0.64 (m, 2H). MS: 589 (M+1).
oaN 0 1H-NMR (400 MHz, CD30D) 6: 7.34 (s, 1H), H I \ = 7.10 (m, 2H), 6.41 (s, 1H), 4.96 (m, 1H), 4.62 1/114 N (m, 2H), 4.58 (t, J = 6.8 Hz, 2H), 3.93-3.70 (m, 2H), 2.44 (m, 3H), 1.47-1.26 (m, 1H), 1.26-1.02 (m, 24H), 0.70-0.42 (m, 6H). MS: 479.4 (M+1)+.
0 1H-NMR (400 MHz, CDCI3) 6: 7.42 (s, 1H), 7.18 oaN
(s, 2H), 6.29-6.26 (m, 2H), 5.26 (m, 1H), 5.01 (t, H 1 \ =
1/115 N J = 6.8 Hz, 2H), 4.61 (t, J = 6.4 Hz, 2H), 3.73 (d, d J = 7.6 Hz, 2H), 2.62 (s, 3H), 1.27-1.55 (m, 27H), 0.89-1.21 (m, 4H). MS: 479.4 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.23 (d, J =
5.2 Hz, 1H), 7.40 (s, 1H), 7.17 (s, 2H), 6.58 (s, 11 1\ = 1H), 4.97 (m, 1H), 4.72 (t, J = 6.8 Hz, 2H), 4.55 N
alp (t, J = 6.4 Hz, 2H), 3.84 (m, 2H), 2.53 (m, 3H), 1.35-1.56 (m, 27H), 0.84 (m, 2H). MS: 465.4 (M+1)+.
# Structure Analytical data a 1H-NMR (400 MHz, CDCI3) 6: 7.29 (s, 1H), 7.05 oaN
(s, 2H), 6.26 (m, 1H), 6.16 (m, 1H), 5.10 (m, H \ .
1/117 N 1H), 4.85 (t, J = 6.8 Hz, 2H), 4.47 (m, 2H), 3.53-0-1 3.84 (m, 2H), 2.50 (m, 3H), 1.12-1.89 (m, 23H), 0.27-0.85 (m, 6H). MS: 477.1 (M+1)+.
o 1H-NMR (400 MHz, CDCI3) 6: 7.28 (m, 1H), 7.09 oaN
(m, 2H), 6.95 (m, 4H), 6.22-6.18 (m, 2H), 5.18 H I \ .
N (m, 1H), 4.93 (t, J = 6.8 Hz, 2H), 4.51 (t, J = 6.8 1/118 Hz, 2H), 3.94 (d, J = 7.6 Hz, 2H), 2.65 (m, 2H), ijk 2.56-2.48 (m, 4H), 2.29 (m, 2H), 1.24 (s, 18H).
IW MS: 499.4 (M+1)+.
oa a 1H-NMR (400 MHz, CDCI3) 5:7.40 (m, 1H), 7.17 H1 \ it (m, 2H), 6.20 (m, 2H), 5.24 (m, 1H), 4.99 (t, J =
6.8 Hz, 2H), 4.58 (m, 2H), 3.70-3.91 (m, 2H), 2.60 (s, 3H), 1.31-1.62 (m, 22H), 0.23-0.98 (m, 9H). MS: 479.6 (M+1)t o\.... o 1H-NMR (CDCI3, 300 MHz) 6: 0.67-0.68 (2H, m), 0.87-1.03 (12H, m), 1.33-1.36 (12H, m), 1.56-N
1.57 (2H, m), 2.59 (3H, s), 3.82-3.84 (2H, d, J =
1/120 N --( 7.2 Hz), 4.06 (2H, s), 4.57 (2H, t, J = 6.6 Hz), d 0 5/ 5.20 (2H, t, J = 6.6Hz), 5.18-5.23 (1H, m), 6.17-6.19 (1H, m), 6.32 (1H, s), 6.50 (1H, s), 6.80 (1H, s). MS: 496.5 (M+1).
v3.
1H-NMR (CDCI3, 300 MHz) 6: 0.65-0.74 (2H, m), 0.97-1.06 (6H, m), 1.29-1.34 (9H, m), 1.53-1.58 N
H (4H, m), 1.96-2.00 (2H, m), 2.06-2.13 (1H, m), 1/121 N --( 2.61 (3H, s), 3.48-3.56 (2H, m), 3.82 (2H, d, J =
d 0 9.9 Hz), 3.99-4.01 (2H, m), 4.11-4.17 (3H, m), 5.58-5.61 (1H, m), 6.26 (1H, s), 6.48 (1H, s), 6.80 (1H, s). MS: 482.5 (M+1).
ov.3N o 1H-NMR (CDCI3, 400 MHz) 6: 0.67-0.69 (2H, m), N 0.98-1.02 (3H, m), 1.36 (18H, m), 1.57 (6H, m), H-11--) ______________ / \ N 2.60 (3H, s), 3.78-3.80 (2H, d, J = 7.2 Hz), 4.58 0õ __.? (2H, t, J = 6.8 Hz), 4.99 (2H, t, J = 6.8 Hz), 5.21-5.23 (1H, m), 6.19-6.21 (1H, m), 6.32 (1H, s), 7.05 (2H, s). MS: 466.2 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 8.18 (d, J = 8.4 H o Hz, 1H), 7.59 (s, 1H), 7.27 (m, 1H), 6.43 (m, S'N1H) 6.35 (s 1H) 4.52 (s 1H) 3.79 (d J = 7.2 o2 /\ N \ = s92* , , , , , , 1/123 N N Hz, 2H), 3.49 (d, J = 6.4 Hz, 2H), 3.04 (s, 3H), H
d 2.62 (s, 3H), 1.62 (m, 9H), 1.54 (m, 3H), 1.46 (m, 6H), 1.26 (m, 12H), 0.97 (m, 3H), 0.60 (m, 2H). MS: 637.3 (M+1).
# Structure Analytical data 1H-NMR (400 MHz, CDCI3) 6: 8.18 (d, J = 8.0 o HoxNN Hz, 1H), 7.58 (s, 1H), 7.24 (m, 1H), 6.30 (s, 1H), H 1 \ ii sp2*
H 6.17 (m, 1H), 4.49 (s, 1H), 3.86-3.72 (m, 6H), 1/124 o 1 N
3.45 (m, 2H), 2.62 (s, 3H), 1.53-1.70 (m, 16H), 1.34-1.31 (m, 12H), 0.98 (m, 3H), 0.60 (m, 2H).
MS: 602.3 (M+1).
o 1H-NMR (400 MHz, CDCI3) 6: 8.17 (d, J = 8.4 Fi2N-15N Hz, 1H), 7.58 (s, 1H), 7.24 (m, 1H), 6.52 (m, s924_ 1H), 6.30 (s, 1H), 6.17 (br s,1H), 5.28 (br s, 1H), 1/125 N H 4.54 (m, 1H), 3.76 (m, 2H), 3.54 (m, 2H), 2.61 d (s, 3H), 1.45-1.62 (m, 12H), 1.35-1.31 (m, 18H), 0.98 (m, 3H), 0.60 (m, 2H). MS: 587.4 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.14 (d, J =
O 8.0 Hz, 1H), 7.85 (m, 1H), 7.82 (s, 1H), 7.52 (s, ol-DNIF1 1 \. s 24_ 1H), 7.42 (m, 1H), 6.64 (s, 1H), 4.60 (m, 2H), 1/126 N N 4.32 (t, J = 6.0 Hz, 2H), 3.82 (m, 2H), 3.42 (m, H
d 2H), 3.10 (m, 1H), 2.52 (s, 3H), 1.54 (s, 9H), 1.43 (m, 3H), 1.18 (m, 12H), 0.88 (m, 3H), 0.59 (m, 2H). MS: 558.7 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.17 (d, J =
O 8.4 Hz, 1H), 7.89 (m, 1H), 7.86 (s, 1H), 7.56 (s, of-JNIE'ilsp24_ 1H), 7.46 (m, 1H), 6.73 (s, 1H), 4.50 (d, J = 5.6 1/127 N N Hz, 2H), 4.18 (d, J = 5.6 Hz, 2H), 3.87 (m, 2H), H
d 3.39 (m, 2H), 2.58-2.54 (m, 3H), 1.58 (s, 9H), 1.46 (m, 3H), 1.26-1.22 (m, 6H), 1.23 (s, 9H), 0.89 (m, 3H), 0.66 (m, 2H). MS: 572.2 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.13 (d, J =
/OH 0 8.4 Hz, 1H), 7.73 (s, 1H), 7.65 (m, 1H), 7.52 (s, \ ii, so24_ 1H), 7.40 (m, 1H), 6.65 (s, 1H), 4.34 (m, 1H), H i N 3.82 (m, 2H), 3.37 (m, 2H), 3.12 (m, 2H), 2.52 d (s, 3H), 1.54 (s, 9H), 1.51-1.38 (m, 7H), 1.31 (m, 2H), 1.22-1.06 (m, 12H), 0.89 (m, 3H), 0.65 (m, 2H). MS: 574.1 (M+1)+.
1H-NMR (400 MHz, CDCI3) 6: 8.16 (d, J = 8.4 o Hz, 1H), 7.57 (s, 1H), 7.25 (m, 1H), 6.39 (11, NN' \ 4, SP24_ 1H), 6.27 (s, 1H), 4.83 (s, 1H), 3.77 (m, 2H), 1/129 N H 3.53 (m, 2H), 2.60 (s, 3H), 1.61 (s, 9H), 1.58 (m, d 3H), 1.29 (m, 18H), 0.98 (m, 3H), 0.59 (m, 2H).
MS: 588.3 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.12 (d, J =
02 8.4 Hz, 1H), 7.95 (m, 1H), 7.74 (s, 1H), 7.52 (s, -sNs924_ 1H), 7.40 (m, 1H), 6.62 (s, 1H), 3.85 (m, 2H), N N
H 3.59 (m, 2H), 3.29 (m, 2H), 3.01 (s, 3H), 2.53 (s, d 3H), 1.54 (s, 9H), 1.45 (m, 3H), 1.16 (m, 12H), 0.87 (m, 3H), 0.56 (m, 2H). MS: 594.0 (M+1)+.
Structure Analytical data 11-1-NMR (400 MHz, DMSO-d6) 6: 8.14 (d, JLJ =
o 8.4 Hz, 1H), 7.74 (s, 1H), 7.52 (s, 1H), 7.46 (m, N \ =s924_ 1H), 7.40 (m, 1H), 6.69 (s, 1H), 4.01-3.81 (m, 5H), 3.35 (m, 2H), 2.52 (s, 3H), 1.71 (m, 2H), 1.60-1.40 (m, 14H), 1.25-1.05 (m, 12H), 0.92-0.81 (m, 3H), 0.59 (m, 2H). MS: 572.1 (M+1)+.
1H-NMR (CDCI3, 300 MHz) 6: 0.68-0.69 (2H, m), oa 0 cF3 0.85-0.96 (2H, m), 0.99-1.08 (3H, m), 1.20-1.42 N , 411, 1 (5H, m), 1.59-1.62 (3H, m), 1.94 (2H, t, J = 5.1 \
H
Hz), 2.57 (3H, s), 3.65 (2H, d, J = 7.2 Hz), 4.44 1/132 (2H, t, J = 5.1 Hz), 4.56 (2H, t, J =
6.9 Hz), 4.98 4 (2H, t, J = 6.9 Hz), 5.20 (1H, m), 6.14-6.15 (2H, m), 6.73 (1H, d, J = 1.8 Hz), 7.28 (1H, d, J = 1.8 Hz). MS: 503 (M+1)+.
Example 2 o, sa 0 H 1 \
d2 Step 1: 1-(CvclohexvImethyl)-5-(3,5-di-tert-butvlphenv1)-2-methvl-N-(1-oxidothietan-3-v1)-1 H-pvrrole-3-carboxamide (2) A solution of compound of Example 1/14 (96 mg, 0.2 mmol) in DCM (6 mL) was treated with m-chloroperoxybenzoic acid (99 mg, 0.4 mmol) in an ice-bath for 1 h and then allowed to warm to rt and stirred for 3 h. The mixture was quenched with aq. Na2S03and extracted with EA (3x 30 mL). The organic layer was separated and washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep.
HPLC to give the target compound 2 (38 mg, 40%). 11-1-NMR (400 MHz, DMSO-d6) 6: 8.15 (d, J =
8.0 Hz, 1H), 7.36 (s, 1H), 7.16 (d, J = 1.6 Hz, 2H), 6.53 (s, 1H), 4.40-4.33 (m, 1H), 4.04-3.99 (m, 2H), 3.77 (d, J = 6.8 Hz, 2H), 3.30-3.27 (m, 2H), 2.50 (s, 3H), 1.45-1.38 (m, 3H), 1.31-1.16 (m, 21H), 0.97-0.85 (m, 3H), 0.67-0.57 (m, 2H). MS: 497.1 (M+1).
Examples 2/1 to 2/3 The following Examples were prepared from the corresponding thioether similar as described in Example 2:
# Structure Analytical data oõsa N 0 1H-NMR (400 MHz, CDCI3) 6: 8.19 (d, J =
8.4 Hz, 1H), nn õ, 7.58 (d, 1H), 7.24 (d, 1H), 6.37-6.34 (m, 2H), 4.74-4.67 1 \ . 'S(1\i 0 )\---- (m, 2H), 4.21-4.16 (m, 2H), 3.78 (d, J - 6.8 Hz, 2H), 3.35-2/1 N " 3.30 (m, 2H), 2.60 (s, 3H), 1.61 (s, 9H), 1.58-1.53 (m, d 3H), 1.34-1.25 (m, 12H), 0.99-0.96 (d, 3H), 0.68-0.60 (m, 2H). MS: 576.0 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 7.28-7.27 (m, 1H), 7.13 (t, o,,sa o 4 1H), 7.00 (t, 1H), 6.18 (s, 1H), 6.02 (d, J = 7.2 Hz, 1H), 11 1 \ = 4.66-4.59 (m, 1H), 4.19-4.13 (m, 2H), 3.72 (d, J = 7.2 Hz, 2H), 3.22-3.16 (m, 2H), 2.59 (s, 3H), 1.53 (m, 3H), 1.42 d (m, 3H), 1.41-1.31 (m, 12H), 1.00-0.98 (m, 3H), 0.89-0.86 (m, 2H), 0.77-0.74 (m, 2H), 0.66-0.63 (m, 2H). MS: 595.0 (M+1).
o o 1H-NMR (400 MHz, CDCI3) 6: 7.31(s, 1H), 7.10 (s, 1H), 1------,,,, 1g,-..o 6.31 (s, 1H), 6.26 (d, J = 8.0 Hz, 1H), 4.69-4.63 (m, 1H), , d2/3 NN,r 4.19-4.14 (m, 2H), 3.80-3.73 (m, 4H), 3.28-3.22 (m, 2H), 2.60 (s, 3H), 1.66-1.55 (m, 15H), 1.38-1.30 (m, 9H), 1.02-0.98 (m, 3H), 0.65-0.61 (m, 2H). MS: 588.3 (M+1).
Example 3 9, o.-13, o N
H I \ .=
N
d 3 Step 1: 1-(CyclohexvImethvI)-5-(3,5-di-tert-butvlphenv1)-N-(1,1-dioxidothietan-3-v1)-2-methvI-1H-ovrrole-3-carboxamide (3) To a solution of compound 2 (67 mg, 0.14 mmol) in DCM (2 mL), cooled to 0 C, was added titanium isopropoxide (42 pL, 0.14 mmol) followed by hydrogen peroxide (58 pL, 0.56 mmol) and the solution was stirred at 0 C for 15 min. The ice-bath was removed and stirring was continued at rt for 1 h. The mixture was diluted with DCM (10 mL) and quenched by addition of H20 (10 mL). The organic layers was separated and washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep.
HPLC to give the target compound 3 (40 mg, 56%). 1H-NMR (400 MHz, DMSO-d6) 6: 8.20 (d, J = 3.6 Hz, 1H), 7.37 (s, 1H), 7.16 (d, J = 1.6 Hz, 2H), 6.55 (s, 1H), 4.53-4.47 (m, 3H), 4.28-4.23 (m, 2H), 3.77 (d, J = 7.2 Hz, 2H), 2.52 (s, 3H), 1.45-1.43 (m, 3H), 1.31-1.20 (m, 21H), 0.94-0.86 (m, 3H), 0.66-0.61 (m, 2H). MS: 513.3 (M+1).
Example 4 InN 0 H I= \ *
d 4 Step 1: N-(Azetidin-3-v1)-1-(cyclohexvImethvI)-5-(3,5-di-tert-butvlphenv1)-2-methvI-1H-pvrrole-3-carboxamide hydrochloride (4a) Compound of Example 1/15 (400 mg, 0.71 mmol) was treated with HCl/CH3OH (20 mL) at rt for 18 h. The solvent was evaporated to give intermediate 4a (355 mg, 100%) as a colorless solid, which was used without further purification.
Step 2: 1-(CyclohexvImethvI)-5-(3,5-di-tert-butvlphenv1)-N-(1-(2-methoxvacetvl)azetidin-3-v1)-2-methyl-1H-pyrrole-3-carboxamide (4) To a mixture of compound 4a (100 mg, 0.2 mmol) and DIPEA (78 mg, 0.6 mmol) in DCM (15 mL) was added 2-methoxyacetyl chloride (26 mg, 0.24 mmol) at 0 C and the mixture was stirred for 2 h. Then it was quenched with H20 (20 mL) and extracted with DCM
(3x 20 mL).
The organic layer was separated and washed with brine and dried over Na2SO4.
After filtration, the filtrate was evaporated and purified by prep. HPLC to give the target compound 4 (56 mg, 52%). 1H-NMR (400 MHz, CDCI3) 6: 7.38 (t, J = 1.8 Hz, 1H), 7.17 (d, J = 1.6 Hz, 2H), 6.96 (br s, 1H), 6.50 (s, 1H), 4.39 (br s, 2H), 4.04 (s, 1H), 3.96-3.87 (m, 2H), 3.73 (d, J =
7.2 Hz, 2H), 3.66-3.63 (m, 1H), 3.48-3.43 (m, 1H), 3.38 (s, 3H), 2.58 (s, 3H), 1.53-1.49 (m, 3H), 1.37-1.28 (m, 21H), 0.99-0.95 (m, 3H), 0.68-0.61 (m, 2H). MS: 536.2 (M+1).
Example 5 ---1NoN 0 H I= \ 411 d ste,D1: N-(1-Acetvlazetidin-3-v1)-1-(cyclohexvImethvI)-5-(3,5-di-tert-butvlphenyl)-2-methyl-1H-pvrrole-3-carboxamide (5) To a mixture of compound 4a (100 mg, 0.2 mmol) and DIPEA (78 mg, 0.6 mmol) in DCM (15 mL) was added acetyl chloride (19 mg, 0.24 mmol) at 0 C and the mixtures was stirred for 2 h. Then it was quenched with H20 (20 mL) and extracted with DCM (3x 20 mL).
The organic layer was separated and washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep. HPLC to give the target compound 5 (59 mg, 54%).
1H-NMR (400 MHz, DMSO-d6) 6: 7.98 (t, J = 5.6 Hz, 1H), 7.36 (t, J = 1.6 Hz, 1H), 7.15 (d, J
= 1.6 Hz, 2H), 6.29 (s, 1H), 4.27-4.18 (m, 2H), 3.99-3.96 (m, 1H), 3.79 (d, J
= 7.2 Hz, 2H), 3.31-3.27 (m, 1H), 3.10-3.03 (m, 1H), 2.53 (s, 3H), 1.83 (s, 3H), 1.46-1.43 (m, 3H), 1.30 (s, 18H), 1.24-1.15 (m, 3H), 0.97-0.85 (m, 3H), 0.68-0.60 (m, 2H). MS: 506.1 (M+1).
Example 6 oaN jo__, y NH
d os-Step 1: Methyl 6-(tert-butyl)-4-(1-(cyclohexylmethyl)-5-methyl-4-(oxetan-3-ylcarbamoy1)-1 H-pyr r ol-2-v1) picolinate (6a) To a mixture of compound P1(3.0 g, 9.4 mmol), 5-bromo-1-(cyclohexylmethyl)-2-methyl-N-(oxetan-3-y1)-1H-pyrrole-3-carboxamide (similar prepared as in Example 1) (4.3 g, 10.6 mmol), K2CO3 (3.12 g, 22.6 mmol) and TBAB (180 mg, 0.54 mmol) in 1,4-dioxane (10 mL) and H20 (4 mL) was added Ph(PPh3)2Cl2 (180 mg, 0.24 mmol) under N2. Under microwave conditions, the solution was heated at 100 C for 1.5 h. Water was added and the solution was extracted with EA. The organic layer was washed with brine, dried over NaSO4, filtered, concentrated and purified by CC (PE/EA = 3/1) to give compound 6a (1.8 g, 41%) as a colorless solid.
Step 2: 6-(tert-Buty1)-4-(1-(cyclohexylmethyl)-5-methyl-4-(oxetan-3-ylcarbamoy1)-1H-pyrrol-2-vl)picolinic acid (6b) To a stirred solution of compound 6a (1.65 g, 3.54 mmol) in a mixture of THF
(15 mL) and H20 (5 mL) was added LiOH=H20 (300 mg, 5.64 mmol) and this mixture was stirred at 60 C
for 3 h. The solution was adjusted to pH = 2-3 with 1M HCI. Then the mixture was extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (PE/EA = 2/1) to give compound 6b (1.3 g, 81%) as a colorless powder.
Step 3: N,6-Di-tert-butyl-4-(1-(cyclohexylmethyl)-5-methyl-4-(oxetan-3-ylcarbamoy1)-1 H-p g r ol-2-v1)picolinamide (6) A mixture of compound 6b (150 mg, 0.33 mmol), tert-butylamine (36 mg, 0.48 mmol), HATU
(207 mg, 0.54 mmol) and DIPEA (146 mg, 1.14 mmol) in DMF (5 mL) was stirred at rt for 20 min. The mixture was washed with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (PE/EA =
2/1) to give compound 6 (42 mg, 30%) as a colorless powder. 1H-NMR (CDCI3, 300 MHz) 6:
8.19 (s, 1H), 7.94 (s, 1H), 7.39 (s, 1H), 6.45 (s, 1H), 6.38 (d, J = 6.9 Hz, 1H), 5.20 (q, J = 6.9 Hz, 1H), 4.97 (t, J = 6.9 Hz, 2H), 4.60 (t, J = 6.9 Hz, 2H), 3.84 (d, J = 6.9 Hz, 2H), 2.60 (s, 3H), 1.66 (m, 2H), 1.51 (s, 9H), 1.40 (s, 9H), 1.38-1.29 (m, 3H), 1.03-0.97 (m, 3H), 0.68-0.61 (m, 2H).
MS: 509 (M+1).
Examples 6/1 to 6/9 The following Examples were prepared similar as in Example 6:
# Structure Analytical data ojN o 1H-NMR (CDCI3, 300 MHz) 6: 7.33 (s, 1H), 7.26 (s, 1H), 6.42 N (s, 1H), 6.33 (d, J = 6.9 Hz, 1H), 5.20 (q, J
= 6.9 Hz, 1H), H I \ \ /N \ / 4.96 (t J = 6.9 Hz, 2H), 4.58 (t, J = 6.9 Hz, 2H), 3.84 (d, J =
,'N6/1 -s-N ' Y 6.9 Hz', 2H), 2.92 (s, 3H), 2.59 (s, 3H), 1.73-1.62 (m, 2H), c:,r-N\ 1.53 (s, 9H), 1.43 (s, 9H), 1.38-1.30 (m, 4H), 1.03-0.97 (m, 0) 3H), 0.72-0.63 (m, 2H).MS: 523 (M+1).
n1H-NMR (CDCI3, 400 MHz) 6: 7.44 (d, 1H, J = 1.6 Hz), 7.25 o (d, 1H, J = 8.0 Hz), 7.16 (dd, 1H, J = 8.0 Hz, 1.6 Hz), 6.17 (S, N
= \ mt 1H), 6.09-6.07 (m, 1H), 5.60 (d, 1H, J = 8.0 Hz), 4.18-4.09 H I
6/2N NH (m, 3H), ' .(m' ' 3.75 " - 3 3 99-3 96 2H) (d 2H J 7.2 Hz)' ' 3 55-W-d ( 3.49 (m, 2H), 3.29 (t, 2H, J = 6.4 Hz), 2.62 (s, 3H), 2.00-1.96 cF3 (m, 2H), 1.58-1.47 (m, 5H), 1.44 (s, 9H), 1.41-1.33 (m, 3H), 1.06-1.00 (m, 3H), 0.67-0.62 (m, 2H). MS: 562 (M+1).
n1H-NMR (CDCI3, 400 MHz) 6: 7.43 (d, 1H, J = 1.6 Hz), 7.33 O (d, 1H, J = 7.6 Hz), 7.16 (dd, 1H, J = 7.6 Hz, 1.6 Hz), 6.17 (s, NN \ * 0 1H), 5.75 (m, 2H), 5.60 (t, 2H, J = 7.2 Hz), 4.19-4.14 (m, 1H), H I =
N NH 3.99-3.96 (m, 2H), 3.75 (d, 2H, J = 7.6 Hz), 3.55-3.48 (m, d 22H), 2.61 (s, 3H), 2.04-1.96 (m, 5H), 1.54-1.46 (m, 5H), 1.44 (s, 9H), 1.41-1.36 (m, 3H), 1.03-1.05 (m, 3H), 0.67-0.62 (m, 2H). MS: 480 (M+1).
n1H-NMR (CDCI3, 400 MHz) 6: 7.40 (d, 1H, J = 1.2 Hz), 7.24 o (d, 1H, J = 7.6 Hz), 7.13 (dd, 1H, J = 8.0 Hz, 1.2 Hz), 6.15 (s, NN \ M 1H), 5.74 (d, 1H, J = 4.8 Hz), 5.60 (d, 1H, J = 7.2 Hz), 4.18-H
6/4 I =
4.15 (m, 1H), 3.99-3.96 (m, 2H), 3.75 (d, 2H, J = 7.2 Hz), dN W /NH 3.55-3.49 (m, 2H), 3.01-3.00 (d, 3H, J = 4.8 Hz), 2.61 (s, 3H), 1.56-1.53 (m, 5H), 1.47 (s, 9H), 1.41-1.36 (m, 3H), 1.01-0.99 (m, 3H), 0.62-0.87 (m, 2H). MS: 494 (M+1).
n1H-NMR (CDCI3, 400 MHz) 6: 7.43 (d, 1H, J = 1.6 Hz), 7.24 o (dd, 1H, J = 8.0 Hz, 1.6 Hz), 7.08 (d, 1H, J = 8.0 Hz), 6.18 (s, N
= \ * 1H),5.61 (t, 2H, J = 7.2 Hz), 4.18-4.14 (m, 1H), 3.99-3.96 (m, H I
6/5 2H), 3.75 75 (d 2H J - 8.0 Hz) 3 55-3 49 (m 2H) 3.12 (s 3H) d , 2.82 (s, 3H), 2.61 (s, 3H), 1.99-1.96 (m, 2H), 1.53-1.48 (m, 5H), 1.42-1.23 (m, 12H), 1.01-1.00 (m, 3H), 0.64-0.61 (m, 2H). MS: 508 (M+1).
# Structure Analytical data 1H-NMR (CDCI3, 400 MHz) 6:7.40 (d, 1H, J = 1.2 Hz), 7.22 a 0 (d, 1H, J = 8.0 Hz), 7.13 (dd, 1H, J = 8.0 Hz, 1.2 Hz), 6.14(s, 0 1H), 5.60 (t, 2H, J = 7.2 Hz), 4.18-4.14 (m, 1H), 4.00-3.96 (m, N
H I \ 41 3H), 3.73 (d, 2H, J = 7.2 Hz), 3.55-3.48 (m, 2H), 2.61 (s, 3H), 6/6 N NH 2.09-1.96 (m, 5H), 1.78-1.74 (m, 2H), 1.68-1.65 (m, 1H), d a 11..2569-.11..5139 rim; 44HH)): 11..5031-.11..4035 ((mm:
312HH)),016.46.10-16.396(m 2H). MS:
562 (M+1).
1H-NMR (CDCI3, 400 MHz) 6:7.41 (d, 1H, J = 1.6 Hz), 7.25 a0 (d, 1H, J = 8.0 Hz), 7.14 (dd, 1H, J = 8.0 Hz, 1.6 Hz), 6.15 (s, N 0 1H), 5.79 (t, 2H, J = 6.0 Hz), 5.60 (d, 1H, J = 8.0 Hz), 4.18-H I \ . 4.15 (m, 1H), 4.00-3.95 (m, 2H), 3.75 (d, 2H, J = 7.6 Hz), 6/7 N NH 3.55-3.49 (m, 2H), 3.29 (t, 2H, J = 6.4 Hz), 2.61 (s, 3H), 2.00-d 1.96 (m, 2H), 1.82-1.74 (m, 4H), 1.71-1.67 (m, 4H), 1.51-1.43 (m, 12H), 1.41-1.32 (m, 6H), 1.19-1.05 (m, 5H), 0.66-0.69 (m, 2H). MS: 576 (M+1).
n 0 0,3 1H-NMR (400 MHz, DMSO-d6) 6: 8.14 (s, 1H), 7.80-7.67 (m, 2H), 7.55-49 (m, 2H), 6.72 (s, 1H), 4.01-3.82 (m, 5H), 3.35 H I \
6/8 N NH (111, 2H), 2.55 (s, 3H), 1.75-1.67 (m, 2H), 1.59-1.44 (m, 5H), d \ 1.36 (s, 9H), 1.34-1.24 (m, 3H), 0.98 (m, 3H), 0.63 (m, 2H).
MS: 548.3 (M+1)+.
a 0 CF 1H-NMR (400 MHz, DMSO-d6): 68.41 (d, J = 8.0 Hz, 1H), 0 7.80-7.67 (m, 2 H), 7.52 (d, J = 8.0 Hz, 2H), 6.73 (s, 1H), I-I I \ * 3.99-3.83(m, 5H), 3.72 (m, 1H), 3.40-3.32 (m, 2H), 2.55 (s, 6/9 N NH 3H), 1.86-1.80 (m, 2H), 1.76-1.67 (m, 4H), 1.62-1.47 (m, 6H), d0 (1m.4+01_ )õ.1 0 (m, 8H), 0.98 (s, 3H), 0.65 (m, 2H). MS: 574.3 Example 7 o\.._ 0 N
N
Step 1: Ethyl 2-methyl-1-(piperidin-1-ylsulfony1)-1H-ovrrole-3-carboxylate (7a) To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (1.0 g, 6.52 mmol) in dry DMF (10 mL) was added NaH (172 mg, 7.17 mmol) in portions and the resulting mixture was stirred at rt for 30 min. A solution of piperidine-1-sulfonyl chloride (1.32 g, 7.17 mmol) in dry DMF (4 mL) was added and the resulting mixture was stirred at rt for 3 h. The mixture was quenched with aq. NH4CI and diluted with EA. The organic phase was washed with water and brine and Step 2: Ethyl 5-bromo-2-methy1-1-(piperidin-1-ylsulfony1)-1H-pyrrole-3-carboxylate (7b) To a solution of compound 7a (600 mg, 2 mmol) in dry DMF (8 mL) was added NBS
(409 mg, 2.3 mmol) in portions at 0 C and this mixture was stirred at rt for 3 h.
The mixture was diluted with EA and washed with water and brine. The organic phase was dried over Na2SO4, concentrated and purified by CC (PE/EA = 15/1) to give compound 7b (700 mg) as a pale-yellow solid.
Step 3: Ethyl 5-(3,5-di-tert-butylpheny1)-2-methy1-1-(piperidin-1-ylsulfony1)-1H-pyrrole-3-carboxylate (7c) A mixture of compound 7b (700 mg, 1.85 mmol), 2-(3,5-di-tert-butylphenyI)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (519 mg, 2.22 mmol) and Pd(PPh3)4 (107 mg) in degassed 1,2-dimethoxyethane (5 mL) and 2M Na2CO3 (8 mL) was heated to 100 C for 30 min under microwave irradiation. The mixture was cooled and diluted with EA and washed with water and brine. The organic phase was dried over Na2SO4, concentrated and purified by CC
(PE/EA = 100/1 to 80/1) to give compound 7c as a colorless solid (500 mg).
Step 4: 5-(3,5-Di-tert-butylpheny1)-2-methy1-1-(piperidin-1-ylsulfony1)-1H-pyrrole-3-carboxylic acid (7d) A mixture of compound 7c (300 mg, 0.614 mmol), Li0H-1120 (503 mg, 12.3 mmol) and NaOH (125 mg) in 1,4-dioxane (5 mL) and water (3 mL) was stirred and heated to 120 C for min under microwave irradiation. The mixture was cooled and acidified by 2M
HCI to 20 pH-2 and then extracted with EA. The combined extracts were washed with water and brine, dried over Na2SO4, concentrated and purified by CC (PE/EA = 10/1 to 2/1) to give compound 7d (250 mg) as a colorless solid.
Step 5: 5-(3,5-Di-tert-butylpheny1)-2-methyl-N-(oxetan-3-y1)-1-(piperidin-1-ylsulfony1)-1 H-pv r r ole -3- carboxamide (7) 25 To a solution of compound 7d (100 mg, 217 pmol), oxetan-3-amine (18 mg, 238 pmol) and HATU (124 mg, 326 pmol) in dry DMF (2 mL) at 0 C was added DIPEA (42 mg, 326 pmol) and the resulting mixture was stirred at rt overnight. The mixture was diluted with water, extracted with EA and the combined extracts were washed with water and brine.
The organic phase was dried over Na2SO4, concentrated and purified by CC (PE/EA = 3/1 to 2/1) to give compound 7 (80 mg, 72%) as a colorless solid. 1H-NMR (400 MHz, CDCI3) 6: 7.41 (1H, s), 7.28 (2H, s), 6.22 (1H, s), 6.19 (1H, d, J = 7.2 Hz), 5.23-5.17 (1H, m), 4.99 (2H, t, J = 6.8 Hz), 4.55 (2H, t, J = 6.4 Hz), 2.81 (3H, s), 2.74 (4H, m), 1.34 (23H, m), 0.85 (1H, m). MS:
516.4 (M+1)+.
Examples 7/1 to 7/8 The following Examples were prepared similar as in Example 7:
# Structure Analytical data oa o 11-I-NMR (400 MHz, CDCI3) 5: 7.41 (1H, s), 7.26 (2H, s), 6.22 N
H I \(1H, s), 6.20 (1H, d, J = 8.0 Hz), 5.21-5.18 (1H, m), 4.99 (2H, 7/1 N 411 t, J = 7.2 Hz), 4.55 (2H, t, J = 6.4 Hz), 3.28 (2 H, m), 2.81 :SO2 (3H, s), 2.20 (2H, m), 1.42 (2H, m), 1.34 (18H, s), 1.23 (1H, pm), 0.95 (2H, m), 0.83 (3H, d, J = 6.8 Hz). MS: 530.3 (M+1)+.
0 1H-NMR (400 MHz, CDCI3) 5: 7.42 (1H, s), 7.28 (2H, m), 6.22 N (1H, s), 6.19 (1H, m), 5.21-5.17 (1H, m), 4.99 (2H, t, J = 6.8 H I \ II Hz), 4.55 (2H, t, J = 6.4 Hz), 3.23 (1H, m), 3.14 (1H, m), 2.81 7/2 N (3H, s), 2.15 (1H, m), 1.68 (1H, m), 1.61-1.57 (1H, m), 1.50-0:S 2 1.45 (1H, m), 1.34 (20H, s), 0.90 (1H, m), 0.69 (3H, d, J = 6.4 ......01 Hz). MS: 530.3 (M+1)+.
0\3N 0 N 1H-NMR (400 MHz, DMSO-d6) 5: 8.53 (1H, d, J = 6.4 Hz), H 1 \ II 7.42 (1H, s), 7.24 (2H, s), 6.56 (1H, s), 4.98-4.92 (1H, m), N 4.72 (1H, t, J = 6.8 Hz), 4.53 (1H, t, J = 6.4 Hz), 3.13 (2H, m), 7/3 2so2 2.71 (3H, s), 1.68-1.49 (3H, m), 1.34-1.20 (19H, m), 0.68 .....91 (6H, m), 0.40-0.36 (1H, m). MS: 544.4 (M-i-1).
N
H , * 1H-NMR (400 MHz, DMSO-d6) 5: 8.50 (1H, d, J =
6.4 Hz), I \
7/4 N7.41 (1H, s), 7.21 (2H, s), 6.63 (1H, s), 4.95-4.91 (1H, m), 4.72 (1H, t, J = 6.8 Hz), 4.52 (1H, t, J = 6.4 Hz), 2.71-2.69 :S02 (7H, m), 1.40 (8H, s), 1.34 (18H, s). MS: 530.3 (M+1)+.
a 0\._3 0 N
H , . 1H-NMR (400 MHz,DMSO-d6) 5: 8.53 (1H, d, J
= 6.4 Hz), I \ 7.41 (1H, s), 7.23 (2H, s), 6.65 (1H, s), 4.98-4.92 (1H, m), N 4.73 (1H, t, J = 6.4 Hz), 4.53 (1H, t, J = 6.4 Hz), 3.11 (1H, m), 7/5 ,So2 2.71 (3H, s), 2.36 (3H, s), 1.63 (2H, m), 1.48 (1H, m), 1.32 ----N
b(18H, s), 1.27-0.95 (5H, m). MS: 544.4 (M+1)+.
0\3N 0 N \ .
H 1H-NMR (400 MHz, CDCI3) 6:8.52 (1H, d, J = 6.8 Hz), 7.42 I\
N (1H, s), 7.25 (2H, s), 6.66 (1H, s), 4.94 (1H, m), 4.72 (2H, t, J
7/625o2 = 6.8 Hz), 4.53 (2H, t, J = 6.4 Hz), 2.93 (2H, t, J = 6.8 Hz), MS: 556.5 (M+1).
2.71 (3H, s), 2.62 (2H, s), 1.52-1.40 (6H, m), 1.31 (22H, m).
+
# Structure Analytical data o HON 1H-NMR (400 MHz, DMSO-d6): 6 7.75 (1H, t, J = 6.4 Hz), H I \ II 7.39 (1H, s), 7.24 (2H, s), 6.62 (1H, s), 4.50 (1H, br s), 3.17 7/7 N (2H, d, J = 6.0 Hz), 2.77-2.68 (7H, m), 1.30 (19H, m), 1.21 01:SO2 (5H, m), 1.07 (6H, s). MS: 532.4 (M+1)+.
o H2 N , \ .
I ` 1H-NMR (400 MHz,CDCI3): 6 7.41 (s, 1H), 7.28 (s, 2H), 6.22 7/8 N (s, 1H), 5.59 (br, s, 2H), 2.84 (s, 3H), 2.76-2.73 (m, 4H), 1.34 :SO2 (s, 18H), 1.26 (m, 6H). MS: 460.2 (M+1)+.
Example 8 ?rij 0 j 5-0 d ,/
Step 1: Ethyl 5-acetyl-1-(cyclohexylmethyl)-2-methy1-1H-pyrrole-3-carboxylate (8a) To a stirred solution of ethyl 1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (8.0 g, 32.1 mmol, prepared according to Example "Id) and 1-methylvinyl acetate (6.4 g, 64.2 mmol) in 1,2-dichloroethane (100 mL) was added p-toluenesulfonic acid monohydrate (250 mg, 1.45 mmol) under N2 and the mixture was stirred and heated to ref lux overnight. After cooling rt the mixture was diluted with water and extracted with DCM twice. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC
(PE/EA = 30/1) to give compound 8a (5.7 g, 61%) as a yellow solid.
Step 2: (E)-Ethyl 1-(cyclohexylmethyl)-2-methyl-5-(3-(pyridin-2-ynacryloy1)-1H-pyrrole-3-carboxylate (8b) To a solution of compound 8a (5.4 g, 18.5 mmol) and picolinaldehyde (4.0 g, 37.4 mmol) in THF (60 mL) was added DBU (3.1 g, 20.4 mmol) and the solution was stirred at rt for 3 d.
The solution was quenched with aq. NH4CI and extracted with EA twice. The combined organic layers were washed with brine and dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 20/1) to give compound 8b (3.8 g, 54%) as a yellow solid.
Step 3: Ethyl 1-(cyclohexylmethyl)-2-methy1-5-(3-(pyridin-2-y1)propanoy1)-1H-pyrrole-3-carboxylate (8c) To a solution of compound 8b (3.7 g, 9.7 mmol) in Me0H (100 mL) was added Pd/C
(370 mg) and the mixture was stirred at rt under H2 (15 psi) overnight. The solution was filtered, concentrated and purified by CC (PE/EA = 20/1) to give compound 8c (3.2 g, 86%) as a colorless solid.
Step 4: Ethyl 1-(cyclohexylmethyl)-5-(1-(N-(methoxycarbonyl)sulfamoypindolizin-3-y1)-2-methyl-1H-pyrrole-3-carboxylate (8d) A solution of compound 8c (3.0 g, 7.8 mmol) in dry toluene (50 mL) was refluxed with a Dean-Stark tube to remove water under N2 for 10 min and then (methoxycarbonyl-sulfamoyl)triethylammonium hydroxide inner salt (Burgess reagent, 3.8 g, 15.9 mmol) was added to the mixture. The mixture was heated to ref lux for further 30 min and cooled to rt.
The solution was quenched with aq. NH4CI and extracted with EA twice. The combined organic layers were washed with brine and dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 3/1) to give compound 8d (2.1 g) as a yellow solid.
Step 5: Ethyl 1-(cyclohexylmethyl)-2-methy1-5-(1-(piperidin-1-ylsulfonyl)indolizin-3-y1)-1 H-pyrrole-3-carboxylate (8e) To a solution of compound 8d (700 mg, 1.4 mmol) in ACN (20 mL) was added 1,5-dibromopentane (383 mg, 1.68 mmol) and K2CO3 (483 mg, 3.5 mmol) and the mixture was stirred overnight at ref lux. The resulting solution was cooled to rt and further K2CO3 (483 mg, 3.5 mmol) was added. The solution was stirred again overnight at ref lux.
After cooling to rt the mixture was diluted with water and extracted with EA twice. The combined organic layers were washed brine, dried over Na2SO4, filtered and concentrated to dryness. CC
(PE/EA =
10/1) afforded compound 8e (610 mg, 85%) as an oil.
Step 6: 1-(Cyclohexylmethyl)-2-methyl-5-(1-(piperidin-1-ylsulfonyl)indolizin-3-y1)-1H-pyrrole-3-carboxylic acid (8f) To a stirred solution of compound 8e (600 mg, 1.17 mmol) in a mixture of DMSO
(15 mL) and H20 (2 drops) was added KOtBu (655 mg, 5.85 mmol) and the mixture was stirred at 85 C for 4 h. After cooling to rt the pH was adjusted to pH 2-3 with 1M HCI
and then the mixture was extracted with EA. The organic layer was washed with water and brine, dried over Na2SO4, concentrated and purified by CC (PE/EA = 2/1) to give compound 8f (450 mg, 80%) as a yellow solid.
Step 7: 1-(Cyclohexylmethyl)-2-methyl-N4(3-methyloxetan-3-y1)methyl)-5-(1-(piperidin-1-vlsulfonypindolizin-3-y1)-1H-pyrrole-3-carboxamide (8) A mixture of compound 8f (150 mg, 0.31 mmol), (3-methyloxetan-3-yl)methanamine (62 mg, 0.62 mmol), HATU (207 mg, 0.54 mmol) and DIPEA (146 mg, 1.14 mmol) in DMF (5 mL) was stirred at rt for 20 min. The resulting solution was diluted with water and extracted with EA twice. The combined organic layers were washed with water three times and brine consecutively, dried over Na2SO4, concentrated and purified by prep. TLC
(PE/EA = 1/1) to give compound 8 (30 mg, 16%) as a pale yellow powder. 1H-NMR (CDCI3, 400 MHz) 6: 8.05 (d, 1H, J = 9.2 Hz), 7.81 (d, 1H, J = 6.8 Hz), 7.10-7.05 (m, 2H), 6.77-6.73 (m, 1H), 6.47 (s, 1H), 6.10 (t, 1H, J = 6.0 Hz), 4.55 (d, 2H, J = 6.0 Hz), 4.42 (d, 2H, J = 6.0 Hz), 3.56 (d, 2H, J
= 6.0 Hz), 3.52 (d, 2H, J = 7.2 Hz), 3.00 (m, 4H), 2.64 (s, 3H), 1.67-1.62 (m, 4H), 1.57-1.53 (m, 5H), 1.37-1.25 (m, 6H), 0.99-0.95 (m, 3H), 0.61-0.57 (m, 2H). MS: 567.1 (M+1)+.
Examples 8/1 to 8/2 The following Examples were prepared similar as in Example 8:
Structure Analytical data HO 1H-NMR (CDCI3, 400 MHz) 6: 8.06 (d, 1H, J
= 8.8 Hz), / SO2Ni\--) 7.82 (d, 1H, J = 6.8 Hz), 7.10-7.05 (m, 2H), 6.77-6.73 (m, 1H), 6.48 (s, 1H), 6.20(m, 1H), 3.52 (d, 2H, J = 7.2 8/1 d N Hz), 3.41 (d, 2H, J = 6.0 Hz), 3.00 (m, 4H), 2.63 (s, 3H), \I 1.67-1.63 (m, 4H), 1.60-1.53 (m, 3H), 1.44-1.37 (m, 15H), 0.99-0.95 (m, 3H), 0.61-0.57 (m, 2H). MS: 555.1 (M+1)+.
01H-NMR (CDCI3, 400 MHz) 6: 8.06 (d, 1H, J = 8.8 Hz), / SO2Nr--) 7.82 (d, 1H, J = 6.8 Hz), 7.11-7.06 (m, 2H), 6.76 (t, 1H, J
= 5.4 Hz), 6.49 (s, 1H), 6.22 (d, 1H, J = 7.2 Hz), 5.24-8/2 N 5.19(m, 1H), 5.00 (t, 1H, J = 7.2 Hz), 4.57 (t, 1H, J = 7.2 d NI Hz), 3.52 (d, 2H, J = 7.2 Hz), 3.00 (m, 4H), 2.62 (s, 3H), 1.67-1.52 (m, 9H), 1.39-1.24 (m, 4H), 0.99-0.95 (m, 3H), 0.61-0.57 (m, 2H). MS: 539.1 (M+1).
Example 9 oo\ 0 H \ /11 Step 1: 1-(CyclohexvImethvI)-2-methvI-1H-ovrrole-3-carboxvlic acid (9a) To a solution of 1-(cyclohexylmethyl)-2-ethyl-1H-pyrrole-3-carboxylate (prepared according to Example 1d, 875 mg, 3.5 mmol) in Et0H (50 mL) was added 5M KOH (10 mL). The mixture was stirred and heated to reflux overnight. After cooling to rt the solvent was concentrated and the pH of the remaining aq. mixture was adjusted to <2 with 4M HCI. The mixture was extracted with EA three times and the combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep. HPLC to give pure product 9a as a colorless solid.
Step 2: 1-(CyclohexylmethvI)-2-methvl-N-(oxetan-3-v1)-1H-pyrrole-3-carboxamide (9b) To a solution of 9a (505 mg, 2.29 mmol) in DMF (15 mL) was added HATU (1.74 mg, 4.58 mmol) and DIPEA (1.48 mg, 11.5 mmol). The mixture was stirred for 60 min and then oxetan-3-amine (185 mg, 2.52 mmol) was added. The mixture was stirred for additional 18 h, quenched with ice water and extracted with EA. The organic layer was separated, washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep. HPLC to give 9b (398 mg, 63%) as a colorless solid.
Step 3: 5-Bromo-1-(cyclohexvImethvI)-2-methyl-N-(oxetan-3-v1)-1H-pyrrole-3-carboxamide To a solution of 9b (555 mg, 2 mmol) in dry THF (10 mL) was added NBS (374 mg, 2.1 mmol) at ¨78 C under N2. The mixture was stirred for 5 min and quenched with a cold aq.
solution of NH4CI. The organic layer was separated and the aq. layer extracted repeatedly with EA. The combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by CC (EA/PE = 1/60) to give compound 9c (630 mg, 89%).
Step 4: 5-(3-tert-Butv1-5-(N-tert-butyl-N-methvIsulfamovl)phenv1)-1-(cyclohexvImethvI)-2-methyl-N-(oxetan-3-v1)-1H-pwrole-3-carboxamide (9) Compound 9c (86 mg, 244 pmol), compound P12 (100 mg, 244 pmol) and Cs2CO3 (238 mg, 732 pmol) in 1,4-dioxane/water (10:1, 2.2 mL) were stirred at rt. Pd(PPh3)4 (0.03 eq) was added under N2 and the mixture was stirred and heated under microwave irradiation to 120 C for 2 h. The mixture was cooled to rt, filtered and purified by prep.
HPLC to give target 9 (81.5 mg, 60%) as a colorless solid. 11-1-NMR (400 MHz, DMSO-d6) 6: 8.32-8.30 (d, J = 6.4 Hz, 1H), 7.69 (m, 2H), 7.54-7.53 (t, J = 1.4 Hz, 1H), 6.75 (s, 1H), 4.96 (m, 1H), 4.74-4.70 (t, J
= 7.0 Hz, 1H), 4.57-4.53 (t, J = 6.2 Hz, 1H), 3.85-3.82 (m, 1H), 2.97 (s, 3H), 2.53 (s, 3H), 1.48-1.45 (m, 3H), 1.35 (s, 9H), 1.24-1.20 (m, 12H), 0.92 (m, 3H), 0.61 (m, 2H). MS: 558.3 (M+1)+.
Examples 9/1 to 9/15 The following Examples were prepared similar as in Example 9, using the corresponding borononic ester building blocks prepared as or similar as described above:
# Structure Analytical data ojN o 0, p 1H-NMR (400 MHz, DMSO-d6) 6: 8.33 (d, J = 6.8 Hz, ;S=NO 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.76 (s, 1H), N
H I \ / 1'1 7.65 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 3.8 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 4.98 (d, J = 6.8 Hz, 1H), 4.75-4.71 9/1 di .
(t, J = 7.0 Hz, 2H), 4.58-4.54 (t, J = 6.6 Hz, 2H), 3.85 (d, J = 7.2 Hz, 2H), 3.19-3.16 (m, 4H), 2.54 (s, 3H), 1.46 (s, 7H), 1.35 (m, 5H), 0.92 (d, J = 5.2 Hz, 3H), 0.64-0.60 (t, J = 6.6 Hz, 2H). MS: 539.2 (M+1)+.
0 0õ0 HO 1H-NMR (400 MHz, DMSO-d6) 6: 7.95 (d, J = 8.0 Hz, / \ N I \ / N? s'._ No 1H), 7.75 (s, 1H), 7.63-7.61 (m, 1H), 7.56 (s, 1H), 7.41-7.39 (m, 1H), 7.35-7.33 (m, 1H), 6.73 (s, 1H), 3.84-3.82 9/2 di *
(d, J = 7.6 Hz, 2H), 3.59 (br s, 1H), 3.19-3.17 (m, 6H), 2.56 (s, 3H), 1.46 (s, 7H), 1.35 (m, 5H), 1.08 (s, 6H), 0.91 (m, 3H), 0.64-0.61 (m, 2H). MS: 555.1 (M+1)+.
HO 1H-NMR (400 MHz, DMSO-d6) 6: 7.68 (m, 2H), 7.55 ?r N I \ . (m, 2H), 6.69 (s, 1H), 3.99 (s, 1H), 3.84-3.82 (d, J = 6.8 Hz, 2H), 3.17-3.16 (d, J = 6.0 Hz, 2H), 2.96 (s, 3H), 9/3 N /2.54 (s, 3H), 1.48-1.46 (m, 3H), 1.34 (s, 9H), 1.24 (s, d 02s-N),_ 12H), 1.08 (s, 6H), 0.93 (m, 3H), 0.62 (m, 2H). MS:
574.2 (M+1)+.
0\3N 0 1H-NMR (400 MHz, DMSO-d6) 6: 8.36 (d, J=6.4Hz, N 0 1H), 8.22 (d, J=8.4Hz, 1H), 7.84 (s, 1H), 7.61 (s, 1H), H
( 7.51 (m, 1H), 6.83 (s, 1H), 5.03 (m, 1H), 4.79 (m, 2H), 9/4 N 41 4.61 (m, 2H), 3.90 (m, 2H), 2.58 (s, 3H), 1.62 (s, 9H), d 1.50 (m, 3H), 1.30-1-20 (m, 12H), 0.95 (m, 3H), 0.67 (m, 2H). MS: 544.2 (M+1)+.
Ov3N 0 1H-NMR (400 MHz, DMSO-d6) 6: 8.31 (d, J=7.2Htz, N 0 1H), 7.79 (d, J=8.4Hz, 1H), 7.57 (s, 1H), 7.43 (m, 1H), Hg':=0 ( 6.76 (s, 1H), 4.98 (m, 1H), 4.73 (m, 2H), 4.56 (m, 2H), 'N
C / 3.84 (m, 2H), 3.09 (s, 3H), 2.51 (s, 3H), 1.54 (s, 9H), 1.43 (m, 3H), 1.21 (s, 9H), 0.91 (m, 3H), 0.89 (m, 3H), 0.61 (m, 2H). MS: 558 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.31 (d, J=6.4Hz, N,0 1H), 7.81 (d, J=8.0Hz, 1H), 7.58 (s, 1H), 7.43 (m, 1H), H I \ *
9/6 N ( 6.76 (s, 1H), 4.96 (m, 1H), 4.72 (m, 2H), 4.54 (m, 2H), N __ 3.83 (d, 2H), 3.59 (m, 2H), 2.51 (s, 3H), 1.55 (s, 9H), d 1.43 (m, 3H), 1.27 (m, 12H), 1.18 (m, 3H), 0.88 (m, 3H), 0.60 (m, 2H). MS: 572.3 (M+1)+.
9-\ 0 1H-NMR (400 MHz, DMSO-d6) 6: 8.30 (d, J=6.4Hz, Np 1H), 8.17 (d, J=8.0Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), H I \ *
, __ 7.42 (m, 1H), 6.77 (s, 1H), 4.97 (m, 1H), 4.74 (m, 2H), 9/7 N HN 4.55 (m, 2H), 3.84 (d, 2H), 2.52 (s, 3H), 1.55 (m, 11H), d 1.44 (m, 3H), 1.19 (d, 3H), 1.08 (s, 6H), 0.89 (m, 6H), 0.63 (m, 2H). MS: 558.3 (M+1).
# Structure Analytical data HO 1H-NMR (400 MHz, DMSO-d6) 6: 8.14 (d, J=8.4Hz, ?Chi I \ Art ,o 1H), 7.75 (s, 1H), 7.55-7.45 (m, 2H), 7.42 (m, 1H), 6.71 s, (s, 1H), 4.61 (s, 1H), 3.85 (m, 2H), 3.15 (m, 2H), 2.52 9/8 N W HN ( (s, 3H), 1.54 (s, 9H), 1.45-1.40 (m, 3H), 1.20-1.06 (m, d 12H), 1.07 (s, 6H), 0.92-0.80 (m, 3H), 0.56 (m, 2H).
MS: 560.3 (M+1)+.
HO 1H-NMR (400 MHz, DMSO-d6) 5: 7.78 (d, J=8.4Hz, N
?CH I\ 0 jõic, 1H), 7.60-7.45 (m, 2H), 7.41 (m, 1H), 6.71 (s, 1H), 4.61 N li 6IN ( (s, 1H), 3.84 (m, 2H), 3.17 (m, 2H), 3.08 (s, 3H), 2.53 i (s, 3H), 1.54 (s, 9H), 1.46-1.40 (m, 3H), 1.22 (s, 9H), d 1.27-1.18 (m, 3H), 1.04 (s, 6H), 0.93-0.80 (m, 3H), 0.62 (m, 2H). MS: 574.3 (M+1)+.
HO 1H-NMR (400 MHz, DMSO-d6) 6: 7.80 (d, J=8.4Hz, ?Ch I \ M2o, 1H), 7.62-7.44 (m, 2H), 7.41 (m, 1H), 6.71 (s, 1H), 4.61 N W SsN ( (s, 1H), 3.84 (m, 2H), 3.62 (m, 2H), 3.15 (m, 2H), 2.52 (s, 3H), 1.54 (s, 9H), 1.45-1.41 (m, 3H), 1.35-1.16 (m, d c 15H), 1.07 (s, 6H), 0.96-0.80 (m, 3H), 0.63 (m, 2H).
MS: 588.3 (M+1)+.
HO 1H-NMR (400 MHz, DMSO-d6) 6: 8.14 (d, J=8.4Hz, ?(Ni I \ e2o 1H),7.62(s, 1H)1,7.543-76.50 (m,2H),.7.42 (m,1H),63.72 9/11 N W HN ____ (s, 1H), 4.61 ), 61 H .8 (s, ), (m, 2H), 318 (m, 2H), 2.6 (s, 3H), 1.560-1.50 (m, 11H), 1.49-1.40 (m, 3H), 1.25-d 1.21 (m, 3H), 1.08 (s, 12H), 0.93-0.81 (s, 6H), 0.61 (m, 2H). MS: 574.1 (M+1)+.
Oa 0 1H-NMR (400 MHz, CDCI3) 6: 0.68-0.71 (2H, m), 1.01-( 1.07 (12H, m), 1.37-1.45 (3H, m), 1.58 (3H, m), 2.58 (3H, s), 3.41 (2H, d, J = 5.6 Hz), 3.65 (2H, d, J = 7.2 9/1 2 N - Hz), 4.57 (2H, t, J = 6.4 Hz), 4.97-5.00 (2H, t, J = 6.4 0) F Hz), 5.04 (1H, s), 5.20-5.22 (1H, m), 6.17 (2H, d, J =
F F
7.6 Hz), 6.20 (1H, s), 7.58 (1H, d, J = 2.4 Hz), 8.20 (1H, d, J = 2.0 Hz). MS: 507.1 (M+1)+.
Oa 0 K 1H-NMR (400 MHz, DMSO-d6) 6: 0.67-0.69 (2H, m), 0.86-1.02 (12H, m), 1.29-1.36 (3H, m), 1.51-1.53 (3H, 9/13 N - m), 2.45 (3H, s), 3.76 (2H, m), 4.12 (2H, s), 4.54 (2H, 0) F m), 4.72 (2H, m), 4.94 (1H, m), 6.72 (1H, s), 8.07 (1H, F F
m), 8.28 (1H, m), 8.45 (1H, m). MS: 508.1 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.24 (m, 1H), 8.03 (m, 1H), 7.92 (m, 1H), 6.64 (s, 1H), 4.94 (m, 1H), 4.71 N , N
(m, 2H), 4.53 (m, 2H), 3.94 (s, 2H), 3.71 (m, 2H), 2.49 9/14 N - (s, 3H, partial overlay with solvent signal), 1.59-1.52 0) F FF (m, 2H), 1.50-1.25 (m, 4H), 1.10-1.00 (m, 2H), 0.94 (s, 9H), 0.76 (m, 2H); MS: 508.1 (M+1)+.
Structure Analytical data ojN o 1H-NMR (300 MHz, CDCI3) 5: 7.45-7.42 (m, 2H), 6.43 (s, 1H), 6.35 (d, 1H, J = 6.9 Hz), 5.20 (m, 1H), 4.99 (t, 11)11 \N 2H, J = 6.9 Hz), 4.58 (t, 2H, J = 6.9 Hz), 3.84 (d, 2H, J
9/15 N --( =6.9 Hz), 2.61 (s, 3H), 1.66 (m, 3H), 1.41 (s, 9H), 1.30-1.38 (m, 3H), 0.97-1.03 (m, 3H), 0.63 (m, 2H).
MS: 478.2 (M+1).
Example 10 n H I \ I H
V--"N N
dNI
Step 1: Indolizine-1-carboxylic acid (10a) 5 A solution of ethyl indolizine-1-carboxylate (1.3 g, 6.88 mmol, prepared according J. Org.
Chem. 1999, 64:7618) and 10% aq. NaOH (120 mL) in THF (10 mL) was heated to 50 C
overnight. The resulting solution was concentrated and adjusted to pH 1 by conc. HCI. The solution was extracted twice with EA. The combined organic layers were washed with brine, dried with Na2SO4, filtered and concentrated to give intermediate 10a (0.50 g, 45%) as a 10 colorless solid.
Step 2: N-tert-Butvlindolizine-1-carboxamide (10b) A solution of intermediate 10a (500 mg, 3.11 mmol), HATU (1.42 g, 3.73 mmol) and DIPEA
(1.2 g, 9.33 mmol) in DMF (10 mL) was stirred at rt for 30 min, then tert-butylamine (273 mg, 3.73 mmol) was added and the solution was stirred for another 0.5 h. The mixture was quenched with water and extracted three times with EA. The combined organic layers were washed with water and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 5/1) to give intermediate 10b (410 mg, 61%) as a colorless solid.
Step 3: 3-Bromo-N-tert-butvlindolizine-1-carboxamide (10c) A solution of intermediate 10b (100 mg, 463 pmol) and CuBr2.2 H20 (124 mg, 556 pmol) in ACN (10 mL) was stirred at rt for 1.5 h. The mixture was quenched with sat.
aq. NH4CI and extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 20/1) to give intermediate 10c (50 mg, 37%) as a yellow solid.
Step 4: Ethyl 541-(tert-butvIcarbamovpindolizin-3-v1)-1-(cyclohexylmethvI)-2-methvI-1 H-pyr r ol e -3- carboxyl ate (10d) To a solution of intermediate 10c (50 mg, 169 pmol), P18 (59.5 mg, 203 pmol), K2CO3 (58 mg, 423 pmol) and TBAB (10 mg) in a mixture of 1,4-dioxane (1 mL) and water (0.5 mL) was added Pd(PPh3)2Cl2 (10 mg) under N2 and the solution was heated to 85 C for 1 h under microwave irradiation (120 W). After cooling to rt the resulting solution was poured into a mixture of water and EA and the aq. phase was extracted twice with EA. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 5/1) to give intermediate 10d (30 mg, 38%) as a colorless solid.
Step 5: 5-(14 tert-ButvIcarbamovI)indolizin-3-v1)-1-(cyclohexvImethvI)-2-methvl-1H-pwrole-3-carboxylic acid (10e) To a solution of intermediate 10d (156 mg, 337 pmol) in a mixture of DMSO (1.5 mL) and water (one drop) was added KOtBu (76 mg, 674 pmol) and the solution was stirred at 80 C
overnight. The mixture was quenched with water, the pH was adjusted to 5 with 1M HCI and extracted twice with DCM. The combined organic layers were washed with water three times and brine consecutively, dried over Na2SO4, filtered and concentrated to give intermediate 10e (143 mg, 98%) as a colorless solid.
Step 6: N-tert-Butv1-3-(1-(cyclohexvImethvI)-5-methyl-4-(tetrahvdro-2H-pvran-4-vIcarbamov1)-1H-pwrol-2-v1)indolizine-1-carboxamide (10) A solution of intermediate 10e (143 mg, 329 pmol), HATU (150 mg, 394 pmol) and DIPEA
(127 mg, 986 pmol) in dry DMF (2 mL) was stirred for 30 min at rt, then 4-aminotetrahydropyran (40 mg, 394 pmol) was added and the solution was stirred for another 0.5 h. The mixture was quenched with water and extracted twice with EA. The combined organic layers were washed with water three times and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to give 10 (25 mg, 15%) as a colorless solid. 1H-NMR (CDCI3, 400 MHz) 6: 0.54-0.60 (2H, m), 0.96-0.98 (3H, m), 1.25-1.28 (4H, m), 1.44-1.51 (13H, m), 1.97-2.01 (2H, m), 2.64 (3H, s), 3.50-3.55 (4H, m), 3.97-3.99 (2H, m), 4.15-4.4.19 (1H, m), 5.58-5.60 (1H, d, J = 8.0 Hz), 5.67 (1H, s), 6.35 (1H, s), 6.63-6.67 (1H, m), 6.83 (1H, s), 6.99-7.03 (1H, m), 7.73 (1H, d, J = 7.6 Hz), 8.37 (1H, d, J =
9.2 Hz). MS: 519.2 (M+1).
Example 10/1 The following Example was prepared similar as in Example 10:
Structure Analytical data 01 0 0 1H-NMR (CDCI3, 400 MHz) 6: 0.61-0.63 (2H, m), 0.96-0.98 0 ((36HH: mm)),, 21 ..3624-(13.3H6 s(4) F13,.51111):315.533(-21H.55d(2J1-1., m7 1H.z6)4-31..7702 z I _ 1 Oil N 3.73 (4H, m), 4.56-4.59 (2H, m), 4.98-5.01 (2H, m), 5.20-d \I 5.22 (1H, m), 6.21-6.22 (1H, m), 6.43 (1H, s), 6.60-6.64 (1H, m), 6.87 (1H, s), 6.93-6.97 (1H, m), 7.70-7.72 (1H, m), 7.90-7.92 (1H, m). MS: 503.1 (M+1)+.
Example 11 N J,N
0\õ..) c 111 H \
d 5484 tert-Butyl)spi roich roman-4,1'-cyclopropan1-6-0-1-(cyclohexvImethvI)-N-(2,2-dimethvl-3-morpholino-3-oxopropv1)-2-methyl-1H-pyrrole-3-carboxamide (11) To a solution of Example 1/91 (106 mg, 0.2 mmol) in DMF (5 mL) was added HATU
(152 mg, 0.4 mmol) and DIPEA (129 mg, 1 mmol). The mixture was stirred for 60 min and then morpholine (87 mg, 1 mmol) was added into the mixture. The mixture was stirred overnight and quenched with ice water and extracted with EA. The organic layer was separated and washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated and purified by prep. HPLC to give compound 11(54 mg, 45%) as a colorless solid.
(400 MHz, DMSO-d6) 6: 7.26 (t, 1H), 6.89 (s, 1H), 6.48 (s, 1H), 6.26 (s, 1H), 4.28 (t, 2H), 3.65 (d, 2H), 3.57 (s, 8H), 3.37 (m, 2H), 2.47 (s, 3H), 1.84 (t, 2H), 1.51 (m, 3H), 1.26 (m, 12H), 1.17 (s, 6H), 0.98 (m, 5H), 0.71 (m, 2H), 0.66 (m, 2H). MS: 604.3 (M+1).
Example 11/1 to 11/7 The following Examples were prepared similar as in Example 11:
Structure Analytical data HN
0 1H-NMR (400 MHz, DMSO-d6) 6: 7.60 (t, 1H), 7.29 (t, 1H), 6.90 (s, 1H), 6.48 (s, 1H), 6.30 (s, 1H), 4.29 (t, 2H), 3.65 11/i (d, 2H), 3.27 (d, 2H), 3.56 (s, 3H), 2.47 (s, 3H), 1.84 (t, N* 2H), 1.50 (m, 3H), 1.29 (m, 12H), 1.07 (s, 6H), 0.95 (m, 0 5H), 0.88 (m, 2H), 0.67 (m, 2H). MS: 548.4 (M+1).
# Structure Analytical data o \
N
/ 0 1H-NMR (400 MHz, CDCI3) 6: 6.96 (s, 1H), 6.87 (s, 1H), 3\--1\-IN 6.43 (s, 1H), 6.14 (s, 1H), 4.32 (t, 2H), 3.63 (d, 2H), 3.52 11/2 / \ (d, 2H), 3.02 (s, 6H), 2.58 (s, 3H), 1.91 (t, 2H), 1.57 (m, N * 3H), 1.37 (m, 12H), 1.29 (s, 6H), 1.02 (m, 5H) ,0.82 (m, 0) o 2H), 0.66 (m, 2H). MS: 562.8 (M+1).
o H(N-SrFiN 0 1H-NMR (400 MHz, CDCI3) 6: 7.00 (m, 2H), 6.42 (m, 2H), 6.11 (s, 1H), 4.33 (t, 2H), 3.61 (d, 2H), 3.50 (m, 4H), 2.56 =
11/3 o / \ (m, 5H), 1.91 (t, 2H), 1.56 (m, 3H), 1.32 (m, 12H), 1.26 (s, OH N lp 6H), 1.00 (m, 5H), 0.84 (m, 2H), 0.65 (m, 2H).
MS: 606.4 0) o (M+1).
o 1H-NMR (400 MHz, DMSO-d6) 6: 7.87 (t, 1H), 7.31 (t, 1H), o HP------\HN 6.90 (s, 1H), 6.48 (s, 1H), 6.33 (s, 1H), 4.28 (t, 2H), 3.67 o,) = (d, 2H), 3.46 (m, 2H), 3.29 (m, 2H), 3.23 (m, 2H), 2.97 (s, 11/4-,s / \ 3H), 2.48 (s, 3H), 1.86 (t, 2H), 1.84(m, 3H), 1.27 (m, o' N p0 12H), 1.03 (s, 6H), 0.98 (m, 5H), 0.87 (m, 2H), 0.66 (m, 0) 2H). MS: 640.4 (M+1).
o 1H-NMR (400 MHz, DMSO-d6) 5:7.60 (t, 1H), 7.29 (t, 1H), o 73rHN 6.90 (s, 1H), 6.48 (s, 1H), 6.31 (s, 1H), 4.64 (t, 1H), 4.29 (t, 2H), 3.66 (d, 2H), 3.39 (m, 2H), 3.33 (m, 2H), 3.11 (m, 11/5 HO / \ 2H), 2.47 (s, 3H), 1.84 (t, 2H), 1.50 (m, 3H), 1.26 (m, 0 12H), 1.02 (s, 6H), 0.94 (m, 5H), 0.87 (m, 2H), 0.67 (m, CI) 2H). MS: 578.4 (M+1).
H\I--rN 1H-NMR (400 MHz, DMSO-d6) 6: 7.66 (t, 1H), 7.30 (t, 1H), o 6.90 (s, 1H), 6.48 (s, 1H), 6.30 (s, 1H), 4.42 (t, 1H), 4.28 If (t, 2H), 3.66 (d, 2H), 3.37 (m, 2H), 3.29 (d, 2H), 3.09 (m, 11/6 / \ 2H), 2.48 (s, 3H), 1.84 (t, 2H), 1.52 (m, 5H), 1.29 (m, OH N p0 12H), 1.06 (s, 6H), 0.98 (m, 5H), 0.88 (m, 2H), 0.67 (m, 0) 2H). MS: 592.5 (M+1).
o Fir\--Sv7iN 1H-NMR (400 MHz, DMSO-d6) 5:7.66 (t, 1H), 7.29 (t, 1H), o 6.90 (s, 1H), 6.48 (s, 1H), 6.29 (s, 1H), 4.36 (t, 1H), 4.28 1/ (t, 2H), 3.67 (d, 2H), 3.29 (m, 4H), 3.03 (m, 2H), 2.48 (s, 11/7 / \ 3H), 1.86 (t, 2H), 1.51 (m, 3H), 1.41 (m, 16H), 0.99 (s, HO 0) 1104 0 6H), 0.89 (m, 5H), 0.88 (m, 2H), 0.66 (m, 2H).
MS: 606.5 (M+1).
Example 12 o H2N \ .
I
N
d12 Step 1: Ethyl 5-(3-bromo-5-(tert-butyl)pheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (12a) To a solution of compound P18a (643 mg, 1.71 mmol) in 1,4-dioxane/H20 (3 mU0.8 mL) 1,3-dibromo-5-(tert-butyl)benzene (595 mg, 2.05 mmol), Cs2CO3 (1.11 g, 3.42 mmol) and Pd(PPh3)4 (66 mg, 0.17 mmol) were added under N2. The mixture was stirred under microwave at about 110 C for 2.5 h. Removal of the solvents and purification by prep. TLC
(PE/EA = 20/1) yielded compound 12a (275 mg, 35%) as yellow solid.
Step 2: Ethyl 5-(3-(tert-buty1)-5-cyclopropylpheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (12b) To a solution of compound 12a (275 mg, 0.60 mmol) in toluene/H20 (2 mU0.1 mL) cyclopropylboronic acid (154 mg, 1.80 mmol), tricyclohexylphosphine (17 mg, 0.06 mmol), K3PO4 (505 mg, 2.11 mmol) and Pd(OAc)2 (7 mg, 0.03 mmol) were added under N2.
The mixture was stirred at 100 C for 3 h, then concentrated and purified by prep.
TLC (PE/EA =
20/1) to yield compound 12b (150 mg, 60%) as a colorless solid.
Step 3: 5-(3-(tert-Buty1)-5-cyclopropylpheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylic acid (12c) To a solution of 10% NaOH in water/Me0H (10 mL, 1:1) was added compound 12b (150 mg, 0.36 mmol) and the mixture was stirred at 70 C for 3 h. Then 2M HCI was added to adjust the pH to 4. The mixture was extracted with EA and removal of the organic solvents gave the crude compound 12c (100 mg, 90%).
Step 4: 5434 tert-Buty1)-5-cyclopropylpheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxamide (12) To a solution of compound 12c (50 mg, 0.125 mmol) in DCM (5 mL) was added (C0C1)2 (160 mg, 1.25 mmol) dropwise and then a drop of DMF under N2. The mixture was stirred at rt for 1 h and then concentrated. Then NH3 in THF was added and the mixture was stirred for 1 min, concentrated and purified by prep. HPLC to afford compound 12 (15 mg, 35%) as a colorless solid. 1H-NMR (500 MHz, CDCI3) 6: 0.63-0.66 (m, 4H), 0.91-1.00 (m, 5H), 1.34-1.38 (m, 12H), 1.54 (m, 3H), 1.93 (m, 1H), 2.62 (s, 3H), 3.72 (d, 2H), 5.44 (br s, 2H), 6.19 (s, 1H),6.75 (s, 1H), 7.11-7.14 (m, 2H). MS (m/z): 393 (M+1).
Example 13 to Example 15 y_ 03 o , 0 0 0\ 0 OH 0 03N
H I \ H I \ * H I \
dCF3 CF3 13 0) 14 0) 15 Step 1: Methyl 3-(1-(cyclohexylmethyl)-5-methy1-4-(oxetan-3-vIcarbamov1)-1H-pyrrol-2-v1)-5-(trifluoromethyl)benzoate (13) A mixture of 5-bromo-1-(cyclohexylmethyl)-2-methyl-N-(oxetan-3-y1)-1H-pyrrole-carboxamide (1.54 g, 4.66 mmol), compound P68 (1.50 g, 4.24 mmol), K2CO3 (1.46 g, 10.6 mmol) and TBAB (60 mg, 0.18 mmol) in 1,4-dioxane/H20(10 mL/5 mL) was added Ph(PPh3)2Cl2 (300 mg) under N2. The solution was heated under microwave conditions at 100 C for 1.5 h. Water was added and the solution was extracted with EA. The organic layer was washed with brine, dried over NaSO4, filtered, concentrated and purified by CC (PE/EA
= 5/1) to give compound 13 (1.12 g, 63%) as a colorless solid.
Step 2: 3-(1-(CyclohexvImethyl)-5-methy1-4-(oxetan-3-vIcarbamov1)-1H-pyrrol-2-y1)-5-(trifluoromethypbenzoic acid (14) To a stirred solution of compound 13 (680 mg, 1.42 mmol) in a mixture of THF
(10 mL) and H20 (3 mL) was added Li0H.1-120 (420 mg, 10 mmol) and this mixture was stirred at 60 C for 3 h. The mixture was adjusted to pH = 2-3 with 1M HCI and then extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC
(PE/EA = 2/1) to give compound 14 (640 mg, 97%) as a colorless powder.
Step 3: 5-(3-(tert-Butylcarbamov1)-5-(trifluoromethyl)pheny1)-1-(cyclohexylmethyl)-2-methyl-N-(oxetan-3-v1)-1H-pyrrole-3-carboxamide (15) A mixture of compound 14 (160 mg, 0.34 mmol), tert-butylamine (26 mg, 0.36 mmol), HATU
(94.2 mg, 0.36 mmol) and DIPEA (97.4 mg, 0.76 mmol) in DMF (5 mL) was stirred at rt for 20 min. The mixture was diluted with EA and the organic layer was washed with brine, dried over Na2SO4, concentrated and purified by prep. TLC to give compound 15 (46 mg, 26%) as a colorless powder. 1H-NMR (CDCI3, 300 MHz) 6: 7.89 (m, 2H), 7.69 (s, 1H), 6.35 (s, 1H), 6.25 (d, 1H, J = 7.2 Hz), 5.99 (s, 1H), 5.20 (m, 1H), 4.99 (t, 2H, J = 7.2 Hz), 4.58 (t, 2H, J =
7.2 Hz), 3.77 (d, 2H, J = 6.9 Hz), 2.60 (s, 3H), 1.61 (m, 3H), 1.50 (s, 9H), 1.33-1.38 (m, 3H), 0.99-1.03 (m, 3H), 0.63 (m, 2H). MS: 520 (M+1).
Examples 15/1 to 15/9 Using similar procedures as described in Example 15 the following Examples have been prepared:
# Structure Analytical data 0 Y 1H-NMR (CDCI3, 300 MHz) 6: 7.65 (s, 1H), 7.60 (s, 1H), ov.3o N N\ 7.59 (s, 1H), 6.32 (s, 1H), 6.21 (d, 1H, J = 6.9 Hz), 5.20 15/1 H I \ . (q, 1H, J = 7.2 Hz), 4.99 (t, 2H, J = 7.2 Hz), 4.57 (t, 2H, J
N = 7.2 Hz), 3.77 (d, 2H, J = 6.9 Hz), 2.87 (s, 3H), 2.60 (s, d c,3 3H), 1.61 (m, 3H), 1.53 (s, 9H), 1.33-1.38 (m, 3H), 0.99-1.03 (m, 3H), 0.65 (m, 2H). MS: 534 (M+1).
o 1H-NMR (DMSO-d6, 300 MHz) 6: 8.56 (d, 1H, J =
7.5 Hz), oa 0 NH 8.32 (d, 1H, J = 6.9 Hz), 8.19 (d, 2H, J = 12.3 Hz), 7.87 N (s, 1H), 6.85 (s, 1H), 4.95 (q, 1H, J = 7.2 Hz), 4.72 (t, 2H, 15/2 H I \ * J = 7.2 Hz), 4.54 (t, 2H, J = 7.2 Hz), 4.14(q, 1H, J = 6.9 N Hz), 3.87 (d, 2H, J = 7.2 Hz), 2.54 (s, 3H), 1.51 (m, 3H), d 0,3 1.35-1.19(m, 9H), 1.33-1.38 (m, 3H), 0.98-0.94(m, 3H), 0.68 (m, 2H). MS: 506 (M+1).
0 y , 1H-NMR (CDCI3, 300 MHz) 6: 7.88 (s, 2H), 7.69 (s, 1H), uN 0 NH ` 6.29(s, 1H), 6.21 (d, 1H, J = 6.9 Hz), 5.20(q, 1H, J = 7.2 N
15/3 H I \ * Hz), 4.99 (t, 2H, J = 7.2 Hz), 4.59 (t, 2H, J =
7.2 Hz), 3.76 N (d, 2H, J = 6.9 Hz), 2.87 (s, 3H), 2.60 (s, 3H), 1.85 (q, 2H, C) 0,3 J = 7.5 Hz), 1.57 (m, 3H), 1.43 (s, 6H), 1.28 (m, 3H), 0.95 (t, 3H, J = 7.5 Hz), 0.68 (m, 2H). MS: 534 (M+1).
0\3N o 1H-NMR (400 MHz, DMSO-d6) 6: 8.26 (d, J = 6.8 Hz, 1H), N
. 7.45 (s, 1H), 7.32 (s, 1H), 7.14 (s, 1H), 6.68 (s, 1H), 4.98-H I \ 4.93 (m, 1H), 4.73-4.70 (t, J = 7.0 Hz, 2H), 4.56-4.53 (t, J
15/4 N/ = 6.6 Hz, 2H), 3.83 (d, J = 7.2 Hz, 2H), 2.83 (s, 3H), 2.52 C) 0 Ny (s, 3H), 1.45 (s, 12H), 1.40 (s, 9H), 1.27-1.20 (m, 3H), 0.97-0.89 (m, 3H), 0.66-0.60 (m, 2H). MS: 522 (M+1).
oao 1H-NMR (400 MHz, DMSO-d6) 6: 8.28 (d, 1H), 7.83 (s, N 1H), 7.76 (s, 1H), 7.70 (s, 1H), 7.51 (d, 1H), 6.96 (s, 1H), H I \ . 4.98-4.94 (d, 1H), 4.73-4.71 (t, 2H), 4.56-4.54 (t, 2H), 15/5 N 3.82-3.81 (d, 2H), 2.52 (s, 3H), 1.50-1.40 (m, 3H), 1.40 C) 0 NH (s, 9H), 1.34 (s, 9H), 1.29-1.15 (d, 3H), 0.96-0.93 (m, 3H), 0.66-0.61 (m, 2H). MS: 508 (M+1).
oao 1H-NMR (400 MHz, DMSO-d6) 6: 8.30-8.27 (t , 2H), 7.83 N (s, 1H), 7.72 (s, 1H), 7.53 (s, 1H), 6.70 (s,1H), 4.98-4.94 H I \ * (d, 1H), 4.73-4.71 (t, 2H), 4.56-4.54 (t, 2H), 4.15-4.11 (m, 15/6 N 1H), 3.83-3.81 (d, 2H), 2.53 (s, 3H), 1.47 (m, 3H), 1.34 (s, NH
C) 0 ,. 9H), 1.31-1.26(m, 3H), 1.19-1.18(d, 6H), 0.96-0.91 (m, 3H), 0.65-0.63 (m, 2H). MS: 494 (M+1).
OH 1H-NMR (400 MHz, DMSO-d6) 6: 7.48-7.46 (t, 2H), 7.44 NNN I\ lik 0, 1H), 7.31 (s, 1H), 7.14 (s, 1H), 6.61 (s, 1H), 3.82-3.81 C) (d, 2H), 3.17-3.16 (d, 2H), 2.82 (s, 3H), 2.53 (s, 3H), Ni 1.47-1.45 (m, 12H), 1.29-1.20 (m, 12H), 1.08 (s, 6H), 0 / 0.98-0.87 (m, 3H), 0.67-0.61 (m, 2H). MS: 538 (M+1).
# Structure Analytical data OH 0 1H-NMR (400 MHz, DMSO-d6) 6: 7.81 (s, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 7.47-7.45 (m,1H), 6.62 (s, NfiN-I 1 \ * 1H), 4.63 (s, 1H), 3.82-3.80 (d, 2H), 3.18-3.16 (d, 2H), d 15/8 N 2.54 (s, 3H), 1.50-1.48 (m, 3H), 1.39 (s, 9H), 1.34 (s, 9H), 0 N7 1.29-1.17 (m, 3H), 1.08 (s, 6H), 1.00-0.95 (m, 3H), 0.70-0.63 (m, 2H). MS: 524 (M+1).
OH 0 1H-NMR (400 MHz, DMSO-d6) 6: 8.29-8.28 (d, 1H), 7.82 NN
H I \ ip, (s, 1H), 7.71 (s, 1H), 7.52 (s, 1H), 7.49-7.47 (m, 1H), 6.62 I
(s, 1H), 4.63 (m, 1H),4.16-4.11 (m, 1H),3.82-3.81 (d, d 2H), 3.18-3.16 (d, 2H), 2.54 (s, 3H), 1.49-1.47 (m, 3H), NH
_ 1.34 (s, 12H), 1.31-1.17 (m, 6H), 1.08 (s, 6H), 0.96-0.92 O )--- (m, 3H), 0.66-0.64 (m, 2H). MS: 510 (M+1).
Example 16 MeO 0 N I \ *
N
d16 Step 1: 1-(CyclohexvImethvI)-5-(3,5-di- terf-butylphenv1)-2-methvI-1H-pwrole-3-carboxamide (16a) To a solution of 1-(cyclohexylmethyl)-5-(3,5-di-tert-butylpheny1)-2-methyl-1H-pyrrole-3-carboxylic acid (410 mg, 1.0 mmol) in DMF (25 mL) was added HATU (456 mg, 1.2 mmol) in an ice-water bath below 10 C. The mixture was stirred for 60 min and then NH4CI (81 mg, 1.5 mmol) was added to the mixture. The mixture was stirred for additional 12 h, quenched with ice water and extracted with EA. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, evaporated and purified by prep. HPLC to give compound 16a as a colorless solid.
Step 2: 1-(CyclohexvImethvI)-5-(3,5-di-terf-butylphenv1)-N-(4-methoxybutv1)-2-methvI-1 H-pv r r ol e -3- carboxami d e (16) A mixture of compound 16a (82 mg, 0.2 mmol) and 1-chloro-4-methoxybutane (27 mg, 0.22 mmol) in DMF (5 mL) was added NaH (60%, 24 mg, 0.6 mmol) at 0 C and the mixture was stirred overnight under Ar at_90 C, quenched with ice water and extracted with EA. The organic layer was separated, washed with brine, dried over Na2504, filtered, evaporated and purified by prep. HPLC to give compound 16 (16 mg, 16%) as a colorless solid.
(400 MHz, DMSO-d6) 6: 7.63-7.60 (t, J = 5.8 Hz, 1H), 7.35 (s, 1H), 7.16-7.15 (d, J = 1.6 Hz, 2H), 6.49 (s, 1H), 3.77-3.75 (d, J = 6.8 Hz, 2H), 3.34-3.31 (t, J = 5.8 Hz, 2H), 3.22 (s, 3H), 3.17-3.16 (d, J = 6.0 Hz, 3H), 2.52 (s, 3H), 1.51-1.50 (t, J = 3.0 Hz, 4H), 1.46-1.43 (d, J = 9.2 Hz, 3H), 1.31 (s, 18H), 1.27-1.21 (t, J = 11.2 Hz, 3H), 0.94-0.89 (t, J = 10.8 Hz, 3H), 0.65-0.62 (d, J = 11.2 Hz, 2H). MS: 495 (M+1).
Example 17/1 to 17/374 The following Examples were prepared similar as described above:
# Structure Analytical data 1H-NMR (CDCI3, 500 MHz) 6: 7.82 (d, 1H), 7.61 o HN (d, 1H), 7.24 (d, 1H), 6.27 (s, 1H), 5.61 (d, 1H), 4.24-4.15 (m, 3H), 3.98 (d, 2H), 3.78 (d, 2H), 3.52 17/1 / \ 110 (dd, 2H), 2.62 (s, 3H), 1.98 (dd, 2H), 1.66-1.51 (m, N 9 k 16H),1.43-1.30 (m, 12H), 1.00-0.97 (m, 3H), 0.66-CH ,-.-N
0 ) 0.60 (m, 2H). MS: 654.3 (M+1).
\
0 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 HN (d, 1H), 6.12 (s, 2H), 4.33 (t, 2H), 3.65-3.59 (m, / \ 4H), 3.17-2.82 (m, 2H), 2.64-2.60 (m, 6H), 2.12 17/2 N 10, 0 (br s, 2H), 1.90 (t, 2H), 1.58-1.56 (m, 3H), 1.45-1.28(m, 12H), 1.03-1.00 (m, 5H), 0.88-0.84 (m, O)12H), 0.72-0.66 (m, 2H). MS: 539.3 [M+1]t 0\\ 0 s--1H-NMR (400 MHz, DMSO-d6) 6: 7.58 (t, 1H), 6.97 z=
(t, 1H), 6.90 (d, 1H), 6.49 (d, 1H), 6.34 (s, 1H), HN 4.28 (t, 2H), 3.67 (d, 2H), 3.20 (q, 2H), 2.96 (q, 17/3 / \ 2H), 2.88 (s, 3H), 2.49 (s, 3H), 1.85 (t, 2H), 1.69-N .
0 1.62 (m, 2H), 1.51-1.49 (m, 3H), 1.35-1.25 (m, 12H), 0.99-0.87 (m, 7H), 0.72-0.63 (m, 2H). MS:
&570.4 [M+1]t =
\
o=s6,--\_\_\
a 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 (d, 1H), 6.06 (s, 1H), 5.77 (t, 1H), 4.33 (t, 2H), HN 3.64 (d, 2H), 3.39 (q, 2H), 3.02 (t, 2H), 2.90 (s, 17/4 /\
N * 3H), 2.59 (s, 3H), 1.94-1.86 (m, 4H), 1.69-1.50 (m, 7H), 1.46-1.35 (m, 12H), 1.03-1.00 (m, 5H), 0.87-0 0.84 (m, 2H), 0.72-0.64 (m, 2H). MS:
583.3 [M+1]+.
0) 1 Q1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 \ o "'IHN (d, 1H), 6.11 (d, 1H), 4.33 (t, 2H), 4.06-4.00 (m, 1H), 3.89-3.83 (m, 1H), 3.78-3.63 (m, 4H), 3.36-/ \ 3.31 (m, 1H), 2.59 (s, 3H), 2.01-1.89 (m, 5H), 0 1.60-1.56 (m, 4H), 1.38-1.34(m, 12H), 1.03-1.00 MS: 519.3 (M+1).
(m, 5H), 0.86-0.85 (m, 2H), 0.69-0.63 (m, 2H).
& 1 # Structure Analytical data 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 L-ci HN (d, 1H), 6.11 (d, 1H), 4.33 (t, 2H), 4.06-4.00 (m, / \ 1H), 3.89-3.83 (m, 1H), 3.78-3.63 (m, 4H), 3.36-17/6 N *
0 3.31 (m, 1H), 2.59 (s, 3H), 2.01-1.89 (m, 5H), 1.60-1.56 (m, 4H), 1.38-1.34 (m, 12H), 1.03-1.00 C(m, 5H), 0.86-0.85 (m, 2H), 0.69-0.63 (m, 2H). I) 1 MS: 519.3 (M+1) HN¨____\ 0 1H-NMR (400 MHz, CDCI3) 6: 10.04 (s, 2H), 6.97 (s, 1H), 6.44 (s, 1H), 6.17 (br s, 1H), 6.11 (s, 1H), C---0 HN 4.33 (t, 2H), 4.11-4.02 (m, 3H), 3.64 (d, 2H), 3.60-+ICI / \ 3.34 (s, 4H), 3.05-2.87 (m, 2H), 2.57 (s, 3H), 1.90 17/7 N *
0 (t, 3H), 1.56-1.52 (m, 3H), 1.38-1.35 (m, 12H), 1.04-1.02 (m, 5H), 0.86-0.85 (m, 2H), 0.672-0.65 ) 1 (m, 2H). MS: 534.4 (M¨CI)+.
HO\
1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 HN (d, 1H), 6.08-6.03 (m, 2H), 4.66 (t, 1H), 4.42 (dd, 17/8 / \
*
0 4H), 4.33 (t, 2H), 3.80-3.78 (m, 4H), 3.64 (d, 2H), N
2.57 (s, 3H), 1.90 (t, 2H), 1.56 (s, 3H), 1.42-1.35 (m, 12H) , 1.04-0.99 (m, 5H), 0.87-0.84 (m, 2H), 0.72-0.66 (m, 2H). MS: 535.3 (M+1).
0) 1 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.84 FIN (br s, 1H), 6.42 (d, 1H), 6.09 (br d, 1H), 4.33 (t, 2H), 3.86-3.84 (m, 4H), 3.63 (d, 2H), 2.99 (br s, 17/9 / \
N *
0 4H), 2.58 (s, 3H), 1.90 (t, 2H), 1.58-1.56 (m, 3H), 1.45-1.32 (m, 12H), 1.04-0.96 (m, 5H), 0.87-0.84 (m, 2H), 0.70-0.65 (m, 2H). MS: 520.1 (M+1).
0) 1 c;,s0____\ o 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 0' HN (d, 1H), 6.05 (s, 1H), 5.92 (t, 1H), 4.34 (t, 2H), / \ 3.64 (d, 2H), 3.31 (t, 2H), 3.09-3.06 (m, 2H), 2.96 17/10 N *
0 (td, 2H), 2.58 (s, 3H), 2.18 (d, 2H), 1.91-1.84 (m, 5H), 1.59-1.56 (m, 3H), 1.38-1.35 (m, 12H), 0 1.04-0.99 (m, 5H), 0.87-0.84 (m, 2H), 0.73-0.65 (m, ) 1 2H). MS: 581.4 (M+1).
oõ4 1H-NMR (400 MHz, CDCI3) 6: 6.95 (d, 1H), 6.72 (t, :? 0 1H), 6.42 (d, 1H), 6.15 (s, 1H), 4.33 (t, 2H), 4.11 HN (d, 2H), 3.95 (dd, 2H), 3.77 (td, 2H), 3.63 (d, 2H), o 17/11 / \
*
0 2.87 (s, 3H), 2.59 (s, 3H), 2.15-2.08 (m, 2H), 1.89 (t, 2H), 1.79 (d, 2H), 1.60-1.53 (m, 3H), 1.46-1.38 (m, 12H), 1.04-1.00 (m, 5H), 0.86-0.83 (m, 2H), N
0.73-0.65 (m, 2H). MS: 611.3 (M+1).
0) 1 0, 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 osa_..\ o HN (d, 1H), 6.05 (s, 1H), 5.91 (t, 1H), 4.34 (t, 2H), 3.64 (d, 2H), 3.58-3.44 (m, 2H), 3.28-3.19 (m, 2H), / \3.09-3.01 (m, 1H), 2.90-2.80 (m, 2H), 2.58 (s, 3H), 0 2.38-2.33 (m, 1H), 2.01-1.96 (m, 1H), 1.90 (t, 2H), (m, 5H), 0.87-0.64 (m, 4H). MS: 567.3 (M+1).
1.59-1.54 (m, 3H), 1.44-1.35 (m, 12H), 1.04-1.00 0) 1 # Structure Analytical data o--, 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 HN (d, 1H), 6.06 (s, 1H), 5.93 (s, 1H), 4.83 (d, 2H), / \
0 4.53 (d, 2H), 4.33 (t, 2H), 3.64 (d, 2H), 2.58 (s, 3H), 1.90 (t, 2H), 1.74 (s, 3H), 1.59 (br s, 3H), 1.38-1.35 (m, 12H), 1.04-1.00 (m, 5H), 0.87-0.84 (m, 2H), 0.69-0.66 (m, 2H). MS: 505.3 (M+1).
0) =
O-o 1H-NMR (400 MHz, CDCI3) 6: 6.95 (d, 1H), 6.89 \¨N HN (br s, 1H), 6.42 (d, 1H), 6.24 (br s, 1H), 4.33 (t, \
/ \ 2H), 4.14 (br s, 2H), 3.96-3.86 (m, 4H), 3.64-3.52 *
0 (m, 4H), 3.36 (br s, 1H), 3.01 (br s, 3H), 2.58 (s, 3H), 1.90 (t, 2H), 1.57 (br s, 3H), 1.43-1.26 (m, 12H), 1.03-1.02 (m, 5H), 0.88-0.83 (m, 2H), 0.69-) = 0.66 (m, 2H). MS: 548.4 (M+1).
o, 1H-NMR (400 MHz, CDCI3) 6: 6.88 (d, 1H), 6.35 0---'-q (d, 1H), 6.12 (d, 1H), 6.02 (s, 1H), 4.89-4-85 (m, o HN 1H), 4.26 (t, 2H), 3.57 (d, 2H), 3.38 (m, 1H), 3.20-3.15 (m, 1H), 3.10-3.02 (m, 1H), 2.97 (dd, 1H), 17/15 / \ 2.52-2.46 (m, 4H), 2.31-2.26 (m, 1H), 1.84-1.82 N *
0 (m, 2H), 1.52-1.50 (m, 3H), 1.37-1.26 (m, 12H), 0.96-0.93 (m, 5H), 0.80-0.77 (m, 2H), 0.65-0.59 0) 1 (m, 2H). MS: 553.3 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 7.98 (s, 1H), 6.95 HO-...(CLI4 HN (d, 1H), 6.82 (br s, 1H), 6.41 (d, 1H), 6.23 (s, 1H), / \ 4.63 (d, 2H), 4.30 (t, 2H), 3.61 (d, 2H), 2.56 (s, o 17/16 N * 3H), 1.86 (t, 2H), 1.56-1.51 (m, 3H), 1.42-1.36 (m, o 12H), 1.02-0.96 (m, 5H), 0.82-0.79 (m, 2H), 0.70-0.63 (m, 2H). MS: 559.3 (M), 418.2 (M-0) = C6H10N203)+.
o 6 o ---\ (d, 1H), 6.80 (br s, 1H), 6.44 (d, 1H), 6.25 (br s, H2N-..[N HN 1H-NMR (400 MHz, CDCI3) : 8.18 (s, 1H), 6.98 1H), 6.15 (s, 1H), 5.68 (br s, 1H), 4.72 (d, 2H), 17/17 o / \
N IP
0 4.34 (t, 2H), 3.65 (d, 2H), 2.60 (s, 3H), 1.90 (t, 2H), 1.58-1.55 (m, 3H), 1.38-1.35 (m, 12H), 1.04-0.99 (m, 5H), 0.87-0.84 (m, 2H), 0.73-0.66 (m, 0) = 2H). MS: 559.3 (M+1).
1H-NMR (400 MHz, DMSO-d6) 6: 8.29 (s, 1H), N HN 8.01 (t, 1H), 7.87 (d, 1H), 6.91 (d, 1H), 6.48 (d, / \ 1H), 6.42 (s, 1H), 4.29-4.26 (m, 4H), 3.68 (d, 2H), 17/18 N 10, 0 2.50 (s, 3H), 1.85 (t, 2H), 1.51-1.49 (m, 3H), 1.35-1.25 (m, 12H), 0.99-0.94 (m, 5H), 0.90-0.64 (m, ) = 9H). MS: 516.3 (M+1).
HO
1H-NMR (400 MHz, DMSO-d6) 6: 12.17 (s, 1H), o (3h-1\-IN 7.53 (t, 1H), 6.91 (d, 1H), 6.49 (d, 1H), 6.42 (s, 1H), 4.28 (t, 2H), 3.67 (d, 2H), 3.12 (d, 2H), 2.49 17/19 / \
0 (s, 3H), 2.12 (d, 2H), 1.85 (t, 2H), 1.52-1.50 (m, 3H), 1.35-1.24 (m, 12H), 1.00-0.87 (m, 13H), 0.72-0.65 (m, 2H). MS: 549.1 (M+1).
0) =
# Structure Analytical data o 1H-NMR (400 MHz, DMSO-d6) 6: 7.66 (t, 1H), 7.54 -----)-T-IN (br s, 1H), 6.89 (d, 1H), 6.82 (s, 1H), 6.48 (d, 1H), / \ 6.37 (s, 1H), 4.27 (t, 2H), 3.65 (d, 2H), 3.11 (d, &
0 1H), 2.46 (s, 3H), 1.97 (s, 2H), 1.84 (t, 2H), 1.51-= 1.49 (m, 3H), 1.34-1.26 (m, 12H), 0.99-0.88 (m, 13H), 0.70-0.62 (m, 2H). MS: 548.3 (M+1).
o ,f o 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 (d, 1H), 6.08 (s, 1H), 6.00 (d, 1H), 4.64-4.60 (m, HN 1H), 4.34 (t, 2H), 3.65 (d, 2H), 3.54-3.48 (m, 2H), 17/21 / \ 3.14-3.09 (m, 2H), 2.59 (s, 3H), 1.90 (t, 2H), 1.59-1.53 (m, 3H), 1.45-1.34 (m, 12H), 1.04-1.00 (m, 5H), 0.87-0.84 (m, 2H), 0.73-0.62 (m, 2H). MS:
&
0 = 503.4 (M+1).
HO..,_, 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 o (d, 1H), 6.05 (s, 1H), 5.89 (d, 1H), 4.85-4.84 (m, HN 1H), 4.62-4.58 (m, 1H), 4.35-4.29 (m, 3H), 3.65 (d, 17/22 / \ 2H), 2.96-2.89 (m, 1H), 2.58-2.50 (m, 4H), 1.90 (t, N *
0 2H), 1.57 (m, 6H), 1.42-1.25 (m, 12H), 1.03-1.00 0) = (m, 5H), 0.88-0.84 (m, 2H), 0.72-0.66 (m, 2H).
MS: 519.3 (M+1).
HO
>____\ 0 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 F3c HN (d, 1H), 6.13 (t, 1H), 6.08 (s, 1H), 4.34 (t, 2H), / \ 4.14-4.10 (m, 1H), 3.75-3.63 (m, 4H), 2.58 (s, 3H), 17/23 N *
1.90 (t, 2H), 1.59-1.54 (m, 3H), 1.45-1.35 (m, 0 ) = 12H), 1.04-0.99 (m, 5H), 0.87-0.84 (m, 2H), 0.72-0.65 (m, 2H). MS: 547.3 (M+1).
H
0,1\10 1H-NMR (400 MHz, CDCI3) 6: 7.96 (s, 1H), 6.95 's¨( 0 HN (d, 1H), 6.45 (d, 1H), 6.41 (d, 1H), 6.14 (d, 1H), 6.11 (s, 1H), 4.34 (t, 2H), 3.64 (d, 2H), 2.58 (s, 17/24 1 \ 110, 3H), 1.90 (t, 2H), 1.57 (br s, 3H), 1.49-1.34 (m, N
0 12H), 1.04-0.99 (m, 5H), 0.87-0.85 (m, 2H), 0.72-CI) 0.65 (m, 2H). MS: 550.2 (M+1).
=
o, Ns, ¨I
`----1 0 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 (d, 1H), 6.08 (s, 1H), 6.02 (d, 1H), 4.65-4.58 (m, FIN 1H), 4.34 (t, 2H), 4.18-4.13 (m, 2H), 3.64 (d, 2H), 17/25 / \3.22-3.17 (m, 2H), 2.57 (s, 3H), 1.91 (t, 2H), 1.57 N
0 (br s, 3H), 1.37-1.34 (m, 12H), 1.03-1.00 (m, 5H), 0.88-0.85 (m, 2H), 0.72-0.64 (m, 2H). MS: 523.2 & 11 (M+1).
# Structure Analytical data o 1H-NMR (400 MHz, DMSO-d6) 5: 11.45 (s, 1H), o- ---HN o 7.59 (br s, 1H), 6.90 (d, 1H), 6.48 (d, 1H), 6.35 (s, ---TIN 1H), 4.28 (t, 2H), 3.66 (d, 2H), 3.37 (s, 2H), 3.17-17/26 /\ 3.14 (m, 3H), 2.46(s, 2H), 1.85 (t, 2H), 1.51-1.49 0 (m, 3H), 1.34-1.25 (m, 12H), 1.10 (s, 6H), 0.98-0.95 (m, 5H), 0.88-0.86 (m, 2H), 0.68-0.62 (m, 0) = 2H). MS: 612.3 (M+1).
1H-NMR (400 MHz, DMSO-d6) 5: 7.41 (br s, 1H), HN HN 6.91 (d, 1H), 6.49 (d, 1H), 6.45 (s, 1H), 4.28 (t, 2H), 3.67 (d, 2H, J = 6.8 Hz), 3.09 (d, 2H, J = 6.4 =NCI /\ Hz), 2.49 (s, 3H), 2.01-1.84 (m, 4H),1.52-1.49 (m, 17/27 N *
0 3H), 1.35-1.23 (m, 12H), 1.00-0.94 (m, 11H), 0.89-CIA
0) = 0.87 (m, 2H), 0.70-0.65 (m, 2H). MS: 506.2 [(M¨
+.
o 1H-NMR (400 MHz, DMSO-d6) 5: 7.77 (t, 1H), 7.66 HN HN (s, 1H), 6.90 (d, 1H, J = 2.0 Hz), 6.49 (d, 1H, J =
---- / \ 2.0 Hz), 6.37 (s, 1H), 4.28 (t, 2H), 3.66 (d, 2H, J =
0 *
0 6.8 Hz), 3.29 (d, 2H), 2.49 (s, 3H), 1.85 (t, 2H), CI) = 1.76 (s, 3H), 1.52-1.50 (m, 3H), 1.35-1.22 (m, 18H), 0.99-0.87 (m, 7H), 0.71-0.65 (m, 2H). MS:
548.4 (M+1).
o HO---( 1H-NMR (400 MHz, DMSO-d6) 5: 7.68-7.63(m, NH 2H), 6.91 (d, 1H, J = 2.4 Hz), 6.49 (d, 1H, J = 2.0 0 Hz), 6.39 (s, 1H), 4.28 (t, 2H), 3.68 (d, 2H, J = 6.8 7)1\-IN Hz), 3.32 (d, 2H, J = 6.0 Hz), 2.49 (s, 3H), 2.40 (t, 17/29 2H), 2.27 (t, 2H), 1.85 (t, 2H), 1.52-1.50 (m, 3H), / \
N IP1.34-1.23 (m, 12H), 1.21 (s, 6H), 0.99-0.97 (m, o 5H), 0.89-0.87 (m, 2H), 0.71-0.65 (m, 2H). MS:
0) = 606.4 (M+1).
HO¨' r-NH 1H-NMR (400 MHz, CDCI3) 5: 7.48 (s, 2H), 6.97 o (d, 1H, J = 2.0 Hz), 6.54(t, 1H), 6.43 (d, 1H,J =
V)-7-1N 2.4 Hz), 6.13 (s, 1H), 4.33 (t, 2H), 3.97 (s, 2H), / \
17/30 N lip 0 3.63 (d, 2H, J = 7.6 Hz), 3.45 (d, 2H, J =
6.8 Hz), 2.58 (s, 3H), 1.90 (t, 2H), 1.58 (br s, 3H), 1.49-0) if 1.28 (m, 18H), 1.04-1.00 (m, 5H), 0.86-0.84 (m, 2H), 0.73-0.65 (m, 2H).
HO 1H-NMR (400 MHz, CDCI3) 5: 7.32 (s, 1H), 6.97 \---)r-NH (d, 1H, J = 1.6 Hz), 6.43 (d, 1H, J = 2.0 Hz), 6.40 O
o (t, 1H), 6.12 (s, 1H), 4.34 (t, 2H), 3.88 (br s, 2H), Vrl\-1N 3.64 (d, 2H, J = 7.2 Hz), 3.42 (d, 2H, J =
6.4 Hz), 17/31 / \ 2.58 (s, 3H), 2.37 (br s, 2H), 1.90 (t, 2H), 1.57-0 1.54 (m, 3H), 1.46-1.38 (m, 18H), 1.05-1.00 (m, 0)5H), 0.87-0.84 (m, 2H), 0.73-0.68 (m, 2H). MS:
= 578.3 (M+1).
# Structure Analytical data 0S-NH 11-1-NMR (400 MHz, DMSO-d6) 6: 7.68 (t, 1H), 7.09 7ri-IN (s, 1H), 6.91 (d, 1H, J = 1.6 Hz), 6.49(d, 1H, J =
1.6 Hz), 6.38 (s, 1H), 4.28 (t, 2H), 3.68 (d, 2H, J =
o /\ 7.2 Hz), 3.62 (t, 2H), 3.25 (t, 4H), 3.17 (s, 3H), 17/32 , N *
0 2.50 (s, 3H), 1.85 (t, 2H), 1.51-1.49 (m,3H), 1.35 (s, 9H), 1.31-1.28 (m, 9H), 0.99-0.87 (m, 7H), 0) 1 0.71-0.64 (m, 2H). MS: 628.3 (M+1).
9 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H,J =
2.0 O r Hz), 6.43 (d, 1H,J = 2.0 Hz), 6.33 (t, 1H), 6.13 (s, 1H), 5.34 (br s,1H), 4.33 (t, 2H), 3.64 (d, 2H, J =
)-7-IN
7.2 Hz), 3.48 (d, 2H,J = 6.4 Hz), 2.58 (s, 3H), / \
N 110 2.47-2.42 (m, 1H), 1.90 (m, 2H), 1.58-1.54 (m, 3H), 1.46-1.33 (m, 18H), 1.21-1.17 (m, 2H), 1.04-0.94 (m, 7H), 0.86-0.84 (m, 2H), 0.73-0.65 (m, d = 2H). MS: 610.2 (M+1).
i-OH
r 0 1H-NMR (400 MHz, CDCI3) 6: 6.95 (d, 1H), 6.66 ot\NH (br t, 1H), 6.42 (d, 1H), 6.21 (m, 1H), 6.08 (s, 1H), HN 4.33 (m, 2H), 3.87-3.82 (m, 2H), 3.68-3.56 (m, o 17/34 / \ 8H), 3.46-3.44 (m, 2H), 2.56 (s, 3H), 1.99-1.95 (m, N *
0 2H), 1.90 (t, 2H), 1.70-1.57 (m, 7H), 1.43-1.32 (m, 12H), 1.03-1.00 (m, 5H), 0.87-0.84 (m, 2H), 0.71-O)1 0.65 (m, 2H). MS: 634.3 (M+1).
1H-NMR (400 MHz, CDCI3) 6: 8.31-8.25 (m, 1H), 0 0 NH 7.87 (s, 1H), 6.97 (d, 1H, J = 2.0 Hz), 6.44 (d, 1H, 0 J = 2.0 Hz) ,6.29 (t, J = 6.6 Hz, 1H), 6.11 (s, 1H), o----s Hz), 3.35 (d, 2H, J = 6.4 Hz), 3.06 (dd, J = 4.0, J =
17/35 / \
N *16.0 Hz, 1H), 2.79 (dd, J = 6.0, J = 16.0 Hz, 1H), o)2.58 (s, 3H), 1.85 (t, 2H), 1.59-1.54 (m, 3H), 1.47-111 1.38 (m, 18H), 1.05-1.00 (m, 5H), 0.88-0.84 (m, 2H), 0.74-0.69 (m, 2H). MS: 663.1 (M+1).
OH 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 oi----\ o HN (d, 1H), 6.30 (t, 1H), 6.18 (s, 1H), 6.09 (s, 1H), 4.65 (d, 2H), 4.42 (d, 2H), 4.34 (t, 2H), 3.82 (d, /\
17/36 N 2H), 3.64 (d, 2H), 2.57 (s, 3H), 1.90 (t, 2H), 1.57 lp 0 (s, 3H), 1.38-1.34 (m, 12H), 1.04-0.99 (m, 5H), (m+1).
"311 0 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 s\_...r FIN (d, 1H), 6.08-6.05 (m, 2H), 4.33 (t, 2H), 3.64 (d, / \ 2H), 3.36 (d, 2H), 3.02 (t, 3H), 2.58 (s, 3H), 2.44 17/37 N *
(d, 2H), 1.98-1.89 (m, 4H), 1.84-1.57 (m, 4H), 1.43-1.35 (m, 12H), 1.04-0.99 (m, 5H), 0.87-0.84 (m, 2H), 0.72-0.64 (m, 2H). MS: 565.3 (M+1).
0) 11 # Structure Analytical data OH 1H-NMR (400 MHz, CDCI3) 6: 6.96 (d, 1H), 6.42 o,s0L¨.
(d, 1H), 6.19 (t, 1H), 6.11 (s, 1H), 4.34 (t, 2H), 3.64 (d, 2H), 3.41 (d, 2H), 2.98-2.83 (m, 4H), 2.58 /\
17/38 N (s, 3H), 2.25 (td, 2H), 1.90 (t, 2H), 1.77-1.74 (m, *
0 2H), 1.59-1.54 (m, 3H), 1.44-1.38 (m, 12H), 1.04-0.99 (m, 5H), 0.87-0.84 (m, 2H), 0.72-0.66 (m, ) = 2H). MS: 581.3 (M+1).
002_\HN 0 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 (d, 1H), 6.08 (s, 1H), 4.33 (t, 2H), 3.85-3.77 (m, / \ 4H), 3.63 (d, 2H), 3.54 (s, 2H), 3.26 (s, 3H), 2.39 17/39 N lip, 0 (s, 3H), 1.90 (m, 2H), 1.67-1.57 (m, 7H), 1.38-1.34 (m, 12H), 1.04-1.00 (m, 5H), 0.86-0.84 (m, 2H), 0.72-0.65 (m, 2H). MS: 563.3 (M+1).
0) =
HO
cO;0 0 1H-NMR (400 MHz, DMSO-d6) 6: 12.49 (br s, 1H), N 7.46 (t, 1H), 6.90 (d, 1H), 6.48 (d, 1H), 6.36 (s, 17/40 / \
0 1H), 4.28 (t, 2H), 3.74 (dd, 2H), 3.66 (d, 2H), 3.36-N
3.27 (m, 4H), 2.47 (s, 3H), 1.86-1.84 (m, 4H), 1.51-1.45 (m, 5H), 1.35-1.23 (m, 12H), 1.00-0.87 O)1(m, 7H), 0.71-0.64 (m, 2H).
orYO 1H-NMR (400 MHz, DMSO-d6) 6: 7.28-7.24 (m, o 2H), 7.03 (br s, 1H), 6.90 (d, 1H), 6.48 (d, 1H), i\-IN
6.34 (s, 1H), 4.28 (m, 2H), 3.70-3.65 (m, 4H), \
N
0 3.32-3.30 (m, 4H), 2.48 (s, 3H), 1.93-1.84 (m, 4H), *
1.51-1.42 (m, 5H), 1.35-1.24 (m, 12H), 1.00-0.85 (m, 7H), 0.71-0.63 (m, 2H). MS: 576.1 (M+1).
CI) =
oq1H-NMR (300 MHz, CDCI3) 6: 7.22 (d, J = 7.8 Hz, o 1H), 7.01 (s, 1H), 6.23 (s, 1H), 6.19 (d, J = 5.4 Hz, HN
1H), 5.26-5.20 (m, 1H), 4.99 (t, J = 5.1 Hz, 2H), / \ 4.58 (t, J = 4.8 Hz, 2H), 3.76 (d, J = 5.4 Hz, 2H), 17/42 N lip 2.96 (d, J = 15.9 Hz, 2H), 2.60 (s, 3H), 1.57-1.51 0) F (m, 3H), 1.37--1.25 (m, 19H), 0.98-0.96 (m, 4H), 0.64-0.58 (m, 2H). MS: 483.4 (M+1).
o--\ 0 1H-NMR (400 MHz, DMSO-d6) 6: 7.78 (t, 1H), 7.35 HN (t, 1H), 7.15 (d, 2H), 6.47 (s, 1H), 4.60 (dd, 2H), / \ 4.33 (t, 2H), 3.75 (d, 2H), 3.43 (t, 2H), 3.14-3.06 17/43 N * (n, 1H), 1.52 (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.21 0) (m, 21H), 0.94-0.83 (m, 3H), 0.67-0.60 (m, 2H).
MS: 479.4 (M+1).
o 1H-NMR (400 MHz, DMSO-d6) 6: 7.74 (t, 1H), 7.36 N (s, 1H), 7.15 (d, 2H), 6.51 (s, 1H), 4.49 (t, 1H), / \ 4.40 (d, 2H), 4.30 (d, 2H), 3.75 (d, 2H), 3.55 (dd, N * 2H), 3.46 (d, 2H), 2.52 (s, 3H), 1.80 (t, 2H), 1.45 0) (d, 3H), 1.31-1.19 (m, 21H), 0.95-0.90 (m, 3H), 0.67-0.59 (m, 2H). MS: 523.4 (M+1).
# Structure Analytical data o 1H-NMR (400 MHz, DMSO-d6) 6: 7.35 (t, 1H), 7.15 (d, 2H), 6.28 (s, 1H), 4.76 (t, 1H), 4.27-4.02 (m, Ho/N / \ 3H), 3.79 (d, 2H), 3.60-3.57 (m, 1H), 3.34 (in 17/45 N . solvent signal, 1H), 2.53 (s, 3H), 1.46-1.43 (m, d 3H), 1.30-1.21 (m, 21H), 0.94-0.85 (m, 3H), 0.68-0.60 (m, 2H). MS: 465.1 (M+1).
o oiY 1H-NMR (400 MHz, DMSO-d6) 5: 8.16 (s, 1H), HN 7.49 (d, 1H), 7.36 (m, 2H), 7.15 (d, 1H), 4.66 (d, o / \ 2H), 4.54 (d, 2H), 3.76 (d, 2H), 3.57 (s, 3H), 3.14 N * (s, 2H), 2.50 (s, 3H), 1.45 (d, 3H), 1.31-1.13 (m, 21H), 0.95-0.84 (m, 3H), 0.68-0.60 (m, 2H). MS:
d 537.4 (M+1).
037\ o 1H-NMR (400 MHz, DMSO-d6) 5: 7.81 (t, 1H), 7.20 HN (t, 1H), 7.15 (s, 1H), 6.98 (s, 1H), 6.53 (s, 1H), IP
0 / \
\ ' 4.41 (d, 2H), 4.27 (d, 2H), 3.76 (d, 2H), 3.48 (s, 17/47 N * 2H), 3.41 (d, 2H), 3.32 (s, 3H), 2.52 (s, 3H), 1.46 d (br d, 3H), 1.40(s, 3H), 1.33-1.24(m, 12H), 0.96-0.61 (m, 9H). MS: 521.3 (M+1).
, oOH 1H-NMR (500 MHz, CDCI3) 5: 7.26 (d, J =
1.5 Hz, \....../ FIN 1H), 7.01 (d, J = 1.0 Hz, 1H), 6.22 (s 2H), 4.08 (br / \ s, 1H), 3.83-3.74 (m, 4H), 3.71 (d, J =
7.5 Hz, 2H), 17/48 N *
N--- 3.66 (s, 3H), 3.45 (d, J = 6.0Hz, 2H), 2.61 (s, 3H), 1.82-1.80 (m, 1H),1.66-1.53 (m, 15H), 1.41-1.36 d a MS: 564.3 (M+1).
(m, 9H), 1.03-1.01 (m, 3H), 0.70-0.64 (m, 2H).
HO 1H-NMR (500 MHz, CDCI3) 6: 7.27 (d, J =
1.5 Hz, o -IN 1H), 7.03 (d, J = 1.5 Hz, 1H), 6.40 (t, J
= 6.5 Hz, ----I\
1H), 6.20 (s, 1H), 3.70 (d, J = 7.0 Hz, 2H), 3.67 (s, 17/49 / \ 3H), 3.66 (d, J = 6.5 Hz, 2H), 2.60 (s, 3H), 1.57-d N * N ...... 1.54 (m, 12H), 1.38 (s, 9H), 1.31 (s, 6H), 1.03-1.01 (m, 3H), 0.71-0.65 (m, 2H). MS: 550.4 (M+1).
_v o 4 1H-NMR (400 MHz, DMSO-d6) 5: 12.20 (s, 1H), HOOC N 8.05 (s, 1H), 6.90 (d, 1H), 6.47 (d, 1H), 6.40 (s, H I \ * 0 1H), 4.27-4.29 (t, 2H), 3.66-3.67 (d, 2H), 2.49-2.51 N
d (m, 3H), 1.84-1.87(t, 2H), 1.50-1.52 (t, 3H), 1.25-1.35 (m, 14H), 0.96-1.03 (m, 7H) ,0.66-0.69 (d, 2H), 0.64 (d, 2H). MS: 519.2 (M+1).
o 4 1H-NMR (400 MHz, DMSO-d6) 6:12.32 (s, 1H), HOOC 7.40-7.43 (t, 1H), 6.90 (d, 1H), 6.48 (d, 1H), 6.35 2cN
H I \ * 0 (s, 1H), 4.27-4.29 (t, 2H), 3.65-3.67 (d, 2H), 3.46-17/51 N 3.47 (d, 2H), 2.48 (s, 3H), 1.83-1.86 (t, 2H) , 1.49-C) 1.51 (m, 3H), 1.25-1.35 (m, 12H) , 0.93-1.00 (m, 7H), 0.87-0.89 (m, 4H), 0.66-0.69 (m, 2H). MS:
533.3 (M+1)+.
# Structure Analytical data o 4 1H-NMR (400 MHz, DMSO-d6) 6:12.66 (s, 1H), 6.90-6.90 (d, 1H), 6.49 (d, 1H), 6.09 (s, 1H), 3.96-4.42 (m, 6H), 3.67-3.69 (d, 2H), 3.38 (s, 1H), 2.45 17/52 HOOC 4N I \ = 0 N
d (s, 3H), 1.83-1.86 (t, 2H), 1.50-1.51 (m, 3H) , 1.25-1.34 (m, 12H), 0.98-1.02 (m, 5H), 0.87 (m, 2H), 0.65-0.68 (m, 2H). MS: 519.1 (M+1).
o 4 11-1-NMR (400 MHz, DMSO-d6) 6: 12.26 (s, 1H), 6.91 (d, 1H), 6.50 (d, 1H), 5.95 (s, 1H), 4.27 (t, CN 1 \ .
0 2H 4.09-4.11 m 2H 3.68 d 2H 2.95 m 2H
), ( , ), ( , ), ( , ), 17/53 HOOC N 2.46-2.51 (m, 1H), 2.24 (s, 3H), 1.81-1.86 (m, 4H), d 1.23-1.52 (m, 17H), 0.96-1.05 (m, 5H), 0.85-0.87 (m, 2H), 0.65-0.73 (m, 2H). MS: 547.3 (M+1)+.
o 4 1H-NMR (400 MHz, DMSO-d6) 6:12.42 (s, 1H), 6.91 (d, 1H), 6.49 (d, 1H), 5.94 (s, 1H), 4.27 (t, N I \ . 0 2H), 3.84 (m, 2H), 3.67 (d, 2H), 3.13 (s, 2H), 2.24 Hooc0 d 17/54 N (s, 3H), 1.92 (d, 2H), 1.84 (t, 2H), 1.50-1.52 (m, 3H), 1.23-1.34 (m, 14H), 1.16 (m, 3H), 0.96-1.01 (m, 5H), 0.86-0.88 (m, 2H), 0.68-0.70 (m, 2H).
MS: 561.4 (M+1)+.
HOOCv:\ o 1H-NMR (400 MHz, DMSO-d6) 6:12.15 (s, 1H), 4 7.76 (d, 1H), 6.91 (d, 1H), 6.49 (d, 1H), 6.42 (s, N 1H), 4.47-4.53 (m, 1H), 4.28 (t, 2H), 3.67 (d, 2H), H I \ ill o 2.88-2.92 (d, 1H), 2.47 (s, 3H), 2.24-2.40 (m, 4H), d 1.84-1.87 (m, 2H), 1.49-1.51 (m, 3H), 1.24-1.35 (m, 12H), 0.94-0.98 (m, 5H), 0.87-0.89 (m, 2H), 0.62-0.68 (m, 2H). MS: 533.3 (M+1)+.
HOOC o 4 1H-NMR (400 MHz, DMSO-d6) 6:12.07 (s, 1H), 7.75 (d, 1H), 6.91 (d, 1H), 6.49 (d, 1H), 6.43 (s, N
H I \ . 0 1H), 4.27-4.31 (m, 3H), 3.68 (d, 2H), 2.71 (t, 1H), 17/56 N 2.48 (s, 3H), 2.38-2.41 (m, 2H), 2.34-2.37 (m, 2H), d 2.16-2.19 (m, 2H), 1.48-1.50 (m, 3H), 1.23-1.35 (m, 12H), 0.93-0.98 (m, 5H), 0.87-0.90 (m, 2H), 0.65-0.68 (m, 2H). MS: 533.3 (M+1)+.
Hooc 1H-NMR (400 MHz, DMSO-d6) 6: 12.06 (s, 1H), 0, o 4 7.28 (d, 1H), 6.90 (d, 1H), 6.47 (d, 1H), 6.38 (s, 'N 1H), 4.28 (t, 2H), 3.66 (d, 3H), 2.48 (s, 3H), 2.09-H I \ 4I 0 2.14 (m, 1H), 1.90-1.94(m, 2H), 1.84-1.86 (m, d 4H), 1.49-1.51 (m, 3H), 1.24-1.39 (m, 16H), 0.97-1.00 (m, 5H), 0.91-0.94 (m, 2H), 0.62-0.70 (m, 2H). MS: 561 (M+1)+.
HOOC
U 0 1 1H-NMR (400 MHz, CD30D) 5: 6.98 (s, 1H), 6.50 (d, 1H), 6.32 (s, 1H), 4.33 (t, 2H), 3.92 (m, 1H), N
H I \ * 0 3.73 (d, 2H), 2.58 (m, 1H), 2.52 (s, 3H), 2.09 (m, 17/58 N 2H), 1.91 (m, 2H), 1.56-1.77 (m, 9H), 1.30-1.42 d (m, 12H), 1.01-1.07 (m, 5H), 0.88-0.90 (m, 2H), 0.67-0.76 (m, 2H). MS: 561 (M+1)+.
# Structure Analytical data , o 4 1H-NMR (400 MHz, CDCI3) 6: 6.97 (s, 1H), 6.43 (d, 1H), 6.06 (s, 1H), 5.80 (s, 1H), 4.33 (m, 2H), N 3.63 (d 2H) 3.25 (m, 2H), 2.59 (s, 3H), 2.25-2.32 HOOC H I \ * 0 "
(m, 1H), 2.01-2.06 (m, 2H), 1.89-1.91 (m, 4H), N
C)1.52-1.56 (m, 4H), 1.42-1.48 (m, 2H), 1.25-1.38 (m, 12H),1.00-1.07 (m, 7H), 0.84-0.86 (m, 2H), 0.67-0.73 (m, 2H). MS: 575.5 (M+1)+.
HOOC ,..N 1H-NMR (400 MHz, DMSO-d6) 6: 12.22 (s, 1H), N 7.42 (m, 1H), 7.19 (s, 1H), 7.15 (s, 1H), 6.97 (S, H I \ = 1H), 6.49 (s, 1H), 3.76 (d, 2H), 3.36 (s, 2H), 2.50 17/60 N (s, 3H), 1.47 (d, 3H), 1.40 (s, 3H), 1.30-1.23 (m, d 12H), 1.08 (s, 6H), 0.93 (m, 3H), 0.84 (m, 2H), 0.76 (m, 2H), 0.64 (m, 2H). MS: 507.3 (M+1)+.
0 4 1H-NMR (400 MHz, DMSO-d6) 5: 12.48 (s, 1H), HOOC 7.56 (m, 1H), 7.19 (s, 1H), 7.15 (s, 1H), 6.97 (s, 0 N I \ * 1H), 6.49 (s, 1H), 3.73-3.77 (m, 4H), 3.27-3.32 (m, 4H), 2.50 (s, 3H), 1.85 (d, 2H), 1.45-1.50 (m, 5H), d 1.40 (s, 3H), 1.30-1.23 (m, 12H), 0.95 (m, 3H), 0.84 (m, 2H) 0.76 (m, 2H), 0.64 (m, 2H). MS: 549 (M+1)+
0 0 4 1H-NMR (400 MHz, DMSO-d6) 5: 7.34 (m, 1H), 7.29 (s, 1H), 7.19 (s, 1H), 7.14 (s, 1H), 7.04 (s, I N I \ = 1H), 6.97 (s, 1H), 6.47 (s, 1H), 3.76 (d, 2H), 3.65 d (m, 2H), 3.34-3.28 (m, 4H), 2.51 (s, 3H), 1.91 (d, 2H), 1.45-1.50 (m, 4H), 1.40 (s, 3H), 1.30-1.20 (m, 12H), 0.92 (m, 3H), 0.83 (m, 2H), 0.76 (m, 2H), 0.64 (m, 2H). MS: 548.3 (M+1)+
0 4 1H-NMR (400 MHz, CDCI3) 5: 7.25 (s, 1H), 7.13 (m, 1H), 7.00 (m, 1H), 6.15 (s, 1H), 5.86 (m, 1H), I:01 I \ Ilk 3.98 (m, 2H), 3.71 (d, 2H), 3.38 (m, 2H), 3.29 (m, 17/63 N 2H), 2.62 (s, 3H), 1.85 (m, 1H), 1.68 (m, 2H), 1.53 d (m, 3H), 1.40 (s, 3H), 1.38-1.33 (m, 14H), 1.00 (m, 3H), 0.87 (m, 2H), 0.75 (m, 2H), 0.64 (m, 2H). MS:
505.4 (M+1)+.
OH 0 4 1H-NMR (400 MHz, DMSO-d6) 5: 7.54 (m, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 6.98 (s, 1H), 6.53 (s, N
cca-NH I \ * 1H), 4.78 (s, 2H), 3.77 (d, 2H), 3.59 (m, 4H), 3.22 d 17/64 N (d, 2H), 2.52 (s, 3H), 1.60-1.45 (m, 4H), 1.40-1.34 (m, 5H), 1.30-1.23 (m, 12H), 0.93 (m, 3H), 0.83 (m, 2H), 0.76 (m, 2H), 0.64 (m, 2H). MS: 521.3 (M+1)+.
0 4 1H-NMR (400 MHz, CDCI3) 5: 7.25 (s, 1H), 7.12 ca 0 (s, 1H), 7.00 (s, 1H), 6.15 (s, 1H), 5.89 (d, 1H), N
H 4.69 (m, 1H), 4.00-3.90 (m, 2H), 3.82 (m, 1H), I \ .
17/65 N 3.75-3.70 (m, 3H), 2.61 (s, 3H), 2.31 (m, 1H), 1.88 d (m, 1H), 1.56 (m, 3H), 1.42 (m, 3H), 1.41-1.33 (m, 12H), 1.00 (m, 3H), 0.88 (m, 2H), 0.75 (m, 2H), 0.65 (m, 2H). MS: 477.4 (M+1)+.
# Structure Analytical data 0N 4 1H-NMR (400 MHz, CDCI3) 6: 7.25 (s, 1H), 7.12 .µ 0 (s, 1H), 7.00 (s, 1H), 6.15 (s, 1H), 5.89 (d, 1H), ' H I \ Mk 4.00-3.91 (m, 2H), 3.83 (m, 1H), 3.75-3.71 (m, 17/66 N 3H), 2.61 (s, 3H), 2.31 (m, 1H), 1.88 (m, 1H), 1.53 d (m, 3H), 1.42 (m, 3H), 1.41-1.33 (m, 12H), 1.00 (m, 3H), 0.87 (m, 2H), 0.75 (m, 2H), 0.65 (m, 2H).
MS: 477.2 (M+1)+.
O H 0 4 1H-NMR (400 MHz, CDCI3) 5: 7.26 (s, 1H), 7.13 Ni,' N
S (m, 1H), 7.01 (s, 1H), 6.30 (m, 1H), 6.22 (s, 1H), O fr-1 1 \ . 3.71 (d, 2H), 3.47 (d, 2H), 3.02 (s, 3H), 2.61 (s, 17/67 N 3H), 1.54 (m, 3H), 1.43 (s, 9H), 1.39-1.26(m, ) 12H), 0.99 (m, 3H), 0.87 (m, 2H) 0.75 (m, 2H), 0.65 (m, 2H). MS: 556.3 (M+1)+.
N 1H-NMR (400 MHz, CDCI3) 6: 7.26 (m, 1H), 7.14 (m, 1H), 7.02 (m, 1H), 6.22 (m, 1H), 6.06 (m, 1H), H I \ . 3.71 (d, 2H), 3.43 (d, 2H), 3.21 (s, 3H), 2.61 (s, d 17/68 N 3H), 1.53 (m, 3H), 1.49 (s, 3H), 1.42-1.33 (m, 12H), 1.20 (s, 6H), 0.99 (m, 3H), 0.87 (m, 2H), 0.74 (m, 2H), 0.65 (m, 2H). MS: 493.5 (M+1)+.
n 0 , 1H-NMR (400 MHz, DMSO-d6) 6: 8.20 (d, 1H, J =
8.0 Hz), 7.93 -7.90 (m, 2 H), 7.58 (d 1H, J = 8.0 N\----N \ . 1 Hz), 6.91 (s, 1H), 3.95-3.85 (m, 5H), 3.51-3.50 (m, H I \ 2H), 3.38-3.34 (m, 2H), 2.55-2.50 (m, 3H), 1.72-17/69 N 0 1.62 (m, 2 H), 1.56 (m, 4 H), 1.55-1.45 (m, 7H), d c,3 1.23 (m,9 H), 0.95-0.86 (m, 3H), 0.67-0.64 (m, 2H). MS: 624.3 (M+H)+.
,N-N
N: ...k.,...õ o 4 1H-NMR (400 MHz, DMSO-d6) 6: 7.85 (m, 1H), N 7.19 (m, 1H), 7.14 (m, 1H), 6.96 (m, 1H), 6.43 (s, H N
H I \ iir 1H), 3.76 (d, 2H), 3.52 (m, 2H), 3.07 (m, 2H), 2.50 17/70 N (s, 3H), 1.46 (m, 2H), 1.39 (s, 3H), 1.29-1.22 (m, C) 12H), 0.96-0.91 (m, 3H), 0.85-0.81 (m, 2H), 0.77-0.75 (m, 2H), 0.65-0.62 (m, 2H). MS: 503.2 (M+1)+.
0 4 1H-NMR (400 MHz, DMSO-d6) 6: 8.27 (m, 1H), N
INIµ Y--NN 7.19 (s, 1H), 7.15 (s, 1H), 6.98 (s, 1H), 6.56 (s, l'N-NH H I \ 1, 1H), 4.61 (d, 2H), 3.79 (d, 2H), 2.53 (s, 3H), 1.46 17/71 N (m, 3H), 1.40 (s, 3H), 1.30-1.22 (m, 12H), 0.96-d 0.90 (m, 3H), 0.85-0.79 (m, 2H), 0.78-0.75 (m, 2H), 0.68-0.60 (m, 2H). MS: 489.2 (M+1)+.
Oa 0 0 y_ N
\ 1H-NMR (400 MHz, DMSO-d6) 5: 8.10 (d, 1H), 7.56 (s,1H), 7.49 (d, 1H), 7.43 (d, 1H), 7.35 (s, N
H I \ .. 1H), 6.72 (s, 1H), 6.03 (s, 1H), 3.84-3.94 (m, 5H), 17/72 N 3.36 (m, 2H), 2.53 (s, 3H), 1.67-1.70 (m, 8H), 1.53 C) NH
0 (m, 2H), 1.45 (m, 3H), 1.23 (m, 3H), 1.12 (s, 9H), 0.88 (m, 3H), 0.60 (m, 2H). MS: 574.3 (M+1)+.
# Structure Analytical data HOk_N
1H-NMR (400 MHz, DMSO-d6) 6: 11.93 (s, 1H), o o HN 7.61 (d, 1H), 7.18 (t, 1H), 7.14 (d, 1H), 6.97 (s, 1H), 6.47 (s, 1H), 3.76(d, 2H), 3.17-3.12 (m, 2H), 17/73 / \
N # 2.51 (s, 3H), 1.70-1.66 (m, 2H), 1.46 (d, 3H), 1.40 (s, 3H), 1.30-1.13 (m, 12H), 0.95-0.62 (m, 9H).
MS: 521.2 (M+1).
0) 11 k o 1H-NMR (400 MHz, DMSO-d6) 5: 7.61 (t, 1H), 7.18 HN (d, 1H), 7.15 (d, 1H), 6.97 (s, 1H), 6.86 (s, 1H), / \ 6.47 (s, 1H), 3.76 (d, 2H), 3.114-3.09 (m, 2H), 17/74 N . 2.51 (s, 3H), 1.67-1.63 (m, 2H), 1.46 (d, 3H), 1.40 (s, 3H), 1.30-1.21 (m, 12H), 1.09 (s, 6H), 0.95-0.62 (m, 9H). MS: 520.4 (M+1).
0) II
a0 y 1H-NMR (CDCI3, 300 MHz) 5: 7.99 (s, 1H), 7.76 0 NH (s, 2H), 6.28 (s, 1H), 6.10 (s, 1H), 5.68 (d, 1H, J =
N 8.0 Hz), 4.16 (m, 1H), 3.98 (m, 2H), 3.79 (d, 2H, J
H I \ .
N = 7.2 Hz), 3.53 (m, 2H), 2.62 (s, 3H), 1.98 (m, 2H), 1.58-1.52 (m, 5H), 1.49 (s, 18H), 1.40-1.33 NH
01, 3H), 1.00 (m, 3H), 0.64 (m, 2H). MS: 579.2 d o 1H-NMR (400 MHz, CDCI3) 6: 8.67 (d, 1H, J = 8.8 o HO Hz), 8.33 (d, 1H, J = 7.2 Hz), 7.90 (d, 1H, J = 8.8 KN
N
H 1 \ lit Hy Hz), 7.72-7.68 (m, 1H), 7.55-7.47 (m, 2H), 6.34 (s, 1H), 6.19 (t, 1H, J = 6.0 Hz), 4.62 (s, 1H), 3.68-17/76 3.63 (m, 1H), 3.42 (d, 2H, J = 6.0 Hz), 3.31-3.26 S=0 W 8 (m, 1H), 2.676 (s, 3H), 1.48 (br s, 3H), 1.28 (s, 6H), 1.26 (s, 3H), 1.21 (s, 9H), 0.94-0.86 (m, 3H), 0.52-0.47 (m, 2H). MS: 554.3 (M+1).
H
N-N
1\,1, jchN 0 V 1H-NMR (400 MHz, CDCI3) 5: 7.27 (m, 1H), 7.09 N (m, 1H), 6.98 (m, 1H), 6.29 (m, 1H), 6.15 (s, 1H), 17/77 H I \ . 3.76 (d, 2H, J = 7.6 Hz), 3.71 (d, 2H, J =
7.2 Hz), 2.64 (s, 3H), 1.55-1.52 (m, 9H), 1.48 (s, 3H), 1.41-N
d 1.24 (m, 12H), 1.00 (m, 3H), 0.86 (m, 2H), 0.74 (m, 2H), 0.66 (m, 2 H). MS: 531.4 (M+1)+.
o3 0 1H-NMR (400 MHz, CDCI3) 6: 7.26 (t, 1H), 7.13 (t, N 1H), 7.00 (t, 1H), 6.13 (s, 1H), 4.93 (br s, 1H), HO 4.61 (d, 2H), 4.47 (d, 2H), 3.91 (s, 2H), 3.82 (d, / \
CH
17/78 N 10, 2H), 3.71 (d, 2H), 3.12 (s, 3H), 2.38 (s, 3H), 1.58-1.53 (m, 3H), 1.42 (s, 3H), 1.36-1.25 (m, 12H), 1.01-0.98 (m, 3H), 0.86 (dd, 2H), 0.74 (dd, 2H), 0.68-0.60 (m, 2H). MS: 521.3 (M+1).
\ 1H-NMR (400 MHz, CDCI3) 5: 6.97 (d, 1H), 6.43 0 (d, 1H), 6.06 (s, 1H), 5.76 (t, 1H), 4.33 (t, 2H), HN 3.64 (d, 2H), 3.39 (q, 2H), 2.75-2.65 (m, 2H), 2.59 17/79 / \ (s, 3H), 2.56 (s, 3H), 1.90(t, 2H), 1.83-1.79(m, N * 2H), 1.57-1.51 (m, 7H), 1.45-1.33 (m, 12H), 1.03-O)1o 1.00 (m, 5H), 0.87-0.84 (m, 2H), 0.71-0.65 (m, 2H). MS: 567.3 [M+1]t # Structure Analytical data o--zI s 1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 n\r\¨\ 0 (d, 1H), 6.08 (s, 1H), 5.99 (t, 1H), 4.34 (t, 2H), µ-' HN 3.64 (d, 2H), 3.59-3.54 (m, 2H), 3.14 (t, 2H), 2.92 /\ (s, 3H), 2.58 (s, 3H), 2.19-2.12 (m, 2H), 1.90 (t, 0 2H), 1.57 (br s, 3H), 1.44-1.36 (m, 12H), 1.04-1.00 (m, 5H), 0.87-0.84 (m, 2H), 0.72-0.65 (m, 2H).
0) Ill MS: 555.3 [M+1r.
OH 1H-NMR (400 MHz, CDCI3) 6: 6.95 (d, 1H), 6.42 c;IsD____\ o (d, 1H), 6.13 (t, 1H), 6.08 (s, 1H), 4.34 (t, 2H), 0' HN 3.64 (d, 2H), 3.50 (dt, 2H), 3.41 (d, 2H), 2.86 (dd, / 2H), 2.58 (s, 3H), 2.14-1.99 (m, 4H), 1.90 (m, 2H), 17/81 N\ .
0 1.59-1.41 (m, 3H), 1.38-1.28 (m, 12H), 1.04-0.99 (m, 5H), 0.88-0.85 (m, 2H), 0.73-0.65 (m, 2H).
CI) I MS: 597.4 (M+1).
o 17/82 N N¨ MS: 495.3 (M+H)+.
d a 1H-NMR (400 MHz, DMSO-d6) 6: 8.23 (d, 1H, J =
HN 8.0 8.0 Hz), 7.96-7.71 (m, 3H), 7.57 (d, 1H, J = 8.0 H \
N Hz), 6.88 (s, 1H), 3.95-3.85 (m, 5H), 3.38-3.32 (m, I IF
0 2H), 2.55 (m, 3H), 1.72-1.68 (m, 2H), 1.56-1.45 d c3 (m, 7H), 1.24-1.21 (m, 3H), 1.08 (m, 6H), 0.93-0.88 (m, 3H), 0.79-0.75 (m, 3H), 0.68-0.59 (m, 2H). MS: 598.3 (M+H)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.06-8.04 (m, N 1µ1 \
1 1H), 7.89-7.88 (m, 2H), 7.57 (d, 1H, J =
8.0 Hz), H I \ . S=0 6.88 (s, 1H), 3.95-3.88 (m, 6H), 3.56-3.52 (m, 2H), 17/84 N 8 2.38-3.33 (m, 2H), 2.56 (m, 3H), 1.95-1.92 (m, C) cF, 4H), 1.72-1.69(m, 2H), 1.56-1.46 (m, 5H), 1.33 (m, 6H), 1.26-1.23 (m, 3H), 0.94-0.91 (m, 3H), 0.67-0.64 (m, 2H). MS: 610.3 (M+H)+.
1H-NMR (400 MHz, DMSO-d6) 6: 7.99 (d, 1H, J =
a 0 N 8.4 Hz), 7.90-7.88 (m, 2H), 7.56 (d, 1H, J
= 8.0 H \ .
N = Hz), 6.88 (s, 1H), 3.95-3.85 (m, 5H), 3.63-3.58 (m, 17/85 N 8 2H), 3.38-3.32 (m, 2H), 2.55 (m, 3H), 1.72-1.68 C) cF3 (m, 2H), 1.55-1.46 (m, 5H), 1.34-0.95 (m, 15H), 0.92-0.89 (m, 3H), 0.66-0.64 (m, 2H). MS: 612.3 HO 1H-NMR (300 MHz, CDCI3) 6: 6.99 (s, 1H), 6.89 1 N I \ II (s, 1H), 6.18 (s, 1H), 6.15 (m, 1H), 4.27 (s, 2H), 3.67 (d, J = 7.2 Hz, 2H), 3.39 (d, J = 5.7 Hz, 2H), N
d 2.60 (s, 3H), 1.59-1.53 (m, 3H), 1.36-1.33 (m, 18H), 1.25 (m, 8H), 1.01 (m, 3H), 0.67-0.66 (m, 2H). MS: 495.4 (M+1)+.
# Structure Analytical data 1H-NMR (400 MHz, CDCI3) 6: 0.55-0.64 (m, 2H), a , 0.83-0.89 (m, 2H), 1.02-1.10 (m, 2H), 1.26 (s, 9H), 1.35-1.44 (m, 2H), 1.53-1.61 (m, 2H), 1.75-1.84 HN
N
H .11.6 Hz, 2H), 3.85-3.88 (m, 2H), 3.98-4.01 (m, On, 3H), 1.97-2.00 (m, 2H), 2.64 (s, 3H), 3.53 (t, J
I \ * 0 F3c¨d2H), 4.12-4.21 (m, 1H), 4.74 (s, 1H), 5.65 (d, J =
7.6 Hz, 1H), 6.38 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H). MS: 652.2 [M+1].
a0 1H-NMR (400 MHz, DMSO-d6) 6: 8.10 (d, 1H), N HN¨' 7.56 (s,1H), 7.49 (d, 1H), 7.43 (d, 1H), 7.35 (s, H I \ * =-10 1H), 6.72 (s, 1H), 6.03 (s, 1H), 3.84-3.94 (m, 5H), 17/88 N ii 0 3.36 (m, 2H), 2.53 (s, 3H), 1.67-1.70 (m, 8H), 1.53 d OH (M, 2H), 1.45 (m, 3H), 1.23 (m, 3H), 1.12 (s, 9H), 0.88 (m, 3H), 0.60 (m, 2H). MS: 574.3 (M+1)4".
HN. ja 1H-NMR (400 MHz, DMSO-d6) 6: 8.13 (d, o FIN J=8.4Hz, 1H), 7.78 (s, 1H), 7.63 (d, J=8.4Hz, 1H), H II
0 N = 7.54 (m, 2H), 7.42 (m, 1H), 6.71 (s, 1H), 4.13 (m, I \ S0 17/89 N II 1H), 3.84 (m, 2H), 3.31 (m, 2H), 2.53 (s, 3H), 2.39 0 (m, 1H), 2.21 (m, 1H), 1.89 (d, 1H), 1.66 (m, 1H), d 1.55 (s, 9H), 1.45 (m, 3H) , 1.32-1.21 (m, 12H), 0.84 (m, 3H), 0.60 (m, 2H). MS: 585.3 (M+1) .
Fi2N 0 0 11-I-NMR (400 MHz, DMSO-d6) 6: 8.13 (d, J=
H I \ * C HN:< 8.4Hz, 1H), 7.76 (s, 1H), 7.53 (s, 1H), 7.43 (m, CXN
o 2H), 7.30 (s, 1H), 7.04 (s, 1H), 6.67 (s, 1H), 3.84 17/90 N 8 (m, 2H), 3.69 (m, 2H), 3.37-3.30 (m, 4H), 2.52 (s, C) 3H), 1.92 (m, 2H), 1.55-1.44 (m, 14H), 1.22-1.16 (m, 12H), 0.96-0.82 (m, 3H) , 0.62 (m, 2H). MS:
629.3 (M+1)+.
9µ
1H-NMR (400 MHz, DMSO-d6) 6: 8.29 (m, 1H), HN 8.15 (d, J=8.4Hz, 1H), 7.78 (s, 1H), 7.54 (s, 1H), N
H I \ = ,,c, 7.43 (m, 1H), 6.73 (s, 1H), 4.54-4.48 (m, 3H), 17/91 N 0 4.28-4.21 (m, 2H), 3.85 (m, 2H), 2.53 (s, 3H), 1.55 C) (s, 9H), 1.44 (m, 3H), 1.20-1.16 (m, 12H), 0.95-0.80 (m, 3H), 0.64 (m, 2H). MS: 592.3 (M+1)+.
s 0---zsa 1H-NMR (400 MHz, DMSO-d6) 6: 8.13 (d, o J=8.4Hz, 1H), 7.78 (s, 1H), 7.63 (m, 1H), 7.52 (s, N Hy 1H), 7.41 (m, 1H), 6.72 (s, 1H), 4.14 (m, 1H), 3.84 H I \ .0 s-n Tr-- (m, 2H), 3.31-3.22 (m, 1H), 3.13-3.08 (m, 2H), 17/92 N 0 d 2.53 (s, 3H), 2.11-2.00(m, 4H), 1.55 (s, 9H) , 1.45 (m, 3H) , 1.21-1.16 (m, 12H) , 0.95-0.88 (m, 3H) , 0.61 (m, 2H). MS: 620.3 (M+1)+.
# Structure Analytical data 0 j< 1H-NMR (400 MHz, DMSO-d6) 6: 8.12 (d, HN J=8.4Hz, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 7.44 (m, Hoy I \ * 4=0 1H), 6.23 (s, 1H), 4.39 (s, 1H), 3.86-3.78(m, 4H), 17/93 N 0 3.27 (m, 2H), 2.27 (s, 3H), 1.55 (s, 9H), 1.45-1.38 d (m, 7H), 1.22-1.17 (m, 12H), 1.14 (s, 3H), 0.93-0.82 (m, 3H), 0.64 (m, 2H). MS: 586.4 (M+1)+.
HNj< 1H¨NMR (400 MHz, CDCI3) 6: 8.17 (d, J=8.4Hz, HON I \ 11 =10 ii 1H), 7.57 (s, 1H), 7.22 (m, 1H), 6.24 (s, 1H), 4.70 (m, 1H), 4.55-4.48 (m, 3H), 4.12 (m, 2H), 3.77 (m, N
d 0 2H), 2.57 (s, 3H), 1.62 (s, 9H), 1.54 (m, 3H), 1.34-1.28 (m, 12H), 1.01-0.92 (m, 3H), 0.62 (m, 2H).
MS: 544.3 (M+1)+.
ao 1H-NMR (400 MHz, DMSO-d6) 6: 8.12 (d, N lit Hy J=8.8Hz, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 7.45 (m, I =_,.
1H), 6.27 (s, 1H), 4.32 (s, br, 1H), 3.95-3.80 (m, I \ S=0 17/95 N 8 4H), 3.29 (m, 2H), 2.87 (s, 3H), 2.26 (s, 3H), 1.78 d (m, 2H), 1.59-1.44(m, 14H), 1.22-1.012(m, 12H), 0.96-0.91 (m, 3H), 0.63 (m, 2H). MS: 586.4 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 8.07 (d, 1H, J = 8.8 QHz), 7.82 (d, 1H, J = 7.2 Hz), 7.10-7.05 (m, 2H), N sS 6.76 (t, 1H, J = 6.0 Hz), 6.43 (s, 1H), 5.60 (d, 1H, HjC¨I µ0 J = 7.6 Hz), 4.19-4.15 (m, 1H), 3.99-3.96 (m, 2H), 17/96 7---N N 3.55-3.50 (m, 4H), 3.01 a, 4H, J = 5.6 Hz), 2.63 d 0 (s, 3H), 2.00-1.97 (m, 2H), 1.67-1.63 (m, 4H), 1.51-1.48 (m, 4H), 1.38-1.26 (m, 6H), 0.99-0.95 (m, 3H), 0.60-0.56 (m, 2H). MS: 567.1 (M+1)+.
a 1H-NMR (400 MHz, DMSO-d6) 6: 8.23 (d, 1H, J =
o HN 8.0 Hz), 7.94-7.91 (m, 1H), 7.86 (s, 1H), 6.56 (d, N
H \ =, 1H, J = 8.0 Hz), 6.88 (s, 1H), 3.94-3.85 (m, 5H), 17/97 N 6 3.38-3.31 (m, 2H), 1.78 (m, 3H), 1.72-1.68 (m, d c,3 2H), 1.55-1.45 (m, 5H), 1.23-1.21 (m, 3H), 1.15 (m, 9H), 0.93-0.88 (m, 3H), 0.65-0.62 (m, 2H).
MS: 584.2 (M+1)+.
o 1H-NMR (400 MHz, DMSO-d6) 6: 8.13 (d, Fly J=8.4Hz, 1H), 7.74 (s, 1H), 7.67 (t, J=5.6Hz, 1H), H I= \ 11 s=o 7.53 (s, 1H), 7.42 (m, 1H), 6.65 (s, 1H), 3.84(m, d 8 2H), 3.19 (m, 2H), 2.53 (s, 3H), 1.55 (s, 9H), 1.44 (m, 3H), 1.24-1.16 (m, 12H), 1.07 (t, J= 6.8Hz, 3H), 0.97-0.82 (m, 3H), 0.63 (m, 2H). MS: 516.3 (M+1)+.
6,N o N
Hy 1H-NMR (400 MHz, DMSO-d6) 6: 8.12 (d, J=8.4Hz, 1H), 7.74 (s, 1H), 7.64 (m, 1H), 7.51 (s, H I \ * =0 1H), 7.40 (m, 1H), 6.63 (s, 1H), 3.83 (m, 2H), 2.75 17/99 N 0 (M, 1H), 2.72 (s, 3H), 1.54 (s, 9H), 1.44 (m, 3H), d 1.24-1.16 (m, 12H), 0.92-0.82 (m, 3H), 0.62 (m, 4H), 0.49 (m, 2H). MS: 528.3 (M+1)+.
# Structure Analytical data o , 1H-NMR (400 MHz, CDCI3) 6: 8.20 (d, J=8.8Hz, rN __,, ni 1H), 7.58 (s, 1H), 7.24 (m, 1H), 6.17 (s, 1H), 4.49 \ IP =() (s, br, 1H), 4.19 (m, 4H), 3.78 (m, 2H), 3.07 (m, 17/100 ' N
d 0 4H), 2.41 (s, 3H), 1.62 (s, 9H), 1.55 (m, 3H), 1.34-1.26 (m, 12H), 1.02-0.93 (m, 3H), 0.63 (m, 2H).
MS: 606.3 (M+1)+.
a CF3 1H-NMR (CDCI3, 500 MHz) 6: 8.05 (d, 1H), 7.56 0 NH (d, 1H), 7.22 (dd, 1H), 6.21 (s, 1H), 5.54 (d, 1H), N
H I \ . ,...c, 4.95 (t, 1H), 4.12-4.08 (m, 1H), 3.92 (d, 2H), 3.72-17/101 N 8 3.65 (m, 4H), 3.46 (dt, 2H), 2.56 (s, 3H), 1.94-1.90 d (m, 2H), 1.54 (s, 9H), 1.48-1.42 (m, 9H),1.31-1.23 (m, 4H), 0.94-0.90 (m, 3H), 0.57-0.52 (m, 2H).
MS: 598.2 (M+1).
a Fõ 1H NMR (CDCI3, 500 MHz) 6: 7.77 (d, 1H), 7.63 --..N--- (d, 1H), 7.27-7.25 (m, 1H), 6.26 (s, 1H), 5.60 (d, H
N \ 411 I = 1H), 4.20-4.16 (m, 1H), 4.02-3.97 (m, 3H), 3.92-17/102 N ii 3.88 (m, 1H), 3.78 (d, 2H), 3.52 (t, 2H), 2.82-2.76 C) (m, 2H), 2.63 (s, 3H), 2.13-2.11 (s, 1H), 1.98 (dd, 2H), 1.89-1.87 (d, 1H), 1.63-1.32 (m, 19H), 1.35-0.60 (m, 11H). MS: 652.2 (M+1).
0ON 0 1H-NMR (CDCI3, 400 MHz) 6: 7.97 (s, 1H), 7.72 (s, 1H), 7.56 (s, 1H), 6.25 (s, 1H), 5.65 (d, 1H, J =
N
H \ 8.0 Hz), 4.16-4.18 (m, 1H), 3.98 (d, 2H, J
= 11.2 I lio 17/103 N Hz), 3.74 (d, 2H, J = 6.8 Hz), 3.52 (t, 2H, J = 11.2 C) Hz), 2.63 (s, 6H), 1.98 (d, 2H, J = 11.6 Hz), 1.48-1.55 (m, 5H), 1.33-1.38 (m, 12H), 0.99 (br s, 3H), 0.59-0.66 (m, 2H). MS: 479.3 (M+1)+.
0 1H-NMR (CDCI3, 400 MHz) 6: 7.76 (d, 1H), 7.42 a 0 (d, 1H), 6.16 (s, 1H), 5.60 (d, 1H, J = 7.6 Hz), 4.61 N (t, 2H, J = 6.4 Hz), 4.14-4.17 (m, 1H), 3.96-3.99 H I \ lik 0 (m, 2H), 3.71 (d, 2H, J = 6.8 Hz), 3.53 (dd, 2H), d 17/104 N 2.86 (t, 2H, J = 6.4 Hz), 2.61 (s, 3H), 1.96-1.99 (m, 2H), 1.47-1.55 (m, 5H), 1.35-1.47 (m, 12H), 0.98-1.02 (m, 3H), 0.62-0.68 (m, 2H). MS: 507.3 (M+1)+.
HO 1H-NMR (CDCI3, 400 MHz) 6: 7.14 (d, 2H, J = 5.6 a 0 Hz), 6.11 (s, 1H), 5.59 (d, 1H, J = 8.0 Hz), 4.81 (d, N 1H, J = 3.2 Hz), 4.29-4.39 (m, 2H), 4.14-4.18 (m, H I \ . 0 1H), 3.97 (d, 2H, J = 11.2 Hz), 3.70 (d, 2H, J = 7.2 d 17/105 N Hz), 3.49-3.55 (m, 2H), 2.60 (s, 3H), 1.96-2.18 (m, 4H), 1.83 (d, 2H, J = 4.4 Hz), 1.37-1.58 (m, 17H), 1.03-1.05 (m, 3H), 0.67-0.70 (m, 2H). MS: 509.3 (M+1)+.
Q0 1H-NMR (DMSO-d6, 400 MHz) 6: 7.92 (d, 1H, J =
N HN 8.0 Hz), 7.57 (s, 1H), 7.55 (s, 0.25H), 7.45 (s, 1H), H I \ 41 7.41 (s, 0.50H), 7.38 (d, 1H, J = 8.0 Hz), 7.21 (s, 17/106 N12.rf 8 0.25H), 6.78 (s, 1H), 3.85-3.94 (m, 5H), 3.33-3.38 dP (m, 2H), 2.54 (s, 3H), 1.68-1.71 (m, 2H), 1.46-1.55 F2,,c (m, 5H), 1.21-1.26 (m, 3H), 1.11 (s, 9H), 0.89-0.94 (m, 3H), 0.60-0.67 (m, 2H). MS: 582.3 (M+1)+.
# Structure Analytical data oa 1H-NMR (CDCI3, 400 MHz) 6: 8.31 (d, 1H, J =
HN--<OH 11.2 Hz), 7.82 (s, 1H), 7.63 (d, 1H, J =
11.2 Hz), .
N 6.39 (s, 1H), 5.66 (d, 1H, J = 10.4 Hz), 5.10 (s, H I \ S=0 1H), 4.12-4.19 (m, 1H), 3.98-4.01 (m, 2H), 3.82 (d, d 17/107 N 8 2H), 3.49-3.57 (m, 4H), 2.63 (s, 3H), 2.31-2.34 (m, 3 1H),1.97-2.01 (m, 2H), 1.55-1.64 (m, 3H), 1.22-CF 1.34 (m, 3H), 1.17 (s, 6H), 0.56-1.03 (m, 7H). MS:
600.3 (M+1)+.
00N1H-NMR (CDCI3, 400 MHz) 6: 8.29 (d, 1H, J = 8.4 0 __I Hz), 7.79 (s, 1H), 7.60 (d, 1H, J
= 8.4 Hz), 6.39 (s, N
H I \ iii HT , OH 1H), 6.33 (s, 1H), 5.70 (d, 1H, J = 7.6 Hz), 4.14-=.=1/4, 4.21 (m, 1H), 3.98-4.01 (m, 2H), 3.90-3.93 (m, 17/108 N \W 8 2H), 3.81 (d, 2H), 3.50-3.56 (m, 2H), 2.63 (s, 3H), d 3 1.97-2.00 (m, 2H), 1.97 (br s, 1H), 1.78 (t, 2H), CF
1.50-1.60 (m, 5H), 1.24-1.37 (m, 9H), 1.00 (br s, 3H), 0.57-0.64 (m, 2H). MS: 614.4 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 8.29 (d, 1H, J = 8.4 oa 0 Hz), 7.80(d, J = 1.2 Hz, 1H), 7.61 (dd, J = 1.6 Hz, N
J - 8.4 Hz 1H) 6.36 (s 1H) 5 60-5 62 (d J = 8.0 H 1 \ = =(::0 Hz, 1H), 5.29 (s, 1H), 4.13-4.18 (m, 1H), 3.97-4.00 17/109 N 8 (m, 2H), 3.81 (d, J = 6.8 Hz, 2H), 3.49-3.56 (m, ) u3 2H), 3.27 (s, 3H), 3.17 (s, 2H), 2.63 (s, 3H), 1.97-2.00 (m, 1H), 1.48-1.57 (m, 4H), 1.31-1.38 (m, 3H), 1.23 (s, 6H), 0.97-1.00 (m, 3H), 0.57-0.64 (m, 2H). MS: 614.4 (M+1)+.
a 1H-NMR (300 MHz, CDCI3) 6: 0.60-0.68 (2H, m), 0 1.00-1.04(3H, m), 1.27-1.61 (9H, m), 1.98-2.02 HN
N (2H, m), 2.65 (3H, s), 2.74 (3H, d, J = 5.1 Hz), H I \
N W ¨() 3.54 (2H, dt), 3.83 (2H, d, J = 7.2 Hz), 3.99-4.02 17/110 0 (2H, m), 4.13-4.23 (1H, m), 4.64-4.69 (1H, m), d c3 5.63 (1H, d, J = 2.1 Hz), 6.38 (1H, s), 7.65 (1H, d, J = 8.1 Hz), 7.85 (1H, s), 8.26 (1H, d, J = 8.1 Hz).
MS: 542.2 (M+1)+.
1H-NMR (300 MHz, CDCI3) 6: 0.57-0.69 (2H, m), a0 f 0.87 (t, 3H, J = 7.5 Hz), 1.02 (3H, br s), 1.23-1.57 N I-11(10H, d), 1.96-2.02 (2H, m), 2.64 (3H, s), 3.00 (q, H I \ 41 s=0 2H, J = 6.6 Hz), 3.53 (2H, t, J = 11.1 Hz), 3.82 17/111 N 8 (2H, d, J = 7.2 Hz), 3.98-4.03 (2H, m), 4.11-4.22 d cF, (1H, m), 4.78 (1H, t, J = 5.9 Hz), 5.68 (1H, d, J =
8.1 Hz), 6.39 (1H, s), 7.64 (1H, d, J = 8.1 Hz), 7.83 (1H, s), 8.24 (1H, d, J = 8.1 Hz). MS: 570.3 [M+1]+.
1H-NMR (300 MHz, CDCI3) 6: 0.57-0.69 (2H, m), a0 I 0.98.1.01 (3H, m), 1.10 (6H, d, J = 8.1 Hz), 1.32-N HN-- 1.40 (3H, m), 1.48-1.62 (5H, m), 1.97-2.02 (2H, H I \ a .,,,, m), 2.65 (3H, s), 3.50-3.63 (3H, m), 3.82 (2H, d, J
17/112 N µmrf 8 . 7.2 Hz), 3.98-4.03 (2H, m), 4.13-4.23 (1H, m), d u3 4.53-4.55 (2H, m), 5.64 (1H, d, J =
7.8 Hz), 6.39 (1H, s), 7.64 (1H, dd, J = 8.4, 1.5 Hz), 7.84 (1H, d, J = 1.2 Hz), 8.29 (1H, d, J = 8.4 Hz). MS: 570.3 [M+1]+.
# Structure Analytical data 1H-NMR (300 MHz, CDCI3) 6: 0.65-0.69 (2H, m), a 0 Ci j< 1.03 (3H, br s), 1.26 (9H, s), 1.33-1.37 (3H, m), N HII1.48-1.61 (7H, m), 2.00 (2H, dd, J = 12.6, 2.1 Hz), H I \ * S=0 2.64 (3H, s), 3.53 (2H, dt, J
= 11.6, 1.8 Hz), 3.83 d 17/113 N 8 (2H, d, J = 7.2 Hz), 3.99-4.03 (2H, m), 4.16-4.19 3 (1H, m), 5.52 (1H, s), 5.63 (1H, d, J = 7.8 Hz), CF
6.43 (1H, s), 7.71 (1H, d, J = 1.8 Hz), 7.82 (1H, d, J = 1.5 Hz). MS: 618.3 [M+1].
1H-NMR (400 MHz, CDCI3) 6: 6.97 (d, 1H), 6.43 ,s-NH2 HN (d, 1H), 6.06 (s, 1H), 5.79 (br s, 1H), 4.88 (s, 2H), o-b / \ 4.33 (t, 2H), 3.63 (d, 2H), 3.40-3.44 (m, 2H), 3.13 17/114 N lp 0 (t, 2H), 2.58 (s, 3H), 1.99-1.89 (m, 4H), 1.63-1.56 (m, 7H), 1.45-1.32 (m, 12H), 1.04-1.00 (m, 5H), 0.87-0.84 (m, 2H), 0.72-0.65 (m, 2H). MS: 584.3 ) 111 [M+1r.
1H-NMR (400 MHz, DMSO-d6) 6: 8.03 (d, 1H), N HN 7.95 (s, 1H), 7.82-7.69 (m, 3H), 7.57-7.55 (m, 1H), H I \ 11 6.86 (s, 1H), 3.94-3.85 (m, 5H), 3.38-3.30 (m, 2H), 17/115 N 8 2.55 (s, 1H), 1.72-1.69 (m, 2H), 1.54-1.45 (m, 5H), d F F 1.24-1.20 (m, 3H), 1.10 (s, 9H), 0.93-0.87 (m, 3H), 0.66-0.59 (m, 2H). MS: 566.2 [M+1]t a0 1H-NMR (400 MHz, CDCI3) 6: 8.20 (d, 1H), 7.61 N HN (d, 1H), 7.34 (d, 1H), 7.29 (d, 1H), 6.42 (d, 1H), H I \ . S=0 5.65 (d, 1H), 4.51 (s, 1H), 4.21-4.17 (m, 1H), 4.00-17/116 N 8 3.97 (m, 1H), 3.76 (d, 2H), 3.56-3.49 (m, 2H), C) 2.01-1.98 (m, 2H), 1.62-1.44(m, 16H), 1.31 (s, 9H), 1.07-1.05 (m, 3H), 0.80-0.75 (m, 2H). MS:
558.3 [M+1].
1H-NMR (400 MHz, CDCI3) 6: 8.21 (d, J = 8.0 Hz, a0 õ 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 8.0 Hz, N
HN J = 1.6 Hz, 1H), 6.30 (s, 1H), 5.85 (d, J = 8.0 Hz, H I \ . S=0 1H), 4.73 (s, 2H), 4.58 (s, 1H), 4.21-4.14 (m, 1H), 17/117 HO N 8 4.00 (dd, J = 10.0 Hz, J = 2.0 Hz, 2H), 3.83 (d, J =
d 7.2 Hz, 2H), 3.53 (td, 2H), 2.02 (dd, J = 12.4 Hz, J
= 2.0 Hz, 2H), 1.62-1.52 (m, 14H), 1.38-1.36 (m, 12H), 1.04-0.96 (m, 3H), 0.65-0.56 (m, 2H). MS:
570.3 ([M-OH]).
1H-NMR (400 MHz, CDCI3) 6: 8.17 (d, J = 8.4 Hz, a 0 FIN_., 1H), 7.57 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.45 (s, "
N 1H), 6.35 (d, J = 7.6 Hz, 1H), 5.03 (s, 2H), 4.56 (s, H I \ a =lo 1H), 4.19-4.17 (m, 1H), 3.97 (d, J = 11.6 Hz, 2H), 3.83 (d, J = 6.8 Hz, 2H), 3.54 (t, J = 11.2 Hz, 2H), d 1.98 (d, J = 12.0 Hz, 2H), 1.62-1.49(m, 14H), 1.30-1.22 (m, 12H), 0.93-0.88 (m, 3H), 0.59-0.53 (m, 2H). MS: 570.2 ([M-F]).
# Structure Analytical data 1H-NMR (400 MHz, CDCI3) 5: 8.21 (d, J = 8.4 Hz, a 0 J 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.28-7.25 (m, 1H), N Hy 6.68 (s, 1H), 6.21 (d, J = 8.0 Hz, 1H), 4.55 (s, 1H
H I \ * s=0 ), 4.24-4.21 (m, 1H), 4.01-3.98 (m, 2H), 3.87 (d, J
17/119 CI 8 . 7.2 Hz, 2H), 3.55 (td, J = 11.6 Hz, J =
1.6 Hz, (---) 2H), 2.04-2.01 (d, 2H), 1.61-1.54 (s, 13H), 1.48-1.25 (m, 13H), 0.99 (br s, 3H), 0.69-0.64 (m, 2H).
MS: 592.3 [r\A-F1].
-.....)_\ 0 1H-NMR (400 MHz, CD30D) 5: 6.96 (d, 1H, J
=
HN HN 1.6 Hz), 6.48 (d, 1H, J = 2.0 Hz), 6.29 (s, 1H), 0 / \ 4.30 (t, 2H), 3.71(d, 2H, J = 7.6 Hz), 3.42 (s, 2H), 17/120 i-NH N 410 3.08 (q, 2H), 2.52 (s, 3H), 1.88 (t, 2H), 1.57-1.54 (m, 3H), 1.37-1.27 (m, 18H), 1.07-0.98 (m, 8H), 0.86 (dd, 2H), 0.72-0.67 (m, 2H). MS: 577.5 CI) 1 [M+1].
1H-NMR (400 MHz, CDCI3) 5: 7.57 (br s, 1H), 7.27 HN HN (d, 1H), 7.13 (t, 1H), 7.01 (t, 1H), 6.88 (t, 1H), 6.25 (s, 1H), 4.15 (q, 1H), 3.71 (d, 2H, J = 7.2 Hz), 17/121 HO---O iN \ * 3.54-3.41 (m, 2H), 2.59 (s, 3H), 1.55-1.53 (m, 3H), 1.42-1.30 (m, 24H), 1.03 (br s, 3H), 0.88-0.86 (m, 2H), 0.76-0.73 (m, 2H), 0.68-0.62 (m, 2H). MS: ) II 550.4 [M+1r.
1H-NMR (400 MHz, CDCI3) 6: 7.26 (s, 1H), 7.13 HN HN (s, 1H), 7.01-6.95 (m, 3H), 6.27 (s, 1H), 3.81 (s, y0 / \ 2H), 3.70 (d, 2H, J = 6.8 Hz), 3.59 (d, 2H, J = 6.0 17/122 oN Hz), 3.40 (s, 3H), 2.62 (s, 3H), 1.58-1.52 (m, 3H), / 0) 1.47-1.24 (m, 21H), 1.00 (br s, 3H), 0.88-0.84 (m, 2H), 0.75-0.72 (m, 2H), 0.66-0.62 (m, 2H). MS:
I 550.4 [M+1]t 1H-NMR (400 MHz, CD300) 5: 6.87 (d, 1H), 6.39 HN HN (d, 1H), 6.20 (s, 1H), 4.22 (t, 2H), 3.96-3.91 (m, 1H), 3.62 (d, 2H), 3.37 (q, 2H), 2.44 (s, 3H), 1.80 17/123 HO-- iN \ *
0 (t, 3H), 1.49-1.46 (m, 3H), 1.33-1.19 (m, 23H), 1.00-0.86 (m, 5H), 0.80-0.77 (m, 2H), 0.66-0.62 ) 11 (m, 2H). MS: 578.4 [M+1r.
0 1H-NMR (400 MHz, CD30D) 5: 6.88 (d, 1H), 6.39 HN HN (d, 1H), 6.21 (s, 1H), 4.22 (t, 2H), 3.68 (s, 2H), yo / \ 3.62 (d, 2H), 3.33 (s, 2H), 3.28 (s, 3H), 2.45 (s, 17/124 o / 0) * 0 3H), 1.79 (t, 3H), 1.48-1.46 (m, 3H), 1.32-1.19 (m, 21H), 0.97-0.90 (m, 5H), 0.80-0.77 (m, 2H), 0.66-1 0.62 (m, 2H). MS: 578.4 [M+1].
a 0 Lõ,J< 1H-NMR (400 MHz, DMSO-d6) 5: 7.92 (d, 1H), 7.81-7.78 (m, 2H), 7.59 (t, 1H, J = 55.2 Hz), 7.57 N 'i H I \ * s=o (d, 1H, J = 8.0 Hz), 6.86 (s, 1H), 3.94-3.85 (m, 17/125 N 8 5H), 3.54 (q, 2H), 3.36 (t, 2H), 2.58 (s, 3H), 1.72-d F F 1.69 (m, 2H), 1.54-1.45 (m, 5H), 1.33 (s, 9H), 1.29-1.20 (m, 6H), 0.94-0.86 (m, 3H), 0.67-0.61 (m, 2H). MS: 594.3 [M+1].
# Structure Analytical data a 0 HyJ 1H-NMR (400 MHz, DMSO-d6) 6: 8.04 (d, 1H), N 7.96 (s, 1H), 7.82-7.55 (m, 4H), 6.84 (s, 1H), 4.07 H I \ * S=0 17/126 N 8 (d, 2H), 3.94-3.84 (m, 3H), 3.35 (dd, 2H), 2.55 (s, [1? F F 3H), 2.32-2.28 (m, 1H), 1.74-1.24 (m, 10H), 1.11 (s, 9H). MS: 538.2 [M+1]t HNJ 1H-NMR (400 MHz, DMSO-d6) 6: 8.03 (d, 1H), --):11 1 \ . 0 7.93 (s, 1H), 7.82-7.53 (m, 4H), 6.83 (s, 1H), 3.89 0 OH N \mu 8 (d, 2H), 3.36 (d, 2H), 2.54 (s, 3H), 1.47-1.45 (m, d F 0.85 (m, 3H), 0.66-0.60 (m, 2H). MS: 582.2 F 3H), 1.24-1.21 (m, 3H), 1.10-1.09 (m, 15H), 0.93-[M+1]t O 1H-NMR (400 MHz, DMSO-d6) 6: 8.02 (d, 1H), --:HN 7.95 (s, 1H), 7.82-7.56 (m, 3H), 7.48 (t, 1H), 7.19 11 I \ .
=-Ici (br s, 1H), 6.85 (br s, 1H), 6.78 (s, 1H), 3.89 (d, 0 NH2 N 8 2H), 3.31 (d, 2H), 2.54 (s, 3H), 1.47-1.45 (m, 3H), d F F 1.28-1.21 (m, 3H), 1.10 (s, 9H), 1.07 (m, 6H), 0.93-0.86 (m, 3H), 0.66-0.59 (m, 2H). MS: 581.3 [M+1].
OH
HyJ 1H-NMR (400 MHz, DMSO-d6) 6: 8.03 (m, 1H), N 7.94 (s, 1H), 7.81-7.55 (m, 4H), 6.86 (s, 1H), 3.90 I \ . e=0 (d, 2H), 3.60 (dd, 4H), 3.22 (d, 2H), 2.55 (s, 3H), N
d F 8 F
17/129 1.58-1.45 (m, 5H), 1.38-1.35 (m, 2H), 1.28-1.21 (m, 3H), 1.10 (s, 9H), 0.93-0.85 (m, 3H), 0.67-0.59 (m, 2H). MS: 596.3 [M+1].
HyJ 1H-NMR (400 MHz, DMSO-d6) 6: 8.02 (d, 1H), N 7.93 (s, 1H), 7.82-7.55 (m, 4H), 6.79 (s, 1H), 3.89 c OyH I \ li S=0 HO N
d 8 F (d, 2H, J = 6.8 Hz), 3.19-3.15 (m, 2H), 2.54 (s, F
1.20 (m, 3H), 1.13 (s, 6H), 1.10 (s, 9H), 0.94-0.87 3H), 1.72-1.68 (m, 2H), 1.47-1.44 (m, 3H), 1.23-(m, 3H),0.66-0.60(m, 2H). MS: 596.3 [M+1].
a y_ 1H-NMR (CDCI3, 400 MHz) 6: 7.62 (s, 1H), 7.47-HN
O 7.53 (m, 1H), 6.23 (s, 1H), 5.61 (d, J = 7.6 Hz, N 0 1H), 5.22 (s, 1H), 4.14-4.19 (m, 1H), 3.98 (d, J =
H I \ * 10.4 Hz, 2H), 3.76 (d, J = 7.2 Hz, 2H), 3.66 (s, 17/131 N 2H), 3.52 (t, J = 10.0 Hz, 2H), 2.62 (s, 3H), 1.96-C) c3 2.00 (m, 2H), 1.47-1.59 (m, 5H), 1.31-1.43 (m, 12H), 0.96-1.03 (m, 3H), 0.61-0.67 (m, 2H). MS:
562.3 (M+1)+.
a Y 1H-NMR (CDCI3, 400 MHz) 6: 7.65-7.70 (m, 2H), o HN 7.51 (d, J = 7.6 Hz, 1H), 6.28 (s, 1H), 5.61 (d, J =
N 0 8.0 Hz, 1H), 4.74 (s, 1H), 4.15-4.19 (m, 1H),3.98 H I \ * (d, J = 12.0 Hz, 2H), 3.78 (d, J = 6.8 Hz, 2H), 3.52 17/132 N (t, J = 11.2 Hz, 2H), 2.63 (s, 3H), 1.99 (d, J = 11.2 d CF3 Hz, 1H), 1.64 (s, 6H), 1.47-1.58 (m, 5H), 1.34-1.39 (m, 3H), 1.25 (s, 9H), 0.98-1.03 (m, 3H), 0.61-0.67 (m, 3H). MS: 590.3 (M+1)+.
# Structure Analytical data Q o 11-I-NMR (CDCI3, 400 MHz) ö: 0.79-0.88 (m, 2H), HN2 1.26 (s, 9H), 1.49-1.58 (m, 2H), 1.89-2.00 (m, 4H), N
2.17-2.26 (m, 1H), 2.40-2.51 (m, 2H), 2.66 (s, 3H), ==0 N 8 3.52 (t, J = 12.0 Hz, 2H), 3.99 (d, J =
12.0 Hz, 17/133 2H), 4.13-4.15 (m, 3H), 4.71 (s, 1H), 5.62 (d, J =
cF3 8.0 Hz 1H), 6.39 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H). MS: 592.2 1?
F (M-F1)+.
0 1H-NMR (400 MHz, CDCI3) 6: 8.33 (d, 1H, J
= 8.4 N
17/134 Hy Hz), 7.80 (s, 1H), 7.63 (d, 1H, J = 8.4 Hz), 6.42 (s, oH I \ ik, -..o 1H), 6.37 (t, 1H), 4.74 (s, 1H), 3.81 (d, 2H, J = 6.8 HO N
0 Hz), 3.33 (d, 2H, J = 6.4 Hz), 2.63 (s, 3H), 2.31 (s, c 3 2H), 1.58-1.56 (m, 3H), 1.35-1.32 (m, 3H), 1.26 (s, d 9H), 1.10-1.01 (m, 9H), 0.67-0.60 (m, 2H). MS:
614.3 (M+1)+.
0 j< 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J
= 8.4 Hz), 7.79 (s, 1H), 7.61 (d, 1H, J= 8.4 Hz), 6.89 (s, 0 il 17/135 I \ . 1=0 1H), 6.39 (s, 1H), 6.30-6.24 (m, 2H), 4.72 (s, 1H), cF3 3.79 (d, 2H, J = 6.8 Hz), 3.45-3.44 (m, 2H), 2.61 (s, 3H), 1.90 (t, 2H), 1.57-1.52 (m, 3H), 1.33-1.27 H2N d (m, 18H), 0.99 (s, 3H), 0.64-0.58 (m, 2H). MS:
613.3 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 8.23 (d, 1H, J =
Hy 8.4 Hz), 7.91 (d, 1H, J = 8.8 Hz), 7.84 (m, 2H), N 7.66 (t, 1H), 7.51 (d, 1H), 6.81 (s, 1H), 3.90 (d, c OyH 1 \ 11 S=0 ii 21 H.4,5J(m= ,63.8HH),z1).,233.-111.2-30.0(6m73H, 2),H1).,125.5(7s,(9dH, 3),H1,.J1 d 0 HN = 4.4 Hz), 2.54 (s, 3H), 1.68-1.64 (m, 2H), 1.47-N
(s, 6H), 0.92-0.84 (m, 3H), 0.68-0.60 (m, 2H). MS:
627.3 (M+1)+.
o 11-1-NMR (400 MHz, CDCI3) 5: 8.31 (d, 1H, J = 8.4 0 j< Hz), 7.80 (s, 1H), 7.62 (d, 1H, J = 8.4 Hz), 6.29 (s, HO-kr--NN =m Hy 1H), 4.72 (s, 1H), 4.55-4.50 (m, 1H), 4.29-4.24 (m, lip -=0 1H), 4.16-4.09 (m, 2H), 3.80 (d, 2H, J =
7.2 Hz), o 3.74-3.69 (m, 1H), 3.29-3.26 (m, 2H), 2.41 (s, 3H), d CF3 1.55 (br s, 3H), 1.34-1.32 (m, 3H), 1.27 (s, 9H), 1.00 (br s, 3H), 0.65-0.61 (m, 2H). MS: 614.2 (M+1)+.
0., 0 i 1mHz-)N7M8R1(4( s001MH ) Hz,.6C2D(Cd13)1H5: 8.32J8 (d0, J6.=428(.0s, HN'-' .IN
H I \ . -=C0 1H), 6.16 (d, 1H, J = 8.8 Hz), 4.72 (s, 1H), 4.17 (br 17/138 N 8 s, 1H), 3.84-3.74 (m, 4H), 3.66-3.57 (m, 2H), 2.62 d c3 (s, 3H), 1.91-1.81 (m, 3H), 1.62-1.55 (m, 4H), 1.37-1.31 (m, 3H), 1.26 (s, 9H), 1.00 (br s, 3H), 0.64-0.58 (m, 2H). MS: 584.2 (M+1)+.
# Structure Analytical data (A o 1H-NMR (400 MHz, CDCI3) 6: 8.32 (d, 1H, J
= 8.0 HN=-C:3 Hz), 7.81 (s, 1H), 7.62 (d, 1H, J = 8.0 Hz), 6.42 (s, H \
N 1H), 6.18 (d, 1H, J = 8.8 Hz), 4.71 (s, 1H), 4.17 (br I . , 17/139 N 8 s, 1H), 3.84-3.74 (m, 4H), 3.65-3.58 (m, 2H), 2.62 C) u3 (s, 3H), 1.91-1.81 (m, 3H), 1.62-1.55 (m, 4H), 1.37-1.31 (m, 3H), 1.26 (s, 9H), 1.00-0.96 (m, 3H), 0.67-0.59 (m, 2H). MS: 584.2 (M+1)+.
oa o 1H-NMR (400 MHz, CD30D) 6: 8.25 (d, 1H, J
=
N FII(CF3 8.0 Hz), 7.94 (s, 1H), 7.83 (d, 1H, J = 8.4 Hz), H I \ 41 =-0 6.75 (s, 1H), 4.08-3.95 (m, 5H), 3.84 (dd, 2H), d 17/140 N 0 3.53 (t, 2H), 2.60 (s, 3H), 1.90-1.87 (m, 2H), 1.70-3 1.58 (m, 5H), 1.36-1.33 (m, 3H), 1.06-1.02 (m, CF
3H), 0.73-0.67 (m, 2H). MS: 610.2 (M+1)+.
a 01H-NMR (400 MHz, DMSO-d6) 6: 8.92 (d, 1H, J =
HN1CF3 8.8 Hz), 8.20 (d, 1H, J = 8.0 Hz), 7.93 (d, 1H, J =
N
H I \ = s=c1 8.4 Hz), 7.90 (s, 1H), 7.56 (d, 1H, J = 8.0 Hz), ii 6.90 (s, 1H), 4.15-4.10 (m, 1H), 3.95-3.85 (m, 5H), C) u3 3.39-3.36 (m, 2H), 2.55 (s, 3H), 1.71 (dd, 2H), 1.57-1.47 (m, 5H), 1.23-1.21 (m, 6H), 0.95-0.87 (m, 3H),0.68-0.61 (m, 2H). MS: 624.2 (M+1)+.
a 0 1H-NMR (400 MHz, DMSO-d6) 6: 8.92 (d, 1H, J =
HNCF3 8.8 Hz), 8.20 (d, 1H, J = 8.0 Hz), 7.93 (d, 1H, J =
N
H I \ II s=0 8.4 Hz), 7.90 (s, 1H), 7.56 (d, 1H, J = 8.0 Hz), ii 6.90 (s, 1H), 4.15-4.10 (m, 1H), 3.95-3.85 (m, 5H), C) u3 3.39-3.36 (m, 2H), 2.55 (s, 3H), 1.71 (dd, 2H), 1.57-1.47 (m, 5H), 1.23-1.21 (m, 6H), 0.95-0.87 (m, 3H), 0.68-0.61 (m, 2H). MS: 624.2 (M+1)+.
F3c. 1H-NMR (400 MHz, CDCI3) 6: 8.29 (d, 1H, J
= 8.4 Q0 Hz), 7.82 (s, 1H), 7.63 (d, 1H, J = 9.6 Hz), 6.38 (s, N HN'T 1H), 5.61 (d, 1H, J = 8.0 Hz), 4.89 (s, 1H), 4.19-H I \ . =-Ici 4.15 (m, 1H), 4.00-3.98 (m, 2H), 3.81 (d ,2H, J =
17/143 N 8 9.2 Hz), 3.55-3.49 (m, 2H), 2.65-2.57 (m, 5H), C) u3 1.98 (dd, 2H), 1.58-1.48 (m, 5H), 1.36-1.31 (m, 9H), 1.00-0.99 (m, 3H), 0.66-0.60 (m, 2H). MS:
652.3 (M+1)+.
a CN
0 11-1-NMR (400 MHz,DMSO-d6) 6: 9.34 (s, 1H), 8.25 N HN)7(d, 1H, J = 8.4 Hz), 7.98 (d, 1H, J = 9.2 Hz), 7.94 H I \ * 0 (s, 1H), 7.58 (d, 1H, J = 7.6 Hz), 6.92 (s, 1H), 17/144 N 8 3.97-3.85 (m, 5H), 3.36 (t, 2H), 2.56 (s, 3H), 1.72-C) u3 1.70 (m, 2H), 1.57-1.45 (m, 7H), 1.32-1.19 (m, 5H), 0.93 (br s, 3H), 0.69-0.64 (m, 2H). MS: 593.3 (M+1)+.
# Structure Analytical data 1H-NMR (400 MHz, CDCI3) 6: 8.34 (br s, 1H), 8.19 a 0 HNCo (d, 1H, J = 8.4 Hz), 7.94 (d, 1H, J = 8.8 Hz), 7.90 N (s, 1H), 7.56 (d, 1H, J = 8.0 Hz), 6.90 (s, 1H), 4.62 H I \ = :---0 (d, 2H, J = 6.0 Hz), 4.19 (d, 2H, J = 6.4 Hz), 4.20-17/145 N 0 d 3.85 (m, 5H), 3.38-3.36 (m, 2H), 2.55 (s, 3H), CF 1.72-1.69 (m, 2H), 1.56-1.42 (m, 8H), 1.235-1.22 (m, 3H), 0.98-0.86 (m, 3H), 0.69-0.61 (m, 2H).
MS: 698.3 (M+1)+. =
OH
1H-NMR (400 MHz, DMSO-d6) 6: 8.22 (d, 1H, J =
a 0 8.0 Hz), 7.92 (d, 1H, J = 8.0 Hz), 7.88 (s, 1H), N E11;1 7.55 (d, 1H, J = 7.6 Hz), 7.41 (d, 1H, J = 9.2 Hz), Hs=0 6.88 (s, 1H), 3.95-3.85 (m, 5H), 3.36 (t, 2H), 3.13-17/146 N 8 3.09 (m, 1H), 2.55 (s, 3H), 1.72-1.69 (m, 2H), d CF3 1.57-1.47 (m, 5H), 1.24-1.22 (m, 3H), 0.96-0.89 (m, 12H), 0.64-0.58 (m, 2H). MS: 614.3 (M+1)+.
0 1H-NMR (400 MHz, CDCI3) 6: 8.26 (d, 1H, J = 8.0 a c7 Hz), 7.85 (s, 1H), 7.65 (dd, 1H, J = 8.4 Hz, J = 1.2 o Hz), 6.38 (s, 1H), 5.63 (d, 1H, J = 8.0 Hz), 4.98 N Flt\r (M, 1H), 4.39-4.35 (m, 4H), 4.21-4.14 (m, 1H), H I \ . s=o 4.00-3.98 (m, 2H), 3.82 (d, 2H, J
= 7.2 Hz), 3.53 N 8 (td, 2H), 3.22 (d, 2H, J = 6.4 Hz), 2.64 (s, 3H), d cF3 2.01-1.97 (m, 2H), 1.63-1.33 (m, 8H), 1.30 (s, 3H), 1.01-0.98 (m, 3H), 0.69-0.63 (m, 2H). MS: 612.3 (M+1)+.
a0 0 1H-NMR (400 MHz, DMSO-d6) 6:7.80 (d, J =
1.2 N Hz, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.46(d, J = 8.0 H I \ * NN Hz, 1H), 6.67 (s, 1H), 3.95-3.80 (m, 5H), 3.78.3.35 17/148 N (M, 5H), 2.54 (s, 3H), 1.71-1.67 (m, 2H), 1.57-1.47 d c3 (m, 5H), 1.34-1.25 (m, 9H), 0.97-0.91 (m, 3H), 0.71-0.63 (m, 2H). MS: 546.8 (M+1)+.
OH
O''''=1H-NMR (400 MHz, CDCI3) 6:7.50 (d, J = 1.2 Hz, cL 0 0 1H), 7.31 (d, J = 1.6 Hz, 1H), 6.22 (s, 1H), 5.97 (br s, 1H), 4.76-4.78 (m, 1H), 3.71 (d, J = 7.2 Hz, 2H), ril 1 \ . N 3.46 (d, J = 2.0 Hz, 3H), 3.10-3.15 (m, 1H), 2.76-N \ 2.83 (m, 2H), 2.59 (s, 3H), 2.28-2.36 (m, 2H), d c3 1.54-1.60 (m, 3H), 1.41 (s, 6H), 1.34-1.37 (m, 3H), 0.98-1.04 (m, 3H), 0.63-0.70 (m, 2H). MS: 560.3 0 1H-NMR (400 MHz, CDCI3) 6:8.21 (d, 1H, J = 8.4 N HN1CF3 Hz), 7.82 (s, 1H), 7.63 (d, 1H, J =
8.0Hz), 6.39 (s, ____ H I \ =1:21 1H), 6.12 (br s, 1H), 5.17 (d, 1H, J =
10.0 Hz), O N Illr 8 4.14-4.06 (m, 1H), 3.80 (d, 2H, J = 7.2 Hz), 3.43 17/150 HO d c3 (br s, 1H), 2.60 (s, 3H), 1.86 (t, 2H), 1.56-1.54 (m, 3H), 1.38 (d, 3H, J = 6.4 Hz), 1.31-1.24 (m, 9H), 0.98 (s, 3H), 0.62-0.54 (m, 2H). MS: 654.2 (M+1)+.
# Structure Analytical data a 1H-NMR (400 MHz, CDCI3) 6: 8.18 (d, 1H, J =
8.0 O Hz), 7.61 (d, 1H), 7.30 (d, 1H), 6.29 (s, 1H), 5.67 N HN1CF3 (d, 1H, J = 8.0 Hz), 4.81 (d, 1H, J = 9.6 Hz), 4.19-H I \ 411 =0 4.16 (m, 1H), 4.05-3.98 (m, 3H), 3.78 (d, 2H, J =
17/151 N 8 7.2 Hz), 3.56-3.50 (m, 2H), 2.62 (s, 3H), 2.00-1.97 d (m, 2H), 1.60-1.49 (m, 14H), 1.38-1.29 (m, 6H), 0.98 (m, 3H), 0.62-0.57 (m, 2H). MS: 612.3 (M+1)+.
O 1H-NMR (400 MHz, CDCI3) 6: 8.16 (d, 1H, J
= 8.4 N HN1 Hz), 7.60 (d, 1H), 7.28 (d, 1H), 6.27 (s, 1H), 6.12 s=0 (br s, 1H), 5.25 (d, 1H, J = 16.0 Hz), 4.08-4.00 (m, O N 8 1H), 3.77 (d, 2H, J = 7.2 Hz), 3.43 (br s, 2H), 2.60 17/152 HO d (s, 3H), 1.87-1.83 (m, 2H), 1.60-1.52 (m, 12H), 1.38 (d, 3H, J = 6.8 Hz), 1.33-1.21 (m, 9H), 0.97 (s, 3H), 0.63-0.58 (m, 2H). MS: 642.3 (M-i-1).
1H-NMR (CDCI3, 400 MHz) 6: 0.60-0.67 (m, 2H), o 0.73-0.76 (m, 2H), 0.86-0.88 (m, 2H), 0.96-0.99 (m, 3H), 1.24 (s, 6H), 1.27-1.40 (m, 12H), 1.42 (s, o / \ 3H), 1.49-1.59 (m, 3H), 1.86 (t, J
= 7.2 Hz, 2H), 17/153 N 10 2.61 (s, 3H), 3.38-3.43 (m, 2H), 3.64 (s 3H), 3.71 (d, J = 7.2 Hz, 2H), 5.84-5.86 (m, 1H), 6.15 (s, ) 1 1H), 7.00 (s, 1H), 7.13 (s, 1H), 7.25 (s, 1H). MS:
535.4 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 0.58-0.67 (m, 2H), o o 0.73-0.76 (m, 2H), 0.86-0.88 (m, 2H), 0.93-0.99 )1... 0--.N
H (m, 3H), 1.29-1.38 (m, 12H), 1.42 (s, 3H), 1.49-o \ / \ 1.56 (m, 3H), 2.26-2.31 (m, 2H), 2.60 (s, 3H), 17/154 N lip 2.70-2.76 (m, 2H), 3.05-3.11 (m, 1H), 3.70-3.72 (m, 5H), 4.66-4.76 (m, 1H), 5.87 (d, J = 6.8 Hz, ) 11 1H), 6.16 (s, 1H), 7.00 (s, 1H), 7.13 (s, 1H), 7.25 (s, 1H). MS: 519.3 (M+1)+.
1H-NMR (400 MHz, CDCI3) 6: 7.39 (s, 1H), 7.20 o o (s, 1H), 7.08 (s, 1H), 6.19 (s, 1H), 5.97-6.00 (m, H 1H), 4.74-4.84 (m, 1H), 3.73 (d, 2H, J = 6.8 Hz), HO I \3.06-3.11 (m, 1H), 2.76-2.81 (m, 2H), 2.60 (s, 3H), 17/155 N ilp 2.25-2.33 (m, 2H), 1.54 (d, 2H, J = 6.4 Hz), 1.43 I(s, 3H), 1.32-1.35 (m, 3H), 0.99-1.06 (m, 3H), ) OH 0.87-0.90 (m, 2H), 0.75-0.77 (m, 2H), 0.59-0.68 (m, 2H). MS: 507.3 [M+1]+.
1H-NMR (CDCI3, 400 MHz) 6: 0.59-0.65 (2H, m), Cla o j< 0.97-0.99 (3H, m), 1.23 (9H, s), 1.29-1.33 (3H, m), N FIN 1.49-1.58 (6H, m), 1.96-1.99 (2H, m), 2.62 (3H, s), H I \ . S=0 2.69 (3H, s), 3.52 (2H, dt, J
= 9.6, J = 1.2 Hz), II
17/156 N d 0 3.80 (2H, d, J = 6.8 Hz), 3.98 (2H, d, J =
10.8 Hz), 4.11-4.21 (1H, m), 4.45 (1H, s), 5.61 (1H, d, J =
8.0 Hz), 6.27 (1H, s), 7.25 (1H, s), 8.05 (1H, d, J =
8.8 Hz). MS: 530.3 (M+1)+.
# Structure Analytical data a 1H-NMR (CDCI3, 400 MHz) 6: 0.60-0.66 (2H, m), . , 0.97-1.00 (3H, m), 1.20-1.25 (11H, s), 1.32-1.37 N FINil (rrI, 3H), 1.47-1.49 (m, 6H), 1.97 (2H, dd, J = 12.0, H I = 2.0 Hz), 2.62 (3H, s), 3.52 (2H, td, J = 10.0, 1.6 \ . so 17/157 N 8 Hz), 3.80 (2H, d, J = 6.8 Hz), 3.98 (2H, d, J = 11.2 C) Br Hz), 4.15-4.17 (m, 1H), 5.11 (1H, s), 5.61 (1H, d, J
= 8.0 Hz), 6.32 (1H, s), 7.40 (1H, dd, J = 8.4, 1.6 Hz), 7.70 (1H, d, J = 1.2 Hz), 8.17 (1H, d, J = 8.4 Hz). MS: 594.2/596.2 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 0.57-0.65 (2H, m), a 0 FIN j< 0.97-1.00 (3H, m), 1.27 (9H, s), 1.29-1.33 (3H, rrl), N 1.49-1.58 (6H, m), 1.96-2.00 (2H, m), 2.63 (3H, s), H I \ . S=0 3.53(2H, td, J = 11.6, 1.2 Hz), 3.81 (2H, d, J = 7.2 17/158 N 8 Hz), 4.00 (2H, d, J = 10.8 Hz), 4.14-4.18 (1H, m), d CN 5.13 (1H, s), 5.64 (1H, d, J = 8.0 Hz), 6.38 (1H, s), 7.65 (1H, dd, J = 8.0, 1.6 Hz), 7.79 (1H, d, J = 1.6 Hz), 8.16 (1H, d, J = 8.4 Hz). MS: 541.3 (M-1-1)+.
a1H-NMR (CDCI3, 400 MHz) 6: 6.87 (s, 1H), 6.47 0 cF3 (s, 1H), 6.32 (s, 1H), 6.60 (d, J = 8.0 Hz, 1H), 4.95 (t, J = 6.0 Hz, 1H), 4.14-4.18 (m, 1H), 3.98 (d, J =
H 1 µ \ N 11.2 Hz, 2H), 3.82 (d, J = 7.6 Hz, 2H), 3.52 (t, J =
17/159 N ' i( NH 11.2 Hz, 2H), 3.11 (d, J = 6.0 Hz, 1H), 2.61 (s, C) 3H), 1.98 (d, J = 11.2 Hz, 2H), 1.46-1.58 (m, 6H), 1.27-1.36 (m, 2H), 1.01-1.04 (m, 12H), 0.69-0.74 (m, 2H). MS: 535.3 (M+1)+.
a 1H-NMR (CDCI3, 400 MHz) 6: 0.59-0.67 (m, 2H), CF3 0 93-1 00 (m 3H) 1 26-1 37 (m 4H) 1.49 (s 6H) N i 1.52-1.65 (m, 5H), 1.99 (d, 2H, J =
13.6 Hz), 2.63 H I \ . -=1:;$ (s, 3H), 3.53 (t, 2H, J = 11.2 Hz), 3.81 (d, 2H, J =
17/160 N 0 6.8 Hz), 3.99(d, 2H, J = 11.2 Hz), 4.12-4.20 (m, d u3 1H), 5.07 (s, 1H), 5.63 (d, 1H, J = 7.6 Hz), 6.39 (s, 1H), 7.63 (d, 1H, J = 8.4 Hz), 7.83 (s, 1H), 8.25 (d, 1H, J = 8.4 Hz). MS: 638.2 (M+1)+.
JF3 1H-NMR (CDCI3, 400 MHz) 6: 0.58-0.65 (m, 2H), N HN 0.91-1.00 (m, 3H), 1.16-1.34 (m, 10H), 1.44 (s, H I \ . S=0 6H), 1.57 (d, 1H, J = 8.0 Hz), 1.88 (t, 2H, J = 10.0 O N 8 Hz), 2.63 (s, 3H), 3.41-3.48 (m, 2H), 3.81 (d, 2H, J
17/161 HO d u3 =8.8Hz), 5.14 (s, 1H), 5.99 (t, 1H, J =
7.6 Hz), 6.40 (s, 1H), 7.65 (d, 1H, J = 11.2 Hz), 7.84 (s, 1H), 8.25 (d, 1H, J = 11.2 Hz). MS: 668.3 (M+1)+.
C) _lch 0 V
N 1H-NMR (400 MHz, CDCI3) 6:7.28 (m, 1H), 7.11 H N . (m, 1H), 6.99 (m, 1H), 6.19 (m, 1H), 6.14 (s, 1H), H I \ 3.71 (d, 2H, J = 7.2 Hz), 3.58 (d, 2H, J =
7.2 Hz), 17/162 N 2.59 (s, 3H), 1.62 (m, 3H), 1.55-1.46 (m, 9H), d 1.42-1.26 (m, 12H), 1.00 (m, 3H), 0.86 (m, 2H), 0.74 (m, 2H), 0.65 (m, 2 H). MS: 547.4 (M+1)+.
# Structure Analytical data O 1H-NMR (CDCI3, 400 MHz) 6: 0.57-0.66 (m, 2H), N
-7c_ Fly'-'` 0.97-1.01 (m, 3H), 1.25 (s, 6H), 1.30 (s, 12H), H I \ 1.50-1.54 (m, 3H), 1.62 (s, 9H), 1.86 (t, J = 7.4 17/163 o N W ,= Hz, 2H), 2.61 (s, 3H), 3.41-3.46 (m, 2H), 3.77 (d, J
HO d .7.2 Hz, 2H), 4.71 (s, 1H), 5.96-5.98 (m, 1H), 6.26 (s, 1H), 7.24 (s, 1H), 7.58 (s, 1H), 8.17 (d, J
= 8.8 Hz, 1H). MS: 602.3 (M+1)+.
00, 1H-NMR (400 MHz, CDCI3) 6: 0.53-0.63 (m, 2H), 0 j< 0.96-0.98 (m, 3H), 1.15-1.19 (m, 2H), 1.25 (s, 9H), N Hy 1.28-1.33 (m, 5H), 1.47-1.54 (m, 5H), 1.97-2.00 H I \ * S=0 (M, 2H), 2.62 (s, 3H), 3.21 (s, 3H), 3.50-3.56 (m, 17/164 N 8 2H), 3.78-3.80 (m, 2H), 3.97-4.00 (m, 2H), 4.20 do . (br s, 1H), 5.62 (d, J =8.0 Hz, 1H), 5.89(s, 1H), I 6.29 (s, 1H), 7.39-7.42 (m, 2H), 8.18 (d, J = 8.0 Hz, 1H). MS: 586.4 ([M+H]).
1H-NMR (CDCI3, 400 MHz) 6: 0.58-0.70 (m, 2H), ON) 0 0.86-1.11 (m, 3H), 1.17 (s, 9H), 1.21 (s, 9H), 1.23-N Hy 1.34 (m, 5H), 1.38-1.57 (m, 3H), 1.96-2.00 (m, H I \ 411 s=o 2H), 2.62 (s, 3H), 3.48-3.56 (m, 2H), 3.79-3.81 (m, d 17/165 N 8 4H), 3.97-4.00 (m, 2H), 4.13-4.19 (m, 1H), 4.88 (s, 0 1H), 5.61 (d, J = 8.0 Hz, 1H), 6.28 (s, 1H), 6.93 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H). MS: 602.2 (M+1) .
1H-NMR (CDCI3, 400 MHz) 6: 0.58-0.67 (m, 2H), oa 0 J, 0.93-0.99 (m, 3H), 1.24 (s, 9H), 1.30-1.33 (m, 3H), N Hy 1.51-1.58 (m, 5H), 1.97-2.01 (m, 2H), 2.62 (s, 3H), H I \ II s=o 3.53 (t, J = 11.2 Hz, 2H), 3.79 (d, J = 7.2 Hz, 2H), 17/166 N 8 3.99 (d, J = 11.2 Hz, 2H), 4.11-4.21 (m, 1H), 4.69 P (s, 1H), 5.61 (d, J = 7.6 Hz, 1H), 6.34 (s, 1H), d ,30 7.33-7.34 (m, 2H), 8.06 (d, J = 8.0 Hz, 1H). MS:
600.3 (M+1)+.
I 1H-NMR (CDCI3, 400 MHz) 6: 0.58-0.66 (m, 2H), O
0.93-1.04 (m, 3H), 1.23 (s, 9H), 1.27-1.32 (s, 9H), N HN'S= 1.54-1.56 (m, 3H), 1.88 (t, J = 7.6 Hz, 2H), 2.60 =
H I \ S0 7c0 N W 8 (s, 3H), 3.43 (t, J = 6.0 Hz, 2H), 3.79 (d, J = 6.8 Hz, 2H), 4.79 (s, 1H), 5.96 (d, J = 8.0 Hz, 1H), HO d=
o0H,2 6.32 (s, 1H), 6.64 (t, J = 73.6 Hz, 1H), 7.26 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H). MS: 612.3 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 0.72-0.78 (m, 2H), o cF3 1.03-1.07 (m, 3H), 1.22-1.28 (m, 15H), 1.34-1.37 I (m, 2H), 1.49-1.59 (m, 4H), 1.89 (t, J =
7.2 Hz, c) H \ 4. ,.., 0 N 2H), 3.48-3.53 (m, 2H), 4.00 (d, J = 7.6 Hz, 2H), NC
HO d HN1< 4.77 (s, 1H), 6.31 (t, J = 5.6 Hz, 1H), 6.64 (s, 1H), 7.71 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.85 (d, J = 0.8 Hz, 1H), 8.40 (d, J = 8.0 Hz, 1H). MS: 625.2 (M+1)+.
oy\
,0 1H-NMR (CD30D, 400 MHz) 6: 0.57-0.64 (m, 2H), 0.99-1.03 (m, 3H), 1.24 (s, 6H), 1.25 (s, 9H), 1.27-HO H I \ . So 1.44 (m, 3H), 1.51-1.53 (m, 3H), 1.86 (t, J = 7.6 17/169 o N HN< Hz, 2H), 3.38 (t, J = 7.6 Hz, 2H), 4.31 (d, J = 7.6 NH2 \--0 Hz, 2H), 6.67 (s, 1H), 7.86 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.93 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H). MS:
# Structure Analytical data 643.2 (M+1)+.
o 1H-NMR (400 MHz, CDCI3) 6: 8.11 (d, 1H, J = 8.4 A F Hz), 7.81 (s, 1H), 7.55-5.53 (m, 1H), 7.42-7.39 (m, HO ts,, 0 F 1H), 6.37 (s, 1H), 6.11 (d, 1H, J = 8.4 Hz), 4.62 (s, N ,0 17/170 H I \ * 2H), 3.81 (d, 2H, J = 6.8 Hz), 2.61-2.53 (m, 5H), N HN, 2.43-2.38 (m, 2H), 1.56-1.54 (m, 3H), 1.48 (s, 3H), \--0 -\ 1.38-1.25 (m, 3H), 1.23 (s, 9H), 0.98-0.88 (m, 3H), 0.65-0.58 (m, 2H). MS: 594.2 (M+1)4.
o FloA,. o 1H-NMR (400 MHz, DMSO-d6) 5:12.14 (s, 1H), 7.79 (d, 1H, J = 8.0 Hz), 7.19 (t, 1H, J = 1.6 Hz), N 7.14(t, 1H, J = 1.6 Hz), 6.97(t, 1H, J = 2.0 Hz), HI \ * 6.55 (s, 1H), 4.47-4.42 (m, 1H), 3.76 (d, 2H, J=
17/171 N 7.2 Hz), 2.51 (s, 3H), 2.42-2.37 (m, 2H), 2.10-2.05 d 4 (m, 2H), 1.45-1.47 (m, 3H), 1.40-1.21 (m, 18H), 0.95-0.72 (m, 10H). MS: 519.3 (M+1)+.
1H-NMR (400 MHz, CD30D) 5: 0.56-0.63 (m, 2H), N Hy 17/172 0.87-0.93 (m, 3H), 1.12 (s, 9H), 1.14 (s, 6H), 1.20-H I \
7c0 N W 8S= 1.23 (m, 3H), 1.44-1.47 (m, 3H), 1.75 (br s, 2H), 2.47 (s, 3H), 3.26 (br s, 2H), 3.81 (d, J = 7.2 Hz, HO d 0 Fõ 2H), 6.51 (s, 1H), 7.36 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H). MS: 630.3 [M+1].
HN 1H-NMR (400 MHz, DMSO-d6) 5: 0.60-0.67 (m, rj:11 2H), 0.88-0.97 (m, 3H), 1.09 (s, 6H), 1.14 (s, 9H), - OH N8 1.21-1.23 (m, 3H), 1.45-1.48 (m, 3H), 2.53 (s, 3H), 17/173 3.34-3.36 (m, 2H), 3.87 (d, J = 6.8 Hz, 2H), 6.79 P
d F3c (s, 1H), 7.48-7.58 (m, 3H), 7.72 (s, 1H), 8.00 (d, J
= 8.0 Hz, 1H), 12.19 (br s, 1H). MS: 616.2 [M+1].
OH
1H-NMR (400 MHz, DMSO-d6) 5: 0.59-0.66 (m, ..., =0,,,,, o 2H), 0.90-0.94 (m, 3H), 1.13 (s, 9H), 1.19-1.22 (m, Hy 3H), 1.45-1.48 (m, 3H), 2.25-2.40 (m, 4H), 2.52 (s, N
H I \ = S=0 3H), 2.85-2.95 (m, 1H), 3.87 (d, J = 6.8 Hz, 1H), d 0 / 8 4.48-4.54 (m, 1H), 6.81 (s, 1H), 7.48 (s, 1H), 7.58 (dd, J = 8.0, J = 1.6 Hz, 1H), 7.72 (s, 1H), 7.94 (d, F3c J = 8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 12.15 (s, 1H). MS: 614.2 [M+1r.
a 1H-NMR (400 MHz, CDCI3) 5: 1.05-1.10 (m, 3H), o Hy 1.26 (s, 12H), 1.49-1.80 (m, 7H), 1.97-2.00 (m, N
H I \ . ==0. 2H), 2.65(s, 3H), 3.30 (br s, 1H), 3.53(t, J = 11.2 17/175 N 0 Hz, 2H), 3.99 (dd, J = 10.4 Hz, 1.6 Hz, 2H), 4.10-d 0F3 4.23 (m, 1H), 4.68 (s, 1H), 5.62 (d, J = 8.0 Hz, 1H), 6.42 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H). MS: 582.2 [M+1}.
# Structure Analytical data 11-1-NMR (400 MHz, CDCI3) 6: 0.64 (s, 3H), 0.99-Q0 , 1.07 (m, 4H), 1.25 (s, 9H), 1.32-1.39 (m, 2H), N HN 1.46-1.54 (m, 4H), 1.98 (dd, J = 12.4 Hz, 2.0 Hz, H I \ * .=.0 2H), 2.65 (s, 3H), 3.53 (td, J = 11.2 Hz, 2.0 Hz, 17/176 N 8 2H), 3.99 (dd, J = 11.2 Hz, 2.0 Hz, 2H), 4.04 (s, (1Y--- cF3 2H), 4.12-4.21 (m, 1H), 4.70 (s, 1H), 5.63 (d, J =
7.2 Hz, 1H), 6.38 (s, 1H), 7.25 (s, 1H), 7.62 (d, J =
8.4 Hz, 1H), 7.81 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H).
MS: 584.3 [M+1]t 1H-NMR (400 MHz, CDCI3) 6: 0.86 (d, J = 6.4 Hz, a 0 2H), 0.96-0.99 (m, 2H), 1.26 (d, J = 2.0 Hz, 9H), HIN1-< 1.49-1.55 (m, 4H), 1.96-2.01 (m, 5H), 2.62-2.64 N
H I \ * =.1D (M, 3H), 3.52 (td, J = 11.2 Hz, 2.0 Hz, 2H), 3.92 17/177 N 8 (d, J = 6.4 Hz, 1H), 3.99 (dd, J = 8.4 Hz, 2.4 Hz, )= cF3 2H), 4.04 (d, J = 7.2 Hz, 1H), 4.11-4.23 (m, 1H), 4.71 (s, 1H), 5.61 (d, J = 7.2 Hz, 1H), 6.36 (s, 1H), 7.61 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.80 (br s, 1H) , 8.32 (d, J = 8.0 Hz, 1H). MS: 570.2 [M+1]t o .1-__, 0 v 1H-NMR (400 MHz, CDCI3) 6: 7.28 (s, 1H), 7.11 N
H N (M, 1H), 6.99 (m, 1H), 6.25 (m, 1H), 6.15 (s, 1H), H 1 \ . 3.72 (m, 4H), 2.92 (m, 2H), 2.61 (s, 3H), 1.54 (m, 17/178 N 3H), 1.42 (s, 3H), 1.40-1.25 (m, 12H), 1.00 (m, d 3H), 0.86 (m, 2H), 0.75 (m, 2H), 0.65 (m, 2 H).
MS: 519 (M+1)+.
o j< 1H-NMR (CDCI3, 400 MHz) 6: 0.58-0.65 (m, 2H), C 0.98-0.99 (m, 3H), 1.26 (s, 9H), 1.29-1.32 (m, 2H), IN Hri 1 \ 411 e =o 1.55-1.56 (m, 4H), 2.59 (s, 3H), 2.73 (d, J = 7.6 o II
79 N = Hz, 1H), 2.99-3.05 (m, 1H), 3.80 (d, J =
7.6 Hz, x O OH d cF3 2H), 3.88-4.58 (m, 4H), 4.74 (s, 1H), 6.33 (s, 1H), 7.60 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.77 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H). MS: 598.2 (M+1)+.
0 1H-NMR (CDCI3, 400 MHz) 6: 0.60-0.63 (m, 2H), N Ily 0.99 (br s, 3H), 1.24 (s, 6H), 1.27 (s, 9H), 1.30-1 \ *e =o 1.36 (m, 3H), 1.54-1.56 (m, 3H), 2.58 (s, 3H), ii 17/180 N o 2.93-2.98 (m, 1H), 3.79 (d, J = 6.8 Hz, 2H), 3.88-O 0H d u3 4.48 (m, 4H), 4.84 (s, 1H), 6.35 (s, 1H), 7.61 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H). MS: 626.3 (M+1)+.
HO 1H-NMR (400 MHz, DMSO-d6) 6: 12.21 (s, 1H), ="\::\ 0 ----\ 8.23 (d, 1H, J = 8.4 Hz), 7.92 (d, 2H, J = 8.0 Hz), o N
NH 7.84 (d, 2H, J= 8.4 Hz), 6.91 (s, 1H), 4.47-4.44 H I \ . S=0 (M, 1H), 3.89 (d, 2H, J = 6.8 Hz), 2.54 (s, 3H), 17/181 N ii o 2.42-2.37 (m, 2H), 2.11-2.06 (m, 2H), 1.47-1.45 d cF3 (m, 3H), 1.36-1.32 (m, 3H), 1.23-1.20 (m, 3H), 1.15 (s, 9H), 0.93-0.85 (m, 3H), 0.66-0.61 (m, 2H).
MS: 626.3 (M+1)+.
# Structure Analytical data OH
ONa 1H-NMR (400 MHz, CDCI3) 5: 8.31 (d, 1H, J = 8.4 ---"NH Hz), 7.78 (s, 1H), 7.60 (d, 1H, J = 8.4 Hz), 6.29 (s, N \ . 1 1H), 5.44 (s, 1H), 4.71 (s, 1H), 3.79 (d, 1H, J = 7.2 17/182 H I N S=0 I I Hz), 2.60 (s, 9H), 2.06-1.94 (m, 12H), 1.56-1.54 d 0.57 (m, 2H). MS: 652.2 (M+1) cF, (m, 3H), 1.42-1.26 (m, 12H), 0.99 (br s, 3H), 0.64-+.
a1H-NMR (400 MHz, CDCI3) 5: 0.47-0.50 (m, 2H), O j< 0.85-0.90 (m, 3H), 1.20 (s, 9H), 1.24-1.30 (m, 3H), N HN 1.47-1.55 (m, 5H), 1.97-2.00 (m, 2H), 2.66 (s, 3H), H I \ . o 3.50-3.55 (m, 2H), 3.63-3.65 (m, 2H), 3.96-3.99 17/183 N 8 (m, 2H), 4.17 (s, 1H), 4.76 (s, 1H), 5.62 (s, 1H), d , s 6.34(s, 1H), 7.30 (d, J = 6.4 Hz, 1H), 7.38 (d, J =
8.0 Hz, 1H), 7.59 (d, J = 6.4 Hz, 1H), 8.01 (d, J =
8.0 Hz, 1H). MS: 572.2 (M+1)+.
OH
1H-NMR (400 MHz, CD30D) 5: 0.55-0.59 (m, 2H), 0".= 0.87-0.94 (m, 3H), 1.18-1.27 (m, 13H), 1.48-1.49 \-_-_ , 0 1-11 (m, 2H), 2.41 (q, J = 10.0 Hz, 2H), 2.62-2.65 (s, N
H I \ = S=0 5H), 3.06 (br s, 1H), 3.77 (d, J = 4.2 Hz, 2H), 4.72 17/184 N 8 (t, J = 6.8 Hz, 1H), 6.70 (s, 1H), 7.41 (d, J = 4.8 C) , S Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 7.6 Hz, 1H). MS: 586.2 (M+1)+.
a OH
O 1H-NMR (400 MHz, CDCI3) 5: 0.50-1.46 (m, 11H), 1.62 (s, 6H), 1.93 (d, J = 12.4 Hz, 2H), 2.60 (s, N
H I \ * 3H),2.41 (d, J = 7.6 Hz, 2H), 3.22 (m, 1H),3.45 C), (m, 2H), 3.59 (m, 1H), 3.92 (m, 1H, m, 4.12 (m, 1H), 5.57 (br s, 1H), 6.21 (s, 1H), 7.33-7.50 (m, 4H), 7.82 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H). MS: 489.3 (M+1)+.
a 0_ N
H I \ *
17/186 N MS: 563.3 (M+1)+.
d o A OH 1H-NMR (400 MHz, CD30D) 5: 0.45-1.39 (m, HO 'Ir:L 0 11H), 1.55-1-56 (m, 6H), 2.25-2.33 (m, 2H), 2.50 N (s, 3H), 2.52-2.56 (m, 2H), 2.91-2.96 (m, 1H), H I \ .
N 3.20-3.23 (m, 1H), 3.63-3.66 (m, 1H), 4.57-3.65 d = (m, 1H), 6.46 (s, 1H), 7.31-7.41 (m, 2H), 7.49-7.52 (m, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H). MS: 503.2 (M+1)4".
# Structure Analytical data 1H-NMR (400 MHz, CDCI3) 6: 0.45-0.54 (m, 2H), a NH 0.85-0.90 (m, 4H), 1.24-1.30 (m, 5H), 1.24-1.50 ) 0 (m, 4H), 1.53 (s, 9H), 1.98-2.04 (m, 2H), 2.68 (s, N 3H), 3.37-3.41 (m, 1H), 3.53 (td, J =
11.6, J = 2.2 H I \ ii Hz, 2H), 3.67-3.71 (m, 1H), 3.97 (d, J
= 11.6 Hz, d 17/188 N 1H), 4.18 (br s, 1H), 5.63 (d, J = 6.8 Hz, 1H), 6.06 = (s, 1H), 6.29 (s, 1H), 7.52-7.57 (m, 2H), 7.68 (d, J
= 8.0 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.97 (dd, J
= 8.0, J = 1.2 Hz, 1H), 8.27 (d, J = 1.2 Hz, 1H).
MS: 530.3 (M+1)+.
J1õ NH 1H-NMR (400 MHz, CD30D) 6:0.40-1.37 (m, 11H), 1.40 (s, 9H), 2.23-2.31 (m, 2H), 2.47-2.53 HO ) El.. 0 0 (s, 5H), 2.89-2.93 (m, 1H), 3.32-3.36 (m, 1H), N
17/189 H I \ = 3.69-3.69 (m, 1H), 4.58 (t, J = 8.0 Hz, 1H), 6.47 N (s, 1H), 7.43-7.49 (m, 2H), 7.63 (d, J =
8.4 Hz, C), 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.86 (br s, 1H), 7.93 (dd, J = 8.4, J = 1.6 Hz, 1H), 8.23 (s, 1H). MS:
544.3 (M+1)+.
a 0 \ 1H-NMR (CDCI3, 400 MHz) 6: 0.62-0.69 (m, 2H), N _N NH 1.02 (br s, 3H), 1.28 (s, 9H), 1.34-1.39 (m, 3H), H
17/190 V-1C1 ___________ 1.49-1.64 (m, 5H), 1.97-2.00 (m, 2H), 2.65 (s, 3H), "- N \ __ ' 8 3.53 (t, J = 11.4 Hz, 2H), 3.82 (d, J =
7.2 Hz, 2H), d u3 3.98-4.01 (m, 2H), 4.13-4.19 (m, 1H), 5.24 (s, 1H), 5.54 (d, J = 7.6 Hz, 1H), 6.46 (s, 1H), 8.11 (s, 1H), 8.78 (s, 1H). MS: 585.2 (M+1)+ .
HO F2HCO 1H-NMR (400 MHz, CD30D) 6: 0.50-0.77 (m, 2H), N
H I \ * 1.00-1.10 (M, 3H), 1.26 (s, 6H), 1.37 (s, 9H), 1.49 (s, 9H), 1.18-1.64 (m, 6H), 2.58 (s, 3H), 3.34-3.39 N
C)1 (m, 2H), 3.57-3.73 (m, 2H), 6.16 (t, J = 74.8 Hz, 1H), 6.56 (s, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H). MS: 547.3 [m-Fi]'.
0 1H-NMR (400 MHz, CD30D) 6: 0.63-0.65 (m, 2H), XNN
H I \ * 0.98-1.01 (m, 3H), 1.22 (s, 6H), 1.28-1.29 (m, 3H), 1.33 (s, 9H), 1.54-1.55 (m, 3H), 2.35 (s, 3H), 2.55 N (s, 3H), 3.33 (s, 2H), 3.62 (d, J = 6.8 Hz, 2H), 6.10 d 17/192 (t, J = 75.6 Hz, 1H), 6.46 (s, 1H), 7.22 (d, J = 2.8 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H). MS: 505.4 [M+1].
HO
0 F2HCO 1H-NMR (400 MHz, CD30D) 6: 0.45-0.75 (m, 2H), 0 =(\_ H 1 0.87-1.00 (m, 3H), 1.33 (s, 9H), 1.45 (s, 9H), 1.14-1.61 (m, 6H), 2.34-2.42 (m, 2H), 2.52 (s, 3H), 17/193 N 2.58-2.64 (m, 2H), 3.00-3.07 (m, 1H), 3.53-3.70 d (m, 2H), 4.84-4.69 (m, 1H), 6.10 (t, J =
75.2 Hz, 1H), 6.54 (s, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H). MS: 573.4 [M+1]+.
# Structure Analytical data HO
F2HCO 1H-NMR (400 MHz, CD30D) 6: 0.62-0.65 (m, 2H), o A-A
\----"'N it, H \ 0.96-1.01 (m, 3H), 1.28-1.31 (m, 3H), 1.33 (s, 9H), \
1.53-1.55 (m, 3H) , 2.34 (s, 3H), 2.35-2.41 (m, 17/194 N 2H), 2.53 (s, 3H), 2.58-2.63 (m, 2H), 3.01-3.05 (m, d 1H), 3.61 (d, J = 6.8 Hz, 2H), 4.66 (m, 1H), 6.08 (t, J = 75.6 Hz, 1H), 6.48 (s, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H). MS: 531.3 [M-i-1].
HO 1H-NMR (300 MHz, CDCI3) 6: 0.67-0.72 (m, 2H), 0 86-0 90 (m 1H) 0 98-1 03 (m 12H) 1 26-1 36 o n ¨ (m, 14H), 1.55-1.57 (m, 3H), 2.28-2.35 (m, 2H), 2.60 (s, 3H), 2.75-2.82 (m, 2H), 3.09 (br s, 1H), 17/195 N 3.82 (d, J = 7.5 Hz, 2H), 4.06 (s, 2H), 4.75-4.83 d (m, 1H), 5.94 (d, J = 6.9 Hz, 1H), 6.28 (s, 1H), 6.49 (d, J = 0.9 Hz, 1H), 6.79 (s, 1H). MS: 538.3 (M+1)+.
HO
L. 0 HN-x_ 1H-NMR (400 MHz, CD30D) 6: 0.80-0.89 (m, 2H), 0 'c'y 1.06-1.10 (m, 12H), 1.27-1.42 (m, 15H), 1.59-1.62 (m, 3H), 2.36-2.43 (m, 2H), 2.57-2.64 (m, 5H), 17/196 N 3.02-3.07 (m, 1H), 3.23 (s, 2H), 4.01 (d, 2H), 4.63-4.68 (m, 1H), 6.78 (s, 1H), 6.80 (s, 1H), 6.96 (s, 1H). MS: 537.4 (M+1)+.
OH
\ 1H-NMR (300 MHz, CDCI3) 6: 0.60 (br s, 2H), 0.86 (t, J = 7.5 Hz, 3H), 0.98-1.04 (m, 3H), 1.17 (s, 6H), Eiy< 1.20-1.38 (m, 4H), 1.54-1.61 (m, 6H), 2.27-2.34 N
H I \ * S=0 (m, 2H), 2.60 (s, 3H), 2.77 (s, 5H), 3.05-3.10 (m, 17/197 N 8 1H), 3.53 (br s, 2H), 4.59 (s, 1H), 4.78-4.82 (m, C) . 1H), 6.04 (d, J = 6.6 Hz, 1H) 6.24 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H). MS:
592.3 (M+1)+.
(NN HNj< 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J
= 8.4 ON I \ iip ==o Hz), 7.79 (s, 1H), 7.61 (m, 1H), 6.27 (d, 1H), 4.71 N 8 (s, 1H), 3.79 (m, 2H), 3.71 (m, 8H), 2.40 (s, 3H), cF3 1.56 (m, 3H), 1.35-1.26 (m, 12H), 1.00 (m, 3H), 0.63 (m, 2H). MS: 570.3 (M-i-1).
NN . HNj< 1H-NMR (400 MHz, CDCI3) 6: 8.32 (d, 1H, J
= 8.4 1:32s I \ It --.0 Hz), 7.79 (s, 1H), 7.61 (m, 1H), 6.26 (s, 1H), 4.73 N 8 (s, 1H), 4.17 (m, 4H), 3.80 (m, 2H), 3.07 (m, 4H), C)1.00 u3 2.41 (s, 3H), 1.57 (m, 3H), 1.34-1.27 (m, 12H), 1.00 (m, 3H), 0.64 (m, 2H). MS: 618.2 (M+1)+.
# Structure Analytical data o 1H-NMR (400 MHz, DMSO-d6) 6: 12.19 (s, 1H), K ` 8.22 (d, 1H, J = 8.4 Hz), 7.92 (d, 1H, J = 8.4 Hz), NN
H I \ . =100 7.85 (d, 2H, J = 8.8 Hz), 7.52 (t, J=6.4Hz, 1H), N
d cF30 6.86 (s, 1H), 3.90 (d, 1H, J = 6.8 Hz), 3.35 (m, 2H), 2.54 (s, 3H), 1.46 (m, 3H), 1.22 (m, 3H), 1.09 (s, 9H), 1.06 (s, 6H), 0.95-0.85 (m, 3H), 0.62 (m, 2H). MS: 600.3 (M+1)+.
HO2c HNJ 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J = 8.0 )1N I \ . _,10 Hz), 7.78 (s, 1H), 7.60 (m, 1H), 6.39 (s, 1H), 6.35 (m, 1H), 4.87 (s, 1H), 3.88 (m, 2H), 3.78 (m, 2H), N
d cF38 3.64 (m, 2H), 3.53 (m, 2H), 2.56 (s, 3H), 2.13 (m, 2H), 1.64-1.55 (m, 5H), 1.32-1.26 (m, 12H), 0.99 17/201 o (m, 3H), 0.61 (m, 2H). MS: 642.3 (M+1)+.
H2N-1CKNN o HN<
H I \ . I - 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J = 8.4 Hz), 7.79 (s, 1H), 7.61 (m, 1H), 6.59 (m, 1H), 6.39 --*C) (s, 1H), 6.12 (m, 1H), 5.40 (m, 1H), 4.74 (s, 1H), 17/202 N 0 3.79 (m, 2H), 3.53 (m, 2H), 2.62 (s, 3H), 1.55 (m, d u3 3H), 1.34-1.10 (m, 18H), 1.00 (m, 3H), 0.63 (m, 2H). MS: 599.3 (M+1)+.
0 0 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J
= 8.4 HN" '. Hz), 7.78 (s, 1H), 7.60 (m, 1H), 6.36 (m, 2H), 6.11 H2N N I \ I. =c) (s, br, 1H), 5.98 (s, br, 1H), 4.77 (s, 1H), 3.86 (m, 17/203 0 d 8 2H), 3.79 (m, 2H), 2.60 (s, 3H), 1.97 (m, 2H), 1.73 cF3 (m, 2H), 1.55 (m, 2H), 1.33-1.24(m, 12H), 1.00 (m, 3H), 0.62 (m, 2H). MS: 641.3 (M-F1)+.
0 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J
= 8.4 N
HN Hz), 7.79 (s, 1H), 7.62 (d, 1H, J = 8.4 Hz), 7.00 HNjCKNN
H 1 \ . =-0 (m, 1H), 6.44 (s, 1H), 6.09 (m, 1H), 4.71 (s, 1H), 17/204 N 8 3.77 (m, 2H), 3.49 (m, 2H), 2.82 (d, 3H, J = 4.8 d u3 Hz), 2.61 (s, 3H), 1.56 (m, 3H), 1.36-1.22 (m, 18H), 0.99 (m, 3H), 0.61 (m, 2H). MS: 613.3 (M+1)+.
0 0 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J
= 8.0 N
HN< Hz), 7.78 (s, 1H), 7.61 (m, 1H), 6.58 (m, 1H), 6.40 11N N I \ . =,0 (s, 1H), 5.98 (m, 1H), 4.72 (s, 1H), 3.82 (m, 4H), N
õ
0 3.66 (m, 4H), 2.86 (d, 3H, J = 4.8 Hz), 2.60 (s, 3H), 1.95 (m, 2H), 1.72 (m, 2H), 1.56 (m, 3H), 17/205 0 d 1.36-1.24 (m, 12H), 1.00 (m, 3H), 0.60 (m, 2H).
MS: 655.3 (M+1)+.
a0 FI 1H-NMR (400 MHz, CDCI3) 5:8.20 (d, 1H, J = 8.4 N N_,I Hz), 7.58 (s, 1H), 7.27-7.25 (m, 1H), 6.24 (s, 1H), H I \ 411P o 5.53(s, 1H), 4.48 (s, 1H), 3.78-3.68 (m, 6H), 2.59 17/206 N d o (s, 3H), 2.14 (m, 2H), 1.81-1.74 (m, 2H), 1.62 (s, 9H), 1.54 (s, 6H), 1.32 (m, 12H), 0.98 (m, 3H), 0.61 (m, 2H). MS: 586.3 (M+1)+.
# Structure Analytical data 06,N o j< 1H-NMR (400 MHz, CDCI3) 5: 8.19 (d, 1H, J
= 8.4 N Hy Hz), 7.57 (s, 1H), 7.24 (m, 1H), 6.20 (s, 1H), 5.79 H I \ . S=0 (s, 1H), 4.48 (s, 1H), 3.92 (m, 1H), 4.48-3.78 (m, d 17/207 N 8 3H), 3.73-3.66 (m,2H), 2.78-2.75 (m, 1H), 2.62 (s, 3H), 1.62-1.53 (m, 16H), 1.49-1.33(m, 12H), 0.98 (m, 3H), 0.91-0.89 (m, 1H), 0.62 (m, 2H), 0.48 (m, 1H). MS: 598.3 (M+1)+.
OacN0 I, 1H-NMR (400 MHz, DMSO-d6) 5: 8.15 (d, 1H, J =
N HN 8.4 Hz), 7.91 (s, 1H), 7.76 (s, 1H), 7.53 (s, 1H), H I \ 7.43 (d, 1H, J = 6.8 Hz), 6.77 (s, 1H), 3.85 (s, 4H), 17/208 N 8 3.61-3.55 (m, 2H), 2.54 (s, 3H), 2.30 (m, 2H), d 2.00-1.96 (m, 2H), 1.55 (s, 9H), 1.50-1.44 (m,3H), 1.23-1.19 (m, 3H), 1.16 (s, 9H), 0.90-0.85 (m, 3H), 0.63 (m, 2H). MS: 597.3 (M+1)+.
00, 0 1H-NMR (400 MHz, CDCI3) .5: 8.32 (d, 1H, J = 8.4 N HNHz), 7.80 (s, 1H), 7.62 (d, 1H, J = 6.4 Hz), 6.33 (s, H I \ . 4=0 1H), 5.50 (s, 1H), 4.71 (s, 1H), 3.81-3.67 (m, 6H), 17/209 N 6 2.61 (s, 3H), 2.14 (m, 2H), 1.81-1.74 (m, 2H), 1.56 d u3 (m, 6H), 1.33 (m, 3H), 1.23-1.19 (m, 3H), 1.26 (s, 9H), 0.99 (m, 3H), 0.62 (m, 2H). MS: 598.3 (M+1)+.
1H-NMR (400 MHz, CDCI3) 5: 8.31 (d, 1H, J = 8.4 co,6 0 Hy Hz), 7.79 (s, 1H), 7.60 (d, 1H, J = 6.4 Hz), 6.30 (s, N
H 3.80-3.78 (m, 3H), 3.73-3.70 (m, 2H), 2.77-2.74 1H), 5.75 (s, 1H), 4.71 (s, 1H), 3.93-3.88 (m, 1H), I \ = S=0 II
d 0 (m, 1H), 2.62 (s, 3H), 1.56-1.41 (m, 7H), 1.37-1.31 (m, 3H), 1.26 (s, 9H), 0.99 (m, 3H), 0.90-0.87 (m, 1H), 0.62 (m, 2H), 0.46 (m, 1H). MS: 610.3 (M+1)+.
HNk 1H-NMR (400 MHz, CDCI3) 5: 8.32 (d, 1H, J
= 8.0 ..../N Hz), 7.78 (s, 1H), 7.61(m, 1H), 6.35 (s, 1H), 4.71 cc I \ 411 SI =0 (s, 1H), 3.99 (m, 4H), 3.80 (m, 2H), 3.64 (m, 4H), N
dc38 2.60 (s, 3H), 1.82-1.80 (m, 4H), 1.56 (m, 3H), 1.31 (m, 3H), 1.27 (s, 9H), 0.99 (m, 3H), 0.63 (m, 2H).
MS: 610.3 (M+H)+.
Q0 1H-NMR (400 MHz, CDCI3) 6: 8.19 (d, J=
8.4 Hz, N HN 1H), 7.60 (s, 1H), 7.26 (m, 1H), 6.27 (s, 1H), 5.62 H I \ II 0 (d, J=7.6Hz, 1H), 4.47 (s, 1H), 4.17 (m, 1H), 3.99 17/212 N 8 (m, 2H), 3.89 (m, 2H), 3.53 (m, 2H), 2.65 (s, 3H), d 2.01-1.92 (m, 3H), 1.61 (s, 9H), 1.55-1.49 (m, 4H), 1.46-1.34 (m, 4H), 1.31 (s, 9H), 0.90 (m, 2H). MS:
558.1 (M-i-1).
ON0 1H-NMR (400 MHz, CDCI3) 5: 8.20 (d, J=8.4Hz, N HN< 1H), 7.59 (s, 1H), 7.26 (m, 1H), 6.26 (s, 1H), 5.61 H I \ * 4=0 (d, J=7.6 Hz, 1H), 4.46 (s, 1H), 4.17 (m, 1H), 4.01-17/213 N 6 3.90 (m, 4H), 3.52 (m, 2H), 2.63 (s, 3H), 2.36 (m, _) 1H), 1.98 (m, 2H), 1.86 (m, 3H), 1.69 (s, 9H), ¨ 1.66-1.37 (m, 5H), 1.29 (s, 9H). MS:
544.1 (M+1)+.
# Structure Analytical data a 0 1H-NMR (400 MHz, DMSO-d6) 6: 8.23 (d, Fly< J=8.4Hz, 1H), 7.92 (m, 1H), 7.86 (m, 1H), 7.84 (s, N
H I \ . S=0 1H), 7.55 (m, 1H), 6.87 (s, 1H), 3.99-3.85 (m, 5H), 17/214 N 6 3.34 (m, 2H), 2.57 (s, 3H), 1.87 (m, 1H), 1.71 (m, d u3 2H), 1.53 (m, 2H), 1.34-1.25 (m, 6H), 1.15 (s, 9H), 0.88 (m, 2H). MS: 570.0 (M+1)+.
a 0 1H-NMR (400 MHz, CDCI3) 5: 8.32 (d, J=8.4 Hz, HN 1H), 7.80 (s, 1H), 7.62 (m, 1H), 6.36 (s, 1H), 5.61 N
H I \ * o (d, J=8.0 Hz, 1H), 4.70 (s, 1H), 4.16 (m, 1H), 4.01-17/215 N 8 3.97 (m, 4H), 3.52 (m, 2H), 2.63 (s, 3H), 2.37 (m, CF3 1H), 1.98 (m, 2H), 1.80-1.62 (m, 4H), 1.58-1.41 (m, 4H), 1.27 (s, 9H). MS: 556.0 (M+1)+.
a 0 L., 1H-NMR (400 MHz, CDCI3) 6: 8.30 (d, J=8.4 Hz, F11( 1H), 7.81 (s, 1H), 7.62 (m, 1H), 6.37 (s, 1H), 5.62 N ' -H \
(d, J=8.4Hz, 1H), 4.61 (s, 1H), 4.16 (m, 1H), 4.01-1 . S=0 d 17/216 N 8 3.96 (m, 2H), 3.92 (m, 2H), 3.53 (m, 2H), 2.65 (s, 3H), 2.01-1.90 (m, 3H), 1.62-1.51 (m, 2H), 1.49-1.35 (m, 5H), 1.22 (m, 8H), 0.87 (m, 6H). MS:
584.0 (M+1)+.
Oa 0 1H-NMR (400 MHz, CDCI3) 5: 8.31 (d, J=8.4Hz, 1H), 7.80 (s, 1H), 7.62 (m, 1H), 6.36 (s, 1H), 5.61 N Hy,1 (d, J=7.6 Hz, 1H), 4.62 (s, 1H), 4.17 (m, 1H), 4.01-H I \ 4. S=0 3.95 (m, 4H), 3.52 (m, 2H), 2.63 (s, 3H), 2.37 (m, 0 CF3 1H), 1.97 (d, 2H), 1.89-1.65 (m, 3H), 1.63-1.50 (m, 5H), 1.49 (m, 2H), 1.41 (s, 6H), 0.85 (t, J=7.6Hz, 3H). MS: 570.1 (M+1)+.
a 0 CF3 1H-NMR (400 MHz, CDCI3) 6: 8.19-8.18 (m, 1H), N 7.90-7.86 (m, 4H), 6.92 (s, 1H), 3.96-3.86 (m, 1H), H I \ . s02 3.86-3.83 (m, 2H), 3.38-3.33 (m, 2H), 2.79 (s, 3H), 17/218 N HN ( 1.73-1.69 (m, 4H), 1.58-1.47 (m, 5H), 1.28-1.20 z4S02 (m, 4H), 1.17 (m, 9H), 1.06 (m, 2H). MS:
634.2 µ--.) (M+H)+.
a0 a 1H-NMR (400 MHz, DMSO-d6) 5: 7.99 (s, 1 H), N 7.82 (m, 2 H), 7.59 (s, 1 H), 7.50 (d, 1 H, J = 8 H I \ Hz), 6.75 (s, 1 H), 3.92 (m, 5 H), 3.35 (m, 2 H), 17/219 N . y 2.54 (s, 3 H), 1.71 (m, 2 H), 1.53 (m, 5 H), 1.48 (s, NH 9 H), 1.36 (m, 3 H), 0.98 (m, 3 H), 0.66 (m, 2 H).
d 0 MS: 514.2 (M+1)+.
HO2Cõ, i_ 1H-NMR (DMSO-d6, 500 MHz) 6:12.18 (s, 1H), HN 8.24 (m, 1H), 7.92-7.97 (m, 2H), 7.85-7.87 (m, N
H I \ lp, ,.(:;, 2H), 6.87 (s, 1H), 4.49-4.54 (m, 1H), 3.89-3.91 (m, 17/220 N 8 2H), 2.89-2.95 (m, 1H), 2.42 (s, 3H), 2.31-2.40 (m, d u3 2H), 2.24-2.29 (m, 2H), 1.45-1.47 (m, 3H), 1.20-1.23 (m,3H), 1.15 (s, 9H), 0.87-0.99 (m,3H), 0.60-0.68 (m, 2H). MS: 598.2 (M+1)+.
# Structure Analytical data HO2Cõ, 1H-NMR (CDCI3, 500 MHz) 6: 8.18-8.20 (m, 1H), 0µ 0 HN 7.58 (s, 1H), 7.24-7.25 (m, 1H), 6.28 (s, 1H), 5.99-Aa. "
N 6.01 (m, 1H), 4.76-4.82 (m, 1H), 4.56 (s, 1H), H I is w -='10 3.77-3.79 (m, 2H), 3.07-3.12 (m, 1H), 2.77-2.81 17/221 o (m, 2H), 2.76 (s, 3H), 2.27-2.35 (m, 2H), 1.62 (s, d 9H), 1.53-1.54 (m, 3H), 1.25-1.34 (m, 12H), 0.93-0.97 (m, 3H), 0.60-0.62 (m, 2H). MS: 586.1 (M+1)+.
HO2CNN HNJ 1H-NMR (400 MHz, CDCI3) 6: 8.31 (d, 1H, J = 8.0 \ . 1 Hz), 7.79 (s, 1H), 7.61 (m, 1H), 6.36 (s, 1H), 6.07 H I ` S=0 8 (s, br, 1H), 4.72 (s, 1H), 3.79 (m, 2H), 3.44 (m, 2H), 2.60 (s, 3H), 1.88 (m, 2H), 1.55 (m, 3H), 1.32-1.26 (m, 18H), 0.93 (m, 3H), 0.63 (m, 2H).
d cF, MS: 614.3 (M+H)+.
Ho2c 0 1H-NMR (400 MHz, CD30D) 6: 8.31 (d, 1H, J
=
N
Hy 8.4 Hz), 7.90 (s, 1H), 7.81 (m, 1H), 6.71 (s, 1H), I-1 I \ . s=o 3.94 (m, 1H), 3.82 (m, 1H), 2.59 (s, 3H), 2.27 (m, 17/223 N 8 1H), 2.05 (s, 4H), 1.61-1.52 (m, 5H), 1.45-1.31 (m, d c,3 5H), 1.25 (s, 9H), 1.01 (m, 3H), 0.71 (m, 2H). MS:
626.3 (M+1)+.
HNJ 1H-NMR (400 MHz, CDCI3) 6: 8.29 (d, 1H, J
= 8.4 ....0 s-\ * 1 ii-cl (s, 1H), 3.79 (m, 2H), 3.25 (m, 2H), 2.37 (s, 3H), 0 2.17 (m, 2H), 1.78-1.71 (m, 5H), 1.62-1.47 (m, N
8H), 1.35-1.22 (m, 9H), 0.88 (m, 3H), 0.62 (m, 17/224 Ho2c d u3 2H). MS: 626.3 (M+1)+.
"7 õ,õ,J 1H-NMR (400 MHz, CDCI3) 6: 8.30 (d, 1H, J = 8.0 HO2C N .
b I \ e=o ii (s, 1H), 4.38 (m, 1H), 3.90 (m, 1H), 3.79 (m, 2H), N 0 Hz), 7.79 (s, 1H), 7.61 (m, 1H), 6.30 (s, 1H), 4.72 d u3 3.36 (m, 1H), 3.11 (m, 1H), 2.39 (s, 3H), 2.28 (m, 1H), 1.57-1.47 (m, 6H), 1.45-1.26 (m, 15H), 1.00 (m, 3H), 0.63 (m, 2H). MS: 626.3 (M+1)+.
a1H-NMR (CDCI3, 400 MHz) 6: 8.05 (d, J = 8.0 Hz, o 1H), 7.41 (s, 1H), 7.22 (m, 1H), 6.28 (s, 1H), 5.62 N Hy- (m, 1H), 4.38 (s, 1H), 4.23-4.12 (m, 1H), 4.02-3.95 H I \ * ¨
¨(:) (m, 2H), 3.86 (h, J = 6.8 Hz, 1H), 3.78 (m, 2H), 17/226 N 0 3.53 (m, 2H), 2.62 (s, 3H), 2.02-1.95 (m, 2H), C) 1.60-1.48 (m, 5H), 1.32 (d, J = 6.8 Hz, 6H), 1.30-1.21 (m, 12H), 1.02-0.94 (m, 3H), 0.59 (m, 2H).
MS: 558.3 (M+1)+.
1H-NMR (400 MHz, CDCI3) 6: 8.21 (d, 1H, J = 8.4 N Hy Hz), 7.59 (s, 1H), 7.30-7.26 (m, 1H), 6.29 (s, 1H), H I \ . S=0 5.64 (d, 1H, J = 8.0 Hz), 4.92 (s, 1H), 4.18-4.16 17/227 N 8 (m, 1H), 4.00-3.97 (m, 2H), 3.79 (m, 2H), 3.56-d 3.49 (m, 2H), 2.62 (s, 1H), 2.00-1.97 (m, 2H), 1.68-1.53 (m, 14H), 1.35-1.30 (m, 3H), 1.19 (s, 3H), 0.97 (m, 3H), 0.83-0.81 (m, 2H), 0.63-0.60 # Structure Analytical data (m, 2H), 0.50-0.47 (m, 2H). MS: 570.1 (M+1)+.
,H-NMR (400 MHz, DMSO-d6) 6: 8.19 (d, 1H, J =
N 1111 8.4 Hz), 7.99 (d, 1H, J = 8.0 Hz), 7.54-7.41 (m, H I \ . S=0 3H), 6.71 (s, 1H), 3.95-3.84 (m, 5H), 3.68-3.62 (m, 17/228 N 8 1H), 3.37-3.33 (m, 2H), 2.53 (s, 3H), 1.95-1.88 (m, d 4H), 1.72-1.68 (m, 2H), 1.57-1.45 (m, 16H), 1.23-1.20 (m, 3H), 0.93-0.88 (m, 3H), 0.66-0.61 (m, 2H). MS: 570.1 (M+1)+.
cQo CF3 1H-NMR (400 MHz, CDCI3) 6: 7.65 (s, 1H), 7.37 N 0 (d, 1H, J = 10.4 Hz), 6.41 (s, 1H), 5.62 (d, 1H, J =
H 1 \ = V:3$ 8.0 Hz), 5.07 (s, 1H), 4.16 (m, 1H), 3.99 (m, 2H), 17/229 N 14N--/ 3.83 (m, 2H), 3.53 (m, 2H), 2.63 (s, 3H), 1.98 (m, d F 2H), 1.58-1.49 (m, 5H), 1.38-1.26 (m, 12H), 1.02 (m, 3H), 0.67 (m, 2H). MS: 602.2 (M+H)+.
a CF3 1H-NMR (400 MHz, CDCI3) 6: 8.09 (d, 1H, J
= 9.6 N HN'. Hz), 7.79 (d, 1H, J = 6.4 Hz), 6.38 (s, 1H), 5.61 (d, H I \ 411 =ICI 1H, J = 8.0 Hz), 4.76 (s, 1H), 4.16 (m, 1H),3.98 17/230 N 8 (m, 2H), 3.66 (d, 2H, J = 6.8 Hz), 3.52 (m, 2H), C) F 2.63 (s, 3H), 1.98 (m, 2H), 1.59-1.47 (m, 5H), 1.35-1.24 (m, 12H), 1.00 (m, 3H), 0.58 (m, 2H).
MS: 602.3 (M+H)+.
Do 1H-NMR (400 MHz, CDCI3) 6: 8.18(d, 1H, J
=8.4 N
F CF3 Hz), 7.60 (m, 1H), 6.36 (s, 1H), 5.59 (d, 1H, J =
H 1 \ A g.0 8.0 Hz), 4.79 (s, 1H), 4.16 (m, 1H), 3.98 (m, 2H), 17/231 N --M HN--/ 3.64 (d, 2H, J = 6.8 Hz), 3.52 (m, 2H), 2.62 (s, d 3H), 1.97 (m, 2H), 1.55-1.47 (m, 5H), 1.34-1.28 (m, 12H), 1.01 (m, 3H), 0.62 (m, 2H). MS: 602.2 (M+H)+.
CQ0 1H-NMR (400 MHz, CDCI3) 6: 7.70 (s, 1H), 7.47 N CF3 (s, 1H), 6.35 (s, 1H), 5.61 (d, 1H, J =
8.4 Hz), 4.65 H\ 9 o ii 11 s,, (s, 1H), 4.17 (m, 1H), 3.98 (m, 2H), 3.80 (d, 2H, J
= 7.2 Hz), 3.53 (m, 2H), 2.82 (s, 3H), 2.62 (s, 3H), HN--/
d 1.99 (m, 2H), 1.77-1.63 (m, 5H), 1.58-1.20 (m, 12H), 1.00 (m, 3H), 0.64 (m, 2H). MS: 598.3 (M+H)+.
..
# Structure Analytical data CD0 1H-NMR (400 MHz, CDCI3) 6: 8.13 (s, 1H), 7.58 N cF3 (s, 1H), 6.15 (s, 1H), 5.52 (d, 1H, J =
7.6Hz), 4.65 H 1 \ 4. k,,,, (s, 1H), 4.13-4.06 (m, 1H), 3.93-3.90 (m, 2H), 3.48-3.41 (m, 4H), 2.55 (s, 3H), 2.24 (s, 3H), 1.94-d HN-.._/ 1.90 (m, 2H), 1.53-1.40 (m, 5H), 1.35-1.19 (m, 12H), 0.93 (m, 3H), 0.57-0.51 (m, 2H). MS: 598.3 (M+H)+.
D o 1H-NMR (400 MHz, CDCI3) 6: 8.06 (d, 1H, J = 8.0 Cl Hz), 7.42 (s, 1H), 7.28 (d, 1H, J = 8.4 Hz), 6.26 (s, N
H 4.
9 1H), 5.54-5.52 (m, 1H), 4.90 (s, 1H), 4.10 (m, 1H), 1 \ k.õo 17/234 N HN-.../ 3.92 (m, 2H), 3.74 (m, 2H), 3.46 (m, 2H), 2.55 (s, 8 3H), 1.91 (m, 2H), 1.50-1.32(m, 5H), 1.27-1.17 (m, 12H), 0.93 (m, 3H), 0.55 (m, 2H). MS: 550.2 (M+H)+.
D0 1H-NMR (400 MHz, CDCI3) 6: 7.44 (s, 2H), 6.36 CI
N (s, 1H), 5.59 (d, 1H, J = 6.4 Hz), 5.32 (s, 1H), 4.16 H 1 \410 9s,o (m, 1H), 3.99 (m, 2H), 3.81 (m, 2H), 3.53 (m, 2H), d 17/235 N HN--./ 2.62 (s, 3H), 1.98 (m, 2H), 1.59-1.41 (m, 5H), Cl 1.39-1.25 (m, 12H), 1.03 (m, 3H), 0.69 (m, 2H).
MS: 584.2 (M+H)+.
D 1H-NMR (400 MHz, CDCI3) 6: 8.64 (d, 1H, J = 8.4 o . n Hz), 8.35 (m, 1H), 7.77-7.67 (m, 2H), 7.58-7.48 N (m, 2H), 6.34 (s, 1H), 5.64 (d, 1H, J = 7.6 Hz), H 1 \ . s'il,,o 4.63 (s, 1H), 4.21-4.17 (m, 1H), 4.00-3.97 (m, 2H), 17/236 N HN-..../ 3.71-3.66 (m, 1H), 3.56-3.50 (m, 2H), 3.33-3.27 8 (m, 1H), 2.68 (s, 3H), 2.01-1.98 (m, 2H), 1.57-1.45 (m, 5H), 1.30-1.17 (m, 12H), 0.90-0.84 (m, 3H), 0.51-0.43 (m, 2H). MS: 566.3 (M+H)+.
ON0 1H-NMR (400 MHz, CDCI3) 6: 7.91 (d, 2H, J
= 8.4 N
fiN Hz), 7.44 (d, 2H, J = 8.4 Hz), 6.29 (s, 1H), 5.61 (d, H I \ . .=-Ci 1H, J = 7.6 Hz), 4.49 (s, 1H), 4.17 (m, 1H), 3.98 ii 17/237 N (m, 2H), 3.80 (m, 2H), 3.52 (m, 2H), 2.62 (s, 3H), d 1.98 (m, 2H), 1.59-1.47 (m, 5H), 1.36-1.25 (m, 12H), 0.96 (m, 3H), 0.65 (m, 2H). MS: 516.3 (M+H)+.
oa0 1H-NMR (400 MHz, CDCI3) 6: 7.92 (t, J=8.0 Hz, N HN 1H), 7.21 (d, 1H, J = 6.8 Hz), 7.16 (d, 1H, J =
10.0 H I \ lik =.1:3 Hz), 6.32 (s, 1H), 5.55 (d, 1H, J = 8.0 Hz), 4.74 (s, 17/238 N 8 1H), 4.16 (m, 1H), 3.98 (m, 2H), 3.81 (m, 2H), d F 3.52 (m, 2H), 2.62 (s, 3H), 1.98 (m, 2H), 1.56-1.47 (m, 5H), 1.37-1.21 (m, 12H), 0.99 (m, 3H), 0.63 (m, 2H). MS: 534.2 (M+H)+.
# Structure Analytical data 41110 1H-NMR (400 MHz, CDCI3) 6: 8.58 (d, J=8.4Hz, 1H), 8.26 (d, J=7.6Hz, 1H), 7.67-7.59 (m, 2H), 0 '11 i \ ii 9,.0 7.50-7.38 (m, 2H), 6.31-6.23 (m, 1H), 4.66 (s, 1H), 0 -- N , 3.76-3.70 (m, 3H), 3.63-3.58 (m, 1H), 3.41 (m, d 17/239 1-1N-_/ 2H), 3.25-3.19 (m, 1H), 2.59 (s, 3H), 1.60 (m, 4H), 1.42-1.41 (m, 3H), 1.37-1.35 (m, 3H), 1.31-1.10 (m, 9H), 0.87-0.81 (m, 3H), 0.44-0.38 (m, 2H).
MS: 596.3 (M+H).
HO2c1H-NMR (400 MHz, DMSO-d6) 6: 8.77 (d, LI 0 J=8.4Hz, 1H), 8.24 (d, J=7.6Hz, 1H), 7.93-7.91 N 4111 n (m, 1H), 7.85-7.80 (m, 2H), 7.75-7.68 (m, 2H), H 1 \Ak -,-;,0 7.67-7.59 (m, 1H), 6.75 (s, 1H), 4.56-4.50 (m, 1H), 17/240 N w SFisN'__./ 3.75-3.74 (m, 1H), 3.38 (m, 1H), 2.92-2.87 (m, d 1H), 2.58 (s, 3H), 2.41-2.36 (m, 2H), 2.28-2.26 (m, 2H), 1.39-1.34 (m, 3H), 1.17-1.01 (m, 9H), 0.87-0.85 (m, 3H), 0.82-0.74 (m, 3H), 0.50-0.42 (m, 2H). MS: 580.3 (M+H)+.
1H-NMR (400 MHz, CDCI3) 6: 8.57 (d, J=8.4Hz, 1H), 8.25 (d, J=7.6Hz, 1H), 7.68-7.66 (m, 1H), HO N sil 9 7.61-7.57 (m, 1H), 7.49-7.45 (m, 1H), 7.39 (d, H i \ 4100 ,c;#
J=7.6Hz, 1H), 6.26 (s, 1H), 6.11 (s, br, 1H), 4.73 17/241 N HN-1/ (s, 1H), 3.61-3.57 (m, 1H), 3.37 (m, 2H), 3.24-3.18 d (m, 1H), 2.56 (s, 3H), 1.79-1.76 (m, 2H), 1.40 (m, 3H), 1.18-1.10 (m, 18H), 0.85-0.79 (m, 3H), 0.42-0.40 (m, 2H). MS: 596.3 (M+H)+.
D 1H-NMR (400 MHz, CDCI3) 6: 8.66 (d, J=8.4Hz, 410 0 1H), 8.35 (d, J=7.6Hz, 1H), 7.77-7.67 (m, 1H), N 7.58-7.54 (m, 2H), 7.53-7.51 (m, 1H), 7.50 (d, II 41 S* J=7.6Hz, 1H), 6.32 (s, 1H), 5.65-5.63 (m, 1H), 17/242 N H,N--./ 4.69 (s, 1H), 4.21-4.17 (m, 1H), 3.99-3.96 (m, 2H), C? 3.88-3.82 (m, 1H), 3.56-3.50 (m, 3H), 2.68 (s, 3H), 2.29-2.25 (m, 1H), 2.01-1.97 (m, 2H), 1.77-1.46 (m, 6H), 1.26-1.20 (m, 12H). MS: 538.3 (M+H)+.
HO 0 1H-NMR (400 MHz, CDCI3) 6: 8.66 (d, J=8.4Hz, 1H), 8.34 (d, J=7.6Hz, 1H), 7.74-7.67 (m, 2H), eiN 1 \ 4., g,0 7.58-7.47 (m, 2H), 6.36 (s, 1H), 6.23 (m, 1H), 4.68 0 N 1-1N--/ (s, 1H), 3.87-3.76 (m, 5H), 3.53-3.46 (m, 3H), 2.67 d (s, 3H), 2.28-2.24(m, 1H), 1.72-1.58 (m, 6H), 1.48-1.45 (m, 1H), 1.24(s, 12H). MS: 568.2 (M+H)+.
a1H-NMR (400 MHz, CDCI3) 6: 8.21 (d, 1H, J = 8.0 0 / Hz), 7.39 (d, 1H, J = 8.0 Hz), 7.34 (s, 1H), 6.22 (s, N / 1H), 5.63 (d, 1H, J = 7.2 Hz) , 4.18-4.16 (m, 1H), H I \ . S 3.98 (m, 2H), 3.77 (m, 2H), 3.55-3.50 (m, 2H), d 17/244 N b 2.76-2.63 (m, 5H), 2.01-1.97 (m, 2H), 1.71-1.51 (m, 5H), 1.48 (s, 9H), 1.43-1.32 (m, 3H), 1.24 (s, 9H), 1.04-0.98 (m, 3H), 0.70-0.61 (m, 2H). MS
found: 555.0 (M+1)+.
# Structure Analytical data Q o j< 1H-NMR (CDCI3, 300 MHz) 6: 0.82-0.94 (2H, m), ____________________________ HN 1.01-1.09 (3H, m), 1.22-1.32 (12H, m), 1.44-1.65 (5H, m), 1.97-2.03 (2H, m), 2.63 (3H, s), 3.53 (2H, 17/245 N N 0 m), 3.98-4.03 (2H, m), 4.14-4.21 (1H, m), 4.43-d 0F3 4.49 (2H, m), 4.79 (1H, s), 5.63 (1H, d, J = 7.5 Hz), 6.92 (1H, m), 7.78 (1H, d, J = 9.0 Hz), 8.44 (1H, d, J = 9.0 Hz). MS: 585.2 (M+1)+.
0 H 1H-NMR (300 MHz, CD30D) 6: 0.64-0.89 (m, 9H), oyN
H I \ * 1.03-1.10 (m, 3H), 1.30 (s, 3H), 1.54-1.66 (m, 9H), 1.96-2.10 (m, 2H), 2.25-2.33 (m, 2H), 2.49-2.64 17/246 HO N (m, 4H), 2.92-3.19 (m, 1H), 3.30-3.43 (m, 2H), d 4 3.81-3.83 (m, 2H), 6.40 (s, 1H), 7.09 (s, 1H), 7.23 (s, 1H), 7.40-7.41 (m, 1H), 7.73-7.76 (m, 1H).MS:
521.3 (M+1)+.
a1H-NMR (CDCI3, 400 MHz) 6: 8.11 (d, J = 12.0 0 j< Hz, 1H), 7.56 (s, 1H), 7.47 (d, J = 12.0 Hz, 1H), N 02s6.50 (s, 1H), 6.23 (s, 1H), 5.60 (d, J = 9.6 Hz, 1H), H I \ . NH 4.14-4.20 (m, 1H), 3.97-4.01 (m, 2H), 3.73-3.76 d 17/247 N (m, 2H), 3.49-3.57 (m, 2H), 2.62 (s, 3H), 1.97-2.01 , (m, 2H), 1.50-1.59 (m, 5H), 1.46 (s, 9H), 1.26-1.39 CF
(m, 3H), 0.72-1.01 (m, 3H), 0.59-0.72 (m, 2H).
MS: 584.3 (M+1)+.
oa0 F 1H-NMR (CDCI3, 400 MHz) 6: 7.45 (s, 1H), 7.31 N 02S ( (d, J = 9.6 Hz, 1H), 6.27 (s, 1H), 5.68 (s, 1H), 5.60 H I \ . NH (d, J = 7.6 Hz, 1H), 4.13-4.18 (m, 1H), 3.98 (d, J =
17/248 N 11.6 Hz, 2H), 3.77 (d, J = 7.2 Hz, 2H), 3.52 (m, C) cF, 2H), 2.61 (s, 3H), 1.96-2.00 (m, 2H), 1.53-1.55 (m, 15H), 1.40-1.44 (m, 2H), 1.01-1.03 (m, 3H), 0.66-0.71 (m, 2H). MS: 602.2 (M+1)+.
-4 1H-NMR (400 MHz, CDCI3) 6: 7.77 (s, 1H), 7.64 00 0 NN (s, 1H), 7.61-7.55 (m, 1H), 7.38 (d, J=8.0Hz, 1H), \ I
N \ \ fa 6.35-6.30 (m, 2H), 5.64 (d, 1H, J=7.6Hz), 4.23-H , 4.05 (m, 2H), 4.02-3.96 (m, 2H), 3.83 (d, 2H, 17/249 N 0F3 J=7.2Hz), 3.58-3.48 (m, 2H), 2.64 (s, 3H), 2.03-d 1.96 (m, 2H), 1.62-1.36 (m, 14H), 1.07-1.00 (m,3H), 0.76-0.63 (m,2H). MS: 557.3 (M+H)+.
---- 1H-NMR (400 MHz, CDCI3) 6: 7.76 (s, 1H), 7.65 0 NN (S, 1H), 7.56 (d, 1H, J = 8.0 Hz), 7.35 (d, 1H, J =
..õ...-õ, \ = \ \ 7.6 Hz), 6.34-6.26 (m, 2H), 6.07 (br s, 1H), 4.15-11 I 4.08 (m, 1H), 3.82 (m, 2H), 3.48 (br s, 2H), 2.63 ."---). N
7 co2H 8 CF (s, 3H), 1.93-1.86 (m, 2H), 1.62-1.53 (m, 3H), 1.46-1.34 (m, 9H), 1.28 (m, 6H), 1.24-0.96 (m, 3H), 1.71-0.66 (m, 2H). MS: 587.3 (M+H)+.
# Structure Analytical data 00, 0 0._...-- 1H-NMR (400 MHz, DMSO-d6) 6: 7.59 (s, 1H), \ \N 7.53-7.49 (m, 2H), 7.42-7.37 (m, 1H), 6.69 (s, 1H), N k \ gik. N' 4.01-3.82 (m, 5H), 3.35 (m, 2H), 2.54 (s, 3H), 17/251 N 1.74-1.70 (m, 2H), 1.58-1.43 (m, 5H), 1.42 (s, 9H), d 1.31-1.20 (m, 12H), 1.02-0.92 (m, 3H), 0.67 (m, 2H). MS: 561.3 (M+1)+.
HO
0_......_, 11-I-NMR (400 MHz, CDCI3) 6: 7.53 (s, 1H), 7.44 o (d, 1H, J = 7.6 Hz), 7.25-7.21 (m, 1H), 6.26 (s, "N \ . 1 H), 6.05 (br s, 1H), 4.79 (br s, 1H), 3.77 (m, 1H), H \
17/252 N 3.15-3.05 (m, 1H), 2.81-2.72 (m, 2H), 2.60 (s, 3H), d 2.33-2.28 (m, 2H), 1.60-1.43 (m, 12H), 1.38-1.22 (m, 12H), 1.05-0.96 (m, 3H), 0.62 (m, 2H). MS:
574.8 (M+1)+.
a1H-NMR (400 MHz, CDCI3) 6: 0.35-0.50 (m, 1H), o ,.e 0.65-0.76 (m, 1H), 1.02-1.03 (m, 3H), 1.28 (s, 9H), N Hy- 1.47-1.53 (m, 5H), 1.58-1.65 (m, 3H), 1.68-1.83 H I \ 11 S=0 (m, 3H), 1.98 (m, 2H), 2.71 (s, 3H), 3.52 (m, 2H), e 17/253 N 8 3.80-3.84 (m, 1H), 3.97-4.00 (m, 2H), 4.11-4.20 ., , (m, 1H), 4.71 (s, 1H), 5.61 (d, J = 7.2 Hz, 1H), CF
6.27 (s, 1H), 7.52-7.57 (m, 1H), 7.74 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H). MS: 598.3 (M+1)+.
a1H-NMR (400 MHz, CDCI3) 6: 0.33-0.48 (m, 1H), o 0.66-0.75 (m, 1H), 0.98-1.06 (m, 3H), 1.28 (s, 9H), N HIV" 1.47-1.53 (m, 5H), 1.58-1.65 (m, 3H), 1.68-1.83 H I \ lik =00 (r11, 3H), 1.98 (m, 2H), 2.71 (s, 3H), 3.53 (m, 2H), 17/254 N 8 3.79-3.84 (m, 1H), 3.97-4.00 (m, 2H), 4.14-4.18 =,,õ
d (m, 1H), 4.71 (s, 1H), 5.61 (d, J = 7.2 Hz, 1H), CF
6.27 (s, 1H), 7.52-7.57 (m, 1H), 7.75 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H). MS: 598.3 (M+1)+.
a 0 1H-NMR (400 MHz, CDCI3) 6: 0.96-1.06 (m, 2H), EiN < 1.26 (s, 11H), 1.29-1.40 (m, 4H), 1.47-1.56 (m, N
H I \11 S=0 3H), 2.01-1.96 (m, 2H), 2.70 (s, 3H), 3.49-3.55 (m, 17/255 N 8 3H), 4.02-3.96 (m, 2H), 4.03 (s, 2H), 4.13-4.21 (m, dcF3 1H), 4.69 (s, 1H), 5.62 (d, J = 8.0 Hz, 1H), 6.40 (s, OH 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H). MS: 600.3 (M+1)+.
a0 ,, 1H-NMR (300 MHz, CDCI3) 6: 0.99-1.02 (m, 13H), N HN"'"- 1.26 (s, 9H), 1.28-1.47 (m, 4H), 1.48-1.57 (m, 2H), H I \ 441 =() 1.94-2.00 (m, 4H), 2.64 (s, 3H), 3.52 (m, 2.0 Hz, N 8 2H), 3.90 (m, 2H), 3.97-4.02 (m, 2H), 4.14-4.17 a c3 (m, 1H), 4.72 (s, 1H), 5.62 (d, J = 7.6 Hz, 1H), 6.39 (s, 1H), 7.62 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H).
F F MS: 620.3 (M+1)+.
, # Structure Analytical data a Hõ
11' 1H-NMR (300 MHz, CDCI3) 6: 0.68-0.77 (m, 2H), 0.88-1.30 (m, 13H), 1.35-1.48 (m, 3H), 1.51-1.58 NH
"
(m, 2H), 1.88-2.04 (m, 4H), 2.63-2.64 (m, 3H), I \ * S=0 N 8 3.52 (m, 2H), 3.83-3.88 (m, 2H), 4.02-3.96 (m, Fa u3 2H), 4.11-4.44 (m, 2H), 4.80-4.70 (m, 1H), 5.63 (d, J = 7.6 Hz, 1H), 6.39 (s, 1H), 7.60-7.63 (m, 1H), 7.79-7.80 (m, 1H), 8.32 (d, J = 8.0 Hz, 1H). MS:
602.3 (M+1)+.
0 1H-NMR (400 MHz, CDCI3) 6: 8.45(d, J = 8.4 Hz, Q
0 )L. 1H), 8.18 (s, 1H), 7.74 (s, 1H), 7.65-7.60 (m, 1H), N HN 6.33 (s, 1H), 5.57 (d, 1H, J = 8.0 Hz), 4.12-4.02 H I \ * -=.0 (M, 1H), 3.95-3.89 (m, 2H), 3.76 (d, 2H, J = 6.8 17/258 N 8 Hz), 3.49-3.43 (m, 2H), 2.56 (s, 3H), 1.94-1.90 (m, d CF 2H), 1.51-1.45 (m, 5H), 1.28-1.25 (m, 3H), 1.10 (s, 9H), 0.94-0.93 (m, 3H), 0.59 (m, 2H). MS: 612.3 (M+H)+.
Ho2ct 1H-NMR (CDCI3, 400 MHz) 6: 0.56-0.65 (m, 2H), 0 0.96-1.03 (m, 3H), 1.25 (s, 14H), 1.27-1.42 (m, HN 8H), 1.62-1.64 (m, 2H), 1.98-2.02 (m, 2H), 2.22-N
H I \ 11 o 2.24 (m, 2H), 2.62 (s, 3H), 3.80 (d, J = 7.2 Hz, 17/259 N 0 2H), 3.91-3.95 (m, 1H), 4.81 (s, 1H), 5.57 (d, J =
d u3 8.4 Hz, 1H), 6.33 (s, 1H), 7.60 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.79 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H).
MS: 640.3 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 0.59-0.67 (m, 3H), 0.94-1.03 (m, 5H), 1.14-1.37 (m, 21H), 1.60-1.62 H02cn 0 j< (m, 2H), 2.04-2.12 (m, 1H), 2.63 (s, 3H), 3.80 (d, N Hisil 2H, J = 6.6 Hz), 4.33 (m, 1H), 4.74 (s, 1H), 5.81 H I \ 411 S=0 (d, 1H, J = 8.4 Hz), 6.35 (s, 1H), 7.63 (d, 1H, J =
ii 17/260 single N 8.4 Hz), 7.80 (s, 1H), 8.30 (d, 1H, J =
8.4 Hz). MS:
enantiomer d CF
628.3 (M+1) . Chiral HPLC
(hexane/ethanol/NHEt2 = 70/30/0.2 on Chiralpak IC 5 pm 4.6 x 250 mm, 1 mUm in, T =
30 C): Fit = 7.646 min (2nd eluting enantiomer).
1H-NMR (CDCI3, 400 MHz) 6: 0.59-0.67 (m, 3H), 0.94-1.03 (m, 5H), 1.14-1.37 (m, 21H), 1.60-1.62 H02cn 0 j< (m, 2H), 2.04-2.12 (m, 1H), 2.63 (s, 3H), 3.80 (d, N FIN,' 2H, J = 6.6 Hz), 4.33 (m, 1H), 4.74 (s, 1H), 5.81 H I \ II S=0 (d, 1H, J = 8.4 Hz), 6.35 (s, 1H), 7.63 (d, 1H, J =
17/261 single N 8 8.4 Hz), 7.80 (s, 1H), 8.30 (d, 1H, J =
8.4 Hz). MS:
enantiomer d CF
628.3 (M+1)+; Chiral HPLC
(hexane/ethanol/NHEt2 = 70/30/0.2 on Chiralpak IC 5 pm 4.6 x 250 mm, 1 mUmin, T =
30 C): Fit = 6.256 min (1st eluting enantiomer).
Ho2Cµ
TI 01H-NMR (CDCI3, 400 MHz) 6: 7.04 (s, 2H), 6.29 N
(s, 1H), 6.00 (d, J = 7.6 Hz, 1H), 4.82-4.75 (m, 1H), 3.78 (d, J = 7.2 Hz, 2H), 3.11-3.06 (m, 1H), H--- / \ N
17/262 N ¨ 2.84-2.75 (M, 1H), 2.60 (s, 3H), 2.35-2.24 (m, 2H), d 1.57-1.51 (m, 2H), 1.37 (s, 18H), 1.33-1.25 (m, 4H), 1.02-0.84 (m, 3H), 0.69-0.64 (m, 2H). MS:
508.3 (M+1)+;
# Structure Analytical data OU 1H-NMR (400 MHz, CDCI3) 6: 8.64 (d, 1H, J = 8.4 410 o Hz), 8.33 (d, 1H, J = 7.6 Hz), 7.74-7.64 (m, 2H), N 7.60-7.50 (m, 2H), 6.37 (s, 1H), 5.89 (d, 1H, J =
H I \ 41 ss.., 8.0 Hz), 4.85 (s, 1H), 4.35-4.29 (m, 1H), 3.72-3.63 17/263 N 14N-../ (rn, 1H), 3.33-3.24 (m, 1H), 3.20-3.13 (m, 4H), d 2.66 (s, 3H), 2.42-2.38 (m, 2H), 2.22-2.18 (m, 2H), 1.52-1.45 (m, 3H), 1.30-1.13 (m, 12H), 0.91-0.86 (m, 3H), 0.52-0.42 (m, 2H). MS: 614.2 (M-i-1)+.
HO0 1H-NMR (400 MHz, CDCI3) 6: 8.65 (d, 1H, J
= 8.4 )-\N 4100 Hz), 8.34 (d, 1H, J = 7.6 Hz), 7.78-7.74 (m, 1H), H 1 \ 41 g*07.71-7.66 (m, 1H), 7.59-7.52 (m, 1H), 7.49 (d, J =
N
7.6 Hz, 1H), 6.38 (s, 1H), 6.24 (br s, 1H), 4.63 (s, d 17/264 1H), 3.70-3.66 (m, 1H), 3.45-3.40 (m, 2H), 3.33-3.26 (m, 1H), 2.67 (s, 3H), 1.52-1.47 (m, 3H), 1.33-1.12 (m, 18H), 0.91-0.87 (m, 3H), 0.53-0.45 (m, 2H). MS: 554.3 (M+1)+.
0 1H-NMR (400 MHz, CDCI3) 6: 8.65 (d, 1H, J
= 8.4 H \ 4110 0 Hz), 8.34 (d, 1H, J = 7.6 Hz), 7.75-7.68 (m, 2H), it o 7.58-7.52 (m, 1H), 7.48 (d, J = 7.6 Hz, 1H), 6.33 N 1 110 s . z (s, 1H), 6.04-5.98 (m, 1H), 4.64 (s, 1H), 3.70-3.66 d HN......, (m, 1H), 3.32-3.24 (m, 3H), 3.12-2.92 (m, 4H), 2.66 (s, 3H), 2.21-1.89 (m, 5H), 1.48 (m, 3H), 1.30-1.11 (m, 12H), 0.90 (m, 3H), 0.49 (m, 2H).
MS: 628.3 (M+1)+.
41100 1H-NMR (400 MHz, CDCI3) 6: 8.64 (d, 1H, J
= 8.8 Hz), 8.34 (d, 1H, J = 7.6 Hz), 7.77-7.65 (m, 2H), d HN..õ . (s, 4H), 3.73-3.56 (m, 5H), 3.29 (m, 1H), 2.65 (s, 3H), 1.80 (m, 4H), 1.78 (m, 3H), 1.28-1.18 (m, 12H), 0.88 (m, 3H), 0.47 (m, 2H). MS: 592.3 (M+1)+.
0 1H-NMR (400 MHz, DMSO-d6) 6: 8.77 (d, 1H, J =
0 8.8 Hz), 8.24 (d, 1H, J = 7.6 Hz), 7.86 (s, 1H), H2wAr\N
41100 7.81-7.59 (m, 4H), 7.45 (m, 1H), 7.30 (s, 1H), 7.02 H i \ 41 (s, 1H), 6.69 (s, 1H), 3.79-3.66 (m, 3H), 3.38-3.22 17/267 0 N 8 HN--../ (m, 5H), 2.58 (s, 3H), 1.92 (d, 2H, J =
15.6 Hz), 1.50-1.37 (m, 5H), 1.19-1.13 (m, 3H), 1.02 (s, 9H), 0.82-0.73 (m, 3H), 0.45 (m, 2H). MS: 623.3 (M+1)+.
HO 01H-NMR (400 MHz, DMSO-d6) 6: 8.65 (d, 1H, J =
)<\N 4110 0 8.8 Hz), 8.33 (d, 1H, J = 7.6 Hz), 7.69 (m, 2H), ...... ...... H 1 \ 40o 7.56 (m, 1H), 7.46 (d, 1H, J = 7.6 Hz), 6.39-6.31 S (m, 2H), 4.70 (s, 1H), 3.68-3.64 (m, 1H), 3.54-3.42 17/268 02 c N3 FIN--.../ (m, 4H), 3.30 (m, 1H), 2.87 (m, 2H), 2.66 (s, 3H), 2.18-2.00 (m, 4H), 1.48 (m, 3H), 1.25-1.21 (m, 3H), 1.17 (s, 9H), 0.89 (m, 3H), 0.54 (m, 2H).
MS:644.2 (M+1)+.
# Structure Analytical data O\
1H-NMR (400 MHz, CDCI3) 6: 8.63 (d, 1H, J = 8.4 AI\---\ Hz), 8.32( d, 1H, J = 7.6 Hz), 7.73-7.62 (m, 2H), N. (,,0 7.52 (m, 1H), 7.48-7.38 (m, 2H), 6.45 (s, 1H), 4.85 H 1 \
17/269 N S,' (s, 1H), 3.99-3.63 (m, 9H), 3.35-3.24 (m, 3H), 2.91 I-IN¨/ (m, 2H), 2.64 (s, 3H), 1.49-1.45 (m, 3H), 1.29-1.13 d (m, 12H), 0.88 (m, 3H), 0.47 (m, 2H). MS:
595.5 (M+1)+.
41010,ip 1H-NMR (400 MHz, CDCI3) 5: 8.65 (d, 1H, J = 8.4 Hz), 8.35 (d, 1H, J = 7.6 Hz), 7.69 (m, 2H), 7.58 02SON I \ 41, g- (m, 1H), 7.49 (m, 1H), 6.30 (s, 1H), 4.76 (s, 1H), 84 FIN-...../ 4.06 (m, 4H), 3.69 (m, 1H), 3.30 (m, 1H), 3.02 (m, 4H), 2.65 (s, 3H), 2.39-2.35 (m, 4H), 1.48 (m, 3H), 1.29-1.18 (m, 12H), 0.88 (m, 3H), 0.48 (m, 2H).
MS: 640.4 (M+1)+.
HO2c 1H-NMR (CDCI3, 400 MHz) 6: 8.64 (d, J =
8.4 Hz, U 0 1H), 8.30 (d, J = 7.6 Hz, 1H), 7.80 (m, 1H), 7.74 "N (m, 1H), 7.59 (m, 1H), 7.49 (d, J = 8.4 Hz, 1H), H 1 \ 4104a sH,N1, -/CF3 6.35 (s, 1H), 5.99 (m, 1H), 5.31 (m, 1H), 4.80 (m, 17/271 N W 60 1H), 3.75-3.60 (n, 3H), 3.30 (m, 1H), 3.08 (m, 1H), d 2.82-2.75 (m, 2H), 2.67 (s, 3H), 2.25 (m, 2H), 1.56-1.46 (m, 3H), 1.27-1.17 (m, 6H), 0.95-0.75 (m, 4H), 0.45 (m, 2H). MS: 606.2 (M+1)+;
HO2Cµ
n 0 1H-NMR (400 MHz, CD30D) 5: 0.50-0.58 (m, 2H), _____________ . ( N 0.88-0.92 (m, 3H), 1.08 (s, 9H), 1.19-1.26 (m, 4H), ' HN __ 1.45-1.46 (m, 3H), 2.06 (s, 3H), 2.24-2.32 (m, 2H), H 1 \ M s,, 2.44 (s, 3H), 2.48-2.52 (m, 2H), 2.53 (s, 3H), 2.93 17/272 N W- om (m, 1H), 3.20-3.25 (m, 2H), 3.50-3.61 (m, 1H), 4.58 (m, 1H), 6.33 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H). MS: 558.2 [m-Fl]t 1H-NMR (400 MHz, CDCI3) 5: 0.54-0.64 (m, 2H), 0 0.98-1.00 (m, 3H), 1.07 (s, 9H), 1.18-1.38 (m, 3H), N HN( 1.46-1.56 (m, 3H), 1.96-2.00 (m, 2H), 2.12 (s, 3H), H i \ 41 s,, 2.62 (m, 6H), 3.26 (br s, 1H), 3.49-3.63 (m, 3H), 17/273 N 60 3.96-3.99 (m, 2H), 4.14-4.18 (m, 1H), 4.47 (s, 1H), d 5.60 (d, J = 8.0 Hz, 1H), 6.12 (s, 1H), 7.18 (d, J =
8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H). MS: 544.3 [M+1]t u 0 1H-NMR (400 MHz, CDCI3) 6: 0.57-0.63 (m, 2H), CI ( 0.96-1.04 (m, 3H), 1.25 (s, 9H), 1.34-1.42 (m, 3H), N ______________________________ HN
H I 1.46-1.58 (m, 5H), 1.97-2.00 (m, 2H), 2.62 (s, 3H), \ 41 s,, 17/274 N O 2.77 (s, 3H), 3.49-3.55 (m, 3H), 3.98 (m, 2H), 6 4.11-4.18 (m, 1H), 4.51 (s, 1H), 5.60 (d, J = 7.6 Hz, 1H), 6.21 (s, 1H), 7.28 (d, J =8.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H). MS: 564.2 [M+1]+.
# Structure Analytical data Ho2CN
I o 1H-NMR (400 MHz, CDCI3) 6: 0.57-0.61 (m, 2H), Ci ( 0.98-1.00 (m, 3H), 1.25 (s, 9H), 1.33-1.35 (m, 3H), HN _______________________________ 1.51-1.59 (m, 3H), 2.26-2.33 (m, 2H), 2.60 (s, 3H), H 1 \ . gos 2.77-2.80 (m, 5H), 3.05-3.13 (m, 1H), 3.51-3.55 (m, 1H), 4.53 (s, 1H), 4.73-4.81 (m, 1H), 5.94-5.95 d (m, 1H), 6.23 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H). MS: 578.2 [M+1].
u 0 1H-NMR (400 MHz, CDCI3) 6: 0.59-0.61 (m, 2H), ci a( 0.99-1.04 (m, 3H), 1.19 (s, 9H), 1.23-1.36 (m, 5H), HN 1 \ sHN ___ 1.46-1.53 (m, 3H), 1.98 (m, 2H), 2.62 (s, 3H), 17/276 N ¨W- 60 3.47-3.55 (m, 4H), 3.96-3.99 (m, 2H), 4.15-4.18 d (m, 1H), 5.07 (s, 1H), 5.59 (d, J = 7.6 Hz, 1H), 6.26 (s, 1H), 7.37 (d , J = 8.4 Hz, 1H), 8.10 (d, J =
8.4 Hz, 1H). MS: 584.2 [M+1].
H 02C \
I 0 1H-NMR (400 MHz, CDCI3+ D20) 6: 0.58-0.60 (m, Ci ci( 2H), 0.88-0.89 (m, 3H), 1.29 (s, 9H), 1.32-1.35 (m, HN _______________________________ 3H), 1.51-1.77 (m, 2H), 2.30 (br s, 2H), 2.60 (s, H 1 \ 41 s,µ
3H), 2.73-2.78 (m, 2H), 3.07-3.10 (m, 1H), 3.47-3.54 (m, 3H), 4.73-4.76 (m, 1H), 6.28 (s, 1H), 7.36 d (d, J = 8.4 Hz, 1H), 8.10 (d , J = 8.4 Hz, 1H). MS:
598.2 [M+1].
HONA 1H-NMR (300 MHz, CDCI3) 6: 8.67 (d, J = 8.4 Hz, o ,o N
/ \ I \ * sis=o 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.77-7.45 (m, 4H), N NH 6.42 (s, 1H), 6.21 (t, J = 6.3 Hz, 1H), 4.66 (s, 1H), -A 3.82-3.74 (m, 1H), 3.46-3.34 (m, 3H), 2.68 (s, 3H), 1.93-1.82 (m, 2H), 1.48-1.18 (m, 20H), 0.90-0.80 F-a(m, 3H). MS: 590.3 [M+1].1r.
F
HO2C 1H-NMR (400 MHz, CD30D) 6: 0.63-0.68 (m, 2H), F7 o /---\ 0.95-0.99 (m, 3H), 1.14(s, 9H), 1.25-1.32 (m, 3H), 'N 0 0 ( HN _______________________________ 1.51-1.53 (m, 3H), 2.30-2.38 (m, 2H), 2.48 (s, 3H), H I \ 40, s', 2.54-2.60 (m, 2H), 2.97-3.02 (m, 1H), 3.26-3.28 17/279 N 60 (M, 3H), 3.66 (d, J = 6.8 Hz, 2H), 4.26-4.28 (m, d 2H), 4.38-4.40 (m, 2H), 4.63 (t, J = 8.0 Hz, 1H), 6.44 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 7.40 (d, J =
8.4 Hz, 1H). MS: 588.3 [M+1].
u1H-NMR (400 MHz, CDCI3) 6: 0.57-0.67 (m, 2H), o 0.86-1.00 (m, 3H), 1.24 (s, 9H), 1.25-1.43 (m, 5H), N = HN ( 1.46-1.53 (m, 3H), 1.68-1.71 (m, 2H), 1.80-1.85 H i \ g (m, 2H), 1.95-2.00 (m, 2H), 2.44-2.58 (m, 2H), . , 17/280 N 60 2.60 (s, 3H), 3.21 (m, 3H), 3.49-3.65 (m, 3H), 6 3.96-3.99 (m, 2H), 4.14-4.18 (m, 1H), 4.41 (s, 1H), 5.80 (d, J = 8.0 Hz, 1H), 6.11 (s, 1H), 7.15 (d, J =
8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H). MS: 570.3 [M+1].
# Structure Analytical data RO2Cµ
Ell 0 1H-NMR (400 MHz, CDCI3+ D20) 6: 0.57-0.67 (m, 5H), 1.19-1.31 (m, 14H), 1.57-1.70 (m, 4H), 1.8-N 11) HN ( 1.84 (m, 2H), 2.26-2.33 (m, 2H), 2.42-2.59 (m, H 1 \ 40 s,µ
2H), 2.77 (s, 3H), 3.08-3.10 (m, 2H), 3.19-3.25 (m, 4H), 3.60-3.65 (m, 2H), 6.12 (s, 1H), 7.15 (d, J =
d 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H). MS:
584.3 [M+1].
u 1H-NMR (400 MHz, CDCI3) 6: 9.10 (d, J = 8.8 Hz, NI \ 1H), 9.05-9.03 (m, 1H), 8.39 (d, J = 7.6 Hz, 1H), N HN ( 7.77 (d, J = 7.6 Hz, 1H), 7.67-7.62 (m, 1H), 6.42 H 1 \
=
g (s, 1H), 5.81-5.79 (m, 1H), 4.70 (s, 1H), 4.19-4.17 17/282 N 8b (m, 1H), 4.00-3.97 (m, 2H), 3.58-3.50 (m, 4H), d 2.64 (s, 3H), 1.99-1.95 (m, 2H), 1.57-1.48 (m, 5H), 1.27-1.22 (m, 12H), 0.94-0.89 (m, 3H), 0.45-0.43 (m, 2H). MS: 567.5 (M+H)+.
u1H-NMR (400 MHz, CDCI3) 6: 9.07-9.04 (m, 1H), o / \ N 8.47 (d, J = 7.6 Hz, 1H),8.21 (m, 1H),7.61-7.50 N HN ( (m, 2H), 6.46-6.36 (m, 2H), 5.70-5.69 (m, 1H), H I \ 41 g, 4.20-4.16 (m, 1H), 4.01-3.98 (m, 2H), 3.74-3.70 17/283 N 60 (m, 1H), 3.56-3.51 (m, 2H), 3.38-3.32 (m, 1H), d 2.67 (s, 3H), 2.20-1.95 (m, 2H), 1.58-1.48 (m, 5H), 1.30-1.18 (m, 12H), 0.89-0.84 (m, 3H), 0.50-0.47 (m, 2H). MS: 567.4(M+H)+.
o 1H-NMR (400 MHz, CDCI3) 6: 8.02 (d, J = 8.0 Hz, F2Hco 7C2i1-1 1 \ z\ sHp ( 51 H9)6 701.311(Hdi,J5=.887.0(tHjz=, 17H5),26H.2z9(si_,I)1H4)5, 76.(0s5-17/284 81 W 61so 1H), 3.62-3.58 (m, 1H), 3.44-3.40 (m, 2H), 2.66 (s, 3H), 2.60 (s, 3H), 1.87 (m, 2H), 1.57-1.53 (m, 3H), 1.30-1.20 (m, 18H), 0.98-0.96 (m, 3H), 0.57-0.54 (m, 2H). MS: 625.8 (M+H)+.
u 1H-NMR (400 MHz, CDCI3) 6: 8.03 (d, J = 8.0 Hz, o 1H), 7.32 (d, 1H, J = 8.0 Hz), 6.29 (s, 1H), 5.86 (t, N HN ( J = 75.2 Hz, 1H), 5.58 (m, 1H), 4.47 (s, 1H), 4.17-H I \ . s', 4.15 (m, 1H), 4.01-3.97 (m, 2H), 3.63-3.61 (m, 17/285 N 60 2H), 3.56-3.50 (m, 2H), 2.67 (s, 3H), 2.62 (s, 3H), d 2.01-1.98 (m, 2H), 1.53-1.49 (m, 5H),1.34-1.30 (m, 3H), 1.31 (s, 9H), 1.28-1.20 (m, 3H), 1.01-0.94 (m, 3H), 0.58-0.55 (m, 2H). MS: 595.8 (M+H)+.
Ho2c3C.\ a1H-NMR (400 MHz, CDCI3) 6: 8.26 (d, J = 8.4 Hz, F3c ( 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.14 (s, 1H), 5.98 (br HN 1 \ /\ Hp s, 1H), 4.69 (s, 1H), 3.68-3.63 (m, 1H), 3.42 (m, s, 17/286 N W "o 2H), 3.33-3.27 (m, 1H), 2.84 (s, 3H), 2.57 (s, 3H), d 1.87-1.84 (m, 2H), 1.63-1.52 (m, 3H), 1.43-1.40 (m, 18H), 1.05-0.92 (m, 3H), 0.73-0.70 (m, 1H), 0.48-0.46 (m, 1H). MS: 627.8 (M+H)+.
# Structure Analytical data cQ 1H-NMR (400 MHz, CDC)3) 5: 8.28 (d, J =
8.4 Hz, o 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.15 (s, 1H), 5.63-F3c N HN __ 5.61 (m, 1H), 4.56 (s, 1H), 4.16-4.12 (m, 1H), H i \ 41 s'\ ( 4.00-3.97 (m, 2H), 3.70-3.65 (m, 1H), 3.55-3.50 17/287 N 60 (MI, 2H), 3.34-3.28 (m, 1H), 2.85 (s, 3H), 2.59 (s, d 3H), 2.02-1.97 (m, 2H), 1.64-1.50 (m, 5H), 1.49-1.23 (m, 12H), 1.09-0.93 (m, 3H), 0.72-0.71 (m, 1H), 0.48-0.45 (m, 1H). MS: 597.8 (M+H)+.
c(.._. o N 1H-NMR (400 MHz, CDCI3) 5: 8.35 (d, J =
8.4 Hz, Cl cF3 ( 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H), 5.61-HN __ 5.60 (m, 1H), 4.86 (s, 1H), 4.21-4.13 (m, 1H), 17/288 N 6o 4.00-3.97 (m, 2H), 3.55-3.50 (m, 4H), 2.62 (s, 3H), d 2.00-1.96 (m, 2H), 1.75-1.70 (m, 5H), 1.58-1.22 (m, 12H), 1.10-0.98 (m, 3H), 0.60 (m, 2H). MS:
618.0 (M+H)+.
Ho2c-3C\ 1H-NMR (400 MHz, CDCI3) 5: 8.34 (d, J = 8.4 Hz, N CI CF3 ( HN __ 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H), 6.10 (br H I \ 41 g, s, 1H), 4.89 (s, 1H), 4.85-4.43 (br s, 1H), 3.62-17/289 N 0 3.42 (m, 4H), 2.59 (s, 3H), 1.88-1.84 (m, 2H), d 1.58-1.54 (m, 3H), 1.38-1.20 (m, 18H), 1.03-0.97 (m, 3H), 0.59 (m, 2H). MS: 648.0 (M+H)+.
HO o 1H-NMR (300 MHz, CDCI3) 5: 0.52-0.68 (m, 2H), ci (---'5\N 1 \ = Hp ( 0.92-1.10 (m, 3H), 1.24 (s, 9H), 1.30-1.42 (m, 3H), s 1.52-1.62 (m, 3H), 1.97-2.20 (m, 4H), 2.60 (s, 3H), s 60 2.76 (s, 3H), 2.82-2.93 (m, 2H), 3.40-3.58 (m, 5H), d 4.54 (s, 1H), 6.20-6.25 (m, 2H), 7.26 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H). MS: 642.2 (M+1)+.
HO\ _ 0 HN ( 1H-NMR (300 MHz, CDCI3) 5: 8.03 (d, J =
8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.25 (s, 1H), 6.20 H j\
N
(m, 1H), 4.47 (s, 1H), 3.52 (br s, 2H), 3.39 (m, d IS 2H), 2.96 (s, 1H), 2.77 (s, 3H), 3.25 (s, 3H), 1.40-1.30 (m, 4H), 1.26 (s, 6H), 1.25 (s, 9H), 1.10-0.91 (m, 4H), 0.62 (m, 2H). MS: 552.3 (M+1)+.
Ho2cµ
I 0 V 1H-NMR (CD30D, 400 MHz) 6: 7.14 (s, 2H), 6.67 ., 'N (s, 1H), 4.70 (m, 1H), 3.95 (d, J = 7.2 Hz, 2H), H 1 \ / \ N 3.06 (m, 1H), 2.68-2.59 (m, 2H), 2.58 (s, 3H), 2.41 17/292 N ¨ (m, 2H), 1.63-1.50 (m, 6H), 1.48-1.30 (m, 14H), d 1.20-0.98 (m, 3H), 0.76-0.65 (m, 4H). MS:
506.3 (M+1)+.
# Structure Analytical data o _- 1H-NMR (CDCI3, 300 MHz) 6: 0.59-0.63 (m, 2H), ,-, H HN 0.95-1.02 (m, 3H), 1.25 (s, 9H), 1.30-1.40 (m, 2H), ,-,..).õNõ.../N
I \ 11 =() 1.54-1.56 (m, 3H), 2.00 (s, 1H), 2.58 (s, 3H), 3.79 0-"j - d . (m, 2H), 3.94 (s, 3H), 4.16 (s, 2H), 4.21-4.30 (m, cF3 3H), 5.00 (s, 1H), 6.29 (s, 1H), 7.48 (br s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.76 (s, 1H), 8.30 (d, J =
8.1 Hz, 1H). MS: 625.3 (M+1)+.
o1H-NMR (CD30D, 400 MHz) 6: 0.66-0.74 (m, 2H), , H HN__ 0.95-1.03 (m, 3H), 1.24 (s, 10H), 1.30-1.38 (m, I \ *o 5H), 1.53-1.58 (m, 3H), 2.55 (s, 3H), 3.93-3.97 (m, N -..0 o 4H), 4.10-4.13 (m, 1H), 4.40-4.42 (m, 1H), 4.57-d u3 4.60 (m, 1H), 6.49 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H). MS:
638.3 (M+1)+.
1H-NMR (CDCI3, 300 MHz) 6: 0.61-0.68 (m, 2H), HN 0 0.98-1.00 (m, 3H), 1.27-1.35 (m, 14H), 1.52-1.56 o N HN (M, 2H), 1.71-1.75 (m, 2H), 1.84-1.97 (m, 2H), H I \ . s=o 2.63 (s, 3H), 3.21 (m, 1H), 3.61-3.69 (m, 1H), N 3.76-3.82 (m, 4H), 3.98-4.05 (m, 2H), 4.93-4.98 0 d cF3 (m, 1H), 5.26 (s, 1H), 5.66 (s, 1H), 6.32 (d, J =
10.2 Hz, 1H), 6.48 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H). MS:
653.3 (M+1)+.
a 0 CI 1H-NMR (400 MHz, CDCI3) 6: 7.19 (m, 1 H), 7.11 (s, 1 H), 7.06 (s, 1 H), 6.18 (s, 1 H), 5.63 (d, 1 H, J
N
H I \ . = 7.6 Hz), 4.16 (m, 1 H), 3.98 (m, 2 H), 3.74 (d, 2 17/296 N H, J = 7.2 Hz), 3.53 (m, 2 H), 2.60 (s, 3 H), 1.97 d A (m, 2 H), 1.54 (m, 5 H), 1.47 (s, 3 H), 1.36 (m, 3 H), 1.02 (m, 3 H), 0.86 (m, 2 H), 0.78 (m, 2 H), 0.66 (m,2 H). MS: 469.2 (M+1)+.
LIIN CF3 0 1H-NMR (400 MHz, CDCI3) 6: 7.46 (s, 1 H), 7.37 (m, 2 H), 6.22 (s, 1 H), 5.61 (d, 1 H, J = 8 Hz), H I \ . 4.16 (m, 1 H), 3.98 (m, 2 H), 3.74 (d, 2 H, J = 7.2 17/297 N Hz), 3.53 (m, 2 H), 2.62 (s, 3 H), 1.97 (m, 2 H), d A 1.54 (m, 5 H), 1.45 (s, 3 H), 1.37 (m, 3 H), 1.01 (m, 3 H), 0.86 (m, 2 H), 0.83 (m, 2 H), 0.66 (m, 2 H). MS: 503.3 (M+1)+.
HOOC,õ,, o CI 1H-NMR (400 MHz, DMSO-d6) 6: 7.99 (s, 1 H), N 7.89 (d, 1 H, J = 7.6 Hz), 7.82 (m, 2 H), 7.59 (s, 1 H I \ H), 6.75 (s, 1 H), 4.50 (m, 1 H), 3.86 (d, 2 H, J =
7.2 Hz), 2.88 (m, 2 H), 2.38 (m, 2 H), 2.24 (m, 2 NH H), 1.50 (m, 3 H), 1.39 (s, 9 H), 1.30(m, 3 H), C) o 0.98 (m, 3 H), 0.66 (m, 2 H). MS: 528.2 (M+1)+.
# Structure Analytical data HOOCõ,,cl o CI 1H-NMR (400 MHz, CDCI3) 6: 7.20 (s, 1 H), 7.10 (s, 1 H), 7.06 (s, 1 H), 6.20 (s, 1 H), 6.03 (d, 1 H, J
N
H I \ . = 6.8 Hz), 4.80 (m, 1 H), 3.74 (d, 2 H, J
= 7.2 Hz), 17/299 N 3.09 (m, 1 H), 2.78 (m, 2 H), 2.59 (s, 3 H), 2.30 d A (m, 2 H), 1.56 (m, 3 H), 1.41 (s, 3 H), 1.33 (m, 3 H), 1.02 (m, 3 H), 0.86 (m, 2 H), 0.78 (m, 2 H), 0.65 (m, 2 H). MS: 483.3 (M+1)+.
HOOCõ,, CL
CF3 1H-NMR (400 MHz, CDCI3) 6: 7.46 (s, 1 H), 7.36 (m, 2 H), 6.23 (s, 1 H), 5.98 (m, 1 H, J = 3.6 Hz), N
H I \ . 4.80 (m, 1 H), 3.73 (d, 2 H, J = 6.8 Hz), 3.07 (m, 1 17/300 N H), 2.78 (m, 2 H), 2.60 (s, 3 H), 2.30 (m, 2 H), d ad, 1.54 (m, 3 H), 1.46 (s, 3 H), 1.33 (m, 3 H), 1.00 (m, 3 H), 0.89 (m, 2 H), 0.83 (m, 2 H), 0.64 (m, 2 H). MS: 517.3 (M+1)+.
OH
ON(3IN
0 OH 1H-NMR (300 MHz, CD30D) 6: 0.74-1.03 (m, 8H), 1.29-1.42 (m, 9H), 1.54-1.73 (m, 11H), 1.97-2.09 N
17/301 H I \ * (M, 9H), 2.53 (s, 3H), 3.81 (d, J = 7.2 Hz, 2H), N 6.41 (s, 1H), 7.09 (s, 1H), 7.23 (s, 1H), 7.41 (s, d4 1H). MS: 547.3 (M+1)+.
OH
ONQ
0 1H-NMR (300 MHz, CDCI3) 6: 0.70-0.76 (m, 3H), OH 0.86-0.87 (m, 3H), 0.98-1.00 (m, 3H), 1.25-1.32 N (M, 3H), 1.36 (s, 3H), 1.42-1.55 (m, 3H), 1.59 (s, 17/302 H 1 \ .
6H), 1.90-2.11 (m, 12H), 2.58 (s, 3H), 3.70-3.73 N
d 4 (m, 2H), 5.45 (s, 1H), 6.10 (s, 1H), 7.06 (s, 1H), 7.18 (s, 1H), 7.38 (s, 1H). MS: 561.4 (M+1)+.
a 0 OMe 1H-NMR (CDCI3, 300 MHz): 6 7.76 (s, 1H), 7.60 (s, 1H), 7.54 (d, 1H), 6.27 (s, 1H), 6.11 (m, 1H), N 5.73 (m, 1H), 4.31 (m, 1H), 4.15 (m, 1H), 3.98 (d, H I \ . -- ___. -- 2H, J = 11.2 Hz), 3.77 (d, 2H, J = 6.8 Hz), 3.51 17/303 N (M, 2H), 3.10 (s, 3H), 2.62 (s, 3H), 1.97 (m, 2H), d 0 NH 1.87-1.80 (m, 3H), 1.57 (s, 6H), 1.55-1.49 (m, 2H), 1.40-1.35 (m, 3H), 1.29 (d, 6H, J = 6.4 Hz), 0.98 (m, 3H), 0.61 (m, 2H). MS: 538.2 (M+1)+.
HOOCõ,c o 1H-NMR (400 MHz, CDCI3) 6: 7.60 (s, 1H), 7.52 N (s, 1H), 7.40 (s, 1H), 6.24 (s, 1H), 5.96 (d, 1H, J =
H I \ * 7.2 Hz), 4.80 (m, 1H), 3.73 (d, 2H, J = 6.8 Hz), 17/304 N 3.08 (m, 1H), 2.80 (m, 2H), 2.62 (s, 3H), 2.30 (m, 0) CF 3 2H), 1.57-1.52 (m, 3H), 1.40-1.31 (m, 12H), 1.00 (m, 3H), 0.62 (m, 2H). MS: 519.2 (M+1)+.
# Structure Analytical data 1H-NMR (400 MHz, CDCI3) 6: 7.58 (s, 1H), 7.51 N
H I \ . (s, 1H), 7.39 (s, 1H), 6.21 (s, 1H), 5.89 (m, 1H), 3.72 (d, 2H, J = 7.2 Hz), 3.44 (m, 2H), 2.62 (s, d u3 3H), 1.87 (m, 2H), 1.57-1.51 (m, 3H), 1.39-1.30 (m, 12H), 1.31 (s, 6H),1.00 (m, 3H), 0.62 (m, 2H).
MS: 535.3 (M+1)+.
a HO
0 1H-NMR (400 MHz, CDCI3) 6: 7.74 (s, 1H), 7.63 N (s, 1H), 7.47(s, 1H), 6.26 (s, 1H), 5.67 (d, 1H, J =
H I \ . 7.6 Hz), 4.18 (m, 1H), 3.99 (m, 2H), 3.75 (d, 2H, J
17/306 N = 6.8 Hz), 3.52 (m, 2H), 2.60 (s, 3H), 1.99 (m, 0) CF3 2H), 1.63-1.46 (m, 11H), 1.40-1.33 (m, 3H), 1.00 (m, 3H), 0.62 (m, 2H). MS: 507.2 (M+1).
HOOC, o HO 11-1-NMR (400 MHz, CDCI3) 5: 7.73 (s, 1H), 7.63 (s, 1H), 7.46 (s, 1H), 6.27 (s, 1H), 6.04 (d, 1H, J =
N
H 1 \ 411 7.2 Hz), 4.78 (m, 1H), 3.74 (d, 2H, J = 7.2 Hz), 17/307 N 3.08 (m, 1H), 2.78 (m, 2H), 2.59 (s, 3H), 2.29 (m, d cF, 2H), 1.63 (s, 6H), 1.57-1.52 (m, 3H), 1.39-1.30 (m, 3H), 1.00 (m, 3H), 0.62 (m, 2H). MS: 521.2 HO
HOOCJ<N 0 1H-NMR (400 MHz, CDCI3) 6: 7.69 (s, 1H), 7.65 N (s, 1H), 7.45 (s, 1H), 6.18 (s, 1H), 6.02 (m, 1H), H I \ . 3.72 (d, 2H, J = 6.8 Hz), 3.36 (m, 2H), 2.56 (s, 17/308 N 3H), 1.81 (m, 2H), 1.67 (s, 6H), 1.56-1.50 (m, 3H), d u3 1.38-1.28 (m, 3H), 1.21 (s, 6H), 0.99 (m, 3H), 0.62 (m, 2H). MS: 537.3 (M+1)+.
N -, N
N' J.INF, 0 V 1H-NMR (400 MHz, DMSO-d6) 6: 7.61 (m, 1H), N 7.32 (s, 1H), 7.18 (s, 1H), 6.97 (s, 1H), 6.45 (s, H N
H I \ . 1H), 3.76 (d, 2H, J = 6.8 Hz), 3.46 (d, 2H, J = 6.0 17/309 N OH Hz), 2.46 (s, 3H), 1.47-1.31 (m, 9H), 1.30 (s, 3H), C-1 1.29 (s, 6H), 1.27-1.23 (m, 3H), 0.94 (m, 3H), 0.82(m, 2H), 0.75 (m, 2H), 0.64 (m, 2H). MS:
533.3 (M+1)+.
o ,kh 0 Ilr 1H-NMR (400 MHz, CDCI3) 5: 7.40 (m, 1H), 7.20 N (M, 1H), 7.07 (m, 1H), 6.20 (m, 1H), 6.16 (s, 1H), H N
H I \ 4110 3.72 (d, 2H, J = 7.2 Hz), 3.58 (d, 2H, J = 7.2 Hz), 17/310 N OH 2.59 (s, 3H), 1.59-1.48 (m, 9H), 1.43-1.25 (m, d 12H), 1.00 (m, 3H), 0.87 (m, 2H), 0.75 (m, 2H), 0.62 (m, 2H). MS: 549.4 (M+1)+.
# Structure Analytical data HO000 o N=y¨ 1H-NMR (400 MHz, CDCI3) 6: 7.23 (s, 1H), 6.86 N (s, 1H), 6.16 (m, 1H), 4.78 (m, 1H), 4.52 (m, 2H), H I \ / N 3.13 (m, 1H), 2.79 (m, 2H), 2.59 (s, 3H), 2.36 (m, \ d 17/311 N A 2H), 1.64-1.58 (m, 3H), 1.54 (m, 3H), 1.50-1.37 (m, 14H), 1.02 (m, 3H), 0.83 (m, 4H). MS: 507.1 (M+1)+.
HOOC o , N ' 1H-NMR (400 MHz, CDCI3) 6: 7.17 (s, 1H), 6.78 1----I'vN (s, 1H), 6.00(d, 1H J = 7.2 Hz), 4.79 (m, 1H), 4.52 I \ N
\ / (m, 2H), 3.11 (m, 1H), 2.81 (m, 2H), 2.60 (s, 3H), 17/312 N 2.35 (m, 2H), 1.63-1.53 (m, 6H), 1.44-1.35 (m, H
d ______ 14H), 1.07 (m, 3H), 0.85 (m, 4H). MS: 507.1 (M+1)+.
OH
o 11-1-NMR (400 MHz, CDCI3) 6: 7.40 (s, 1H), 7.21 H0*..N
(s, 1H), 7.08 (s, 1H), 6.22 (s, 2H), 3.73 (d, 2H, J =
N 1 \ * 7.2 Hz), 3.40 (m, 2H), 2.59 (s, 3H), 1.59-1.53 (m, d 17/313 N A 9H), 1.43-1.31 (m, 6H), 1.27 (s, 6H), 1.02-0.96 (m, 3H), 0.89-0.87 (m, 2H), 0.77-0.75 (m, 2H), 0.68-0.61 (m, 2H). MS: 481.3 (M+1)+.
OH
OH 0 1H-NMR (400 MHz, CDCI3) 6: 7.40 (s, 1H), 7.20 cONN (s, 1H), 7.07 (s, 1H), 6.20-6.18 (m, 2H), 3.81-3.72 FI I \ = (m, 6H), 3.43 (m, 2H), 2.59 (s, 3H), 1.66-1.53 (m, d 17/314 N A 13H), 1.43-1.33 (m, 6H), 1.00 (m, 3H), 0.87 (m, 2H), 0.77-0.75 (m, 2H), 0.68-0.61 (m, 2 H). MS:
523.3 (M+1)+.
0 OH i go0 'H-NMR (400 MHz, CDCI3) 6: 7.35 (s, 1H), 7.21 H2N- N----N (s, 1H), 7.06 (s, 1H), 6.55 (s, 1H), 6.21 (s, 1H), H I \ 4", 5.23 (m 2H), 3.85 (m, 2H), 3.71 (d, 2H, J = 6.8 17/315 N Hz), 3.34 (m, 2H), 2.54 (s, 3H), 1.58-1.52 (m, 9H), d A 1.42-1.31 (m, 6H), 0.99 (m, 3H), 0.86 (m, 2H), 0.80-0.74 (m, 2H), 0.67-0.60 (m, 2 H). MS: 516.2 (M+1)+.
O"' õ.....
,.N 0 OH 1H-NMR (400 MHz, CDCI3) 6: 7.38 (s, 1H), 7.26 L..N
(s, 1H), 7.19 (s, 1H), 7.07 (s, 1H), 6.31 (s, 1H), 3.96-3.93 (m, 4H), 3.80 (s, 2H), 3.72 (d, 2H, J =
H I \ * 6.8 Hz), 3.63-3.59 (m, 2H), 3.30 (s, 2H), 2.93-2.89 d 17/316 N A (m, 2H), 2.58 (s, 3H), 1.59-1.49 (m, 9H), 1.42-1.32 (m, 6H), 0.99-0.95 (m, 3H), 0.87 (t, 2H, J = 5.2 Hz), 0.78-0.73 (m, 2H), 0.67-0.59 (m, 2 H). MS:
522.3 (M+1)+.
# Structure Analytical data OH , R ,0 0 'H-NMR (400 MHz, CDCI3) 6:7.40 (s, 1H), 7.19 )S/ (s, 1H), 7.07 (s, 1H), 6.45 (s, 1H), 6.20 (s, 1H), N
H I \ . 3.92-3.88 (m, 2H), 3.73 (d, 2H, J = 6.8 Hz), 3.34 17/317 N (m, 2H), 2.97 (s, 3H), 2.60 (s, 3H), 1.59-1.53 (m, d A 9H), 1.43-1.32 (m, 6H), 1.00 (m, 3H), 0.88 (m, 2H), 0.77-0.74 (m, 2H), 0.68-0.61 (m, 2H). MS:
515.2 (M+1)+.
H 2N 0 0 OH , 'H-NMR (400 MHz, CDCI3) 6: 7.39 (s, 1H), 7.19 CC-j-N (s, 1H), 7.07 (s, 1H), 6.38-6.25 (m, 3H), 6.18 (s, NH I \ 4., 1H), 3.86-3.83 (m, 2H), 3.73-3.57 (m, 6H), 2.56 (s, 17/318 N 3H), 2.01-1.97 (m, 2H), 1.73-1.69 (m, 2H), 1.59-d A 1.53 (m, 9H), 1.43 (s, 3H), 1.40-1.32 (m, 3H), 1.00 (s, 3H), 0.87 (m, 2H), 0.77-0.75 (m, 2H), 0.65-0.63 (m, 2H). MS: 550.3 (M+1)+.
OH 0 OH 1H-NMR (400 MHz, CDCI3) 6: 7.40 (s, 1H), 7.20 ON, a-NN
H S I \ . (s, 1H), 7.07 (s, 1H), 6.22 (m, 1H), 6.20 (s, 1H), 3.74 (d, 2H, J = 6.8 Hz), 3.53-3.42 (m, 4H), 2.93-17/319 2.85 (m, 2H), 2.59 (s, 3H), 2.14-2.01 (m, 4H), d A 1.60-1.54 (m, 9H), 1.43-1.33 (m, 6H), 1.00 (m, 3H), 0.87 (m, 2H), 0.78-0.76 (m, 2H), 0.69-0.62 (m, 2H). MS: 571.3 (M+1)+.
0 OH 1H-NMR (400 MHz, CDCI3) 6: 7.39 (s, 1H), 7.21 0, ON
,S H I \ . (s, 1H), 7.07 (s, 1H), 6.17 (s, 1H), 5.97 (m, 1H), 3.73 (d, 2H, J = 6.8 Hz), 3.32 (m, 2H), 3.09-2.92 17/320 6 N (m, 4H), 2.60 (s, 3H), 2.20-2.17 (m, 2H), 2.01-1.87 d A (m, 3H), 1.59-1.53 (m, 9H), 1.43-1.33 (m, 6H), 1.00 (s, 3H), 0.87 (m, 2H), 0.77-0.75 (m, 2H), 0.68-0.61 (m, 2H). MS: 555.3 (M+1)+.
ii 0.saOH 1H-NMR (400 MHz, CDCI3) 6:7.39 (s, 1H), 7.21 0 (s, 1H), 7.07 (s, 1H), 6.17 (s, 1H), 5.69 (d, 1H, J =
N 7.6 Hz), 5.25-4.23 (m, 1H), 3.74 (d, 2H, J
= 7.2 H I \ * Hz), 3.14-3.06 (m, 4H), 2.60 (s, 3H), 2.39-2.36 (m, d A 2H), 2.21-2.15 (m, 2H), 1.59-1.54 (m, 9H), 1.43-1.33 (m, 6H), 1.00 (m, 3H), 0.87(m, 2H), 0.78-0.75 (m, 2H), 0.68-0.60 (m, 2H). MS: 541.3 (M+1)+.
1H-NMR (CDCI3, 300 MHz) 6: 7.85 (s, 1H), 7.55 a 0 OH (s, 1H), 7.53 (s, 1H), 6.24 (s, 1H), 6.00 (s, 1H), N 5.65(d, 1H, J = 7.6 Hz), 4.16 (m, 1H), 3.98 (d, 2H, H I \ . \ z J = 11.6 Hz), 3.76 (d, 2H, J
= 7.6 Hz), 3.52 (m, 17/322 N 7 2H), 2.62 (s, 3H), 1.98 (m, 2H), 1.89 (s, 1H), 1.61 d 0 NH (s, 6H), 1.58-1.51 (m, 5H), 1.49 (s, 9H), 1.36 (m, 3H), 1.00 (m, 3H), 0.63 (m, 2H). MS: 538.2 (M+1)+.
# Structure Analytical data 1H-NMR (CDCI3, 300 MHz) 6: 7.87 (s, 1H), 7.58 a 0 OH (s, 1H), 7.56 (s, 1H), 6.25 (s, 1H), 6.01 (d, 1H, J =
N 7.6 Hz), 5.65 (d, 1H, J = 8.0 Hz), 4.31 (m, 1H), H I \ . 4.16 (m, 2H), 3.98 (d, 2H, J = 11.2 Hz), 3.76 (d, 17/323 N 2H, J = 7.2 Hz), 3.52 (m, 2H), 2.62 (s, 3H), 1.98 d 0 NH (m, 2H), 1.91 (s, 1H), 1.63 (s, 6H), 1.58-1.48 (m, 5H), 1.40-1.33 (m, 3H), 1.29 (d, 6H, J = 6.4 Hz), 0.99 (m, 3H), 0.63 (m, 2H). MS: 524.2 (M+1)+.
a 0 OMe 1H-NMR (CDCI3, 300 MHz) 6: 7.74 (s, 1H), 7.53 (s, 2H), 6.26 (s, 1H), 5.99 (s, 1H), 5.66 (d, 1H, J =
N
H I \ * 7.6 Hz), 4.17(m, 1H), 3.98 (d, 2H, J =
11.2 Hz), 17/324 N y_ 3.78 (d, 2H, J = 7.2 Hz), 3.53 (m, 2H), 3.10 (s, dNH 3H), 2.62 (s, 3H), 1.97 (m, 2H), 1.57 (s, 6H), 1.51-O 1.50 (m, 5H), 1.47 (s, 9H), 1.34-1.32 (m, 3H), 0.91 (m, 3H), 0.62 (m, 2H). MS 552 (M+1)+.
0ON1H-NMR (CDCI3, 300 MHz) 6: 0.61-0.69 (2H, m), o 4 0.72-0.74 (2H, m), 0.88-0.98 (5H, m), 1.33-1.40 N (3H, m), 1.51-1.62 (7H, m), 1.89-2.01 (4H, m), H I \ * 0 2.61 (1H, s), 3.21 (3H, s), 3.53 (2H, t, J = 11.7 17/325 N Hz), 3.68 (2H, d, J = 6.3 Hz), 3.97-4.01 (2H, m), d OMe 4.14-4.19 (1H, m), 4.33-4.36 (2H, m), 5.59-5.62 (1H, m), 6.09 (1H, s), 6.50 (1H, s), 7.13 (1H, s).
MS: 535.4 (M+1)+.
1H-NMR (400 MHz, DMSO-d6) 6: 0.60-0.67 (m, HOOCõ, o V 2H), 0.75-0.77 (m, 2H), 0.83-0.86 (m, 2H), 0.90-0.95 (m, 3H), 1.21-1.24 (m, 3H), 1.30 (s, 9H), 1.40 N
H I \ . (s, 3H), 1.45-1.47 (m, 3H), 2.27-2.32 (m, 2H), 17/326 N 2.36-2.41 (m, 2H), 2.50 (s, 3H), 2.80-2.94 (m, 1H), C) 3.76 (d, J = 6.8 Hz, 2H), 4.52 (m, 1H), 6.53 (s, 1H), 6.98 (s, 1H), 7.15 (s, 1H), 7.19 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 12.08 (br s, 1H). MS: 505.3 (M+1)+.
OH
0 1H-NMR (400 MHz, CDCI3) 6: 8.20 (d, 1H, J
= 8.8 HOOC ...
N . p Hz), 7.29 (s, 2H), 6.44 (m, 1H), 6.29 (s, 1H), 3.75 H I \ S=O (d 2H J = 7.2 Hz), 3.55 (d, 2H, J = 6.0 Hz), 2.58 17/327 N HµN ( (s, , 3H), 1.70 (s, 6 H), 1.53 (m, 3H), 1.30-1.22 (m, d 18H), 0.97 (m, 3H), 0.57 (m, 2H). MS:
590.3 (M+1)+.
OH
OH
0\oi o 1H-NMR (400 MHz, CDCI3) 6: 8.21 (d, 1H, J = 8.0 lk p Hz), 7.30 (s, 1H), 6.32 (s, 1H), 6.14 (m, 1H), 4.79 H I \ i S:=0 (s, 1H), 3.76 (d, 2H, J = 6.4 Hz), 3.10 (m, 1H), 17/328 N HN ( 2.79 (m, 2H), 2.59 (s, 3H), 2.34 (s, 2H), 1.71 (s, d 6H), 1.54 (m, 3H), 1.30-1.21 (m, 12H), 0.97 (m, 3 H), 0.59 (m, 2 H). MS: 588.3 (M+1)+.
# Structure Analytical data HOOCNh 1H-NMR (400 MHz, CD30D) 6: 7.67 (s, 1H), 7.44 N
H I \ .(m, 2H), 6.31 (s, 1H), 3.75 (d, 2H, J = 6.8 Hz), N
d 0 y 3.39 (s, 2H), 2.46 (s, 3H), 1.44 (m, 3H), 1.37 (m, NH 9H), 1.31-1.19 (m, 12H), 1.13 (m, 6H), 0.92 (m, 3H), 0.60-0.58 (m, 2H). MS: 552.4 (M+1)+.
HOOC,, 1H-NMR (400 MHz, DMSO-d6) 6: 7.88 (d, 1H, J
cL 0 =7.6 Hz), 7.83 (s, 1H), 7.75 (s, 1H), 7.69 (s, 1H), N 7.50 (s, 1H), 6.64 (s, 1H), 4.52 (m, 1H), 3.81 (d, H I \ . 2H, J = 6.8 Hz), 2.92-2.90 (m, 1H), 2.53 (s, 3H), 17/330 N 2.42-2.36 (m, 2H), 2.32-2.27 (m, 2H), 1.49-1.47 d 0 NH (m, 3H), 1.40 (s, 9H), 1.34-1.24 (m, 12H), 0.96-0.92 (m, 3H), 0.66-0.63 (m, 2H). MS: 550.3 (M+1)+.
O-N
(:) jc..... 0 11-I-NMR (400 MHz, CDCI3) 6: 11.02 (s, 1H), 8.19 N ,0 (d, 1H, J = 8.4 Hz), 7.57 (s, 1H), 7.22 (m, 1H), H N
H I \ . S'=0 6.35(m, 1H), 6.27 (s, 1H), 4.55 (s, 1H),3.76-3.70 17/331 N 'NH (m, 4H), 2.92 (m, 2H), 2.60 (s, 3H), 1.61-1.46 (m, d A 12H), 1.35-1.25 (m, 12H), 0.96 (m, 3H), 0.58 (m, 2H). MS: 600.3 (M+1)+
O-N F F
0 JIN 0 F 1H-NMR (400 MHz, CDCI3) 6: 10.82 (s, 1H), 8.33 N
H N p (d, 1H, J = 8.0 Hz), 7.78 (s, 1H), 7.61 (d, 1H, J=
H I \ * S,/=0 8.0 Hz), 6.36 (s, 1H) 6.33 (m, 1H), 4.74 (s, 1H), d 17/332 N /NH 3.83-3.72 (m, 4H), 2.93 (m, 2H), 2.61 (s, 3H), 1.56 _7\ (m, 3H), 1.32 (m, 3H), 1.24 (s, 9H), 1.00 (m, 3H), 0.62 (m, 2H). MS: 612.2 (M+1)+.
0'NI OH
N 1H-NMR (400 MHz, CDCI3) 6: 10.86 (s, 1H), 8.21 H N
\ -0 , , = , , . *
(d 1H J = 8 4 Hz) 7.28 (s 2H), , 6.30 (m 1H), S,= , 17/333 N NH 6.27 (s, 1H), 3.78-3.70 (m, 4H), 2.93 (m, 2H), 2.60 d A (s, 3H), 1.70 (s, 6H), 1.55 (m, 3H), 1.31-1.26 (m, 12H), 0.98 (m, 3H), 0.58 (m, 2H). MS: 602 (M+1)+
H
,N-N 1H-NMR (400 MHz, CDCI3) 6: 8.19 (d, 1H, J
= 8.4 Nõ _IJN 0 Hz), 7.56 (s, 1H), 7.21 (d, 1H, J = 7.6 Hz), 6.52 H
N
N \ m p (m, 1H), 6.26 (s, 1H), 4.57 (m, 1H), 3.97 (m, 2H), 17/334 N W I N e,NH
=.0 3.77 (d, 2H, J = 6.8 Hz), 3.40 (m, 2H), 2.61 (s, d , 312H1):010.589 (m s,9H3)1101;5045(9m(,m3H2),H1)..3m3-s1:.2548r4, (M+1)+
# Structure Analytical data H
,N-N F F
F0 1H-NMR (400 MHz, CD30D) 5: 8.31 (d, 1H, J =
N 8.4 Hz), 7.89 (s, 1H), 7.81 (d, 1H, J =
8.4 Hz), N , H I \ . s..0 6.63 (s, 1H), 3.94 (d, 2H, J =
6.8 Hz), 3.74 (m, d 17/335 N NH 2H), 3.24 (m, 2H), 2.58 (s, 3H), 1.56 (m, 3H), 1.32 _A (m, 3H), 1.26 (s, 9H), 1.02 (m, 3 H), 0.71 (m, 2H).
MS: 596.3 (M+1)4.
H
,NN OH
0 1H-NMR (400 MHz, CDCI3) 6: 8.21 (d, 1H, J
= 8.4 N 0 Hz), 7.24 (s, 2H), 6.49 (s, 1H), 6.28 (s, 1H), 3.97 N
HI \ it s:=0 (m, 2H), 3.76 (d, 2H, J = 7.2 Hz), 3.36 (m, 2H), 17/336 N NH 2.62 (s, 3H), 1.69 (s, 6H), 1.54 (m, 3H), 1.30-1.24 d A (m, 12H), 0.96 (m, 3H), 0.59 (m, 2H).
MS: 586.3 (M+1)+
a O 1H-NMR (400 MHz, CDCI3) 5: 7.61 (m, 1H), 7.39 V (m, 1H), 7.32 (m, 1H), 6.21 (s, 1H), 5.92 (s, 1H), N 5.62 (d, 1H, J = 8.0 Hz), 4.16 (m, 1H), 3.98 (m, H I \ .., 2H), 3.75 (d, 2H, J = 7.2 Hz), 3.52 (m, 2H), 2.62 17/337 N (s, 3H), 1.99 (m, 2H), 1.57-1.46 (m, 3H), 1.44-1.42 d 0 NH (M, 15H), 1.40 (m, 3H), 1.26 (m, 3H), 1.01 (m, 3H), 0.89 (m, 2H), 0.79 (m, 2H), 0.62 (m, 2H). MS:
534.3 (M-F1)+.
0 V 1H-NMR (400 MHz, CDCI3) 5: 7.62 (s, 1H), 7.38 HOOCNFN N
(s, 1H), 7.31 (s, 1H), 6.34 (m, 1H), 6.22 (s, 1H), H I \ * 5.95 (s, 1H), 3.72 (d, 2H, J = 7.2 Hz), 3.53 (d, 2H, N
d y J = 6.0 Hz), 2.60 (s, 3H), 1.55 (m, 3H), 1.48 (S, NH 9H), 1.43 (s, 3H), 1.30 (m, 9H), 1.00 (m, 3H), 0.89 (m, 2H), 0.78 (m, 2H), 0.62 (m, 2H). MS: 550.3 (M+1)+.
HOOC-3 o V 1H-NMR (400 MHz, CDCI3) 6: 7.61 (m, 1H), 7.39 (m, 1H), 7.32 (m, 1H), 6.23 (s, 1H), 6.00 (m. 1H), N
H I \ . 5.96 (s, 1H), 4.78 (m, 1H), 3.74 (d, 2H, J
= 7.2 17/339 N y Hz), 3.10 (m, 1H), 2.80 (m, 2H), 2.59 (s, 3H), 2.32 dNH (M, 2H), 1.58-1.53 (m, 3H), 1.49 (s, 9H), 1.44 (s, ID 3H), 1.38 (m, 3H), 1.01 (m, 3H), 0.89 (m, 2H), 0.79 (m, 2H), 0.62 (m, 2H). MS: 548.3 (M+1)+.
0 V 1H-NMR (400 MHz, CDCI3) 6: 7.62 (s, 1H), 7.42 N (S, 1H), 7.30 (s, 1H), 6.23 (s, 1H), 6.16 (s, 1H), cH
I \ IIP 6.02 (m, 1H), 3.72 (d, 2H, J = 7.2 Hz), 3.39 (m, N y_. 2H), 2.59 (s, 3H), 1.82 (m, 2H), 1.57-1.52 (m, 3H), 17/340 HO d NH 1.49 (s, 9H), 1.43 (s, 3H), 1.32 (m, 3H), 1.22 (s, 0 6H), 1.00 (m, 3H), 0.89 (m, 2H), 0.78 (m, 2H), 0.62 (m, 2H). MS: 564.3 (M+1)+.
# Structure Analytical data OH 0 V 1H-NMR (400 MHz, CDCI3) 6: 7.61 (m, 1H), 7.40 N (m, 1H), 7.31 (m, 1H), 6.23 (s, 1H), 6.21 (m, 1H), ,CH I \ 41", 5.98 (s, 1H), 3.74-3.73 (m, 6H), 3.44 (d, 2H, J =
N
d 0 y 6.0 Hz), 2.61 (s, 3H), 1.69-1.53 (m, 6H), 1.49 (s, NH 9H), 1.43 (s, 3H), 1.32 (m, 3H), 1.00 (m, 3H), 0.89 (m, 2H), 0.78 (m, 2H), 0.62 (m, 2H). MS: 564.3 (M+1)+.
a OH 1H-NMR (CDCI3, 400 MHz) 6: 0.63-0.66 (m, 2H), 0.76-0.77 (m, 2H), 0.86-0.89 (m, 2H), 0.98-0.99 N (m, 3H), 1.33-1.43 (m, 3H), 1.47 (s, 3H), 1.52-1.56 H I \ = (m, 5H), 1.58 (s, 6H), 1.73 (s, 2H), 2.61 (s, 3H), d 17/342 N 3.52 (t, 2H, J = 12.0 Hz), 3.73 (d, 2H, J
= 8.0 Hz), 3.96-3.99 (m, 2H), 4.15-4.17 (m, 1 H), 5.61 (d, 1H, A
J = 8.0 Hz), 6.17 (s, 1H), 7.07 (s, 1H), 7.20 (s, 1H), 7.39 (s, 1H). MS: 493.2 (M+1)+.
OMe 1H-NMR (CDCI3, 400 MHz) 6: 0.61-0.64 (m, 2H), a 0 0.75-0.77 (m, 2H), 0.86-0.89 (m, 2H), 0.98-0.99 N (m, 3H), 1.32-1.37 (m, 3H), 1.43 (s, 3H), 1.47-1.53 H I \ . (m, 11H), 1.96-2.00 (m, 2H), 2.61 (s, 3H), 3.08 (s, d 17/343 N 1H), 3.53 (t, 2H, J = 12.0 Hz), 3.74 (d, 2H, J = 8.0 Hz), 3.96-3.99 (m, 2H), 4.15-4.17 (m, 1 H), 5.61 A
(d, 1H, J = 8.0 Hz), 6.18 (s, 1H), 7.08 (s, 1H), 7.16 (s, 1H), 7.26 (s, 1H). MS 507.2 (M+1).
0 v 1H-NMR (CDCI3, 400 MHz) 6: 0.62-0.68 (m, 2H), N
(NNZ
I \ 11 0.73-0.75 (m, 2H), 0.85-0.88 (m, 2H), 0.99 (m, 3H), 1.26-1.28 (m, 1H), 1.33 (s, 9H), 1.37-1.39 (m, N
d 2H), 1.42 (s, 3H), 1.52-1.54 (m, 3H), 2.39 (m, 4H), 17/344 0.,..) 2.57 (s, 3H), 3.14-3.19 (m, 1H), 3.70-3.74 (m, 6H), 3.98-4.32 (m, 4H), 6.17 (s, 1H), 7.00 (m, 1H), 7.12 (m, 1H), 7.25 (m, 1H). MS: 532.4 (M+1)+.
0 v 1H-NMR (CDCI3, 400 MHz) 6: 0.63-0.66 (m, 2H), 0.73-0.76 (m, 2H), 0.85-0.88 (m, 2H), 0.99 (m, 0,9,isiHN I \ . 3H), 1.33 (s, 9H), 1.36-1.39 (m, 4H), 1.42 (s, 3H), `S 1.53-1.55 (m, 4H), 1.70-1.80 (m, 1H), 1.88 (d, J =
d 17/345 I N 13.2 Hz, 2H), 2.61 (s, 3H), 2.66 (m, 2H), 2.76 (s, 3H), 3.30 (m, 2H), 3.71 (d, J = 7.2 Hz, 2H), 3.80 (m, 2H), 5.89 (m, 1H), 6.15 (s, 1H), 7.00 (m, 1H), 7.12 (m, 1H), 7.25 (m, 1H). MS: 582.4 (M+1)+.
NNTh cN
N.---NN 0 V 1H-NMR (CDCI3, 400 MHz) 6: 0.64-0.67 (m, 2H), 0.73-0.75 (m, 2H), 0.86-0.88 (m, 2H), 1.00 (m, H I \ .0 3H), 1.33 (s, 9H), 1.34-1.38 (m, 2H), 1.42 (s, 3H), 17/346 N 1.61-1.63 (m, 5H), 2.53 (s, 3H), 2.57 (s, 3H), 2.60-d 3.00 (m, 3H), 3.10-3.30 (m, 5H), 3.67-3.68 (m, 2H), 3.71-3.73 (m, 2H), 6.28 (s, 1H), 7.00 (m, 1H), 7.12 (m, 1H), 7.27 (m, 1H). MS: 533.4 (M+1)+.
# Structure Analytical data (31, ,0 ;K 1H-NMR (CDCI3, 400 MHz) 6: 0.62-0.68 (m, 2H), NTh C-"NN...---NN 0 V 0.75-0.77 (m, 2H), 0.85-0.87 (m, 2H), 1.00 (m, 3H), 1.33 (s, 9H), 1.35-1.38 (m, 2H), 1.43 (s, 3H), 17/347 H I \ . 1.53-1.56 (m, 4H), 2.58-2.64 (m, 9H), 2.77 (s, 3H), N 3.24 (m, 4H), 3.50-3.52 (m, 2H), 3.70 (d, J = 7.2 C) Hz, 2H), 6.17 (s, 1H), 7.02 (m, 1H), 7.14 (m, 1H), 7.28 (m, 1H). MS: 597.4 (M+1)+.
OH 0 OCF3 1H-NMR (400 MHz, CD30D) 5: 0.65-0.74 (m, 2H), Nri 1 \ . 0.82-0.86 (m, 2H), 0.88-0.82 (m, 2H), 0.99-1.04 (m, 3H), 1.21 (s, 6H), 1.28-1.39 (m, 3H), 1.43 (s, N 3H), 1.53-1.56 (m, 3H), 2.56 (s, 3H), 3.32 (s, 2H), d 17/348 A 3.84 (d, J = 7.2 Hz, 2H), 6.51 (s, 1H), 7.07 (m, 1H), 7.11 (m, 1H), 7.23 (m, 1H). MS: 507.3 (M+1)+.
OH 0 OCF3 1H-NMR (400 MHz, CD30D) 5: 0.70-0.73 (m, 2H), N 1 \ ., w 1.01-1.05 (m, 3H), 1.22 (s, 6H), 1.33-1.36 (m, 3H), N i 1.46 (s, 9H), 1.55-1.58 (m, 3H), 2.58 (s, 3H), 3.33 d 17/349 0 NH (s, 2H), 3.90 (d, J = 7.6 Hz, 2H), 6.60 (s, 1H), 7.45 (s, 1H), 7.64 (s, 1H), 7.77 (m, 1H). MS: 552.3 (M+1)+.
HOOCcii3 o OCF3 1H-NMR (400 MHz, CD30D) 5: 0.71-0.74 (m, 2H), N 0.86-0.89 (m, 2H), 0.93-0.95 (m, 2H), 1.02-1.07 H I \ .0 (m, 3H), 1.33-1.36 (m, 3H), 1.47 (s, 3H), 1.57-1.60 17/350 N (m, 3H), 2.37-2.47 (m, 2H), 2.58 (s, 3H), 2.61-2.67 d A (m, 2H), 3.05-3.07 (m, 1H), 3.87 (d, J =
6.8 Hz, 2H), 4.66-4.73 (m, 1H), 6.57 (s, 1H), 7.10 (s, 1H), 7.14(s, 1H), 7.27(s, 1H). MS: 533.2 (M+1)+.
, HOOC o OCF3 1H-NMR (400 MHz, CD30D) 6: 0.69-0.72 (m, 2H), 0.99-1.04 (m, 3H), 1.28-1.35 (m, 3H), 1.46 (s, 9H), N
H I \ . 1.55-1.57 (m, 3H), 2.33-2.41 (m, 2H), 2.55 (s, 3H), 17/351 N y 2.57-2.64 (m, 2H), 3.00-3.05 (m, 1H), 3.89 (d, J =
d 0 NH 7.2 Hz, 2H), 4.64-4.68 (m, 1H), 6.61 (s, 1H), 7.44 (s, 1H), 7.63 (s, 1H), 7.76 (s, 1H). MS: 578.3 (M+1)+.
a0 y 1H-NMR (400 MHz, CDCI3) 5: 0.58-0.60 (m, 2H), N 0.63-1.02 (m, 4H), 1.23-1.68 (m, 12H), 1.94-1.98 H I \ .0 (m, 2H), 2.62 (s, 3H), 3.48 (t, J = 7.2 Hz, 2H), 3.76 17/352 N r--cF3 (d, J = 8.0 Hz, 2H), 3.98 (d, J = 12.4 Hz, 2H), d 0 NH 4.09-4.16 (m, 3H), 5.64-5.66 (m, 1H), 6.24 (s, 1H), 6.69 (s, 1H), 7.40 (s, 1H), 7.57 (s, 1H), 7.70 (s, 1H). MS: 560.3 (M+1)+.
# Structure Analytical data HOOCNI--"NN N,--- 1H-NMR (400 MHz, CDCI3) 5: 7.20 (s, 1H), 6.77 (s, 1H), 6.36 (m, 1H), 4.57 (m, 2H), 3.56 (d, 2H, J
17/353 dN ' = 6.4 Hz), 2.60 (s, 3H), 1.59 (m, 3H), 1.54-1.20 (m, 27H), 1.01 (m, 3H), 0.81 (m, 2H). MS: 511.3 (M+1)+.
HOOCõ, n 0 1H-NMR (400 MHz, CDCI3) 6: 7.21 (s, 1H), 6.79 N=r (s, 1H), 6.03 (d, 1H, J = 6.8 Hz), 4.82 (m, 1H), H I \ \ iN 4.58 (s, 2H), 3.11 (m, 1H), 2.81 (m, 2H), 2.61 (s, 17/354 N 3H), 2.36 (m, 2H), 1.60 (m, 3H), 1.55-1.37 (m, d 21H), 1.05 (m, 3H), 0.83 (m, 2 H). MS:
509.3 (M+1)+.
Nt---Nri 1 \ N=?/¨ 1H-NMR (400 MHz, CDCI3) 5: 7.22 (s, 1H), 6.84 NI (s, 1H), 6.22 (m, 1H), 4.59m, 2H), 3.42 (d, 2H, J =
\ / 6.0 Hz), 2.62 (s, 3H), 1.61 (m, 3H), 1.53-1.42 (m, d N A 8H), 1.36 (s, 9H), 1.28 (s, 6H), 1.04 (m, 3H), 0.87-0.79 (m, 4H). MS: 481.4 (M+1)+.
OH J7¨7-1H-NMR (400 MHz, CDCI3) 6: 7.17 (s, 1H), 6.83 _______________________ r;--,N (s, 1H), 6.24 (m, 1H), 4.54 (m, 2H), 3.42 (d, 2H, J
d 17/356 .5.6 Hz), 2.61 (s, 3H), 1.63-1.54 (m, 6H), 1.45-1.34 (m, 14H), 1.29 (s, 6H), 1.07 (m, 3H), 0.88-0.84 (m, 4H). MS: 481.3 (M+1)+.
OH
--I 1H-NMR (400 MHz, CD30D) 6: 0.59-0.65 (m, 2H), 0.78 (s, 2H), 0.89-0.96 (m, 5H), 1.22-1.29 (m, 5H), N
H \ 1.41 (s, 3H), 1.45-1.48 (m, 2H), 2.30-2.32 (m, 2H), I *
17/357 N 2.49 (s, 3H), 2.54-2.56 (m, 2H), 2.96-2.99 (m, 2H), 3.80 (d, J = 6.8 Hz, 2H), 4.04 (dd, J = 14.4, 7.2 d HN Hz, 2H), 4.60 (br s, 1H), 6.48 (s, 1H), 7.41 (s, 1H), ) 7.60 (s, 1H), 7.69 (s, 1H). MS: 574.3 (M+1)+.
OH
--I 1H-NMR (400 MHz, CD30D) 6: 0.57-0.61 (m, 2H), o'''= V 0.72-0.75 (m, 2H), 0.84-0.86 (m, 2H), 0.92-0.97 ciL 0 N (m, 3H), 1.20-1.28 (m, 3H), 1.33-1.37 (m, 6H), H I \ * 144-1.47 (m, 3H), 2.12-2.19 (m, 2H), 2.44 (s, 3H), 17/358 N 2.45-2.54 (m, 2H), 2.84-2.88 (m, 1H), 3.76 (d, J =
0 6.8 Hz, 2H), 4.46-4.50 (m, 1H), 4.78-4.84 (m, 1H), C) HN 6.45 (s, 1H), 7.37 (s, 1H), 7.56 (s, 1H), 7.63 (s, 1H). MS: 588.4 (M+1)+.
# Structure Analytical data OH
1H-NMR (400 MHz, CD30D) 6: 0.57-0.61 (m, 2H), 0 V 0.72-0.75 (m, 2H), 0.84-0.86 (m, 2H), 0.92-0.97 N (m, 3H), 1.20-1.28 (m, 3H), 1.33-1.37 (m, 6H), H I \ * 144-1.47 (m, 3H), 2.12-2.19 (m, 2H), 2.44 (s, 3H), 17/359 N 2.45-2.54 (m, 2H), 2.84-2.88 (m, 1H), 3.76 (d, J =
0 6.8 Hz, 2H), 4.46-4.50 (m, 1H), 4.78-4.84 (m, 1H), C) HN 6.45 (s, 1H), 7.37 (s, 1H), 7.56 (s, 1H), 7.63 (s, F30 1H). MS: 588.3 (M+1)+.
OH 1H-NMR (400 MHz, CD30D) 6: 0.58-0.61 (m, 2H), o V 0.71-0.74 (m, 2H), 0.83-0.85 (m, 2H), 0.92 (s, 3H), 1.23-1.30 (m, 3H), 1.37 (d, J = 7.2 Hz, 3H), 1.45-1.47 (m, 3H), 1.59 (s, 6H), 2.12-2.20 (m, 2H), 2.44 H I= \ *
17/360 N (d, J = 5.6 Hz, 3H), 2.48-2.55 (m, 2H), 2.86-2.88 0 (M, 1H), 3.75 (d, J = 6.8 Hz, 2H), 4.48 (t, J = 7.6 d HN Hz, 1H), 6.44 (s, 1H), 7.34 (t, J = 1.6 Hz, 1H), 7.43 K (t, J = 1.6 Hz, 1H), 7.50 (t, J = 1.6 Hz, 1H). MS:
F3c 602.4 (M+1)+.
N ,0 \11 17/361 HO S:=-0 O N NH MS: 623.3 (M+1)+.
d=
NC-7, OH
C)".0, 0 N,0 17/362 H I \ li S:=0 MS: 607.2 (M+1)+.
N NH
C) NC-Lc, ON ,0 HI \ 411 S:=0 17/363 N NH MS: 584.3 (M+1)+.
d -A
OH
AI F
N ,0 H I \ . S:=0 MS: 598.3 (M+1)+.
N NH
d A
# Structure Analytical data HO
*
?\----NN 0 H I \ S,:=0 17/365 dNH MS: 572.3 (M+1)+.
¨A
4111. 1H-NMR (400 MHz, CDCI3) 5: 8.68 (s, 1H), 8.08 HO- (d, 1H, J = 8.8 Hz), 7.95 (d, 1H, J = 5.6 Hz), 7.78 -NN
H I \ \ /N (t, 1H, J = 7.6 Hz), 7.58 (s, 1H), 6.75 (d, 1H, J =
17/366 N ' 6.8 Hz), 6.54-6.46 (m, 1H), 3.75 (s, 2H), 3.44 (d, (ii 2H, J = 4.4 Hz), 2.72 (s, 3H), 1.63 (s, 9H), 1.52 (d, 3H, J = 6.8 Hz), 1.33-1.28 (m, 9H), 0.98-0.89 (m, 3H), 0.54-0.48 (m, 2H). MS: 476.3 (M+1)+.
HO N 1H-NMR (400 MHz, CDCI3) 6: 8.08 (s, 1H), 7.47 (t, 7\---N
H I \ . 1H, J = 6.0 Hz), 7.38 (d, 1H, J = 2.4 Hz), 7.29 (d, 1H, J = 2.4 Hz), 6.99 (s, 1H), 3.16 (d, 2H, J = 6.0 Hz), 2.52 (s, 3H), 1.52-1.51 (m, 3H), 1.36-1.25 (m, ci HN 21H), 1.07 (s, 6H), 1.01-0.94 (m, 3H), 0.62-0.58 17/367 d )\ (m, 2H). MS: 558.3 (M+1)+.
OH
1H-NMR (400 MHz, DMSO-d6) 5: 7.59 (d, 1H, J =
2.4 Hz), 7.37 (d, 1H, J = 2.4 Hz), 6.19 (s, 1H), N6.05 (d, 1H, J = 7.2 Hz), 5.86 (s, 1H), 4.77 (t, 1H, H I \ * J = 5.2 Hz), 3.49 (s, 2H), 3.06 (t, 1H, J = 7.2 Hz), 17/368 N 2.77 (t, 2H, J = 9.2 Hz), 2.59 (s, 3H), 2.30 (t, 2H, J
d ci o = 8.8 Hz), 1.57-1.25 (m, 24H), 1.01 (s, 3H), 0.65-HN
?\ 0.60 (m, 2H). MS: 584.3 (M+1)+.
OaN 1H-NMR (400 MHz, CDCI3) 5: 10.17 (s, 1H), 8,67 O / \ (d, J = 6.0 Hz, 1H), 8.41 (d, J = 7.6 Hz, 1H), 7.73-N p 7.68 (m, 2H), 6.38 (s, 1H), 5.63 (d, J =
8.0 Hz, H I \ * S,=0 1H), 5.21 (s, 1H), 4.19 (m, 1H), 4.02-3.95 (m, 2H), 17/369 N NH 3.77-3.70 (m, 1H), 3.54 (m, 2H), 3.37-3.30 (m, d A 1H), 2.69 (s, 3H), 2.03-1.97(m, 2H), 1.59-1.42 (m, 5H), 1.29-1.19 (m, 12H), 0.95-0.85 (m, 3H), 0.55-0.46 (m, 2H). MS: 567.3 (M+H)+.
4111H-NMR (300 MHz, CDCI3) 5: 8.66 (d, J = 8.4 Hz, 1H), 8.34 (d, J = 8.4Hz, 1H), 7.80-7.45 (m, 4H), HO)(NN
I \ H I \ * si:?-.0 6.39 (s, 1H), 6.20 (t, J =
6.4 Hz, 1H), 4.70-4.52 17/370 N /1F1 (171, 1H), 3.75-3.60 (m, 1H), 3.41 (m, 2H), 3.36-3.27 (m, 1H), 2.66 (s, 3H), 1.86-1.73 (m, 2H), F--d 1.40-1.01 (m, 21H), 0.95-0.46 (m, 3H). MS:
572.3 [M+1r.
NH2 a 1H-NMR (300 MHz, CDCI3) 5: 0.87-0.68 (m, 2H), ENI 1 \ a 1.30-1.20 (m, 3H), 1.47 (s, 9H), 1.49 (s, 6H), 1.85-=p s,=0 1.50 (m, 6H), 2.79 (s, 3H), 2.95 (s, 3H), 3.80-3.60 17/371 N NH (al, 4H), 4.98 (s, 1H), 5.75 (br s, 1H), 6.44 (s, 1H), d A 6.49 (br s, 1H) ,6.70 (t, J = 6.3Hz, 1H), 7.47 (d, J =
8.4 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H). MS: 579.3 [M+1r.
# Structure Analytical data OH
O'''= 1H-NMR (400 MHz, CDCI3) 6: 8.08 (s, 1H), 7.20 (s, 1H), 6.22 (m, 1H), 4.75-4.69 (m, 1H), 4.51-4.47 (M, 2H), 3.23-3.18 (m, 1H), 2.83-2.81 (m, 2H), 17/372 N 2.61 (s, 3H), 2.43-2.36 (m, 2H), 1.70-1.60 (m, 6H), d o 1.54 (s, 9H), 1.44-1.25 (m, 5H), 1.10-0.81 (m, 7H).
HN MS: 550.3 (M+1)+.
?\---, ---1- 1H-NMR (400 MHz, CDCI3) 6: 8.04 (s, 1H), 7.96 HO)(NN
' \ Hj-4µi iN (S, 1H), 7.05 (s, 1H), 6.29 (m, 1H), 4.51 (m, 1H), 17/373 N \ 3.41 (m, 2H), 2.61 (s, 3H), 1.70-1.60 (m, 6H), 1.56 (s, 9H), 1.54-1.34 (m, 5H), 1.28-1.22 (m, 6H), d HN 1.09-0.80 (m, 7H). MS: 524.3 (M+1)+.
o HO. 1H-NMR (300 MHz, CDCI3) 6: 8.67 (d, J =
8.4 Hz, A 1)1 I \ 4", e:o 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.78-7.40 (m, 4H), N NH 6.42 (s, 1H), 6.32 (br s, 1H), 4.71 (br s, 1H), 4.30-a A 4.11 (m, 1H), 3.78-3.72 (m, 1H), 3.50-3.28 (m, 3H), 2.68 (s, 3H), 1.50-1.10 (m, 23H), 1.95-1.70 (m, 2H). MS: 572.3 [M+1]+.
F
Example 18/1 to 18/5 The following Preparative Examples were prepared similar as described in according the depicted experimental number.
# Structure educt Analytical data Oa HON 1H-NMR (CDCI3, 300 MHz) 6: 7.66 (t, 1H), 7.50 o (s, 1H), 7.36 (t, 2H), 6.21 (s, 1H), 5.63 (d, 1H, J
N
H I \ 411 17/103 = 7.8 Hz), 4.14-4.19 (m, 1H), 3.98 (d, 2H, J =
18/1 N 12.6 Hz), 3.74 (d, 2H, J = 7.2 Hz), 3.53 (t, 2H, J
d Ex.# 6 . 9.9 Hz), 2.62 (s, 3H), 2.31 (s, 3H), 1.96-2.00 (m, 2H),1.30-1.58 (m, 12H), 0.97-1.00 (m, 3H), 0.61-0.66 (m, 2H). MS: 494.3 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 6: 8.29 (d, 1H, J =
a 0 8.4 Hz), 7.81 (s, 1H), 7.62 (dd, 1H, J
= 8.4, J =
HNj<7/10 1.6 Hz), 6.38 (s, 1H), 5.62 (d, 1H), 4.94 (br S, H I \ * S=0 F 8 1H), 4.69 (t, 1H), 4.57 (t, 1H), 4.13-4.20 (m, 1H), 18/2 N 0 Ex.# 3.98-4.00 (m, 2H), 3.81 (d, 2H), 3.53 (td, 2H), d u3 21/1 2.63 (s, 3H), 2.07 (7, 1H), 1.97-2.01 (m, 3H), 1.48-1.57 (m, 5H), 1.28-1.38 (m, 3H), 1.25 (s, 6H), 1.00-1.24 (m, 3H), 0.61-0.67 (m, 2H). MS:
616.3 (M+1)+.
# Structure educt Analytical data oa 0 HON /H-NMR (CDCI3, 400 MHz) ö: 7.70 (d, 1H), 7.41 (s, 1H), 7.20 (d, 1H), 6.15 (s, 1H), 5.62 (d, 1H, J
17/104 = 8.0 Hz), 4.27 (t, 2H, J = 6.0 Hz), 4.13-4.19 (m, N 1 \ . 0 1H), 3.96-3.99 (m, 2H), 3.72 (d, 2H, J = 7.6 Hz), 18/3 N EX.# 3.50-3.55 (m, 2H), 3.02 (t, 2H, J =
6.0 Hz), 2.61 d 6/1 (s, 3H), 1.96-1.99 (m, 2H),1.47-1.58 (m, 5H), 1.32-1.38 (m, 12H), 0.98-1.02 (m, 3H), 0.64-0.72 (m, 2H). MS: 522.3 (M+1)+.
O 0 F 1H-NMR (CDCI3, 400 MHz) 6: 7.21 (s, 1H), 7.15 (s, 1H), 6.13 (s, 1H), 5.44-5.61 (m, 2H), 4.41-17/105 4.44 (m, 1H), 4.14-4.27 (m, 2H), 3.97 (d, 2H, J =
N 1 \ * 0 12.0 Hz), 3.64-3.75 (m, 2H), 3.49-3.55 (m, 2H), 18/4 N Ex.# 2.61 (s, 3H), 2.27-2.31 (m, 2H),1.96-2.00 (m, d 26 2H), 1.38-1.57 (m, 17H), 1.02-1.04 (m, 3H), 0.65-0.72 (m, 2H). 19F-NMR (CDCI3, 376 MHz) 5:
-149.97 (s). MS: 511.4 (M+1)+.
1H-NMR (CDCI3, 400 MHz) 5: 8.20 (d, 1H, J =
Oa 0 HNj<F 8.0 Hz), 7.84 (s, 1H), 7.63 (d, 1H, J = 8.0 Hz), 6.37 (s, 1H), 5.63 (d, 1H, J = 8.0 Hz), 5.04 (t, J =
H I \ * =-Os 6.0 Hz, 1H), 4.13-4.19 (m, 1H), 3.98-4.01 (m, 18/5 N 0 Ex .# 2H), 3.81 (d, J = 7.2 Hz, 2H), 3.49-3.56 (m, 2H), d u3 3.12-3.18 (m 2H) 2.64 (s 3H) 1.97-2.00 (m, Q
' ' ' ' ' 2H), 1.49-1.67 (m, 5H), 1.40 (s, 3H), 1.34 (s, 6H), 0.99-1.12 (m, 3H), 0.62-0.65 (m, 2H). MS:
602.3 (M+1).
Example 19 a 0 H I \ . s=o cF3 d 19 1-(CyclohexvImethyl)-2-methyl-5-(4-sulfamov1-3-(trifluoromethvI)Dtenv1)-N-(tetrahydro-2 H-pyran-4-v1)-1H-pyrrole-3-carboxamide (19) To a solution of compound 17/97 (150 mg, 0.26 mmol) in DCM (5 mL) was added TFA (5 mL) and the solution was stirred at 30 C for 5 h, concentrated and purified by prep. HPLC to give compound 19 (108 mg, 82%) as a colorless solid. 1H-NMR (400 MHz, CDCI3) 6: 0.62-0.66 (2H, m), 1.00-1.04 (3H, m), 1.26-1.57 (8H, m), 1.97-2.01 (2H, m), 2.63 (3H, s), 3.50-3.55 (2H, m), 3.81 (2H, d, J = 7.6 Hz), 3.98-4.00 (2H, m), 4.14-4.17 (2H, m), 5.05-5.07 (2H, m), 5.60 (1H, d, J = 8.0 Hz), 6.35 (1H, s), 7.64 (1H, dd, J = 8.4, 1.6 Hz), 7.82 (1H, s), 8.30 (1H, d, J = 8.0 Hz). MS: 528.2 [M+1]+.
Example 19/1 Using a procedure similar as described in Example 19, the following compound was prepared.
Structure Analytical data n 0ci 1H-NMR (300 MHz, CDCI3) 6: 0.66-0.77(2H, m), 1.05-1.11 (3H, m), 1.27-1.60 (8H, m), 1.98-2.03 (2H, m), 2.64 (3H, s), H I \
s=o 3.55 (2H, dt, J = 1.5, J = 11.4 Hz), 3.83 (2H, d, J = 7.2 Hz), 4.00 (2H, dd, J = 2.4, J = 10.2 Hz), 4.15-4.20 (1H, m), 5.53 (2H, d, J = 7.5 Hz), 5.63 (1H, d, J = 7.5 Hz), 6.41 (1H, s), 7.73 (1H, d, J = 1.8 Hz), 7.79 (1H, s). MS: 562.2 [M+1r.
Example 20 HN-<
H
d20 5434 tert-Buty1)-4-(N-(tert-butypsulfamovOphenv1)-1-(cyclohexylmethyl)-2-fluoro-N-(tetrahvdro-2H-pyran-4-v1)-1H-pwrole-3-carboxam ide (20) To a solution of compound 17/116 (100 mg, 0.18 mmol) in MeCN (30 mL) at rt under N2 was added Selecffluor (83 mg, 234 pmol) and the resulting solution was stirred at 55 C overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The combined organic layer was concentrated and purified by prep. HPLC to give compound 20 (45 mg, 43%) as a colorless solid. 1H-NMR (400 MHz, CDCI3) 6: 8.19 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 1.2 Hz, 1H), 7.27 (t, 1H), 6.51 (d, J = 5.6 Hz, 1H), 5.70 (br s, 1H), 4.48 (5, 1H), 4.02-3.95 (m, 1H), 4.00-3.97 (d, 2H), 3.75 (d, 2H), 3.54 (dd, J = 10.0 Hz, 11.6 Hz, 2H), 2.02-1.99 (m, 2H), 1.61-1.38 (m, 17H), 1.31(s, 9H), 1.05 (br s, 3H), 0.79-0.74 (m, 2H). MS: 576.3 [M+1]+.
Example 20/1 to Example 20/9 Using a procedure similar as described in Example 20, the following compounds were prepared (and optionally subsequently saponified).
# Structure Analytical data a1H-NMR (CDCI3, 400 MHz) 6: 0.73-0.81 (m, 2H), 1.06-1.10 o (m, 3H), 1.27 (s, 9H), 1.41-1.44 (m, 3H), 1.52-1.60 (m, 5H), H 2.01 (d, J = 12.8 Hz, 2H), 3.54 (t, J = 11.2 Hz, 2H), 3.78 (d, S0 I= \ =J = 6.8 Hz, 2H), 3.99(d, J = 11.2 Hz, 2H), 4.15-4.25 (m, 20/1 F N 8 1H), 4.72 (s, 1H), 5.70 (br s, 1H), 6.62 (d, J =
5.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H) 8.32 (d, J = 8.4 Hz, d 1H). 19F-NMR (CDCI3, 376 MHz) 5: -57.70 (s), -127.80. MS:
588.2 (M+1)+.
) 1H-NMR (DMSO-d6, 400 MHz) 6: 0.72-0.78 (m, 4H), 0.86-'---/ n o 0.88 (m, 2H), 0.97-1.02 (m, 3H), 1.30(s, 12H), 1.35 (s, 3H), H 1 \ 1.50-1.55 (m, 3H), 2.30-2.47 (m, 4H), 3.01-3.06 (m, 1H), 3.65 (s, 3H), 3.73 (d, J = 6.4 Hz, 2H), 4.48-4.54 (m, 1H), (--.) 1 6.47 (d, J = 5.2 Hz, 1H), 7.02 (s, 1H), 7.19 (s, 1H), 7.22 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H). MS: 523.3 (M+1)+.
o A, 1H-NMR (DMSO-d6, 400 MHz) 6: 0.76-0.78 (m, 4H), 0.86-HO .0µ 10 0.88 (m, 2H), 0.98-1.03 (m, 3H), 1.30 (s, 12H), 1.40 (s, 3H), N 1.50-1.55(m, 3H), 2.28-2.42(m, 4H), 2.91 (br s, 1H), 3.73 H I \ = (d, J = 6.8 Hz, 2H), 4.47-4.53 (m, 1H), 6.48 (d, J = 5.6 Hz, 1H), 7.02, (s, 1H), 7.20 (d, J = 12.0 Hz, 2H), 7.91 (d, J = 8.0 U 4 Hz, 1H). 19F-NMR (DMSO-d6, 376 MHz) 5: -129.55. MS:
509.3 (M+1)+.
o 1H-NMR (DMSO-d6, 400 MHz) 5: 0.75-0.78 (m, 4H), 0.84--7c N 0.87 (m, 2H), 1.00-1.04 (m, 3H), 1.16 (s, 6H), 1.30 (s, 12H), 20/4 0 F N 3.12-3.15 (m, 2H), 3.59 (s, 1H), 3.73 (d, J = 7.2 Hz, 2H), 1.40 (s, 3H), 1.50-1.55 (m, 3H), 1.72 (t, J = 8.0 Hz, 2H), 0 d 4 \ 6.42 (d, J = 5.2 Hz, 1H), 7.01 (s, 1H), 7.20 (d, J = 12.8 Hz, 2H), 7.63 (t, J = 5.2 Hz, 1H). MS: 539.4 (M+1)+.
O 1H-NMR (DMSO-d6, 400 MHz) 5: 0.74-0.78 (m, 4H), 0.84-0.87 (m, 2H), 0.97-1.03 (m, 3H), 1.13 (s, 6H), 1.24-1.35 (m, -7c il I \ /I 12H), 1.42 (s, 3H), 1.50-1.55 (m, 3H), 1.67-1.71 (m, 2H), 0 F N 3.13-3.19 (m, 2H), 3.73 (d, J = 7.2 Hz, 2H), 6.44 (d, J = 5.2 20/5 HO d 4 Hz, 1H), 7.01 (s, 1H), 7.19 (d, J = 11.6 Hz, 2H), 7.65 (t, J =
5.2 Hz, 1H), 12.17 (br s, 1H). 19F-NMR (DMSO-d6, 376 MHz) 5: -130.03. MS:525.3 (M+1)+.
o 1H-NMR (CD30D, 400 MHz) 5:0.77-0.83 (m, 2H), 1.03-1.08 N 9 (m, 3H), 1.24 (s, 15H), 1.38 (d, J = 10.8 Hz, 3H), 1.56-1.61 H I \ sli s=0 (m, 3H), 1.85 (t, J = 8.0 Hz, 2H), 3.37 (t, J = 8.0 Hz, 2H), N HI* 3.90 (d, J = 6.8 Hz, 2H), 6.62 (d, J = 5.6 Hz, 1H), 7.83 (dd, J
20/6 7Hcc0 F d = 8.4 Hz, 1.6 Hz, 1H), 7.91 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H).
19F-NMR (CD30D, 376 MHz) 5: -57.70, -127.92. MS: 618.3 (M+1)+.
OH
O'''= 1H-NMR (CD30D, 400 MHz) 6: 0.76-0.85 (m, 2H), 1.03-1.08 ,c: 0 CF30 (m, 3H), 1.24 (s, 9H), 1.38 (d, J = 10.0 Hz, 3H), 1.56-1.62 N
H I \ . S=0 (m, 3H), 2.35-2.43 (m, 2H), 2.58-2.64 (m, 2H), 3.02-3.07 (m, 20R 41 1H), 3.91 (d, J = 6.8 Hz, 2H), 4.64-4.68 (m, 1H), 6.69 (d, J =
F,....) C--) 6.0 Hz, 1H), 7.84 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.92 (s, 1H) 8.32 (d, J = 8.4 Hz, 1H). MS: 602.2 (M+1)+.
Structure Analytical data OH 11-1-NMR (CDCI3, 400 MHz) 6: 0.58-0.63 (m, 2H), 0.93-0.96 (m, 3H), 1.19 (s, 9H), 1.26-1.29 (m, 3H), 1.52 (br s, 3H), o 410 o 2.33-2.41 (m, 2H), 2.80-2.85 (m, 2H), 3.12-3.17 (m, 1H), H I \ g.0 3.35 (br s, 1H), 3.55 (br s, 1H), 4.72-4.73 (m, 1H), 4.79-4.85 20/8F N W OM 1H), 6.09-6.10 (m, 1H), 6.55 (d, J = 5.2 Hz, 1H), 7.48 (d, isi J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.69 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.66 (d, J = 8.8 Hz, 1H). MS: 584.3 (M+1)+.
o 4110 9 1H-NMR (CDCI3, 400 MHz) 6: 0.54-0.61 (m, 2H), 0.91-0.94 (m, 3H), 1.19 (s, 9H), 1.21-1.25 (m, 3H), 1.29 (s, 6H), 1.51 N \ =0 (br s, 3H), 1.92 (t, J = 7.6 Hz, 1H), 3.30-3.65 (m, 4H), 4.69-0 F N 4.70 (m 1H) 6 03-6 04 (m 1H) 6.52 (d J = 5.6 Hz 1H) 20/9 HO 7.48 (d, J = 7.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.68 (t, J =
7.6 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 7.6 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H). MS: 600.3 (M+1)+.
Example 21 and Example 22 oC
HN
0 H HNH \ HO \ *
cF3cF3 d21 d 22 Step 1: Methyl 4-(5-(4-(N-(tert-butyl)sulfamoyI)-3-(trifluoromethyl)pheny1)-2-chloro-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxamido)-2,2-dimethylbutanoate (21) To a solution of methyl 4-(5-(4-(N-(tert-butyl)sulfamoy1)-3-(trifluoromethyl)pheny1)-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxamido)-2,2-dimethylbutanoate (100 mg, 0.16 mmol) in dry THF (2 mL) was added a solution of NCS (21.6 mg, 0.16 mmol) in dry THF
(1 mL) at ¨
78 C and the solution was stirred at ¨55 C for 8 h, quenched with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 2/1) and then prep. TLC to give compound 21(75 mg, 72%) as a colorless solid.
Step 2: 4-(5-(4-(N-(tert-Butypsulfamoy1)-3-(trifluoromethyl)pheny1)-2-chloro-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxamido)-2,2-dimethylbutanoic acid (22) To a solution of compound 21(70 mg, 0.10 mmol) in a mixture of Me0H (4 mL) and H20 (0.5 mL) was added KOH (56 mg, 1.0 mmol) and the solution was stirred at 80 C for 1 h, concentrated and adjusted with 1M HCI to pH = 6. The aqueous phase was extracted with EA twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by prep. TLC to give compound 22 (41 mg, 60%) as a colorless solid. 1H-NMR (CDCI3, 400 MHz) 5: 0.60-0.69 (m, 2H), 0.99-1.04 (m, 3H), 1.27 (s, 9H), 1.28-1.34 (s, 8H), 1.40-1.47 (m, 1H), 1.56 (br s, 3H), 1.91 (d, J = 7.2 Hz, 2H), 3.47-3.53 (m, 2H), 3.89 (d, J = 7.2 Hz, 2H), 4.75 (s, 1H), 6.39-6.41 (m, 1H), 6.76 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H). MS: 634.2 (M+1)+.
Example 22/1 to Example 22/2 Using a procedure similar as described in Example 21, the following compound was prepared (and optionally subsequently saponified).
Structure Analytical data 1H-NMR (CDCI3, 400 MHz) 6: 0.49-0.55 (m, 2H), 0.90-0.95 (m, 3H), 1.19 (s, 9H), 1.22 (s, 3H), 1.25-1.40 (m, 3H), Hie< 1.46-1.65 (m, 4H), 2.03-2.06 (m, 2H), 3.35-3.41 (m, 1H), H s=o 3.54 (td, J = 11.2 Hz, 1.6 Hz, 2H), 3.77-3.82 (m, 1H), 3.99-4.01 (m, 2H), 4.23-4.26 (m, 1H), 4.61 (s, 1H), 6.23 (d, J -22/1 cdN 0 7.2 Hz, 1H), 6.74 (s, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.66 (d, J = 8.0 Hz, 1H).
MS: 586.2 (M+1)+.
OH 1H-NMR (CDCI3, 400 MHz) 5: 0.51-0.55 (m, 2H), 0.90-0 0.91 (m, 3H), 1.14 (s, 9H), 1.19-1.37 (m, 3H), 1.49-1.50 HN (m, 3H), 2.34-2.44 (m, 2H), 2.81-2.84 (m, 2H), 3.15-3.17 H \ OM 1H), 3.36-3.42 (m, 1H), 3.77-3.82 (m, 1H), 4.64 (s, 22/2N " 1H), 4.79-4.82 (m, 1H), 6.55 (d, J = 6.8 Hz, 1H), 6.75 (s, dik ci 0 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 8.35 (d, J =
8.0 Hz, 1H), 8.66 (d, J = 8.4 Hz, 1H). MS: 600.2 (M+1)+.
Example 23 Hre<
H
Cid 0 5-(4-(N-( tert-ButypsulfamovI)naphthalen-1-v1)-2,4-dichloro-1-(cyclohexvImethyl)-N-(tetrahydro-2H-ovran-4-v1)-1H-qvrrole-3-carboxamide (23) To a solution of compound 21/1 (100 mg, 0.17 mmol) in THF (3 mL) was added NCS
(46 mg, 0.34 mmol) at rt and the solution was stirred overnight at 50 C, diluted with water and extracted with EA twice. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to give compound 23 (50 mg, 48%) as a colorless solid. 1H-NMR (CDCI3, 400 MHz) 6: 0.55-0.58 (m, 2H), 0.87-0.92 (m, 3H), 1.19 (s, 9H), 1.25 (s, 3H), 1.47-1.52 (m, 2H), 1.58-1.62 (m, 2H), 2.03-2.06 (m, 2H), 3.34-3.40 (m, 1H), 3.56 (td, J = 11.6 Hz, 2.0 Hz, 2H), 3.73-3.78 (m, 1H), 3.97-4.00 (m, 2H), 4.20-4.35 (m, 1H), 4.63 (s, 1H), 6.42 (d, J = 7.2 Hz, 1H), 7.53 (d, J =
7.6 Hz, 1H), 7.59-7.60 (m, 2H), 7.70-7.75 (m, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.69 (d, J = 8.4 Hz, 1H). MS: 620.2 (M+1)+.
Example 24 n0 NNNI N )1'` Nk H I \ -11H
d 24 Step 1: Ethyl 5-(2-bromoacety1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (24a) To a suspension of AlC13 (12.0 g, 90.0 mmol) in dry DCM (100 mL) was added ethyl 1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (prepared according to Example 1d, 10 g, 40.2 mmol) and 2-bromoacetyl bromide (16.0 g, 79.3 mmol) and the solution was stirred at rt for 2 h, poured into ice water and extracted with DCM (3x). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA =
10:1) to afford intermediate 24a (7.0 g, 47%) as a yellow oil.
Step 2: Ethyl 1-(cyclohexylmethyl)-5-(2-(diethoxyphosphorypacety1)-2-methyl-1H-pyrrole-3-carboxylate (24b) A solution of intermediate 24a (7.0 g, 19 mmol) in triethyl phosphite (60 mL) was refluxed for 1h and concentrated to afford crude intermediate 24b (10.1 g) as a yellow oil.
Step 3: Ethyl 5-(2-cyclohexylideneacety1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (24c) To a solution of crude intermediate 24b (10.1 g, 18.97 mmol) in dry THF (70 mL) at 0 C was added NaH (1.86 g, 46.5 mmol). After stirring for 15 min, cyclohexanone (2.3 g, 23 mmol) was added and the solution was stirred overnight at rt, quenched with aq.
NH4CI and extracted with EA twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 10/1) to give intermediate 24c (3.6 g, 51% in two steps) as yellow powder.
Step 4: Ethyl 1-(cyclohexylmethyl)-2-methyl-5-(1,2-diazaspiror4.51dec-2-en-3-y1)-1H-pyrrole-3-carboxylate (24d) To a solution of intermediate 24c (3.6 g, 9.7 mmol) in a mixture of DMSO (20 mL) and water (ten drops) was added KO'Bu (1.86 g, 19.4 mmol) and the solution was heated overnight at 85 C, cooled to rt, poured into water, adjusted to pH-3 with 1N HCI and then extracted with EA (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 1/1) to give intermediate 24d (3.0 g, 90%) as a pale yellow powder.
Step 5: 1-(CyclohexvImethvI)-2-methvI-5-(1,2-diazaspiro[4.51dec-2-en-3-v1)-1H-pwrole-3-carboxylic acid (24e) To a solution of intermediate 24d (1.0 g, 2.9 mmol) in Me0H (15 mL) was added hydrazine monohydrate (290 mg, 5.8 mmol) and the solution was stirred at ref lux overnight, cooled to rt, concentrated and purified by CC (DCM/Me0H = 10:1) to afford intermediate 24e (490 mg, 48%) as a colorless oil.
Step 6: 1-(CyclohexvImethvI)-2-methvI-5-(1,2-diazaspirof4.51dec-2-en-3-v1)-N-(tetrahvdro-2H-pyran-4-yI)-1H-pyrrole-3-carboxamide (24f) A mixture of intermediate 24e (1.00 g, 2.8 mmol), tetrahydro-2H-pyran-4-amine (283 mg, 5.60 mmol), HATU (2.21 g, 5.60 mmol) and DIPEA (1.44 g, 11.2 mmol) in DMF (15 mL) was stirred at rt for 25 min, diluted with H20 and extracted with EA (3x). The combined organic layers were washed with H20 (3x) and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (DCM/Me0H = 80/1) to afford intermediate 24f (881 mg, 71%) as a yellow solid.
Step 7: N-(tert-Butv1)-3-(1-(cyclohexvImethvI)-5-methvl-4-((tetrahvdro-2H-pvran-4-v1)carbamov1)-1H-pwrol-2-v1)-1,2-diazaspirof4.51dec-2-ene-1-carboxamide (24) To a solution of intermediate 24f (150 mg, 0.34 mmol) in dry DCM (3 mL) was added tert-butyl isocyanate (67 mg, 0.68 mmol) at 0 C under N2 and the solution was stirred overnight at rt, washed with 1M HCI and brine consecutively, dried over Na2SO4, filtered, concentrated and purified by prep. TLC (PE/EA = 1/5) to give example 24 (54 mg, 29%) as a colorless solid. 1H-NMR (CDCI3, 400 MHz) 6: 6.42 (s, 1H), 5.80 (s, 1H), 5.57 (d, 1H, J =
7.2 Hz), 4.10-4.17 (m, 3H), 3.99 (dd, 1H, J = 1.6, 11.2 Hz), 3.53 (dt, 1H, J = 1.6, 11.2 Hz), 3.07 (s, 2H), 2.61-2.68 (m, 2H), 2.59 (s, 3H), 1.98 (dd, 1H, J = 2.0, 12.0 Hz), 1.52-1.81 (m, 13H), 1.39 (s, 9H), 1.15-1.20 (m, 3H), 0.98-1.04 (m, 2H). MS: 540.2 (M+1)+.
Example 24/1 to 24/2 Using a procedure similar as described in Example 24, the following compounds were prepared.
# Structure Analytical data a , 0, 4 1H-NMR (CDCI3, 400 MHz) 6: 7.98-8.00 (m, 2H), 7.47-7.56 (m, 3H), 6.40 (s, 1H), 5.52 (d, 1H, J =
N N ,,,Sµ
H I \ / --.. No 8.0 Hz), 4.05-4.15 (m, 3H), 3.98 (m, 2H), 3.51 (m, 02H), 3.08 (s, 2H), 2.54 (s, 3H), 2.43-2.48 (m, 2H), d1.97 (m, 2H), 1.74-1.84 (m, 4H), 1.62-1.68 (m, 5H), 1.50-1.57 (m, 2H), 1.40-1.43 (m, 2H), 1.31-1.35 (m, 3H), 0.82-0.88 (m, 2H). MS: 581.2 (M+1)+.
ici_3N 0 N-(2 1H-NMR (CDCI3, 400 MHz) 6: 6.54 (s, 1H), 6.17 (d, 1H, J = 7.6 Hz), 5.21 (m, 1H), 5.00 (m, 1H), 4.59 N I \ i NIC' (m, 1H), 4.22 (m, 1H), 3.10 (s, 3H), 2.72-2.79 (m, 24/2 2H), 2.58 (s, 3H), 1.76-1.81 (m, 7H), 1.63-1.70 (m, N
W 5H), 1.43-1.51 (m, 5H), 1.26-1.32 (m, 7H), 1.11-d 1.16 (m, 3H), 0.97-1.02 (m, 2H). MS:
523 (M+1)+.
Example 25 n0 I
u3 K
NN µ * HN
H \
d25 5-(4-(14 tert-Butvlam ino)-2,2,2-trifluoroethvI)-3-(trifl uoromethvflphenv1)-1-(cyclohexvImethvI)-2-methyl- N-(tetrahvdro-2H-pyran-4-0-1H-qvrrole-3-carboxam ide (25) To a mixture of crude compound 32 (1.34 mmol) and KHF2 (105 mg, 1.34 mmol) in dry MeCN (5 mL) was added dry CF3CO2H at 0 C and the suspension was stirred for 5 min.
Me3SiCF3 (382 mg, 2.7 mmol) was added, the cooling bath was removed and the mixture was stirred for 20 h at rt, diluted with sat. aq. Na2CO3 (0.5 mL) and stirred for an additional two min, diluted with water and extracted with EA (3x). The combined organic phases were dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA = 1/1) to afford example 25 (45 mg, 6%) as a colorless solid. 1H-NMR (CDCI3, 300 MHz) 6: 7.82 (d, J =
7.5 Hz, 1H), 7.66 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 6.30 (s,1H), 5.63 (d, J = 7.5 Hz, 1H), 4.83 (q, J = 6.6 Hz, 1H), 4.20 (m, 1H), 3.99 (m, 2H), 3.78 (m, 2H), 3.54 (m, 2H), 2.63 (s, 3H), 2.00 (m, 2H), 1.59-1.48 (m, 5H), 1.34-1.29 (m, 3H), 1.04 (s, 9H), 1.00-0.98 (m, 3H), 0.65-0.61 (m, 2H).
MS: 602.4 (M+1)+.
Example 26 r) 0 NNN
H
N Isr ----"c d 26 Step 1: 4-Bromo-2-(tert-butvl)phenol (26a) To a solution of 2-(tert-butyl)phenol (5 g, 33 mmol) in DCM (200 mL) was added tetrabutyl-ammonium tribromide (16.5 mg, 33 mmol) and the mixture was stirred at rt for 12 h, diltued with H20 (50 mL) and extracted with DCM (150 mL). The organic layer was washed with brine and dried over Na2504, concentrated and purified by CC (PE/EA =5/1) to afford compound 26a (6.8 g, 89%) as a clear oil.
Step 2: 2-(tert-Butyl)-4-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-v1)phenol (26h) To a solution of compound 26a (162 mg, 0.71 mmol) in 1,4-dioxane (20 mL) was added B2Pin2 (541 mg, 2.13 mmol) and KOAc (278 mg, 2.84 mmol), followed by Pd(dppf)Cl2 (52 mg, 71 pmol) under Ar and the suspension was heated to 100 C overnight, cooled, concentrated and purified by CC (PE/EA = 50/1 to 10/1) to afford compound 26b (109 mg, 56%) as a colorless solid.
Step 3: 5-(3-(tert-Butyl)-4-hydroxvphenv1)-1-(cyclohexvImethvI)-2-methyl-N-(tetrahvdro-2H-pvran-4-vI)-1H-pvrrole-3-carboxamide (26c) A solution of 5-bromo-1-(cyclohexylmethyl)-2-methyl-N-(tetrahydro-2H-pyran-4-y1)-1H-pyrrole-3-carboxamide (382 mg, 1.0 mmol, prepared similar as described for intermediate 9b), compound 26b (331 mg, 1.2 mmol), Cs2CO3 (487 mg, 1.5 mmol) and Pd(dppf)Cl2 (30 pmol) in 1,4-dioxane and water (10 mL; 20:1) was heated to 90 C overnight, cooled to rt, evaporated, diluted with water and extracted with DCM. The organic layer was dried over MgSO4, filtered, evaporated and purified by CC (hexane/EA = 5/1) to give compound 26c (253 mg, 56%).
Step 4: 2-(tert-Butyl)-4-(1-(cyclohexvImethvI)-5-methvI-4-((tetrahvdro-2H-pvran-4-v1)carb-amov1)-1H-pyrrol-2-v1)phenvl trifluoromethanesulfonate (26d) To a solution of compound 26c (100 mg, 0.22 mmol) in DCM (20 mL) was added TEA
(44 mg, 0.44 mmol) and catalytic amounts of DMAP, followed by Tf20 (74 mg, 0.26 mmol) and the resulting mixture was stirred at rt for 12 h, concentrated and purified by CC (PE/EA =3/1) to afford compound 26d (56 mg, 43%) as a brown solid.
Step 5: 5-(3-(tert-Butv1)-4-(1-isopropv1-1H-pvrazol-5-v1)Phenv1)-1-(cvclohexvImethvI)-2-methyl- N-(tetrahvdro-2H-pvran-4-0-1H-pyrrole-3-carboxam ide (26) A 20-ml microwave vial was charged with compound 26d (100 mg, 0.17 mmol), 1-isopropyl-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole (0.2 mmol, 1.2 eq) and Cs2CO3 (167 mg, 0.51 mmol) dissolved in 1,4-dioxane and water (10 mL, 20:1), followed by Pd(dppf)Cl2 (0.03 eq) under N2. The mixture was heated to 90 C overnight, evaporated, diluted with water and extracted with DCM. The organic layer was separated, dried over Na2SO4, filtered, evaporated and purified by CC (hexane/EA = 5/1) to give compound 26. 1H-NMR (400 MHz, CDCI3) 6: 7.62 (s, 1H), 7.45 (s, 1H), 7.13 (m, 1H), 7.00 (m, 1H), 6.24-6.18 (m, 1H), 5.60 (br d, 1H, J = 6.4 Hz), 4.20-4.15 (m, 1H), 4.01-3.89 (m, 3H), 3.73 (m, 2H), 3.46 (m, 2H), 2.55 (s, 3H), 1.94-1.91 (m, 2H), 1.50-1.43 (m, 8H), 1.39-1.30 (m, 6H), 1.15 (m, 9H), 1.05-0.90 (m, 3H), 0.70-0.57 (m, 2H). MS: 545.4 (M+H).
Example 26/1 to 26/6 Using a procedure similar as described in Example 26, the following compounds were prepared.
# Structure Analytical data a 0 1H-NMR (400 MHz, CDCI3) 6: 7.43-7.38 (m, 2H), 7.06 (m, 1H), 6.94-6.90 (m, 2H), 6.16 (s, 1H), N
H I\ 'W'/ YE1 5.58 (m, 1H), 4.15-4.04 (m, 1H), 3.95-3.88 (m, 26/1 N -- N 2H), 3.72 (m, 2H), 3.46 (m, 2H), 2.56 (s, 3H), d 2.04 (s, 3H), 1.93-1.90 (m, 2H), 1.49-1.47 (m, 5H), 1.32-1.29 (m, 3H), 1.18 (s, 9H), 0.95 (m, 3H), 0.61 (m, 2H). MS: 517.3 (M+H)+.
a 0 1H-NMR (400 MHz, CDCI3) 6: 7.47 (s, 1H), 7.40 k (s, 1H), 7.36 (s, 1H), 7.02 (s, 1H), 6.11 (s, 1H), il I \ . / Nil 5.57 (d, 2H, J = 6.4 Hz), 4.13 (m, 1H), 3.92-3.89 26/2 N -N (m, 2H), 3.71 (m, 2H), 3.46 (m, 2H), 2.55 (s, 3H), d 1.94-1.90 (m, 2H), 1.58 (s, 9H), 1.51-1.50 (m, 5H), 1.34 (m, 3H), 1.91 (m, 9H), 0.97 (m, 3H), 0.61 (m, 2H). MS: 559.4 (M+H)+.
a 0 1H-NMR (400 MHz, CDCI3) 6: 7.40 (s, 1H), 7.36 ) (s, 1H), 7.29 (s, 1H), 7.19 (s, 1H), 7.01 (s, 2H), 11 I \ * / " 6.12 (s, 1H), 5.56 (d, 2H, J
= 6.4 Hz), 4.18-4.16 26/3 N -N (m, 3H), 3.92 (m, 2H), 3.71 (m, 2H), 3.46-3.45 d (m, 2H), 2.56 (s, 3H), 1.93-1.90 (m, 2H), 1.56-1.48 (m, 8H), 1.46 (m, 3H), 1.20 (s, 9H), 0.97 (m, 3H), 0.64 (m, 2H). MS: 531.4 (M+H)+.
1H-NMR (400 MHz, CDCI3) 6: 8.13 (s, 2H), 7.41 cON 0 \ (s, 1H), 7. 15 (m, 1H), 6.94 (d, 1H, J = 7.6 Hz), N -NI ? 6.14 (s, 1H), 5.54 (d, 1H, J = 7.6 Hz), 5.02 (m, H I \ \ /)¨NH 1H), 4.13-4.11 (m, 2H), 3.85 (m, 2H), 3.72 (m, 26/4 N 11 1 N 2H), 3.46 (m, 2H), 2.56 (s, 1H), 1.96-1.91 (m, d 2H), 1.51-1.48 (m, 5H), 1.33-1.32 (m, 3H), 1.23 (d, 6H, J = 6.4 Hz), 1.19 (s, 9H), 0.97 (m, 3H), 0.62 (m, 2H). MS: 572.4 (M+H)+.
Structure Analytical data 1H-NMR (400 MHz, CDCI3) 5: 7.66 (s, 1H), 7.52 o N¨N (s, 1H), 7.19-7.17 (m, 1H), 7.07-7.05 (m, 1H), HO 'ILO , 6.28 (s, 2H), 6.01 (m, 1H), 4.84-4.78 (m, 1H), ."N \ 4.15-3.98 (m, 1H), 3.80 (m, 2H), 3.14-3.05 (m, H
26/5 N 1H), 2.83-2.78 (m, 2H), 2.62 (s, 3H), 2.34-2.26 (m, 2H), 1.57-1.50 (m, 6H), 1.42-1.36 (m, 6H), 1.25 (s, 9H), 1.07-1.02 (m, 3H), 0.72-0.67 (m, 2H). MS: 559.3 (M+H)+.
1H-NMR (400 MHz, CDCI3) 5: 7.69 (s, 1H), 7.46 0 NN (s, 1H), 7.13-7.10 (m,1H), 6.98-6.96 (m,1H), HO2C ' 6.23-6.20 (m, 1H), 6.07 (br s, 1H), 4.03-4.00 (m, 26/6 H N 1H), 3.72 (m, 2H), 3.42-3.38 (m, 2H), 2.53 (s, 3H), 1.83-1.80 (m, 2H), 1.52-1.41 (m, 6H), 1.36-1.29 (m, 6H), 1.20 (s, 6H), 1.15 (s, 9H), 0.98-0.90 (m, 3H), 0.68-0.57 (m, 2H). MS: 575.3 (M-i-H)+.
Example 27 OH
1=1 Fll *
d27 Step 1: 1-(2-Flvdroxv-5-(4,4,5,5-tetramethvI-1,3,2-dioxaborolan-2-AphenvI)ethanone (27a) To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (152 mg, 0.71 mmol) in 1,4-dioxane (20 mL) was added B2Pin2 (541 mg, 2.13 mmol) and KOAc (278 mg, 2.84 mmol), followed by Pd(dppf)Cl2 (52 mg, 71 pmol) under Ar and the resulting suspension was heated to 100 C
overnight, concentrated and purified by CC (PE/EA =50/1 to 10/1) to afford compound 27a (109 mg, 59%) as a colorless solid.
Step 2: Ethyl 5-(3-acetv1-4-hydroxvphenv1)-1-(cyclohexvImethvI)-2-methyl-1H-pvrrole-3-carboxvlate (27b) A solution of ethyl 5-bromo-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (328 mg, 1.0 mmol, prepared similar as described for compound le), compound 27a (314 mg, 1.2 mmol), Cs2CO3 (487 mg, 1.5 mmol) and Pd(dppf)C12 (30 pmol) in 1,4-dioxane and water (10 mL, 20:1) was heated to 90 C overnight, cooled to rt, evaporated, diluted with water and extracted with DCM. The organic layer was dried over MgSO4, filtered, evaporated and purified by CC (hexane/EA = 5/1) to give compound 27b (250 mg, 65%) Step 3: Ethyl 5-(3-acetv1-4-(((trifluoromethvI)sulfonvI)oxv)phenv1)-1-(cyclohexvImethvI)-2-methyl-1H-pwrole-3-carboxvlate (27c) To a solution of compound 27b (84 mg, 0.22 mmol) in DCM (20 mL) was added TEA
(44 mg, 0.44 mmol) and DMAP, followed by Tf20 (75 mg, 0.26 mmol) and the resulting mixture was stirred at rt for 12 h, concentrated to dryness and purified by CC (PE/EA =
3/1) to afford compound 27c (52 mg, 46%) as a brown solid.
Step 4: Ethyl 5-(3-acety1-4-(1-isopropy1-1H-pyrazol-5-y1)0henv1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (27d) A 20-ml microwave vial was charged with compound 27c (93 mg, 0.18 mmol), 1-isopropy1-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole (47 mg, 0.20 mmol) and Cs2CO3 (167 mg, 0.51 mmol) dissolved in 1,4-dioxane and water (10 mL, 20:1), followed by Pd(dppf)C12 (0.03 eq) under N2. The mixture was heated to 90 C overnight, concentrated, diluted with water and extracted with DCM. The organic layer was dried over Na2SO4, filtered, concentrated and purified by CC (hexane/EA = 5/1) to give compound 27d (62 mg, 73%).
Step 5: 5-(3-Acetyl-4-(1-isopropy1-1H-pyrazol-5-yl)phenv1)-1-(cyclohexylmethyl)-2-methyl-1 H-pyrrole-3-carboxylic acid (27e) To a solution of compound 27d (95 mg, 0.20 mmol) in Et0H was added 1M aq. KOH
(8 mL) at rt. The mixture was stirred for 4 h at rt, concentrated, diluted with water (30 mL) and extracted with EA (150 mL). The organic layer was washed with brine, dried over Na2504, filtered, concentrated and purified by CC (hexane/EA = 1/3) to give compound 27e (80 mg, 89%).
Step 6: 5-(3-Acetyl-4-(1 -isopropy1-1H-pyrazol-5-yl)phenv1)-1-(cyclohexylmethyl)-2-methyl-N-(tetrahydro-2H-pyran-4-y1)-1H-pyrrole-3-carboxamide (27f) To a solution of 27e (94 mg, 0.21 mmol) in DMF (2 mL) was added HATU (167 mg, 0.44 mmol), D1PEA (224 mg, 1.74 mmol) and tetrahydro-2H-pyran-4-amine (48 mg, 0.48 mmol).
The mixture was stirred at rt overnight, then 5 mL H20 and 10 mL EA was added into the reaction. The organic layer was separated and the aq. layer was extracted with EA (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to give product 27f (70 mg, 63%).
Step 7: 1-(Cyclohexylmethyl)-5-(3-(2-hyd roxypropan-2-y1)-4-(1-isopropy1-1H-pyrazol-5-yl)pheny1)-2-methyl-N-(tetrahydro-2H-pyran-4-y1)-1H-pyrrole-3-carboxamide (27) A solution of 27f (70 mg, 132 pmol) in THF (4 mL) was cooled to 0 C and treated dropwise with MeMgBr (1M in Et20, 1 mmol). Upon completion of addition, the resulting suspension was allowed to warm to rt and was stirred for 5 h. Sat. aq. NH4C1 (20 mL) was added slowly and the mixture was diluted with EA (20 mL). The layers were separated and the aq. layer was extracted with EA (3x 25 mL). The combined organic layers were dried over MgSO4, filtered, concentrated and purified by prep. HPLC to afford 27 (20 mg, 28%).
1H-NMR (400 MHz, CDCI3) 6: 7.61 (s, 1H), 7.26 (s, 1H), 7.15-7.09 (m, 1H), 6.29-6.22 (m, 2H), 5.65-5.58 (m, 1H), 4.30-4.11 (m, 2H), 4.01-3.92 (m, 2H), 3.84-3.79 (m, 2H), 3.60-3.59 (m, 2H), 2.63 (s, 3H), 2.02-1.95 (m, 2H), 1.59-1.54 (m, 8H), 1.53-1.48 (m, 6H),1.46-1.39 (m, 3H), 1.06-1.00 (m, 3H), 0.72-0.67 (m, 2H). MS: 547.3 (M+H)+.
Example 28 n0 H I \=
N
5-(4-(N-( tert-Butyl)sulfamoy1)-3-(trifluoromethyl)ohenv1)-14(141 uorocyclohexyl)-methyl)-2-methyl- N-(tetrahydro-2H-pyran-4-yI)-1H-oyrrole-3-carboxam ide (28) To a solution of compound 17/255 (200 mg, 0.33 mmol) in DCM (10 mL) was added diethylaminosulfur trifluoride (0.13 mL, 0.65 mmol) in one portion at rt and the mixture was stirred at rt for 1 h, poured into water and extracted with DCM. The organic layer was concentrated and purified by prep. HPLC to give compound 28 (25 mg, 13%) as a colorless solid. 1H-NMR (300 MHz, CDCI3) 6: 0.85-1.10 (m, 2H), 1.25 (s, 11H), 1.39-1.59 (m, 8H), 1.99 (m, 2H), 2.65 (s, 3H), 3.49-3.56 (m, 3H), 3.99 (m, 2H), 4.09-4.24 (m, 3H), 4.71 (s, 1H), 5.64 (d, J = 7.5 Hz, 1H), 6.40 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H). MS: 602.2 (M+1)+.
Example 29 HO o H I \
d 29 Step 1: Methyl 5-(3-(tert-buty1)-5-(1-methylcycloorooyl)oheny1)-4-chloro-1-(cyclohexylmethyl)-2-methyl-1H-oyrrole-3-carboxylate (29a) To a solution of methyl 5-(3-(tert-buty1)-5-(1-methylcyclopropyl)pheny1)-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (368 mg, 0.85 mmol) in ACN (20 mL) was added NCS
(113 mg, 0.85 mmol) and the mixture was stirred at rt for overnight, concentrated and purified by prep. TLC (PE/EA = 50/1) to afford compound 29a (319 mg, 80%) as a pale yellow oil. 11-1-NMR (400 MHz, CDCI3) 6: 0.56-0.70 (2H, m), 0.73-0.76 (2H, m), 0.86-0.89 (2H, m), 0.97-1.03 (3H, m), 1.33 (12H, br s), 1.38 (3H, t, J = 6.8 Hz ), 1.42 (3H, s), 1.53-1.55 (3H, m), 2.55 (3H, s), 3.64 (2H, d, J = 7.2 Hz), 4.33 (2H, q, J = 6.8 Hz), 6.99 (1H, t, J = 1.6 Hz), 7.13 (1H, t, J = 1.6 Hz), 7.29 (1H, t, J = 1.6 Hz).
Step 2: (trans)-3-(5-(3-(tert-Butyl)-5-(1-methvIcvclopropvl)phenv1)-4-chloro-1-(cyclohexvImethvI)-2-methyl-1H-pwrole-3-carboxamido)cyclobutanecarboxvlic acid (29) Compound 29a was saponified and coupled with the amino acid methyl ester and then finally saponified to obtain target compound 29 similar as described above. 11-I-NMR
(300 MHz, CDCI3) 6: 0.53-0.67 (2H, m), 0.74-0.77 (2H, m), 0.86-0.90 (2H, m), 0.94-1.04 (3H, m), 1.26-1.34 (13H, m), 1.43 (3H, s), 1.54 (3H, d, J = 6.3 Hz), 2.27-2.38 (2H, m), 2.60 (3H, s), 2.77-2.84 (2H, m), 3.06-3.17 (1H, m), 3.62 (2H, d, J = 7.2 Hz), 4.75-4.88 (1H, m), 6.97 (1H, s), 7.02 (1H, d, J = 7.8 Hz), 7.11 (1H, s), 7.31 (1H, s). MS: 539.3 [M+1]+.
Example 29/1 to 29/2 Using a procedure similar as described in Example 29, the following compounds were prepared.
Structure Analytical data 1H-NMR (300 MHz, CDCI3) 6: 0.58-0.73 (2H, m), 0.75-HO ciL 0 CI 4 0.81 (2H, m), 0.84-0.89 (2H, m), 0.95-1.04 (3H, m), 1.27-1.36 (5H, m), 1.43 (3H, s), 1.54 (7H, br s), 2.32-29/1 H I \
2.41 (2H, m), 2.43 (3H, s), 2.60-2.69 (2H, m), 3.05-3.09 (1H, m), 3.73 (2H, d, J = 7.2 Hz), 4.61-4.72 (1H, m), 0H 7.06 (1H, d, J = 1.8 Hz), 7.20 (1H, d, J = 1.8 Hz), 7.48 (1H, d, J = 1.8 Hz). MS: 541.3 [m-Fi]t JIõ. 1H-NMR (300 MHz, CDCI3) 6: 0.58-0.66 (2H, m), 0.77-HO 0 CI 4 0.83 (2H, m), 0.85-0.91 (2H, m), 0.94-0.99 (3H, m), 1.25-1.36 (4H, m), 1.44 (3H, s), 1.52 (8H, s), 2.27-2.37 29/2 H I \ *
(2H, m), 2.60 (3H, s), 2.77-2.85 (2H, m), 3.07-3.15 (4H, / m), 3.64 (2H, d, J = 7.2 Hz), 4.76-4.88 (1H, m), 7.00 0 (1H, d, J = 7.2 Hz), 7.04 (1H, t, J =
1.5 Hz), 7.15 (1H, t, J = 1.5 Hz), 7.31 (1H, t, J = 1.5 Hz). MS: 555.3 [M+1]+.
Example 30 and Example 31 0 ca y H \ = 0 H I \ 0 OH
d 30 d 31 Step 1: 1-(CyclohexvImethvI)-2-methvI-5-(8-(proo-1-en-2-vpspirofchroman-4,11-cyclopropar11-6-v1)-N-(tetrahvdro-2H-pvran-4-v0-1H-pwrole-3-carboxamide (30) To a solution of compound P97 (128 mg, 0.39 mmol) 5-bromo-1-(cyclohexylmethyl)-methyl-N-(tetrahydro-2H-pyran-4-y1)-1H-pyrrole-3-carboxamide (180 mg, 471 pmol), K2CO3 (135 mg, 981 pmol) and TBAB (10 mg) in a mixture of 1,4-dioxane (3 mL) and water (1.5 mL) was added Pd(PPh3)2C12 (20 mg) under N2. Under microwave conditions (120 W), the solution was heated at 105 C for 1 h, cooled, poured into a mixture of water and EA and extracted with EA twice. The combined organic layers were washed with water and brine, concentrated and purified by CC (PE/EA = 5/1) and then prep. HPLC to give compound 30 (109 mg, 56%) as a colorless solid.
Step 2: 1-(CyclohexvImethvI)-5-(8-(2-hydroxvpropan-2-vOspirorchroman-4,11-cvclooropanl-6-0-2-methvl-N-(tetrahvdro-2H-pvran-4-v1)-1H-pwrole-3-carboxamide (31) To a stirred mixture of compound 30 (109 mg, 0.22 mmol) and 0s04 (4 mg) in 1,4-dioxane (5 mL) was added a solution of Na104 (200 mg, 0.94 mmol) in water (2 mL). The solution was stirred at 30 C for 2 h, quenched with water and extracted with EA twice. The combined organic layers were washed with brine, concentrated and purified by CC (PE/EA
= 5/1) to give an intermediate as a colorless solid. To a stirred solution of this intermediate in dry THF
(3 mL) was added CH3MgBr (3M, 70 pL, 0.21 mmol) and the mixture was stirred at rt for 2 h, quenched with aq. NH4C1 at 0 C and extracted with EA. The organic layer was concentrated and purified by CC (PE/EA = 3/1) to give compound 31(61 mg, 53%). 111-NMR
(CDCI3 +
D20, 300 MHz) 6: 0.61-0.63 (2H, m), 0.72-0.75 (2H, m), 0.88-0.98 (5H, m), 1.32-1.35 (3H, m), 1.54-1.62 (7H, m), 1.94-1.99 (3H, m), 1.99-2.00 (1H, m), 2.63 (3H, s), 3.53 (2H, t, J =
11.7 Hz), 3.65 (2H, d, J = 7.2 Hz), 3.98 (2H, d, J = 10.8 Hz), 4.13-4.21 (1H, m), 4.44-4.47 (2H, m), 4.86 (3H, m), 5.61 (1H, d, J = 7.5 Hz), 6.08 (1H, s), 6.50 (1H, s), 6.99 (1H, s). MS:
521.4 (M+1)+.
Example 32 and Example 33 a 0 00 0,3 0,3 f., rsi Fl I \ * I *
d32 d33 0 Step 1: 1-(CyclohexvImethyl)-5-(4-formv1-3-(trifluoromethvI)ohenv1)-2-methvl-N-(tetrahvdro-2H-pvran-4-vI)-1H-ovrrole-3-carboxamide (32) A solution of 5-bromo-1-(cyclohexylmethyl)-2-methyl-N-(tetrahydro-2H-pyran-4-y1)-1H-pyrrole-3-carboxamide (2.1 g, 5.5 mmol), (4-formy1-3-(trifluoromethyl)phenyl)boronic acid (1.0 g, 4.6 mmol), K2CO3 (1.0 g, 7.2 mmol), TBAB (50 mg) and Pd(PPh3)2C12 (200 mg) in a mixture of 1,4-dioxane (10 mL) and water (5 mL) in a sealed tube was irradiated in a microwave at 100 C for 2 h, concentrated and purified by CC (PE/EA = 3/2) to give compound 32 (690 mg, 32%) as a yellow solid.
Step 2: 1-(CyclohexvImethvI)-2-methvI-5-(4-(morpholinomethyl)-3-(trifluoromethvl)phenv1)-N-(tetrahvdro-2H-pvran-4-v1)-1H-pwrole-3-carboxamide (33) To a solution of compound 32 (200 mg, 0.42 mmol) and morpholine (87 mg, 1.0 mmol) in DCM (3 mL) was added AcOH (one drop) and NaBH(OAc)3 (212 mg, 1.0 mmol) and the solution was stirred overnight at rt and quenched with sat. NaHCO3. The organic layer was washed with sat. NaHCO3, water and brine, dried over Na2SO4, filtered, concentrated and purified by prep. HPLC to afford compound 33 (33 mg, 14%) as a colorless solid. 1H-NMR
(CDC13, 400 MHz) 6: 7.83 (d, J = 7.6 Hz, 1H), 7.59 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 6.22 (s, 1H), 5.60 (d, J = 8.0 Hz, 1H), 4.12-4.18 (m, 1H), 3.97-4.00 (m, 2H), 3.74-3.77 (m, 6H), 3.70 (s, 2H), 3.52 (m, 2H), 2.62 (s, 3H), 2.50-2.56 (m, 4H), 1.96-2.05 (m, 2H), 1.47-1.51 (m, 3H), 1.32-1.42 (m, 4H), 1.24-1.28 (m, 1H), 0.97-1.02 (m, 3H), 0.58-0.70 (m, 2H).
MS: 548.3 (M+1)+.
Example 34 cia 0 N
N N
o d 34 1-(CyclohexvImethvI)-5-(44(3,3-dimethvImorpholino)methvI)-3-(trifluoromethvflphenv1)-2-methyl-N-(tetrahvdro-2H-pyran-4-v1)-1H-pwrole-3-carboxamide (34) Using similar procedures as described in Example 33 compound 34 was prepared.
(CDCI3, 400 MHz) 6: 7.97 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.21 (s, 1H), 5.60 (d, J = 7.6 Hz, 1H), 4.11-4.18 (m, 1H), 3.98 (d, J = 11.2 Hz, 2H), 3.69-3.77 (m, 6H), 3.52 (m, 2H), 3.42 (s, 2H), 2.62 (s, 3H), 2.46 (m, 2H), 1.98 (m, 2H), 1.47-1.56 (m, 6H), 1.34-1.43 (m, 3H), 1.13 (s, 6H), 0.96-1.05 (m, 3H), 0.61-0.68 (m, 2H). MS: 576.4 (M+1)+.
Additional Examples If one were to use the appropriate building blocks as described in the Examples above, one would obtain the following compounds:
HOOCõ.
CL --(2/
-jH OH i7 OH 0 H I \ __ e _________ Nrri-'n em NhN 1 \ II OCF3 N
d d d , HOOC,,, HOOC"
Oc\ 0 '\3 0 V
H I \ 411 OCF3 CLN
( N N -H I \ \ N
N Vi."-N) Nj5A N
, HOOCõ.CL o V y ot, 0 y N
N
HO H I \ \ ,N H I \ * H I \ *
N NI/ N N
d d d CHF2 cHF2 , HOOCõ. HOOC,,, . a 0 oõ 0 HNj<
N N N
H I \ . H I \ 4. H
N N N
d d HN)\
d F F
OH
Oa 0 0:=3 FINj< N CI
N 1 \ = =i:) C-"il /N \ ir 4i-L P H
N 0 HO si:-.0 N
HNt d F F F3C d F3cC
HN
k ICY I
f , , , OH
q )\----\N F # N F dli 7)71N N=---Ns H H
N* -=10 *
N ==-0 N 11µ4), CY HN \õ......õ
IN
CY HN \õ....._ IN
0) OH
, , , OH OH
--/
Od, 0--,, q 0 c( 0 HO
HN HN i=-'-, I N r----\N
/ \ N%\S / \ N
N
& ,s-N
0 H 0) FIN
OH
OH
O
--/
OH
0-"0 --/ q 0 `Szq ----',..
O r-- 0 HN
HN N
S\ H S\ iN \ .
s i N
-HN-sf 0) OH
OH
OH
CD.L 0 CI CI
Nrla CI CI 0 CI Cl H I \ = SOH I \ . g=0 /N
----NH I \ . g=0 d d , , , HO\__, 0 HO\ 0 HO 0 A CN
= \ HNk i N`
\ i N
Sz.-.0 cy = 1:---0 '-'0 0) =
--/
0 0 0',. F
__________ 0 0 ,p 1...i. D., 0 F F
* * N
/\ iN \ * H I \ = ==0 N HI\l<
N *
0) d OH OH
0'.. F 0',.
EL 0 F CI [D, 0 0 CI Cl N N-J.---___(N.-: N
H I \ = =-,c) H I \ \ / 0 z5/1. ''NH ''' 1 \ = g=.0 FINi< d NH
, , , o o o CI a ci a a a o o N 0 0 z.; SICIN I \ * '--(:) ciii'l I N\ * # =(:) I \ * g=o j NH HN 0/
0' (-----) ---/c d ,\
, , , cl ci ci ci 0, ci I , . Lo ,..,,, I , . ,=0 H0)---N,,,,, , , . 90 _ s-N NH Oz3S N NH N
d -7C o' d ,\
d , HOOC, , HOOC ,.n 0 n L-Ths11===----¨ 1---NIC--)L--FIC>r-NN
H I \ * 4=0 H I \ \ N H I \ \ N
N HN V--"N µ __ /K V---N µ
/( d , d d OC F3 , , , HN N,N HN
\1-1 11 d I
N
V. ---N \
?
H 006 d Hood d H 00d d , , , OH H I \ . SO2 -7c-i H I \ . SO2 --70H H I \ 1, Si 02 d N NH N NH N
NH
7c , -7(N N N rN
OH H I \ II SO2 --7CH I \= SO2 ____NN0õ) I
N NH N NH N
d d ci A
d -A
, , , OH
0 HOOC,, HOy --J
0 '''=.0 o c CI CI
H 'C) 0 [sift!
I . SO2 N , N-4 \ \
H I /N
N NH N \
d 7c d A
d OH
, , , HO\L 0-N
0 ich OH 0 0 N N
H N µ N=
h H N
NN
H I \ * H-ji (I-N
/
N N N
L
d d A
d OH
OH F OH F F
F---( ,o,,, F--( F---( 0 'Aii:L 0 0 . 0 N
H I \ = !HI I \ * Nfil N N N
d A
d d . , , , OH
---I, OH 0 OCF3 HO____EsiN
0 (21'..0,v 0 F
N I \ I. 0 N
H I \ . N
H I \ .
N N N
d, d A,= d , OH
.,, N
0 '=c% 0 OH 02S3N 0 02s N
H I \ . H I \ 4, --C) H 1 \ * SO2NH
N N NH N
d d ____( UN
d , , , OH OH
ON,c::s 0 0'"=c% 0 0N N"N
,O, Auk 0 N N
H I \ * H I \ . HO H
N N N FIN
d A
, d , d and OH
--I
(:)..cic 0 N N
\ / 0 N ii H I \ * =() N HN.<
d .
Protein Expression and Purification Protein expression and purification was done as described in W02010/049144.
TA-FRET Activity Assay This method measures the ability of putative ligands to modulate the interaction between the purified bacterial expressed RORy ligand binding domain (LBD) and synthetic N-terminally biotinylated peptides which are derived from nuclear receptor coactivator proteins such as but not limited to SRC1 (NcoA1), SRC2 (NcoA2, TIF2), SRC3 (NcoA3), PGC1a, PGC16, CBP, GRIP1, TRAP220, RIP140. The peptides used are listed in Table 1 below:
Table 1 Peptide Name (aa OS entry DB entry DNA Sequence range) Protein SRC1(676-700) NP_003734 NM_003743.4 NH2-CPSSHSSLTERHKILHRLLQEGSPS-COOH
TRAP220(631-655) NP_004765 NM_004774 3 NH2-PVSSMAGNTKNHPMLMNLLKDNPAQ-COOH
TIF2(628-651) NP 006531 NM 006540.2 NH2-GQSRLHDSKGQTKLLQLLTTKSDQ-COOH
The ligand-binding domain (LBD) of RORy was expressed as fusion protein with GST in BL-21 (BL3) cells using the vector pDEST15. Cells were lysed by lysozyme-treatment and sonication, and the fusion proteins purified over glutathione sepharose (Pharmacia) according to the manufacturers instructions. For screening of compounds for their influence on the RORy-peptide interaction, the LANCE technology (Perkin Elmer) was applied. This method relies on the binding dependent energy transfer from a donor to an acceptor fluorophor attached to the binding partner of interest. For ease of handling and reduction of background from compound fluorescence LANCE technology makes use of generic fluorophore labels and time resolved detection assays were done in a final volume of 25 pL
in a 384 well plate, in a Tris-based buffer system (20 mM Tris-HCI pH 6.8; 60 mM KCI, 1 mM
DTT; 5 mM MgC12; 35 ng/pL BSA), containing 20-60 ng/well recombinantly expressed RORy-LBD fused to GST, 200-600 nM N-terminally biotinylated peptide, 200 ng/well Streptavidin-xlAPC conjugate (Prozyme) and 6-10 ng/well Eu W1024 ¨ antiGST (Perkin Elmer).
DMSO
content of the samples was kept at 1%.
After generation of the Tris-based buffer system, the potentially RORy modulating ligands were diluted. After this step, protein, peptide and fluorescent acceptor and donor solutions were mixed in the Tris-based buffer system and have been added to the compound dilutions, after this addition of 'detection mix', the assay was equilibrated for 1 h in the dark at rt in FIA-plates black 384 well (Corning). The LANCE signal was detected by a Perkin Elmer EnVisionTM Multilabel Counter. The results were visualized by plotting the ratio between the emitted light at 665 nm and 615 nm. A basal level of RORy-peptide formation is observed in the absence of added ligand. Ligands that promote the complex formation induce a concentration-dependent increase in time-resolved fluorescent signal.
Compounds which bind equally well to both monomeric RORy and to the RORy-peptide complex would be expected to give no change in signal, whereas ligands, which bind preferentially to the monomeric receptor would be expected to induce a concentration-dependent decrease in the observed signal.
To assess the antagonistic potential of the compounds, IC50 values were determined using a Ligand Sensing Assay based on Time-resolved Fluorescence Energy Transfer (TR-FRET) as described above. The normalised TR-FRET assay values, using the following equation:
1000 * 665 nm measurement value/615 nm measurement value, were transferred to the program GraphPad Prism to generate graphs and dose response curves using the following equation:
Equation: Sigmoidal dose-response (variable slope) Y = Bottom + (Top-Bottom)/(1+10^((Log EC50-X)*HillSlope)) X is the logarithm of the concentration. Y is the response.
Y starts at Bottom and goes to Top with a sigmoidal shape.
This is identical to the "four parameter logistic equation". The IC50 values are calculated using this equation. Examples listed below do reduce the signal in the TR-FRET
assay in a dose dependent manner. The Examples of the present invention usually have an inhibition activity (IC50 FRET) ranging from below 100 nM to about 20 pM and typically, from about 150 nM to about 2 pM. The RORy modulating compounds of the invention desirably have an inhibition in the TR-FRET Activity Assay ranging from below 150 nM to about 2 pM. Table 2 lists the p1C50-value of compounds of the invention (FRET). Is is understood that the data illustrated below may have reasonable variation depending on the specific conditions and procedures used by the person conducting the test. The efficacy was determined in comparison to the RORyt inhibitor T0901317 (equals 100%) and the pIC50-value is underlined, when the efficacy of the compound is below 50% of the reference.
RORy Ga14 Reporter Gene Assay Determination of a ligand mediated Ga14 promoter driven transactivation to quantify ligand binding to RORy was performed as follows: DNA encoding three different RORy protein fragments was cloned into vector pCMV-BD (Stratagene). Expression was under control of a CMV promoter and as fusion to the DNA-binding domain of the yeast protein GAL4. The amino acid boundaries of the three proteins and the respective database entries are listed in Table 3. Other vectors used were pFR-Luc (Stratagene) as regulated reporter plasmid. pFR-Luc contains a synthetic promoter with five tandem repeats of the yeast GAL4 binding sites that control expression of the Photinus pyralis (American firefly) lucif erase gene. In order to improve experimental accuracy the plasmid pRL-CMV was cotransfected. pRL-CMV
contains the constitutive CMV promoter, controlling the expression of the Renilla reniformis lucif erase.
Table 3 construct name aa borders (RefSeq) Ref sequence ID
hRORy-LBD aa259-518 NP_005051.2 NP ¨001001523 (RORy, t hRORyt aa1-497 isoform, 497aa) mRORy-LBD aa264-516 NP_035411 All Ga14 reporter gene assays were done in 293T cells (DSMZ (German Collection of Microorganisms and Cell Cultures), Braunschweig, Germany, ACC635) grown in Minimum Essential Medium (MEM) with Phenol Red. The medium is supplemented with 10%
fetal bovine serum, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 1%
Glutamax and 100 units Penicilin/Streptavidin per mL at 37 C in 5% CO2.
For the assay, 5x105 cells were plated per well in 96we11 plates in 100 pL per well, incubated over night at 37 C in 5% CO2. The following day, medium was discarded and the cells were transiently transfected using 20 pL per well of a OptiMEM - PEI-based transfection-reagent (Sigma-Aldrich, 408727) including the three plasmids described above. About 4 h after addition of the transfection solution, fresh MEM (same composition as used for plating cells, but without serum) was added. Then compound stocks, prediluted in MEM (same composition as used for plating cells) were added (final vehicle concentration not exceeding 0.1%).
Cells were incubated for additional 16 h before firefly (FF) and renilla (REN) luciferase activities were measured sequentially in the same cell extract using a Dual-Light-Luciferase-Assay system (Dyer et al., Anal. Biochem. 2000, 282:158). All experiments were done in triplicates.
Applying the Ga14 reporter gene assay as described above, the Examples of the present invention usually have an inhibition activity (IC50 FF resp. IC50 RENnorm) ranging from below 5 nM to about 20 pM and typically, from about 10 nM to about 2 pM. The RORy modulating compounds of the invention desirably have an inhibition in the Gal4 reporter gene assay ranging from below 5 nM to about 1 pM. Table 2 list the pIC50-value of typical examples of compounds of the invention that have an RORy activity in the Ga14 reporter gene assay for firefly (FF) and renilla normalised (REN) luciferase measurements. Is is understood that the data illustrated below may have reasonable variation depending on the specific conditions and procedures used by the person conducting the test. The efficacy was determined in comparison to the RORyt inhibitor T0901317 (equals 100%) and the p1C50-value is underlined, when the efficacy of the compound is below 50% of the reference.
Table 2 Ex. # plCso (FRET/FF/REN) Ex. #
p1C50(FRET/FF/REN) Ex. # plCso (FRET/FF/REN) 1 6.5/6.8/6.9 1/1 6.6/6.6/6.7 1/2 6.9/7.5/7.4 1/3 6.4/7.6/7.5 1/4 6.5/7.5/7.6 1/5 6.0/6.3/6.2 1/6 6.2/6.7/6.7 1/7 6.3/6.8/6.8 1/8 6.5/6.4/6.3 1/9 6.5/6.6/6.7 1/10 6.3/7.5/7.5 1/11 5.7/6.1/6.1 1/12 5.9/6.4/6.5 1/13 5.9/6.2/6.1 1/14 5.7/6.5/6.6 1/15 5.5/5.5/5.5 1/16 5.2/6.1/5.8 1/17 6.7/6.3/6.4 1/18 6.2/7.1/7.0 1/19 6.0/7.0/7.1 1/22 6.0/6.9/6.9 1/24 6.2/6.5/6.5 1/26 5.0/<4.7/<4.7 1/27 4.91<4.71<4.7 1/28 6.1/6.7/6.8 1/29 6.2/7.2/7.2 1/30 5.4/6.4/6.2 1/31 5.7/6.4/6.4 1/32 5.8/6.4/6.2 1/33 6.1/6.6/6.5 1/34 5.9/6.8/6.7 1/35 6.9/6.9/6.9 1/36 6.8/6.5/6.6 1/37 6.5/6.8/6.8 1/38 6.6/7.2/7.3 1/39 6.5/6.9/7.0 1/40 6.6/7.5/7.6 1/41 6.3/6.9/7.0 1/42 6.6/7.5/7.6 1/43 6.0/7.1/7.1 1/44 6.3/7.4/7.3 1/45 6.0/5.6/5.8 1/46 6.5/6.5/6.5 1/47 5.4/<4.7/<4.7 1/48 6.2/6.4/6.4 1/49 4.5/6.2/6.6 1/50 5.8/6.0/6.1 1/51 5.6/5.9/6.1 1/52 6.8/6.4/6.5 1/53 6.8/7.3/7.4 1/54 6.4/6.3/6.4 1/55 6.6/6.8/6.9 1/56 5.5/<4.7/<4.7 1/57 5.6/5.8/5.8 1/58 6.2/6.2/6.2 1/59 6.2/6.3/6.3 1/60 6.0/6.2/6.2 1/61 6.0/6.2/6.2 1/62 6.5/6.4/6.3 1/63 6.2/6.7/6.7 1/64 6.5/6.5/6.5 1/65 6.4/6.6/6.6 1/66 6.4/6.7/6.8 1/67 6.8/7.2/7.3 1/68 5.8/6.7/6.8 1/69 5.8/6.8/6.9 1/70 6.2/6.6/6.6 1/71 5.9/5.8/5.9 1/72 6.0/7.1/7.1 1/73 5.9/7.2/7.2 1/74 5.3/<4.7/<4.7 1/75 5.3/<4.7/<4.7 1176 5.9/5.9/5.8 1/77 6.7/6.9/7.0 1/78 6.5/7.1/7.1 1/79 6.4/7.2/7.2 1/80 6.7/7.5/7.5 1/81 6.7/7.4/7.4 1/82 6.8/7.4/7.4 1/83 6.5/6.9/7.0 1/84 6.8/7.6/7.6 1/85 6.5/7.7/7.7 1/86 6.8/7.6/7.6 1/87 6.5/7.2/7.2 1/88 6.4/6.5/6.5 1/89 6.6/6.3/6.2 1/90 5.7/7.0/6.9 1/91 5.7/7.4/7.4 1/92 6.7/7.0/6.9 1/93 6.7/7.4/7.4 1/94 6.3/7.4/7.3 1/95 6.8/7.0/7.1 1/96 6.7/6.7/6.8 1/97 6.6/7.1/7.0 1/98 6.2/7.3/7.3 1/99 6.4/7.1/7.2 1/100 6.6/7.2/7.2 1/101 6.6/7.2/7.2 1/102 6.3/6.4/6.4 1/103 6.4/7.3/7.3 1/104 6.3/6.8/6.8 1/105 6.6/6.5/6.5 Ex. # p1C50(FRET/FF/REN) Ex. # pIC50(FRET/FF/REN) Ex.
# p1C50(FRET/FF/REN) 1/106 6.1/7.0/7.1 1/107 6.1/7.2/7.2 1/108 5.1/7.2/7.3 1/109 4.91<4.71<4.7 1/110 6.1/7.3/7.4 1/111 6.4/7.4/7.4 1/112 6.3/7.1/7.1 1/113 5.4/<4.7/<4.7 1/114 6.6/6.7/6.8 1/115 6.6/7.3/7.3 1/116 6.9/6.9/6.9 1/117 6.3/6.8/7.0 1/118 6.2/6.5/6.6 1/119 6.7/7.4/7.3 1/120 6.9/7.1/7.3 1/121 6.9/7.0/7.2 1/122 6.8/7.0/7.0 1/123 6.3/6.8/6.8 1/124 6.2/7.5/7.5 1/125 6.1/7.4/7.4 1/126 6.2/7.1/7.0 1/127 6.3/7.5/7.4 1/128 6.3/7.2/7.2 1/129 5.8/7.3/7.3 1/130 6.1/6.8/6.8 1/131 6.3/7.8/7.8 1/132 6.2/6.8/6.8 2 6.6/7.0/7.0 2/1 6.1/6.5/6.5 2/2 6.6/7.0/7.0 2/3 5.8/6.5/6.7 3 6.6/7.4/7.4 4 6.2/6.4/6.4 6.3/7.0/7.2 6 6.2/6.3/6.4 6/1 5.7/6.7/6.7 6/2 5.5/6.5/6A 6/3 5.1/5.9/5.7 6/4 5.0/<4.7/<4.7 6/5 5.6/6.5/6.4 6/6 6.2/6.8/6.7 6/7 6.0/6.5/6.4 6/8 5.0/6.8/7.3 6/9 5.0/6.4/6.2 7 6.5/6.8/6.9 7/1 6.5/6.7/6.8 7/2 6.6/7.0/7.0 7/3 6.6/6.6/6.7 7/4 6.7/7.1/7.1 7/5 6.5/6.3/6.4 7/6 6.4/6.6/6.5 7/7 6.4/6.5/6.6 7/8 6.3/6.0/6.2 8 5.4/7.2/7.2 8/1 5.3/6.8/6.9 8/1 5.6/6.7/6.8 9 6.1/7.1/7.2 9/1 6.3/7.5/7.5 9/2 6.2/7.4/7.5 9/3 6.5/7.1/7.1 9/4 6.2/7.1/7.2 9/5 6.5/7.2/7.2 9/6 6.6/7.7/7.8 9/7 6.3/7.5/7.5 9/8 6.2/7.0/7.1 9/9 6.3/7.2/7.3 9/10 6.5/7.7/7.2 9/11 6.3/7.7/7.8 9/12 5.8/6.3/6.5 9/13 6.0/6.0/6.1 9/14 5.1/6.3/6.2 9/15 6.5/6.5/6.5 10 5.8/6.9/6.9 10/1 4.8/6.7/6.6 11 6.6/6.5/6.5 11/1 6.6/7.3/7.3 11/2 6.6/6.9/6.9 11/3 6.0/6.5/6.5 11/4 6.4/6.9/7.0 11/5 6.5/7.3/7.4 11/6 6.6/8.0/8.2 11/7 6.6/7.1/7.2 12 6.0/6.1/6.2 6.3/6.9/6.9 15/1 5.7/6.6/6.7 15/2 6.0/6.3/6.3 15/3 6.4/7.0/7.1 15/4 5.8/7.3/7.3 15/5 6.1/7.6/7.7 15/6 5.9/7.4/7.4 15/7 5.9/7.2/7.2 15/8 6.0/7.3/7.4 15/9 6.0/6.9/7.0 16 6.8/6.4/6.5 17/1 5.9/8.0/7.9 17/2 6.0/6.6/6.5 17/3 6.4/6.9/6.9 17/4 6.2/6.7/6.7 17/5 6.5/6.4/6.4 17/6 6.6/6.4/6.5 17/7 5.5/<4.7/<4.7 17/8 6.1/7.2/7.2 17/9 6.2/6.8/6.8 17/10 6.4/7.6/7.6 17/11 6.7/7.2/7.2 17/12 6.7/7.2/7.4 17/13 6.2/6.8/6.9 17/14 5.9/5.9/5.7 17/15 6.1/7.2/7.1 17/16 5.4/6.1/6.0 17/17 6.1/6.3/6.4 17/18 6.0/6.1/6.1 17/19 6.1/7.5/7.5 17/20 6.4/7.1/7.1 17/21 6.2/7.0/6.9 17/22 6.0/6.5/6.6 17/23 5.9/6.6/6.6 17/24 5.5/5.8/5.7 17/25 6.5/6.9/7.0 17/26 5.8/7.3/7.3 17/27 5.6/6.3/6.5 17/28 6.6/7.4/7.4 17/29 5.9/6.8/6.7 17/30 6.6/7.7/7.7 17/31 6.0/7.3/7.3 17/32 6.7/7.2/7.2 17/33 6.2/7.1/7.2 Ex. # plCso (FRET/FF/REN) Ex. # plCso (FRET/FF/REN) Ex. # p1C50(FRET/FF/REN) 17/34 5.8/7.0/6.9 17/35 5.8/6.4/6.3 17/36 6.1/6.9/6.9 17/37 5.9/7.1/7.1 17/38 6.0/6.7/6.7 17/39 6.4/6.9/6.8 17/40 5.9/6.9/6.8 17/41 6.4/8.1/8.2 17/42 5.7/7.5/7.6 17/43 6.7/7.4/7.4 17/44 6.2/6.1/6.1 17/45 6.0/6.5/6.4 17/46 6.5/6.5/6.5 17/47 6.7/7.3/7.4 17/48 6.0/7.6/7.5 17/49 5.7/7.0/7.1 17/50 5.5/6.5/6.5 17/51 5.8/6.7/6.7 17/52 5.8/6.7/6.7 17/53 5.8/6.9/6.9 17/54 5.8/7.1/7.2 17/55 5.7/7.5/7.6 17/56 4.9/6.4/6.4 17/57 6.1/7.4/7.5 17/58 5.8/6.7/6.7 17/59 5.7/6.6/6.6 17/60 5.8/7.6/7.6 17/61 6.0/7.4/7.5 17/62 6.5/8.3/8.3 17/63 6.7/7.7/7.6 17/64 6.5/7.8/7.7 17/65 6.7/7.7/7.7 17/66 6.8/7.4/7.4 17/67 6.6/7.7/7.5 17/68 6.8/7.4/7.5 17/69 <4.7/7.2/7.4 17/70 5.9/7.9/7.9 17/71 5.8/6.9/6.8 17/72 5.2/6.1/6.1 17/73 6.0/7.2/7.3 17/74 6.3/7.3/7.2 17/75 5.2/5.8/5.8 17/76 5.7/6.9/6.9 17/77 6.1/8.0/8.1 17/78 6.3/7.3/7.3 17/79 5.8/6.4/6.3 17/80 6.3/6.9/7.0 17/81 6.2/7.1/7.1 17/82 6.1/6.7/6.7 17/83 6.9/8.2/8.3 17/84 <4.7/7.2/7.2 17/85 <4.7/7.4/7.5 17/86 6.5/7.1/7.1 17/87 6.3/6.9/6.9 17/88 6.2/7.7/7.7 17/89 5.8/6.9/6.9 17/90 5.8/7.9/8.0 17/91 6.2/7.1/7.0 17/92 6.0/7.3/7.1 17/93 6.0/6.8/6.9 17/94 5.9/6.8/6.7 17/95 6.2/7.8/7.7 17/96 5.5/6.9/7.0 17/97 6.9/8.0/8.0 17/98 6.5/6.8/6.9 17/99 6.6/6.9/7.0 17/100 6.1/6.9/6.9 17/101 6.1/7.7/7.7 17/102 6.6/6.8/6.9 17/103 6.1/6.7/6.8 17/104 6.3/6.5/6.7 17/105 5.7/6.1/6.3 17/106 6.3/7.3/7.3 17/107 6.0/6.9/6.9 17/108 6.0/6.9/7.1 17/109 6.2/7.2/7.3 17/110 5.7/6.3/6.5 17/111 6.5/7.2/7.3 17/112 6.5/7.4/7.5 17/113 6.3/6.8/6.8 17/114 6.2/6.5/6.4 17/115 6.5/7.9/8.0 17/116 6.2/7.3/7.3 17/117 6.0/7.6/7.7 17/118 5.0/6.3/6.5 17/119 6.3/7.6/7.7 17/120 5.6/6.1/6.0 17/121 6.5/7.6/7.7 17/122 6.4/7.6/7.5 17/123 5.5/7.0/7.0 17/124 6.1/7.4/7.5 17/125 7.1/6.4/6/ 17/126 6.5/6.7/6.9 17/127 6.5/7.1/7.2 17/128 6.7/8.0/8.0 17/129 6.7/8.0/8.0 17/130 6.6/7.5/7.6 17/131 6.3/6.8/6.9 17/132 5.4/6.3/6.2 17/133 5.9/6.3/6.3 17/134 6.4/7.4/7.7 17/135 6.2/6.7/6.7 17/136 6.1/6.6/6.7 17/137 6.3/<4.7/<4.7 17/138 6.7/7.1/7.3 17/139 6.8/7.2/7.4 17/140 6.7/8.0/8.1 17/141 6.5/8.3/8.5 17/142 6.4/7.4/7.6 17/143 6.9/8.2/8.2 17/144 6.3/7.7/7.7 17/145 6.2/7.6/7.7 17/146 6.0/7.4/7.5 17/147 6.1/6.7/6.7 17/148 6.1/7.0/7.0 17/149 5.9/6.6/6.6 17/150 6.3/8.0/8.2 17/151 6.5/8.3/8.3 17/152 6.0/8.2/8.2 17/153 6.5/6.7/6.7 17/154 6.5/7.2/7.3 17/155 6.2/7.0/7.0 17/156 6.5/7.1/7.2 17/157 6.4/7.0/7.1 17/158 6.1/6.1/6.2 17/159 5.8/6.8/6.9 17/160 6.7/7.8/8.0 17/161 6.2/7.6/7.6 17/162 6.1/7.5/7.7 Ex. # p1C50(FRET/FF/REN) Ex. # plCso (FRET/FF/REN) Ex. # p1C50(FRET/FF/REN) 17/163 5.8/7.0/7.2 17/164 5.9/6.4/6.5 17/165 5.3/6.5/6.9 17/166 6.8/7.8/8.0 17/167 6.1/6.6/6.8 17/168 6.0/6.4/6.4 17/169 6.1/6.7/6.7 17/170 6.5/6.8/7.0 17/171 6.1/6.9/6.9 17/172 6.4/7.5/7.5 17/173 6.5/7.3/7.3 17/174 6.7/7.1/7.1 17/175 6.1/6.6/6.7 17/176 6.6/7.1/7.0 17/177 6.8/7.3/7.4 17/178 6.1/7.9/7.9 17/179 6.4/6.1/6.1 17/180 6.2/7.1/7.2 17/181 6.4/7.0/6.9 17/182 6.3/7.8/7.9 17/183 6.7/7.9/8.1 17/184 6.1/6.9/7.1 17/185 6.3/6.4/6.2 17/186 6.4/6.9/7.1 17/187 4.8/<4.7/<4.7 17/188 6.1/6.8/6.9 17/189 5.3/6.3/6.3 17/190 5.8/6.5/6.6 17/191 5.9/7.0/6.9 17/192 5.8/6.5/6.4 17/193 5.6/6.9/7.0 17/194 4.9/6.4/6.5 17/195 6.2/7.6/7.6 17/196 5.4/7.0/7.0 17/197 6.1/7.9/7.7 17/198 6.3/6.8/6.9 17/199 6.2/6.6/6.7 17/200 6.3/6.9/6.9 17/201 6.1/5.7/5.7 17/202 6.5/7.7/7.7 17/203 6.3/7.8/7.8 17/204 6.1/6.7/6.8 17/205 6.1/6.9/7.0 17/206 6.2/7.0/7.2 17/207 6.3/7.9/8.0 17/208 6.4/6.6/6.6 17/209 6.7/7.3/7.6 17/210 6.8/7.9/8.1 17/211 6.3/8.0/8.0 17/212 6.2/7.3/7.4 17/213 6.2/7.1/7.2 17/214 6.6/7.5/7.5 17/215 6.5/7.5/7.3 17/216 6.7/7.8/7.8 17/217 6.9/7.6/7.7 17/218 6.5/7.1/7.3 17/219 6.3/6.9/7.0 17/220 6.5/6.6/6.6 17/221 5.7/7.1/7.1 17/222 6.2/7.4/7.5 17/223 6.4/7.1/7.2 17/224 6.1 /7.1 /7.2 17/225 6.1/7.6/7.6 17/226 6.5/8.2/8.2 17/227 6.3/8.1/8.1 17/228 6.4/7.7/7.7 17/229 6.2/7.2/7.3 17/230 6.6/7.5/7.6 17/231 6.6/7.5/7.7 17/232 6.1/6.8/7.0 17/233 5.8/6.5/6.5 17/234 6.7/7.1/7.2 17/235 6.7/7.6/7.6 17/236 6.2/8.1/8.2 17/237 5.9/6.5/6.5 17/238 6.0/6.9/6.7 17/239 6.0/7.9/8.1 17/240 6.1/7.5/7.6 17/241 5.9/7.7/7.8 17/242 6.4/7.5/7.6 17/243 6.2/7.4/7.6 17/244 5.0/6.2/6.2 17/245 <4.7/5.7/5.7 17/246 5.4/6.1/6.2 17/247 5.9/6.9/7.0 17/248 5.6/6.4/7.3 17/249 6.3/6.6/6.7 17/250 5.8/6.6/6.5 17/251 6.3/6.9/6.9 17/252 5.8/6.5/6.6 17/253 6.2/7.0/7.2 17/254 6.2/6.6/6.6 17/255 5.1/<4.7/<4.7 17/256 6.2/6.8/7.0 17/257 6.3/7.4/7.6 17/258 5.1/<4.7/<4.7 17/259 6.0/7.2/7.2 17/260 5.9/7.3/7.4 17/261 5.9/7.5/7.6 17/262 6.2/7.6/7.8 17/263 6.5/7.9/8.0 17/264 6.2/7.9/7.7 17/265 6.5/7.9/8.0 17/266 6.6/8.3/8.5 17/267 6.1/7.9/8.0 17/268 6.1/7.7/7.8 17/269 6.0/6.9/7.0 17/270 6.2/7.8/8.0 17/271 6.1 /7.1 /7.1 17/272 6.3/6.8/6.9 17/273 5.8/7.2/7.3 17/274 6.6/7.9/7.9 17/275 6.2/7.0/7.0 17/276 6.8/7.9/8.0 17/277 6.4/7.2/7.2 17/278 5.6/7.0/7.0 17/279 5.5/<4.7/<4.7 17/280 6.0/8.1/8.1 17/281 6.0/7.7/7.7 17/282 5.7/6.6/6.7 17/283 6.0/6.7/6.8 17/284 5.9/7.3/7.3 17/285 6.2/7.3/7.4 17/286 5.9/7.4/7.5 17/287 6.2/7.7/7.7 17/288 6.4/7.3/7.3 17/289 5.9/7.1/7.2 17/290 6.2/7.6/7.6 17/291 6.4/7.6/7.7 Ex. # plCso (FRET/FF/REN) Ex. # plCso (FRET/FF/REN) Ex. # p1C50(FRET/FF/REN) 17/292 5.9/7.5/7.4 17/293 5.9/6.6/6.7 17/294 5.5/<4.7/<4.7 17/295 6.0/6.6/6.5 17/296 6.6/7.0/7.1 17/297 6.9/7.2/7.4 17/298 5.6/5.9/6.0 17/299 5.3/7.1/7.5 17/300 6.1/7.3/7.6 17/301 5.7/7.6/7.6 17/302 5.8/7.3/7.2 17/303 5.4/6.3/6.4 17/304 5.8/7.2/7.3 17/305 5.7/6.8/6.7 17/306 5.8/6.8/6.9 17/307 5.5/6.2/6.0 17/308 5.2/6.5/6.4 17/309 6.1/6.7/6.8 17/310 6.0/7.4/7.6 17/311 6.1/7.0/7.2 17/312 6.5/7.2/7.3 17/313 6.0/6.8/6.8 17/314 6.0/7.2/7.1 17/315 5.9/6.5/6.5 17/316 5.6/6.3/6.3 17/317 5.6/6.5/6.5 17/318 5.7/7.7/7.6 17/319 5.7/6.5/6.6 17/320 5.8/7.3/7.3 17/321 6.0/7.3/7.3 17/322 5.4/5.9/6.0 17/323 5.1/5.6/5.7 17/324 5.5/6.8/6.8 17/325 5.6/7.1/7.2 17/326 6.0/7.8/7.9 17/327 6.1/6.8/6.9 17/328 6.3/6.6/6.6 17/329 5.6/6.8/6.9 17/330 5.6/7.3/7.4 17/331 5.9/6.6/6.5 17/332 6.7/6.4/6.4 17/333 6.4/6.4/6.3 17/334 5.9/5.8/5.9 17/335 6.5/5.5/5.6 17/336 6.0/<4.7/<4. 7 17/337 6.0/7.7/7.8 17/338 5.5/7.2/7.2 17/339 5.9/7.6/7.7 17/340 5.8/7.1/7.1 17/341 6.1/7.4/7.6 17/342 6.0/7.1/7.1 17/343 6.3/7.4/7.3 17/344 6.2/7.3/7.5 17/345 6.5/7.3/7.4 17/346 5.3/<4.7/<4.7 17/347 6.4/6.5/6.5 17/348 6.5/6.9/7.0 17/349 6.2/6.8/6.8 17/350 6.0/7.7/7.7 17/351 5.7/6.8/6.9 17/352 6.2/7.5/7.5 17/353 5.7/6.8/6.8 17/354 6.0/7.0/7.0 17/355 6.5/6.6/6.6 17/356 6.4/6.7/6.7 17/357 5.7/6.7/6.8 17/358 6.0/6.3/6.2 17/359 5.5/7.4/7.4 17/360 5.2/7.3/7.4 17/361 5.7/6.4/6.4 17/362 5.9/5.9/5.8 17/363 6.0/7.4/7.5 17/364 6.0/6.9/7.0 17/365 5.9/7.0/7.0 17/366 5.3/6.6/6.3 17/367 5.3/6.4/6.1 17/368 5.1/6.4/6.2 17/369 5.9/7.5/7.5 17/370 5.7/7.2/7.3 17/371 6.2/8.0/8.0 17/372 5.5/6.3/6.2 17/373 5.3/<4.7/<4.7 17/374 5.8/7.3/7.3 18/1 6.1/7.5/7.7 18/2 6.6/8.0/8.2 18/3 5.8/6.1/6.5 18/4 6.1/6.3/6.5 18/5 6.2/7.5/7.5 19 4.9/6.6/6.4 19/1 6.3/6.8/6.8 20 6.4/7.4/7.5 20/1 6.6/7.1/7.3 20/2 6.5/7.0/7.2 20/3 6.2/7.3/7.4 20/4 6.7/6.9/6.9 20/5 6.1/7.0/7.0 20/6 6.3/6.9/6.9 20/7 6.4/6.2/6.2 20/8 6.0/7.0/7.0 20/9 5.9/7.8/7.6 22 6.4/7.5/7.6 22/1 6.8/8.4/8.4 22/2 6.4/8.1/8.0 23 6.7/8.5/8.5 24 5.5/6.4/6.4 24/1 4.9/6.3/6.4 24/2 5.2/<4.7/<4.7 25 5.8/6.3/6.2 26 6.7/7.5/7.6 26/1 6.6/7.4/7.5 26/2 6.7/7.2/7.2 26/3 6.1/6.6/6.8 26/4 5.4/6.6/6.8 26/5 6.5/7.9/8.0 26/6 6.4/7.7/7.9 27 5.7/6.4/6.5 28 5.9/6.6/6.9 29 5.4/7.2/7.2 29/1 5.5/6.8/6.8 29/2 5.6/7.3/7.1 31 5.9/6.9/6.9 33 5.5/6.2/6.3 34 6.4/6.8/7.1
Claims (24)
1. A compound represented by Formula (1) an enantiomer, diastereomer, tautomer, N-oxide, solvate, formulation and pharmaceutically acceptable salt thereof, wherein R1 is selected from H, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, C1-10-alkylene-C3-10-cycloalkyl, C1-10-alkylene-C3-10-heterocycloalkyl, C1-10-alkylene-(5-membered monocyclic heteroaryl), SO2-C1-10-alkyl, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR11, O-C2-6-alkylene-OR11, C1-6-alkyl, halo-C1-6-alkyl, halogen, CO2R11, CONR11R12, COR11, SO y R11, SO3H, SO2NR11R12, NR11COR11, NR11SO2R11, NR11-CO-NR11R12, NR11-SO2-NR11R12, C3-6-cycloalkyl, O-cycloalkyl, C3-6-heterocycloalkyl, O-C3-6-heterocycloalkyl and NR11R12; and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein pyridinone and spiroheterocycle is optionally substituted with 1 to 4 groups independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, OH, O-C1-6-alkyl, O-halo-C1-6-alkyl, oxo, =N-OR32, N(R32), Co-6alkylene-C3-10-cycloalkyl, C0-6-alkylene-C3-heterocycloalkyl, C0-6-alkylene-(5- or 6-membered monocyclic heteroaryl), C1-6-alkylene-O-R31, C0-6-alkylene-CN, O-C3-10-cycloalkyl, O-C1-6-alkylene-O-R32, O-C3-10-heterocycloalkyl, C0-6-alkylene-COOR31, C0-6-alkylene-C(O)R31, C0-6-alkylene-C(O)N(R31)2, C0-6-alkylene-N(R31)C(O)R31, C0-6-alkylene-SO-R31, C0-6-alkylene-SO2-R31, C0-6alkylene-SO2-N(R31)2, C0-6-alkylene-N(R31)SO2-R31, C0-6-alkylene-SO2-C3-10-heterocycloalkyl and C0-6-alkylene-SO2-C3-10-heterocycloalkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, OH, oxo, O-C1-3-alkyl and O-halo-C1-3-alkyl;
wherein aryl and heteroaryl is substituted with at least one group selected from C3-10-cycloalkyl, C4-heterocycloalkyl, C1-4-alkylene-C3-10-cycloalkyl, C1-4-alkylene-(C3-10-heterocycloalkyl), carbon atom linked 5- or 6-membered monocyclic heteroaryl, alkylene-(5- or 6-membered monocyclic heteroaryl), C1-4-alkylene-O-R31, C1-4-alkylene-CN, O-C3-10-cycloalkyl, O-C1-6-alkylene-O-R32, O-C3-10-heterocycloalkyl, C0-6-alkylene-COOR31, C0-6-alkylene-C(O)R31, C0-6-alkylene-C(O)N(R31)2, C0-6-alkylene-N(R31)C(O)R31, C0-6-alkylene-SO-R31, C1-6-alkylene-SO2-R31, C0-6alkylene-SO2-N(R31)2, C0-6-alkylene-N(R31)SO2-R31, SO2-C3-10-heterocycloalkyl, SO2-C3-10-cycloalkyl, C0-6-alkylene-SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, oxo, =N-OR32, OH, O-C1-6-alkyl and O-halo-C1-6-alkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, OH, oxo, =N-OR32, O-C1-3-alkyl and O-halo-C1-3-alkyl; and wherein aryl and heteroaryl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, OH, O-C1-3-alkyl and O-halo-C1-3-alkyl;
or R1 is selected from a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or C1-10-alkyl substituted with a group selected from halogen, CN, OR11, SO y R11, SO3H, NR11SO2R11, SO2NR11R12, CO2R11, CONR11R12, NR11-CO-R11, NR11-CO-NR11R12, NR11-NR11R12, NR11R12 and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or C0-1-alkylene-C3-10-cycloalkyl substituted with a group selected from halogen, CN, SO y R11, NR11SO2R11,SO2NR11R12, CO2R11, CONR11R12, NR11-CO-R11, NR11-CO-NR11R12, NR11-NR11R12 and NR11R12, or C2-10-alkylene-C3-10-cycloalkyl, C2-10-alkylene-O-C3-10-cycloalkyl, C2-10-alkylene-C5-10-heterocycloalkyl, C2-10-alkylene-O-C6-10-heterocycloalkyl and SO2-C1-10-alkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, CN, O-C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, halogen, CO2R11, CONR11R12, COR11, SO2R11, SO2NR11R12, NR11COR11, NR11SO2R11, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl, O-C3-6-heterocycloalkyl, O-C2-6-alkylene-OR11 and NR11R12;
and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein pyridinone, aryl and heteroaryl and spiroheterocycle is optionally substituted with 1 to 4 groups independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, OH, O-C1-6-alkyl, O-halo-C1-6-alkyl, oxo, =N-OR32, N(R32), C0-6-alkylene-C3-10-cycloalkyl, C0-6-alkylene-C3-10-heterocycloalkyl, C0-6-alkylene-(5- or 6-membered monocyclic heteroaryl), C1-6-alkylene-O-R31, C0-6-alkylene-CN, O-C3-10-cycloalkyl, O-C1-6-alkylene-O-R32, O-C3-10-heterocycloalkyl, C0-6-alkylene-COOR31, C0-6-alkylene-C(O)R31, C0-6-alkylene-C(O)N(R31)2, C0-6-alkylene-N(R31)C(O)R31, C0-6-alkylene-SO-R31, C0-6-alkylene-SO2-R31, C0-6-alkylene-SO2-N(R31)2 and C0-6-alkylene-N(R31)SO2-R31, and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, oxo, =N-OR32, OH, O-C1-6-alkyl and O-halo-C1-6-alkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, OH, oxo, =N-OR32, O-C1-3-alkyl and O-halo-C1-3-alkyl;
and R2 is selected from the group consisting of H, C1-6-alkyl, halo-C1-6-alkyl and hydroxy-C1-6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SO y R11, SO3H, NR11SO2R11, SO2NR11R12, C0-6-alkylene-CO2R11, CONR11R12, COR11, NR11-CO-R11, CO-NR11R12, N11-SO2- NR11R12, NR11R12, C1-6-alkyl, halo-C1-6-alkyl, hydroxy-C1-6-alkyl, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl and O-C3-6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1-3-alkyl, halo-C1-3-alkyl and oxo;
R4 is SO2-(CR8R8)y R7, SO2-NR12R7, (CR8R8)x-R10 or C3-6-cycloalkyl, which is spirocyclic fused with C3-10-cycloalkyl;
R5 is selected from H, C1-6-alkyl, halo-C1-6-alkyl, CHO, CON(R52)2 or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of O-C1-6-alkyl, O-halo-C1-6-alkyl and OH;
R6 is selected from H, C1-6-alkyl, halo-C1-6-alkyl or halogen;
R7 is selected from C3-10-cycloalkyl and C3-10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, O-C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, cycloalkyl and heterocycloalkyl;
R8 is independently selected from H, F, C1-3-alkyl, halo-C1-3-alkyl or OH;
R10 is C3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, O-C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1-2-alkyl, halo-C1-
wherein aryl and heteroaryl is substituted with at least one group selected from C3-10-cycloalkyl, C4-heterocycloalkyl, C1-4-alkylene-C3-10-cycloalkyl, C1-4-alkylene-(C3-10-heterocycloalkyl), carbon atom linked 5- or 6-membered monocyclic heteroaryl, alkylene-(5- or 6-membered monocyclic heteroaryl), C1-4-alkylene-O-R31, C1-4-alkylene-CN, O-C3-10-cycloalkyl, O-C1-6-alkylene-O-R32, O-C3-10-heterocycloalkyl, C0-6-alkylene-COOR31, C0-6-alkylene-C(O)R31, C0-6-alkylene-C(O)N(R31)2, C0-6-alkylene-N(R31)C(O)R31, C0-6-alkylene-SO-R31, C1-6-alkylene-SO2-R31, C0-6alkylene-SO2-N(R31)2, C0-6-alkylene-N(R31)SO2-R31, SO2-C3-10-heterocycloalkyl, SO2-C3-10-cycloalkyl, C0-6-alkylene-SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, oxo, =N-OR32, OH, O-C1-6-alkyl and O-halo-C1-6-alkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, OH, oxo, =N-OR32, O-C1-3-alkyl and O-halo-C1-3-alkyl; and wherein aryl and heteroaryl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, OH, O-C1-3-alkyl and O-halo-C1-3-alkyl;
or R1 is selected from a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or C1-10-alkyl substituted with a group selected from halogen, CN, OR11, SO y R11, SO3H, NR11SO2R11, SO2NR11R12, CO2R11, CONR11R12, NR11-CO-R11, NR11-CO-NR11R12, NR11-NR11R12, NR11R12 and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or C0-1-alkylene-C3-10-cycloalkyl substituted with a group selected from halogen, CN, SO y R11, NR11SO2R11,SO2NR11R12, CO2R11, CONR11R12, NR11-CO-R11, NR11-CO-NR11R12, NR11-NR11R12 and NR11R12, or C2-10-alkylene-C3-10-cycloalkyl, C2-10-alkylene-O-C3-10-cycloalkyl, C2-10-alkylene-C5-10-heterocycloalkyl, C2-10-alkylene-O-C6-10-heterocycloalkyl and SO2-C1-10-alkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, CN, O-C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, halogen, CO2R11, CONR11R12, COR11, SO2R11, SO2NR11R12, NR11COR11, NR11SO2R11, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl, O-C3-6-heterocycloalkyl, O-C2-6-alkylene-OR11 and NR11R12;
and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein pyridinone, aryl and heteroaryl and spiroheterocycle is optionally substituted with 1 to 4 groups independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, OH, O-C1-6-alkyl, O-halo-C1-6-alkyl, oxo, =N-OR32, N(R32), C0-6-alkylene-C3-10-cycloalkyl, C0-6-alkylene-C3-10-heterocycloalkyl, C0-6-alkylene-(5- or 6-membered monocyclic heteroaryl), C1-6-alkylene-O-R31, C0-6-alkylene-CN, O-C3-10-cycloalkyl, O-C1-6-alkylene-O-R32, O-C3-10-heterocycloalkyl, C0-6-alkylene-COOR31, C0-6-alkylene-C(O)R31, C0-6-alkylene-C(O)N(R31)2, C0-6-alkylene-N(R31)C(O)R31, C0-6-alkylene-SO-R31, C0-6-alkylene-SO2-R31, C0-6-alkylene-SO2-N(R31)2 and C0-6-alkylene-N(R31)SO2-R31, and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, oxo, =N-OR32, OH, O-C1-6-alkyl and O-halo-C1-6-alkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, OH, oxo, =N-OR32, O-C1-3-alkyl and O-halo-C1-3-alkyl;
and R2 is selected from the group consisting of H, C1-6-alkyl, halo-C1-6-alkyl and hydroxy-C1-6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SO y R11, SO3H, NR11SO2R11, SO2NR11R12, C0-6-alkylene-CO2R11, CONR11R12, COR11, NR11-CO-R11, CO-NR11R12, N11-SO2- NR11R12, NR11R12, C1-6-alkyl, halo-C1-6-alkyl, hydroxy-C1-6-alkyl, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl and O-C3-6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1-3-alkyl, halo-C1-3-alkyl and oxo;
R4 is SO2-(CR8R8)y R7, SO2-NR12R7, (CR8R8)x-R10 or C3-6-cycloalkyl, which is spirocyclic fused with C3-10-cycloalkyl;
R5 is selected from H, C1-6-alkyl, halo-C1-6-alkyl, CHO, CON(R52)2 or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of O-C1-6-alkyl, O-halo-C1-6-alkyl and OH;
R6 is selected from H, C1-6-alkyl, halo-C1-6-alkyl or halogen;
R7 is selected from C3-10-cycloalkyl and C3-10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, O-C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, cycloalkyl and heterocycloalkyl;
R8 is independently selected from H, F, C1-3-alkyl, halo-C1-3-alkyl or OH;
R10 is C3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, O-C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1-2-alkyl, halo-C1-
2-alkyl;
R11 is independently selected from H, C1-6-alkyl, C0-6-alkylene-C3-6-cycloalkyl, C0-6-alkylene-C3-6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C1-3-alkyl, halo-C1-3-alkyl, O-C1-3-alkyl, O-halo-C1-3-alkyl and SO2-C1-3-alkyl;
R12 is independently selected from H, C1-6-alkyl and halo-C1-6-alkyl;
R31 is independently selected from H, C1-6-alkyl, halo-C1-6-alkyl, C0-6-alkylene-C3-6-cycloalkyl, C0-6-alkylene-C3-6-heterocycloalkyl, 5- or 6-membered heteroaryl and 6-membered aryl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, OH, oxo, C1-3-alkyl, halo-C1-3-alkyl, O-C1-3-alkyl, O-halo-C1-3-alkyl and SO2-C1-3-alkyl;
and optionally wherein two R31 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1-4-alkyl and halo-C1-4-alkyl;
R32 is independently selected from H, C1-6-alkyl and halo-C1-6-alkyl;
R52 is independently selected from H, C1-3-alkyl and halo-C1-3-alkyl;
x is independently selected from 1 and 2;
y is independently selected from 0, 1 and 2;
with the proviso that R3 is not an unsubstituted or substituted ring selected from 2. The compound according to claim 1 wherein R1 is selected from H, C1-10-alkyl, C2-0-alkenyl, C2-10-alkynyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, C1-10-alkylene-C3-10-cycloalkyl, C1-10-alkylene-C3-10-heterocycloalkyl, C1-10-alkylene-(5-membered monocyclic heteroaryl), SO2-C1-10-alkyl, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR11, O-C2-6-alkylene-OR11, C1-6-alkyl, halo-C1-6-alkyl, halogen, CO2R11, CONR11R12, COR11, SO y R11, SO3H, SO2NR11R12, NR11COR11, NR11SO2R11, NR11-CO-NR11R12, NR11-SO2-NR11R12, C3-6-cycloalkyl, O-cycloalkyl, C3-6-heterocycloalkyl, O-C3-6-heterocycloalkyl and NR11R12; and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein pyridinone and spiroheterocycle is optionally substituted with a group selected from C3-10-cycloalkyl, C4-heterocycloalkyl, C1-4-alkylene-C3-10-cycloalkyl, C1-4-alkylene-C3-10-heterocycloalkyl, C0-6-alkylene-(5-membered monocyclic heteroaryl), C1-4-alkylene-O-R31, C1-4-alkylene-CN, O-C3-10-cycloalkyl, O-C1-6-alkylene-O-R32, O-C3-10-heterocycloalkyl, C0-6-alkylene-COOR31, C0-6-alkylene-C(O)R31, C0-6-alkylene-C(O)N(R31)2, C0-6-alkylene-N(R31)C(O)R31, C0-6-alkylene-SO2-N(R31)2, C0-6-alkylene-N(R31)SO2-R31, C0-6-alkylene-SO2-C3-10-heterocycloalkyl and C0-6-alkylene-SO-R31, aryl and heteroaryl is substituted with at least one group selected from C3-10-cycloalkyl, C4-heterocycloalkyl, C1-4-alkylene-C3-10cycloalkyl, C1-4-alkylene-C3-10-heterocycloalkyl, C0-6-alkylene-(5-membered monocyclic heteroaryl), C0-6-alkylene-(6-membered monocyclic heteroaryl), C1-4-alkylene-O-R31, C1-4-alkylene-CN, O-C3-10-cycloalkyl, O-C1-6-alkylene-O-R32, O-C3-10-heterocycloalkyl, C0-6-alkylene-COOR31, C0-6-alkylene-C(O)R31, C0-6-alkylene-C(O)N(R31)2, C0-6-alkylene-N(R31)C(O)R31, C0-6-alkylene-SO2-N(R31)2, C0-6-alkylene-N(R31)SO2-R31, C0-6-alkylene-SO2-C3-10-heterocycloalkyl, C0-6-alkylene-SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, oxo, OH, O-C1-6-alkyl and O-halo-C1-6-alkyl, wherein pyridinone, aryl, heteroaryl, spiroheterocycle, alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, OH, O-C1-3-alkyl, O-halo-C1-3-alkyl, O-C3-6-cycloalkyl, O-heterocycloalkyl, oxo, N(R32)2, COOH, CON(R32)2, CN and NR32-COR32;
or R1 is selected from a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or C1-10-alkyl substituted with a group selected from halogen, CN, OR11, SO y R11, SO3H, NR11SO2R11, SO2NR11R12, CO2R11, CONR11R12, NR11-CO-R11, NR11-CO-NR11R12, NR11-NR11R12, NR11-R12 and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or C0-1-alkylene-C3-10-cycloalkyl substituted with a group selected from halogen, CN, SO y R11, NR11SO2R11, SO2NR11R12, CO2R11, CONR11R12, NR11-COR11, NR11-CO-NR11R12, NR11-NR11R12 and NR11R12, or C2-10-alkylene-C3-10-cycloalkyl, C2-10-alkylene-O-C3-10-cycloalkyl, C2-10-alkylene-C5-10-heterocycloalkyl, C2-10-alkylene-O-C6-10-heterocycloalkyl and SO2-C1-10-alkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, CN, O-C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, halogen, CO2R11, CONR11R12, COR11, SO2R11, SO2NR11R12, NR11COR11, NR11SO2R11, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl, O-C3-6-heterocycloalkyl, O-C2-6-alkylene-OR11 and NR11R12;
and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein pyridinone, aryl, heteroaryl and spiroheterocycle are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, CN, C1-6-alkyl, C3-10-cycloalkyl, C3-10-heterocycloalkyl, C0-6-alkylene-(5-membered monocyclic heteroaryl), C0-6-alkylene-(6-membered monocyclic heteroaryl), C0-6-alkylene-O-R31, O-C1-6-alkylene-O-R32, C0-6-alkylene-COOR31, C0-6-alkylene-C(O)R31, C0-6-alkylene-C(O)N(R31)2, C0-6-alkylene-N(R31)C(O)R31, C0-6-alkylene-SO2-N(R31)2, C0-6-alkylene-N(R31)SO2-R31, C0-6-alkylene-SO2-R31, C0-6-alkylene-SO-R31 and C0-6-alkylene-N(R31)2, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, OH, O-C1-3-alkyl, O-halo-C1-3-alkyl, O-C3-6-cycloalkyl, O-C3-6-heterocycloalkyl, oxo, N(R32)2, COOH, CON(R32)2, CN and NR32-COR32, and wherein optionally two adjacent substituents complete a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, oxo, OH, O-C1-6-alkyl and O-halo-C1-6-alkyl;
and R2 is selected from the group consisting of H, C1-6-alkyl, halo-C1-6-alkyl and hydroxy-C1-6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SO y R11, SO3H, NR11SO2-R11, SO2NR11R12, CO2R11, CONR11R12, COR11, NR11-CO-R11, NR11-CO-NR11R12, NR11-SO2-NR11R12, NR11R12, C1-6-alkyl, halo-C1-6, hydroxy-C1-6-alkyl, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl and O-C3-6-heterocycloalkyl;
R4 is SO2-(CR8R8)y R7, SO2-NR12R7 or (CR8R8)x-R10;
R5 is selected from H, C1-6-alkyl, halo-C1-6-alkyl, CHO or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of O-C1-6-alkyl, O-halo-C1-6-alkyl and OH;
R6 is selected from H, halo-C1-6-alkyl or halogen;
R7 is selected from C3-10-cycloalkyl and C3-10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, O-C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, cycloalkyl and heterocycloalkyl;
IR8 is independently selected from H, F, C1-3-alkyl, halo-C1-3-alkyl or OH;
is C3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, O-C1-6-alkyl, O-halo-C1-6-alkyl, halo-C1-6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1-2-alkyl, halo-C1-2-alkyl;
R11 is independently selected from H, C1-6-alkyl, C0-6-alkylene-C3-6-cycloalkyl, C0-6-alkylene-C3-6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C1-3-alkyl, halo-C1-3-alkyl, O-C1-3-alkyl, O-halo-C1-3-alkyl and SO2-C1-3-alkyl;
R12 is independently selected from H, C1-6-alkyl and halo-C1-6-alkyl;
R31 is independently selected from H, C1-6-alkyl, CO-6-alkylene-C3-6-cycloalkyl, C0-6-alkylene-C3-6-heterocycloalkyl, a 6-membered aryl wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl and aryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, halo-C1-3-alkyl, O-C1-3-alkyl, O-halo-C1-3-alkyl and SO2-C1-3-alkyl;
R32 is independently selected from H, C1-6-alkyl and halo-C1-6-alkyl;
x is independently selected from 1 and 2;
y is independently selected from 0, 1 and 2;
with the proviso that R3 is not an unsubstituted or substituted ring selected from
R11 is independently selected from H, C1-6-alkyl, C0-6-alkylene-C3-6-cycloalkyl, C0-6-alkylene-C3-6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C1-3-alkyl, halo-C1-3-alkyl, O-C1-3-alkyl, O-halo-C1-3-alkyl and SO2-C1-3-alkyl;
R12 is independently selected from H, C1-6-alkyl and halo-C1-6-alkyl;
R31 is independently selected from H, C1-6-alkyl, halo-C1-6-alkyl, C0-6-alkylene-C3-6-cycloalkyl, C0-6-alkylene-C3-6-heterocycloalkyl, 5- or 6-membered heteroaryl and 6-membered aryl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, OH, oxo, C1-3-alkyl, halo-C1-3-alkyl, O-C1-3-alkyl, O-halo-C1-3-alkyl and SO2-C1-3-alkyl;
and optionally wherein two R31 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1-4-alkyl and halo-C1-4-alkyl;
R32 is independently selected from H, C1-6-alkyl and halo-C1-6-alkyl;
R52 is independently selected from H, C1-3-alkyl and halo-C1-3-alkyl;
x is independently selected from 1 and 2;
y is independently selected from 0, 1 and 2;
with the proviso that R3 is not an unsubstituted or substituted ring selected from 2. The compound according to claim 1 wherein R1 is selected from H, C1-10-alkyl, C2-0-alkenyl, C2-10-alkynyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, C1-10-alkylene-C3-10-cycloalkyl, C1-10-alkylene-C3-10-heterocycloalkyl, C1-10-alkylene-(5-membered monocyclic heteroaryl), SO2-C1-10-alkyl, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR11, O-C2-6-alkylene-OR11, C1-6-alkyl, halo-C1-6-alkyl, halogen, CO2R11, CONR11R12, COR11, SO y R11, SO3H, SO2NR11R12, NR11COR11, NR11SO2R11, NR11-CO-NR11R12, NR11-SO2-NR11R12, C3-6-cycloalkyl, O-cycloalkyl, C3-6-heterocycloalkyl, O-C3-6-heterocycloalkyl and NR11R12; and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein pyridinone and spiroheterocycle is optionally substituted with a group selected from C3-10-cycloalkyl, C4-heterocycloalkyl, C1-4-alkylene-C3-10-cycloalkyl, C1-4-alkylene-C3-10-heterocycloalkyl, C0-6-alkylene-(5-membered monocyclic heteroaryl), C1-4-alkylene-O-R31, C1-4-alkylene-CN, O-C3-10-cycloalkyl, O-C1-6-alkylene-O-R32, O-C3-10-heterocycloalkyl, C0-6-alkylene-COOR31, C0-6-alkylene-C(O)R31, C0-6-alkylene-C(O)N(R31)2, C0-6-alkylene-N(R31)C(O)R31, C0-6-alkylene-SO2-N(R31)2, C0-6-alkylene-N(R31)SO2-R31, C0-6-alkylene-SO2-C3-10-heterocycloalkyl and C0-6-alkylene-SO-R31, aryl and heteroaryl is substituted with at least one group selected from C3-10-cycloalkyl, C4-heterocycloalkyl, C1-4-alkylene-C3-10cycloalkyl, C1-4-alkylene-C3-10-heterocycloalkyl, C0-6-alkylene-(5-membered monocyclic heteroaryl), C0-6-alkylene-(6-membered monocyclic heteroaryl), C1-4-alkylene-O-R31, C1-4-alkylene-CN, O-C3-10-cycloalkyl, O-C1-6-alkylene-O-R32, O-C3-10-heterocycloalkyl, C0-6-alkylene-COOR31, C0-6-alkylene-C(O)R31, C0-6-alkylene-C(O)N(R31)2, C0-6-alkylene-N(R31)C(O)R31, C0-6-alkylene-SO2-N(R31)2, C0-6-alkylene-N(R31)SO2-R31, C0-6-alkylene-SO2-C3-10-heterocycloalkyl, C0-6-alkylene-SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, oxo, OH, O-C1-6-alkyl and O-halo-C1-6-alkyl, wherein pyridinone, aryl, heteroaryl, spiroheterocycle, alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, OH, O-C1-3-alkyl, O-halo-C1-3-alkyl, O-C3-6-cycloalkyl, O-heterocycloalkyl, oxo, N(R32)2, COOH, CON(R32)2, CN and NR32-COR32;
or R1 is selected from a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or C1-10-alkyl substituted with a group selected from halogen, CN, OR11, SO y R11, SO3H, NR11SO2R11, SO2NR11R12, CO2R11, CONR11R12, NR11-CO-R11, NR11-CO-NR11R12, NR11-NR11R12, NR11-R12 and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or C0-1-alkylene-C3-10-cycloalkyl substituted with a group selected from halogen, CN, SO y R11, NR11SO2R11, SO2NR11R12, CO2R11, CONR11R12, NR11-COR11, NR11-CO-NR11R12, NR11-NR11R12 and NR11R12, or C2-10-alkylene-C3-10-cycloalkyl, C2-10-alkylene-O-C3-10-cycloalkyl, C2-10-alkylene-C5-10-heterocycloalkyl, C2-10-alkylene-O-C6-10-heterocycloalkyl and SO2-C1-10-alkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, CN, O-C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, halogen, CO2R11, CONR11R12, COR11, SO2R11, SO2NR11R12, NR11COR11, NR11SO2R11, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl, O-C3-6-heterocycloalkyl, O-C2-6-alkylene-OR11 and NR11R12;
and R3 is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein pyridinone, aryl, heteroaryl and spiroheterocycle are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, CN, C1-6-alkyl, C3-10-cycloalkyl, C3-10-heterocycloalkyl, C0-6-alkylene-(5-membered monocyclic heteroaryl), C0-6-alkylene-(6-membered monocyclic heteroaryl), C0-6-alkylene-O-R31, O-C1-6-alkylene-O-R32, C0-6-alkylene-COOR31, C0-6-alkylene-C(O)R31, C0-6-alkylene-C(O)N(R31)2, C0-6-alkylene-N(R31)C(O)R31, C0-6-alkylene-SO2-N(R31)2, C0-6-alkylene-N(R31)SO2-R31, C0-6-alkylene-SO2-R31, C0-6-alkylene-SO-R31 and C0-6-alkylene-N(R31)2, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, OH, O-C1-3-alkyl, O-halo-C1-3-alkyl, O-C3-6-cycloalkyl, O-C3-6-heterocycloalkyl, oxo, N(R32)2, COOH, CON(R32)2, CN and NR32-COR32, and wherein optionally two adjacent substituents complete a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from 0, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, oxo, OH, O-C1-6-alkyl and O-halo-C1-6-alkyl;
and R2 is selected from the group consisting of H, C1-6-alkyl, halo-C1-6-alkyl and hydroxy-C1-6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SO y R11, SO3H, NR11SO2-R11, SO2NR11R12, CO2R11, CONR11R12, COR11, NR11-CO-R11, NR11-CO-NR11R12, NR11-SO2-NR11R12, NR11R12, C1-6-alkyl, halo-C1-6, hydroxy-C1-6-alkyl, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl and O-C3-6-heterocycloalkyl;
R4 is SO2-(CR8R8)y R7, SO2-NR12R7 or (CR8R8)x-R10;
R5 is selected from H, C1-6-alkyl, halo-C1-6-alkyl, CHO or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of O-C1-6-alkyl, O-halo-C1-6-alkyl and OH;
R6 is selected from H, halo-C1-6-alkyl or halogen;
R7 is selected from C3-10-cycloalkyl and C3-10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, O-C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, cycloalkyl and heterocycloalkyl;
IR8 is independently selected from H, F, C1-3-alkyl, halo-C1-3-alkyl or OH;
is C3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, O-C1-6-alkyl, O-halo-C1-6-alkyl, halo-C1-6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1-2-alkyl, halo-C1-2-alkyl;
R11 is independently selected from H, C1-6-alkyl, C0-6-alkylene-C3-6-cycloalkyl, C0-6-alkylene-C3-6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C1-3-alkyl, halo-C1-3-alkyl, O-C1-3-alkyl, O-halo-C1-3-alkyl and SO2-C1-3-alkyl;
R12 is independently selected from H, C1-6-alkyl and halo-C1-6-alkyl;
R31 is independently selected from H, C1-6-alkyl, CO-6-alkylene-C3-6-cycloalkyl, C0-6-alkylene-C3-6-heterocycloalkyl, a 6-membered aryl wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl and aryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, halo-C1-3-alkyl, O-C1-3-alkyl, O-halo-C1-3-alkyl and SO2-C1-3-alkyl;
R32 is independently selected from H, C1-6-alkyl and halo-C1-6-alkyl;
x is independently selected from 1 and 2;
y is independently selected from 0, 1 and 2;
with the proviso that R3 is not an unsubstituted or substituted ring selected from
3. The compound according to claim 1 and 2 wherein R1 is selected from H, C1-10-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, C1-10-alkylene-C3-10-cycloalkyl, C1-10-alkylene-C3-10-heterocycloalkyl, C1-10-alkylene-(5-membered monocyclic heteroaryl), wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR11, O-C2-6-alkylene-OR11, C1-6-alkyl, halo-C1-6-alkyl, halogen, CO2R11, CONR11R12, COR11, SO y R11, SO3H, SO2NR11R12, NR11COR11, NR11SO2R11, NR11-CO-NR11R12, NR11-SO2-NR11R12, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl, O-C3-6-heterocycloalkyl and NR11R12;
R2 is selected from the group consisting of H, C1-6-alkyl, halo-C1-6-alkyl and hydroxy-C1-6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SO y R11, SO3H, NR11SO2R11, SO2NR11R12, C0-6-alkylene-0O2R11, CONR11R12, COR11, NR11-CO-R11, CO-NR11R12, NR11-SO2-NR11R12, NR11R12, C1-6-alkyl, halo-C1-6-alkyl, hydroxy-C1-6-alkyl, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl and O-C3-6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1-3-alkyl, halo-C1-3-alkyl and oxo;
R3 is a 6- or 1 0-membered mono- or bicyclic aryl or a 6- to 1 0-membered mono-or bicyclic heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, wherein aryl and heteroaryl is substituted with at least one group selected from C3-6-cycloalkyl, C4-heterocycloalkyl, C1-4-alkylene-C3-10-cycloalkyl, carbon atom linked 5- or 6-membered monocyclic heteroaryl, C1-4-alkylene-O-R31, O-C3-10-cycloalkyl, C(O)R31, C0-6-alkylene-C(O)N(R31)2, SO2-N(R31)2, N(R31)SO2-R31, SO2-C3-10-heterocycloalkyl, SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, oxo, =N-OR32, OH, O-C1-6-alkyl and O-halo-C1-6-alkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and the carbon atom linked 5-or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, OH, oxo, =N-OR32, O-C1-3-alkyl and O-halo-C1-3-alkyl; and wherein aryl and heteroaryl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, OH, O-C1-3-alkyl and O-halo-C1-3-alkyl.
R2 is selected from the group consisting of H, C1-6-alkyl, halo-C1-6-alkyl and hydroxy-C1-6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SO y R11, SO3H, NR11SO2R11, SO2NR11R12, C0-6-alkylene-0O2R11, CONR11R12, COR11, NR11-CO-R11, CO-NR11R12, NR11-SO2-NR11R12, NR11R12, C1-6-alkyl, halo-C1-6-alkyl, hydroxy-C1-6-alkyl, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl and O-C3-6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1-3-alkyl, halo-C1-3-alkyl and oxo;
R3 is a 6- or 1 0-membered mono- or bicyclic aryl or a 6- to 1 0-membered mono-or bicyclic heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, wherein aryl and heteroaryl is substituted with at least one group selected from C3-6-cycloalkyl, C4-heterocycloalkyl, C1-4-alkylene-C3-10-cycloalkyl, carbon atom linked 5- or 6-membered monocyclic heteroaryl, C1-4-alkylene-O-R31, O-C3-10-cycloalkyl, C(O)R31, C0-6-alkylene-C(O)N(R31)2, SO2-N(R31)2, N(R31)SO2-R31, SO2-C3-10-heterocycloalkyl, SO-R31 and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, oxo, =N-OR32, OH, O-C1-6-alkyl and O-halo-C1-6-alkyl, wherein alkylene, cycloalkyl, heterocycloalkyl and the carbon atom linked 5-or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, OH, oxo, =N-OR32, O-C1-3-alkyl and O-halo-C1-3-alkyl; and wherein aryl and heteroaryl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, OH, O-C1-3-alkyl and O-halo-C1-3-alkyl.
4. The compound according to claim 3 wherein R1 is selected from C1-10-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, C1-10-alkylene-C3-10-cycloalkyl, C1-10-alkylene-C3-10-heterocycloalkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR11, O-C2-6-alkylene-OR11, C1-6-alkyl, halo-C1-6-alkyl, halogen, CO2R11, CONR11R12, COR11, SO y R11, SO3H, SO2NR11R12, NR11COR11, NR11SO2R11, CO-NR11R12, NR11 -SO2-NR11R12, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl, O-C36-heterocycloalkyl and NR11R12;
R2 is selected from the group consisting of H, C1-6-alkyl and halo-C1-6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SO y R11, SO3H, NR11SO2R11, SO2NR11R12, C0-6-alkylene-CO2R11, CONR11R12, COR11, NR11-CO-R11, CO-NR11R12, -NR11-SO2-NR11R12, NR11R12, C1-6-alkyl, halo-C1-6-alkyl, hydroxy-C1-6-alkyl, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl and O-C3-6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1-3-alkyl, halo-C1-3-alkyl and oxo.
R2 is selected from the group consisting of H, C1-6-alkyl and halo-C1-6-alkyl, or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SO y R11, SO3H, NR11SO2R11, SO2NR11R12, C0-6-alkylene-CO2R11, CONR11R12, COR11, NR11-CO-R11, CO-NR11R12, -NR11-SO2-NR11R12, NR11R12, C1-6-alkyl, halo-C1-6-alkyl, hydroxy-C1-6-alkyl, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl and O-C3-6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1-3-alkyl, halo-C1-3-alkyl and oxo.
5. The compound according to any of claims 3 to 4 wherein NR1R2 is selected from NH2, NHMe, NHEt, NH i Pr, NH t Bu, NHCH2CONH2, NHCH2CONMe2, NHCH2CH2OH, NHCH2CH(CF3)OH, NHCH2C(CF3)2OH, NHCH2CH2OMe, NHCH2CH2SO2Me, NHCH2CH2SO2NH2, NH(CH2)3OH, NH(CH2)3OMe, NH(CH2)4OH, NH(CH2)4OMe, NH(CH2)5OH, NH(CH2)2CO2H, NH(CH2)3CO2H, NH(CH2)4CO2H, NH(CH2)5CO2H, NHCH2CMe2OH, NHCH(Me)CMe2OH, NHCH2CMe2OMe, NHCH2CMe2CO2H, NHCH2CMe2CONH2, NHCH2CMe2CONHMe, NHCH2CMe2CONMe2, NHCH2CMe2NHSO2Me, NH(CH2)3SOMe, NH(CH2)5SO2Me, NH(CH2)5SO2NH2, NH(CH2)3NHSO2Me, NH(CH2)2O(CH2)2OH, NHCH2CHMeOH, NH(CH2)5SOMe, NH(CH2)3SO2Me, HN~, <>
6. The compound according to any of claims 3 to 5 wherein R3 is selected from wherein R33 is independently selected from H, halogen, CN, C1-6-alkyl, fluoro-C1-6-alkyl, C1-4-alkylene-OH, C1-4-alkylene-O-C1-3-alkyl, C14-alkylene-O-fluoro-C1-3-alkyl, O-C1-6-alkyl, O-fluoro-C1-6-alkyl, NH-C1-6-alkyl, NH-fluoro-C1-6-alkyl, C3-10-cycloalkyl, C(O)N(R37)2, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C1-3-alkyl and fluoro-C1-3alkyl;
R34 is selected from C1-4-alkylene-OH, C1-4-alkylene-O-C1-3-alkyl, C1-4-alkylene-O-fluoro-C1-3-alkyl, C3-10-cycloalkyl, C(O)N(R37)2, SO2N(R37)2, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C1-3-alkyl and fluoro-C1-3-alkyl;
R35 is selected from C1-6-alkyl and fluoro-C1-6-alkyl;
R36 is selected from C1-6-alkyl, fluoro-C1-6-alkyl, C(O)N(R37)2, SO2N(R37)2, R37 is independently selected from H, C1-6-alkyl, halo-C1-6-alkyl, C0-4-alkylene-C3-6-cycloalkyl, C0-4-alkylene-C3-6-heterocycloalkyl, wherein alkyl and alkylene is unsubtituted unsubtituted or substituted with a substituent selected from halogen, OH, O-C1-3-alkyl, CN; and cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, CN, OH, oxo, C1-3-alkyl and fluoro-C1-3-alkyl;
or wherein two R37 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1-4-alkyl and halo-C1-4-alkyl;
R38 is selected from H, C1-3-alkyl and fluoro-C1-3-alkyl;
R39 is selected from H, F, OH, O-C1-3-alkyl, O-halo-C1-3-alkyl;
W is selected from an annelated C5-8-cycloalkyl, an annelated 6-membered aryl or an annelated 5- to 6-membered heteroaryl, wherein cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 2 substituents selected from halogen, methyl or CF3;
X is an annelated saturated heterocycle selected from the group consisting of Y is an annelated 5- or 6-membered carbocycle, an annelated 6-membered aryl or an annelated 6-membered heteroaryl containing 1 to 2 nitrogen atoms, wherein the carbocycle, aryl or heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C1-3-alkyl and fluoro-C1-3-alkyl;
Z is an annelated 6-membered cycle forming a heteroaryl containing 1 to 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C1-3-alkyl and fluoro-C1-3-alkyl;
n is selected from 1 to 4.
R34 is selected from C1-4-alkylene-OH, C1-4-alkylene-O-C1-3-alkyl, C1-4-alkylene-O-fluoro-C1-3-alkyl, C3-10-cycloalkyl, C(O)N(R37)2, SO2N(R37)2, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C1-3-alkyl and fluoro-C1-3-alkyl;
R35 is selected from C1-6-alkyl and fluoro-C1-6-alkyl;
R36 is selected from C1-6-alkyl, fluoro-C1-6-alkyl, C(O)N(R37)2, SO2N(R37)2, R37 is independently selected from H, C1-6-alkyl, halo-C1-6-alkyl, C0-4-alkylene-C3-6-cycloalkyl, C0-4-alkylene-C3-6-heterocycloalkyl, wherein alkyl and alkylene is unsubtituted unsubtituted or substituted with a substituent selected from halogen, OH, O-C1-3-alkyl, CN; and cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, CN, OH, oxo, C1-3-alkyl and fluoro-C1-3-alkyl;
or wherein two R37 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1-4-alkyl and halo-C1-4-alkyl;
R38 is selected from H, C1-3-alkyl and fluoro-C1-3-alkyl;
R39 is selected from H, F, OH, O-C1-3-alkyl, O-halo-C1-3-alkyl;
W is selected from an annelated C5-8-cycloalkyl, an annelated 6-membered aryl or an annelated 5- to 6-membered heteroaryl, wherein cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 2 substituents selected from halogen, methyl or CF3;
X is an annelated saturated heterocycle selected from the group consisting of Y is an annelated 5- or 6-membered carbocycle, an annelated 6-membered aryl or an annelated 6-membered heteroaryl containing 1 to 2 nitrogen atoms, wherein the carbocycle, aryl or heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C1-3-alkyl and fluoro-C1-3-alkyl;
Z is an annelated 6-membered cycle forming a heteroaryl containing 1 to 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C1-3-alkyl and fluoro-C1-3-alkyl;
n is selected from 1 to 4.
7. The compound according to any of claims 3 to 6 wherein R3 is selected from wherein R33 is independently selected from H, halogen, CN, C1-6-alkyl, fluoro-C1-6-alkyl, C1-4-alkylene-OH, C1-4-alkylene-O-C1-3-alkyl, O-C1-6-alkyl, O-fluoro-C1-6-alkyl, C3-6-cycloalkyl;
one R37 is selected from H, C1-6-alkyl, halo-C1-6-alkyl and the other R37 is selected from C1-6-al kyl, halo-C1-6-alkyl, C0-4-alkylene-C3-6-cycloalkyl, C0-4-alkylene-C3-6-heterocycloalkyl, wherein alkyl and alkylene is unsubstituted or substituted with a substituent selected from halogen, OH, O-C1-3-alkyl, CN; and cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, CN, OH, oxo, C1-3-alkyl and fluoro-C1-3-alkyl;
or wherein two R37 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1-4-alkyl and halo-C1-4-alkyl;
W is selected from an annelated C5-8-cycloalkyl, an annelated 6-membered aryl or an annelated 5- to 6-membered heteroaryl, wherein cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 2 substituents selected from halogen, methyl or CF3;
one R37 is selected from H, C1-6-alkyl, halo-C1-6-alkyl and the other R37 is selected from C1-6-al kyl, halo-C1-6-alkyl, C0-4-alkylene-C3-6-cycloalkyl, C0-4-alkylene-C3-6-heterocycloalkyl, wherein alkyl and alkylene is unsubstituted or substituted with a substituent selected from halogen, OH, O-C1-3-alkyl, CN; and cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, CN, OH, oxo, C1-3-alkyl and fluoro-C1-3-alkyl;
or wherein two R37 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C1-4-alkyl and halo-C1-4-alkyl;
W is selected from an annelated C5-8-cycloalkyl, an annelated 6-membered aryl or an annelated 5- to 6-membered heteroaryl, wherein cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 2 substituents selected from halogen, methyl or CF3;
8. The compound according to any of claims 3 to 7 wherein R3 is selected from
9. The compound according to any of claims 3 to 8 wherein R5 is selected from H, C1-6-alkyl, halo-C1-6-alkyl or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of O-C1-6-alkyl, O-halo-C1-6-alkyl and OH;
R6 is selected from H or halogen.
R6 is selected from H or halogen.
10. The compound according to any of claims 3 to 9 wherein R4 is CR8R8-R10;
R8 is independently selected from H, F, C1-3alkyl or halo-C1-3-alkyl;
R10 is C3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl and cycloalkyl.
R8 is independently selected from H, F, C1-3alkyl or halo-C1-3-alkyl;
R10 is C3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl and cycloalkyl.
11. The compound according to any of claims 3 to 10 wherein
12. The compound of any of claims 3 to 11 selected from the group consisting of and an enantiomer, diastereomer, tautomer, N-oxide, solvate and pharmaceutically acceptable salt thereof.
13. The compound according to claim 1 and 2 wherein R1 is selected from a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or C1-10-alkyl substituted with a group selected from halogen, CN, OR11, SO y R11, SO3H, NR11SO2R11, SO2NR11R12, CO2R11, COR11, CONR11R12, NR11-CO-R11, NR11-CO-NR11R12, NR11-SO2-NR11R12, NR11R12 and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or C0-1-alkylene-C3-10-cycloalkyl substituted with a group selected from halogen, CN, SO y R11, NR11SO2R11, SO2NR11R12, CO2R11, CONR11R12, NR11-CO-R11, NR11-CO-NR11R12,NR11-SO2-NR11R12 and NR11R12, or C2-10-alkylene-C3-10-cycloalkyl, C2-10-alkylene-O-C3-10-cycloalkyl, C2-10-alkylene-C5-10-heterocycloalkyl and C2-10-alkylene-O-C5-10-heterocycloalkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, CN, O-C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, halogen, CO2R11, CONR11R12, SO2R11, SO2NR11R12, NR11COR11, NR11SO2R11, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl, O-C3-6-heterocycloalkyl, O-C2-6-alkylene-OR11 and NR11R12;
R2 is selected from the group consisting of H, C1-6-alkyl, halo-C1-6-alkyl and hydroxy-C1-6-alkyl;
or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SO y R11, SO3H, NR11SO2R11, SO2NR11R12, C0-6-alkylene-CO2R11, CONR11R12, COR11, NR11-CO-R11, CO-NR11R12, NR11-SO2NR11R12, NR11R12, C1-6-alkyl, halo-C1-6-alkyl, hydroxy-C1-6-alkyl, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl and O-C3-6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1-3-alkyl, halo-C1-3-alkyl and oxo;
R3 is a 6- or 10-membered mono- or bicyclic aryl or a 6- to 10-membered mono-or bicyclic heteroaryl containing 1 or 2 heteroatom selected from the group consisting of N,O and S, wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, CN, C1-6-alkyl, C3-10-cycloalkyl, C0-6-alkylene-C3-10-heterocycloalkyl, C0-6-alkylene-O-R31, C0-6-alkylene-COOR31, C0-6-alkylene-C(O)R31, C0-6-alkylene-C(O)N(R31)2, C0-6-alkylene-N(R31)C(O)R31, C0-6-alkylene-SO2-N(R31)2, C0-6-alkylene-N(R31)SO2-R31, C0-6-alkylene-SO2-R31, C0-6-alkylene-SO-R31 and C0-6-alkylene-N(R31)2, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, OH, O-C1-3-alkyl, O-halo-C1-3-alkyl, O-C3-6-cycloalkyl, O-C3-6-heterocycloalkyl, oxo, N(R32)2, COOH, CON(R32)2, CN and NR32-COR32, and wherein optionally two adjacent substituents complete a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, oxo, OH, O-C1-6-alkyl and O-halo-C1-6-alkyl.
R2 is selected from the group consisting of H, C1-6-alkyl, halo-C1-6-alkyl and hydroxy-C1-6-alkyl;
or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR11, SO y R11, SO3H, NR11SO2R11, SO2NR11R12, C0-6-alkylene-CO2R11, CONR11R12, COR11, NR11-CO-R11, CO-NR11R12, NR11-SO2NR11R12, NR11R12, C1-6-alkyl, halo-C1-6-alkyl, hydroxy-C1-6-alkyl, C3-6-cycloalkyl, O-C3-6-cycloalkyl, C3-6-heterocycloalkyl and O-C3-6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C1-3-alkyl, halo-C1-3-alkyl and oxo;
R3 is a 6- or 10-membered mono- or bicyclic aryl or a 6- to 10-membered mono-or bicyclic heteroaryl containing 1 or 2 heteroatom selected from the group consisting of N,O and S, wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, CN, C1-6-alkyl, C3-10-cycloalkyl, C0-6-alkylene-C3-10-heterocycloalkyl, C0-6-alkylene-O-R31, C0-6-alkylene-COOR31, C0-6-alkylene-C(O)R31, C0-6-alkylene-C(O)N(R31)2, C0-6-alkylene-N(R31)C(O)R31, C0-6-alkylene-SO2-N(R31)2, C0-6-alkylene-N(R31)SO2-R31, C0-6-alkylene-SO2-R31, C0-6-alkylene-SO-R31 and C0-6-alkylene-N(R31)2, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, OH, O-C1-3-alkyl, O-halo-C1-3-alkyl, O-C3-6-cycloalkyl, O-C3-6-heterocycloalkyl, oxo, N(R32)2, COOH, CON(R32)2, CN and NR32-COR32, and wherein optionally two adjacent substituents complete a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C3-6-heterocycloalkyl, oxo, OH, O-C1-6-alkyl and O-halo-C1-6-alkyl.
14. The compound according to claim 13 wherein NR1R2 is selected from NHCH2CONH2, NHCH2CONMe2, NHCH2CH2OH, NHCH2CH(CF3)OH, NHCH2C(CF3)2OH, NHCH2CH2OMe, NHCH2CH2SO2Me, NHCH2CH2SO2NH2, NH(CH2)3OH, NH(CH2)3OMe, NH(CH2)4OH, NH(CH2)4OMe, NH(CH2)5OH, NH(CH2)2CO2H, NH(CH2)3CO2H, NH(CH2)4CO2H, NH(CH2)5CO2H, NHCH2CMe2OH, NHCH(Me)CMe2OH, NHCH2CMe2OMe, NHCH2CMe2CO2H, NHCH2CMe2CONH2, NHCH2CMe2CONHMe, NHCH2CMe2CONMe2, NHCH2CMe2NHSO2Me, NH(CH2)3SOMe, NH(CH2)5SO2Me, NH(CH2)5SO2NH2, NH(CH2)3NHSO2Me, NH(CH2)2O(CH2)2OH, NHCH2CHMeOH, NH(CH2)5SOMe,
15. The compound according to any of claims 13 to 14 wherein R3 is selected from wherein R33 is selected from C1-6-alkyl and fluoro-C1-6-alkyl;
R34 is selected from halogen, C1-6-alkyl, fluoro-C1-6-alkyl, O-C1-6-alkyl, O-fluoro-C1-6-alkyl, NH-C1-6-alkyl and NH-fluoro-C1-6-alkyl;
R39 is selected from H, F and OH.
R34 is selected from halogen, C1-6-alkyl, fluoro-C1-6-alkyl, O-C1-6-alkyl, O-fluoro-C1-6-alkyl, NH-C1-6-alkyl and NH-fluoro-C1-6-alkyl;
R39 is selected from H, F and OH.
16. The compound according to any of claims 13 to 15 wherein R3 is selected from
17. The compound according to any of claims 13 to 16 wherein R5 is selected from H, C1-6-alkyl, halo-C1-6-alkyl or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of O-C1-6-alkyl, O-halo-C1-6-alkyl and OH;
R6 is selected from H or halogen.
R6 is selected from H or halogen.
18. The compound according to any of claims 13 to 17 wherein R4 is SO2-R7, SO2-NR12R7, CHR8-R19 and (CH)2R19;
R7 is selected from C3-10-cycloalkyl and C3-10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, OH, alkyl, halo-C1-6-alkyl and cycloalkyl;
R8 is independently selected from H, F, C1-3-alkyl or halo-C1-3-alkyl;
R10 is C3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl and cycloalkyl.
R7 is selected from C3-10-cycloalkyl and C3-10-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, OH, alkyl, halo-C1-6-alkyl and cycloalkyl;
R8 is independently selected from H, F, C1-3-alkyl or halo-C1-3-alkyl;
R10 is C3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C1-6-alkyl, halo-C1-6-alkyl and cycloalkyl.
19. The compound according to any of claims 13 to 18 wherein R4 is selected from
20. The compound of any of claims 13 to 19 selected from the group consisting of and an enantiomer, diastereomer, tautomer, N-oxide, solvate and pharmaceutically acceptable salt thereof.
21. The compound of any one of claims 1 to 20 for use as a medicament.
22. The compound of any one of claims 1 to 20 for use in treating ROR .gamma.
mediated inflammatory and autoimmune diseases.
mediated inflammatory and autoimmune diseases.
23. The compound for use of claim 22, wherein the disease is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, psoriatic arthritis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, asthma, mucosal leishmaniasis, multiple sclerosis, systemic sclerosis, type 1 diabetes, Kawasaki disease, Hashimoto's thyroiditis, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thromobotic purpura, myasthenia gravis, Sjorgren's syndrome, scleroderma, ulcerative colitis, epidermal hyperplasia, glomerulonephritis, chronic obstructive pulmonary disease and amyotrophic lateral sclerosis.
24. A pharmaceutical composition comprising the compound of any one of claims 1 to 20 and a pharmaceutically acceptable carrier.
Applications Claiming Priority (5)
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|---|---|---|---|
| US201161566055P | 2011-12-02 | 2011-12-02 | |
| US61/566055 | 2011-12-02 | ||
| EP11009556.9 | 2011-12-02 | ||
| EP11009556 | 2011-12-02 | ||
| PCT/EP2012/004977 WO2013079223A1 (en) | 2011-12-02 | 2012-12-03 | Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
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| CA2856946C CA2856946C (en) | 2016-08-02 |
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| US (1) | US9815851B2 (en) |
| EP (1) | EP2800745B1 (en) |
| JP (1) | JP5918859B2 (en) |
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