WO2011002408A1 - Novel compounds for treatment of neurodegeneration associated with diseases, such as alzheimer's disease or dementia - Google Patents

Novel compounds for treatment of neurodegeneration associated with diseases, such as alzheimer's disease or dementia Download PDF

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WO2011002408A1
WO2011002408A1 PCT/SE2010/050760 SE2010050760W WO2011002408A1 WO 2011002408 A1 WO2011002408 A1 WO 2011002408A1 SE 2010050760 W SE2010050760 W SE 2010050760W WO 2011002408 A1 WO2011002408 A1 WO 2011002408A1
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alkyl
alkylc
methyl
cycloalkyl
imidazol
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PCT/SE2010/050760
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French (fr)
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Jan Blid
Tobias Ginman
Ylva Gravenfors
Sofia KARLSTRÖM
Jacob KIHLSTRÖM
Karin Kolmodin
Johan LINDSTRÖM
Fredrik Rahm
Marie SUNDSTRÖM
Britt-Marie Swahn
Jenny Viklund
Stefan Von Berg
Fredrik Von Kieseritzky
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Astrazeneca Ab
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88Nitrogen atoms, e.g. allantoin
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Novel compounds for treatment of neurodegeneration associated with diseases such as Alzheimer ' s disease or dementia
  • the present invention relates to novel compounds and therapeutically acceptable salts thereof, their pharmaceutical compositions, processes for making them and their use as medicaments for treatment and/or prevention of various diseases.
  • the invention relates to compounds, which are inhibitors of ⁇ -secretase and hence inhibit the formation of amyloid ⁇ (A ⁇ ) peptides and will be used for treatment and/or prevention of A ⁇ -related pathologies such as Alzheimer's disease, Downs syndrome and ⁇ -amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • AD Alzheimer's disease
  • a ⁇ amyloid ⁇ -peptide
  • a ⁇ peptide is an integral fragment of the Type I protein APP (A ⁇ amyloid precursor protein), a protein ubiquitously expressed in human tissues. Since soluble A ⁇ can be found in both plasma and cerebrospinal fluid (CSF), and in the medium from cultured cells, APP has to undergo proteolysis.
  • CSF cerebrospinal fluid
  • ⁇ -cleavages of APP there are three main cleavages of APP that are relevant to the paleobiology of AD, the so-called ⁇ -, ⁇ -, and ⁇ -cleavages.
  • the ⁇ -cleavage which occurs roughly in the middle of the A ⁇ domain in APP is executed by the metalloproteases ADAMlO or ADAM 17 (the latter also known as TACE).
  • the ⁇ -cleavage occuring at the N terminus of A ⁇ , is generated by the transmembrane aspartyl protease Beta site APP Cleaving Enzymel (BACEl).
  • the ⁇ -cleavage is effected by a multi-subunit aspartyl protease named ⁇ -secretase.
  • ADAM 10/ 17 cleavage followed by ⁇ -secretase cleavage results in the release of the soluble p3 peptide, an N-terminally truncated A ⁇ fragment that fails to form amyloid deposits in humans.
  • This proteolytic route is commonly referred to as the non-amyloidogenic pathway.
  • Consecutive cleavages by BACEl and ⁇ -secretase generates the intact A ⁇ peptide, hence this processing scheme has been termed the amyloidogenic pathway.
  • amyloidogenic processing This application focuses on the latter strategy, inhibition or modulation of amyloidogenic processing.
  • Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of patients with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerative disorders. Neurofibrillary tangles also occur in other neurodegenerative disorders including dementia-inducing disorders (Varghese, J., et al, Journal of Medicinal Chemistry, 2003, 46, 4625-4630). ⁇ -amyloid deposits are predominately an aggregate of AB peptide, which in turn is a product of the proteolysis of amyloid precursor protein (APP).
  • APP amyloid precursor protein
  • AB peptide results from the cleavage of APP at the C-terminus by one or more ⁇ - secretases, and at the N-terminus by B-secretase enzyme (BACE), also known as aspartyl protease or Asp2 or Beta site APP Cleaving Enzyme (BACE), as part of the B- amyloidogenic pathway.
  • BACE B-secretase enzyme
  • BACE activity is correlated directly to the generation of AB peptide from APP (Sinha, et al, Nature, 1999, 402, 537-540), and studies increasingly indicate that the inhibition of BACE inhibits the production of A ⁇ peptide (Roberds, S. L., et al, Human Molecular Genetics, 2001, 10, 1317-1324).
  • BACE amyloid- ⁇ -peptide
  • Drugs that reduce or block BACE activity should therefore reduce A ⁇ levels and levels of fragments of A ⁇ in the brain, or elsewhere where A ⁇ or fragments thereof deposit, and thus slow the formation of amyloid plaques and the progression of AD or other maladies involving deposition of A ⁇ or fragments thereof.
  • BACE is therefore an important candidate for the development of drugs as a treatment and/or prophylaxis of A ⁇ -related pathologies such as Downs syndrome, ⁇ -amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • a ⁇ -related pathologies such as Downs syndrome, ⁇ -amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage
  • disorders associated with cognitive impairment such as but not limited to MCI (“mild cognitive impairment")
  • Alzheimer Disease memory loss
  • A is selected from Q- ⁇ alkylheteroaryl, Co- 6 alkylC 3 - 8 cycloalkyl, C 0 ⁇ alkylC 3 . 6 cycloalkenyl, C 0 , 6 alkylC 6 cycloalkynyl or C 0 - 6 alkyl- C3-gheterocyclyl, wherein said A is optionally substituted with one or more R 1 ;
  • B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R 2 ;
  • C is selected from hydrogen, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- 6 alkylC 3 - 6 cycloalkyl, Co.6alkylC 3 - 6 cycloalkenyl, Co- ⁇ alkylC ⁇ cycloalkynyl, Co ⁇ alkylaryl, Co- 6 alkylheteroaryl, Co-ealkylheterocyclyl, C 0 - 6 alkylOR 4 , C 0 ⁇ alkylCO 2 R 4 , C 0-6 alkylN(R 4 ) 2 , halogen,
  • R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Co- 6 alkylC 3 - 6 cycloalkyl,
  • R 2 is selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, Co- 6 alkylC 3 - 6 cycloalkyl,
  • Co. 6 alkylCOR 4 5 CHO, NO 2 , C 0 - 6 alkylCON(R 4 ) 2 , 0(CO)OR 4 , 0(CO)R 4 , O(CO)N(R 4 ) 2 , NR 4 (CO)OR 4 , C 0-6 alkylNR 4 (CO)R 4 , NR 4 (CO)N(R 4 ) 2 , NR 4 (CO)(CO)R 4 , NR 4 (CO)(CO> N(R 4 ) 2 , C 0-6 alkylSR 4 , C 0 - 6 alkylOSO 2 R 4 , Co -6 alkylS0 3 R 4 , C 0-6 alkylSO 2 R 4 , C 0 .
  • R 2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R 6 ;
  • R 3 is selected from halogen, NO 2 , CHO, C 0 - 6 alkylCN, C 0-6 alkylOR 4 , C 1-6 haloalkyl, Co. 6 alkylN(R 4 ) 2 , NR 4 C(O)R 4 , C 0 ⁇ alkylCO 2 R 4 , C 0 .
  • Co- 6 alkylheteroaryl, and Co- ⁇ alkyUieterocyclyl wherein said C h alky!, C 2 _ 6 alkenyl, C 2 ⁇ alkynyl, Co- 6 alkylC 3 - 6 cycloalkyl, Co- ⁇ ahcylaryl, Co- ⁇ alkylheteroaryl, or Co-ealkylhetero- cyclyl is optionally substituted with one or more R 6 ;
  • R 4 is selected from hydrogen, Cr 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 0 - 6alkylC 3 - 6 cycloalkyl, C 0-6 alkylC 3 - 6 cycloalkenyl, Co- 6 alkylC 6 cycloalkynyl, C 0 - 6 alkylaryl, CQ- 6 alkylheteroaryl, Co- ⁇ alkylheterocycl
  • R 4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R 5 is selected from hydrogen, d- ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- 6 alkylC 3 - 6 cycloalkyl, Co -6 alkylC 3 - 6 cycloalkenyl, Co.
  • R may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R 6 is selected from oxo, halogen, nitro, CN, OR 7 , Ci. 6 alkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, Co- 6 alkylaryl, Co ⁇ alkylheteroaryl, Co -6 alkylC 3-6 cycloalkyl, Co- ⁇ alkylheterocyclyl, C 1-6 IIaIo- alkyl, OC 2-6 alkylN(R 7 ) 2 , N(R 7 ) 2 , CON(R 7 ) 2 , NR 7 (CO)R 7 , O(CO)C 1 - 6 alkyl, (CO)OC ⁇ alkyl, COR 7 , SON(R 7 ) 2 , (SO 2 )N(R 7 ) 2 , NR 7 SO 2 R 7 , NR 7 SOR 7 , SO 2 R 7 , SOR 7 , (CO)C 1-6 alkyl- N(R 7 ) 2 ,
  • ⁇ alkynyl, Co -6 alkylaryl, Co- 6 alkylheteroaryl, Co- ⁇ alkylheterocyclyl, or Co- 6 alkylC 3-6 cyclo- alkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR 7 , C 1-6 alkyl, or Ci- ⁇ haloalkyl;
  • R 7 is selected from hydrogen, Ct- ⁇ alkyl, d ⁇ haloalkyl, C 2 . 6 alkenyl, C 2-6 alkynyl, C 3 - 6 cyclo- alkyl, C 3 _ 6 cycloalkenyl, C 6 cycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C 1 .
  • ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 ⁇ cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, cyano, halogen and OCualkyl; or two R 7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OC 1-3 alkyl, cyano and halogen; as a free base or a pharmaceutically acceptable salt thereof.
  • the molecular weight of the compound of formula (I) is more than 300 g/mol. In one embodiment of the present invention, the molecular weight of the compound of formula (I) is less than 600 g/mol.
  • A is selected from C 1-6 alkyl, C 2-6 alkenyl, C ⁇ alkynyl, C 1-6 alkylaryl, C 1-6 alkylheteroaryl,
  • B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R 2 ;
  • C is selected from hydrogen, C h alky., C 2 . 6 alkenyl, C 2 - 6 alkynyl, Co- 6 alkylC 3 . 6 cycloalkyl, Co- 6 alkylC 3 . 6 cycloalkenyl, Co- ⁇ alkylC ⁇ cycloalkynyl, Co ⁇ alkylaryl, Co- 6 alkylheteroaryl, Co-ealkylheterocyclyl, C 0-6 alkylOR 4 , C 0-6 alkylCO 2 R 4 , C 0 - 6 alkylN(R 4 ) 2 , halogen, Co- 6 alkyl- CN, Co- 6 alkylCOR 4 , CHO, NO 2 , C 0 .
  • R 1 is selected from C ⁇ alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl, Co- 6 alkylC 3-6 cycloalkyl,
  • R 2 is selected from Ci_ 6 alkyl, C 2 . 6 alkenyl, C ⁇ alkynyl, Co- 6 alkylC 3 - 6 cycloalkyl, Co_ 6 alkyl- C 3-6 cycloalkenyl, C 0 _ 6 alkylC 6 cycloalkynyl, C 0 ⁇ alkylaryl, C 0-6 alkylheteroaryl, Co- 6 alkyl- heterocyclyl, C 0 - 6 alkylCO 2 R 4 , C 0-6 alkylN(R 4 ) 2 , halogen, C 0 .
  • Ci- ⁇ alkyl, C 2-6 alkenyl, C ⁇ alkynyl, Co -6 alkylC 3-6 cycloalkyl, Co- 6 alkylaryl, Co- 6 alkyl- heteroaryl or Co- ⁇ alkylheterocyclyl is optionally substituted with one or more R 3 , or two R 2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R 6 ;
  • R 3 is selected from halogen, NO 2 , CHO, C 0 _ 6 alkylCN, C 0 . 6 alkylOR 4 , C 1-6 haloalkyl, Co- 6 alkylN(R 4 ) 2 , NR 4 C(O)R 4 , C 0 ⁇ alkylCO 2 R 4 , C 0 .
  • Co- 6 alkylheteroaryl, and Co- ⁇ alkylheterocyclyl wherein said C 1-6 alkyl, C ⁇ alkenyl, C 2-6 alkynyl, Co- 6 alkylC 3-6 cycloalkyl, Co- 6 alkylaryl, Co- 6 alkylheteroaryl, or Co- 6 alkyl- heterocyclyl is optionally substituted with one or more R 6 ;
  • R 4 is selected from hydrogen, Cr 6 alkyl, C 1-3 haloalkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- 6 alkylC 3 - 6 cycloalkyl, Co -6 alkylC 3 ⁇ cycloalkenyl, Co.
  • R 4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R 5 is selected from hydrogen, Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- 6 alkylC 3 - 6 cycloalkyl, Co-6alkylC 3 - 6 cycloalkenyl, Co- ⁇ alkylC ⁇ cycloalkynyl, C 0 - 6 alkylaryl, Co ⁇ alkylheterocyclyl and Co- 6 alkylheteroaryl, wherein said Q- ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 0 - 6 alkylC 3 ⁇ ⁇ cycloalkyl, Co- 6 alkylaryl, Co- 6 alkylheteroaryl or Co- ⁇ alkylheterocyclyl is optionally substituted with one or more R 6 ;
  • R 5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R is selected from oxo, halogen, nitro, CN, OR , Ci_ 6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 0- ⁇ alkylaryl, Co- ⁇ alkylheteroaryl, C 0 . 6 alkylC 3 - 6 cycloalkyl, C h alky lheterocyclyl, C 1-6 halo- alkyl, OC 2-6 alkylN(R 7 ) 2 , N(R 7 ) 2 , CON(R 7 ) 2 , NR 7 (CO)R 7 , O(CO)C 1 - 6 alkyl, (CO)OC i.
  • A is selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, d- ⁇ alkylaryl, Q-ealkylheteroaryl, Co-ealkylCs-scycloalkyl, C 0 ⁇ alkylC 3 .
  • B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R 2 ;
  • C is selected from hydrogen, C ⁇ alkyl, C 2 - 6 alkenyl, C ⁇ alkynyl, C 0 - 6 alkylC 3 - 6 cycloalkyl, Co- ⁇ alkylCs- ⁇ cycloalkenyl, Co- ⁇ alkylC ⁇ cycloalkynyl, Co ⁇ alkylaryl, Co- ⁇ alkylheteroaryl, Co- ⁇ alkylheterocyclyl, C 0-6 alkylOR 4 , C 0 - O aIlCyICO 2 R 4 , C 0 - 6 alkylN(R 4 ) 2 , halogen, C 0-6 alkyl- CN, Co- 6 alkylCOR 4 , CHO, NO 2 , C 0 .
  • R 1 is selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 0-6 alkylC 3 . 6 cycloalkyl, Co- ⁇ alkyl- C 3 - 6 cycloalkenyl, Co- 6 alkylC 6 cycloalkynyl, Co- ⁇ alkylaryl, Co- 6 alkylheteroaryl, C 0 ⁇ alkyl- heterocyclyl, C 0 - 6 alkylCO 2 R 4 , C 0-6 alkylN(R 4 ) 2 , Co- ⁇ alkylOR 4 , halogen, C 0 .
  • R 2 is selected from C 0 - 6 alkyl- Cs- ⁇ cycloalkenyl, Co- 6 alkylC 6 cycloalkynyl, Co- ⁇ alkylaryl, Co- 6 alkylheteroaryl, Co- ⁇ alkylheterocyclyl, C 0 - 6 alkylCO 2 R 4 , C 0-6 alkylN(R 4 ) 2 , halogen, C 0 .
  • R 3 is selected from halogen, NO 2 , CHO, C 0 . 6 alkylCN, C 0 - 6 alkylOR 4 , C 1-6 haloalkyl, Co-6alkylN(R 4 ) 2 , NR 4 C(O)R 4 , C 0-6 alkylCO 2 R 4 , C 0 .
  • Co-6alkylheteroaryl, and Co- ⁇ alkylheterocyclyl wherein said C ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0 - 6 alkylC 3-6 cycloalkyl, C 0 - 6 alkylaryl, C 0 . 6 alkylheteroaryl, or C 0 - 6 alkyl- heterocyclyl is optionally substituted with one or more R 6 ;
  • R 4 is selected from hydrogen, C ⁇ aUcyl, C 1-3 haloalkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- 6alkylC 3 - 6 cycloalkyl, Co -6 alkylC 3 ⁇ cycloalkenyl, Co- 6 alkylC 6 cycloalkynyl, Co- 6 alkylaryl, Co- 6 alkylheteroaryl, Co- ⁇ alkylheterocyclyl, Ci- ⁇ alkylOR 5 , and C !
  • R 4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R 5 is selected from hydrogen, Cr ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co-6alkylC 3 - 6 cycloalkyl, Co- 6 alkylC 3 . 6 cycloalkenyl, Co -6 alkylC 6 cycloalkynyl, Co- 6 alkylaryl, Co- ⁇ alkylheterocyclyl and Co- 6 alkylheteroaryl, wherein said Cr ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 0 - 6 alkyl- C 3 - 6 cycloalkyl, Co- 6 alkylaryl, Co- 6 alkylheteroaryl or Co- ⁇ alkylheterocyclyl is optionally substituted with one or more R 6 ; R 6 is selected from oxo, halogen, nitro, CN, OR 7 , Ci -6 alkyl, C 2-6 alken
  • 6 alkylC 3-6 cyclo- alkyl is optionally substituted with one or more substituents selected from halo, nitro, cyano, OR 7 , d- ⁇ alkyl, or R 7 is selected from hydrogen, Ci- 6 alkyl, Ci- 3 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 ⁇ cyclo- alkyl, Ca- ⁇ cycloalkenyl, Cecycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 ⁇ cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to three substituents selected from hydroxy, cyano, halogen and OC ⁇ alkyl; or two R 7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S
  • A is selected from C t -ealkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, C ⁇ alkylaryl, Ci- ⁇ alkylheteroaryl,
  • B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R 2 ;
  • C is selected from hydrogen, C ⁇ alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl, Co- 6 aIkylC 3 ⁇ cycloalkyl, Co- 6 alkylC 3 - 6 cycloalkenyl, Co ⁇ alkylaryl, Co-ealkylheteroaryl, Co- ⁇ alkylheterocyclyl, C 0-6 alkylOR 4 , C 0-6 alkylC ⁇ 2 R 4 , C 0 - 6 alkylN(R 4 ) 2 , halogen, C 0 - 6 alkylCN, Co-ealkylCOR 4 , NO 2 , Co- 6 alkylCON(R 4 ) 2 , 0(CO)R 4 , C 0 - 6 alkylNR 4 (CO)R 4 , Co -6 alkylSR 4 , C 0 .
  • R 1 is selected from Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co-ealkylCs-ecycloalkyl,
  • R 2 is selected from Ci- 6 alkyl, C 0 . 6 alkylaryl, C 0 - 6 alkylheteroaryl, Co-ealkylheterocyclyl, C 0 - 6 alkylCO 2 R 4 , Co_ 6 alkylN(R 4 ) 2 , halogen, C 0 - 6 alkylCN,
  • Co- 6 alkylaryl, C 0-6 alkylheteroaryl or Co- ⁇ alkylheterocyclyl is optionally substituted with one or more R 3 ,
  • R 2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R 6 ;
  • R 3 is selected from halogen, NO 2 , Co ⁇ alkylCN, C 0 . 6 alkylOR 4 , C 1 Jialoalkyl,
  • Co- 6 alkylC 3 ⁇ cycloalkyl, Co-ealkylaryl, Co- ⁇ alkylheteroaryl, or Co- ⁇ alkylheterocyclyl is optionally substituted with one or more R 6 ;
  • R 4 is selected from hydrogen, Ci- ⁇ alkyl, C ⁇ haloalkyl, C 0 - 6 alkylC 3 - 6 cycloalkyl, C 0 - ⁇ alkylaryl, C 0 - 6 alkylheteroaryl, Co- ⁇ alkyUieterocyclyl, C ⁇ - ⁇ alkylOR 5 , and C 1 - 6 alkylN(R 5 ) 2 , wherein said Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- 6 alkylC 3 - 6 cycloalkyl, Co- ⁇ alkylaryl, Co- 6 alkylheteroaryl or Co- ⁇ al
  • R 5 is selected from hydrogen, Ci- ⁇ alkyl, Co- 6 alkylC 3 - 6 cycloalkyl, C 0 - 6 alkylaryl,
  • Co- ⁇ alkylheterocyclyl and Co- 6 alkylheteroaryl wherein said d- ⁇ alkyl, Co-ealkyl- C3-6cycloalkyl, Co- ⁇ alkylaryl, Co- 6 alkylheteroaryl or Co ⁇ alkylheterocyclyl is optionally substituted with one or more R 6 ;
  • R 5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R 6 ;
  • R 6 is selected from oxo, halogen, nitro, CN, OR 7 , Ci ⁇ alkyl, C 0 . 6 alkylaryl, C 0 -
  • ⁇ alkylheterocyclyl or Co -6 alkylC 3 - 6 cycloalkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR 7 , C ⁇ aUcyl, Ci- 3 haloalkyl, or OC ⁇ haloalkyl;
  • R 7 is selected from hydrogen, Cs- ⁇ cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said C 3 . 6 cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, cyano, halogen and OC ⁇ alkyl; or two R 7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OCi ⁇ alkyl, cyano and halogen.
  • B is phenyl or heteroaryl.
  • R 2 is Ci- ⁇ alkyl, Co- 6 alkylC 3 _ 6 cycloalkyl, halogen, Co. 6 alkylCN or Co- ⁇ alkylOR 4 .
  • R 2 is fluoro, OR 4 or Ci- 6 alkyl.
  • R 2 is halogen, such as fluoro, cyano or Co-ealkylOR 4 .
  • R is fluoro
  • R 4 is hydrogen, Ci- ⁇ alkyl, C ⁇ haloalkyl, Co- 6 alkylC 3 - 6 cycloalkyl or Co- ⁇ alkyUieteroaryl.
  • R 4 is hydrogen, Cr ⁇ alkyl or Ci-shaloalkyl.
  • R 4 is hydrogen
  • A is Ci ⁇ alkyl, Ci-oalkylaryl,
  • Ci_ 6 alkylheteroaryl C 0 - 6 alkylC 3 . 8 cycloalkyl, or Co- ⁇ alkylCs-gheterocyclyl.
  • A is Co- 6 alkylC 3 . 8 cycloalkyl or Co- ⁇ alkyl-Cs-gheterocyclyl.
  • R 1 is C ⁇ alkyl, Co- 6 alkylC 3 ⁇ cycloalkyl, Co ⁇ alkylaryl, C 0 . 6 alkylheteroaryl, Co ⁇ alkylheterocyclyl, C 0 - 6 alkylN(R 4 ) 2 , Co- ⁇ alkylOR 4 , halogen, C 0 - 6 alkylCN, C 0-6 alkylCOR 4 , C 0 - 6 alkylCON(R 4 ) 2 , C 0-6 alkylNR 4 (CO)R 4 5 C 0-6 alkylSR 4 , C M alkylSO 2 R 4 or Co ⁇ alkylSOR 4 .
  • R 1 is Ci- ⁇ alkyl, C 2 - 6 alkynyl, Co -6 alkylC 3-6 cycloalkyl, Co- ⁇ alkylOR 4 , halogen, C 0 - 6 alkylCN or C 0-6 alkylCOR 4 .
  • R 1 is Co- 6 alkylC 3 _ 6 cycloalkyl, Co- 6 alkylOR 4 , halogen or Co- ⁇ alkylCOR 4 .
  • C ⁇ alkyl is methyl or ethyl.
  • C ⁇ alkylaryl is CH 2 -phenyl.
  • Co- 6 alkylC 3 . 6 cycloalkyl is cyclohexyl.
  • Co- ⁇ alkylCs-sheterocyclyl is piperidinyl.
  • Co-ealkylCs-sheterocycryl is
  • A is piperidinyl or cyclohexyl.
  • C is hydrogen, C 1-6 alkyl, C2- 6 alkynyl, Co-ealkylCa-ecycloalkyl,
  • C is selected from hydrogen, C ⁇ - 6 alkyl, Co- 6alkylaryl, C 0-6 alkylheteroaryl, Co- ⁇ alkylCN, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- 6 alkylC 3 - 6 cyclo- alkyl, Co- ⁇ alkylheterocyclyl, C 0-6 alkylOR 4 , Co-6alkylN(R 4 ) 2 , halogen, Co-6alkylCON(R 4 ) 2 , C 0-6 alkylNR 4 (CO)R 4 .
  • C is phenyl, pyridine or pyrimidine.
  • R 3 is halogen, C 0-6 alkylCN, Co ⁇ alkylOR 4 , C 1-6 haloalkyl, C ⁇ alkyl.
  • R 3 is halogen, NO 2 , C 0 - 6 alkylCN, Co- 6 alkylOR 4 , C 1-6 haloalkyl, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Co- ⁇ alkylCs-ecycloalkyl or Co- ⁇ alkylheterocyclyl.
  • R 3 is halogen, C 2 - 6 alkynyl, CN or OR 4 . In one embodiment, R 3 is halogen or C 2 - 4 alkynyl.
  • R 6 is oxo, halogen, CN, OR 7 , C 1-6 alkyl, C 0-6 alkylC 3 - 6 cycloalkyl or C 1 . ⁇ haloalkyl.
  • R 6 is chloro
  • A is Co- 6 alkylC 3 - 8 cycloalkyl or C 0 - 6 alkyl-C 3 . 8 heterocyclyl, wherein said A is optionally substituted with one or more R 1 ;
  • B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R 2 ;
  • C is hydrogen, C ⁇ alkyl, C 2 . 6 alkynyl, Co- 6 alkylC 3 . 6 cycloalkyl, Co- 6 alkylaryl,
  • R 1 is Ci ⁇ alkyl, Co-ealkylCa-ecycloalkyl, C 0-6 alkylOR 4 , halogen or C 0-6 alkylCOR 4 ;
  • R 2 is C 1-6 alkyl, Co -6 alkylC 3 ⁇ cycloalkyl, halogen, Co-ealkylCN or C 0 . 6 alkylOR 4 ;
  • R 3 is halogen, C 2-6 alkynyl, CN or OR 4 ;
  • R 4 is hydrogen, Ci- 6 alkyl, Ci. 3 haloalkyl, Co- 6 alkylC 3 - 6 cycloalkyl or Co- ⁇ alkylheteroaryl; R 6 is oxo, halogen, CN, OR 7 , Co- 6 alkylC 3 - 6 cycloalkyl or Ci- 6 haloalkyl.
  • A is selected from Q-ealkylaryl
  • B is aryl
  • C is Co- 6 alkylaryl or Co -6 alkylheteroaryl, wherein said C 0-6 alkylaryl or Co- 6 alkylheteroaryl is optionally substituted with one or more R 1 ;
  • R 3 is C 0-6 alkylOR 4 ;
  • One embodiment of the present invention is a compound selected from 2-(3'-Methoxybiphenyl-3-yl)-2,5-dimethyl-2H-imidazol-4-amine;
  • the present invention relates to the use of compounds of formula (I) as hereinbefore defined as well as to the salts thereof.
  • Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I).
  • the compounds of the formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I).
  • prodrugs examples include in vivo hydrolysable esters of a compound of the formula (I).
  • An in vivo hydrolysable (or cleavable) ester of a compound of the formula (I) that contains a carboxy or a hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Various forms of prodrugs are known in the art. The definitions set forth in this application are intended to clarify terms used throughout this application. The term "herein" means the entire application.
  • a variety of compounds in the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention takes into account all such compounds, including tautomers, cis- and trans isomers, R- and S- enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • the compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms.
  • optically active forms such as by resolution of racemic forms, by synthesis from optically active starting materials, or synthesis using optically active reagents.
  • separation of the racemic material can be achieved by methods known in the art.
  • Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
  • alkyl used alone or as a suffix or prefix, is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
  • “Co- 6 alkyl” denotes alkyl having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.
  • a subscript is the integer 0 (zero) the group to which the subscript refers to indicates that the group may be absent, i.e. there is a direct bond between the groups.
  • alkenyl used alone or as a suffix or prefix is intended to include both branched and straight-chain alkene or olefin containing aliphatic hydrocarbon groups having from 2 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
  • C 2 - 6 alkenyF' denotes alkenyl having 2, 3, 4, 5 or 6 carbon atoms.
  • alkenyl examples include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut- 1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
  • alkynyl used alone or as a suffix or prefix is intended to include to include both branched and straight-chain alkynyl or olefin containing aliphatic
  • hydrocarbon groups having from 2 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
  • ethynyl e.g. 1-propynyl, 2-propynyl
  • 3-butynyl pentynyl, hexynyl and l-methylpent-2- ynyl.
  • aromatic refers to hydrocarbonyl groups having one or more unsaturated carbon ring(s) having aromatic characters, (e.g. 4n + 2 delocalized electrons) and comprising up to 14 carbon atoms.
  • heteromatic refers to groups having one or more unsaturated rings containing carbon and one or more heteroatoms such as nitrogen, oxygen or sulphur having aromatic character (e.g. 4n + 2 delocalized electrons).
  • aryl refers to an aromatic ring structure made up of from 5 to 14 carbon atoms. Ring structures containing 5, 6, 7 and 8 carbon atoms would be single-ring aromatic groups, for example, phenyl. Ring structures containing 8, 9, 10, 11, 12, 13, or 14 would be polycyclic, for example naphthyl. The aromatic ring can be substituted at one or
  • polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • polycyclic rings i o include, but are not limited to, 2,3 -dihydro- 1 ,4-benzodioxine and 2,3 -dihydro- 1 - benzofuran.
  • cycloalkyl or “carbocyclyl” are intended to include saturated ring groups, having the specified number of carbon atoms. These may include fused or is bridged polycyclic systems. Preferred cycloalkyls have from 3 to 10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, and 6 carbons in the ring structure.
  • C 3-6 cycloalkyl denotes such groups as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkenyl is intended to include unsaturated ring groups, having the specified number of carbon atoms. These may include fused or bridged polycyclic systems. Preferred cycloalkenyls have from 3 to 10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, and 6 carbons in the ring structure. For example, "C 3 . 6 cycloalkenyl” denotes such groups as cyclopropenyl, cyclobutenyl,
  • halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • Counterion is used to represent a small, negatively or positively charged species such as 30 chloride, bromide, hydroxide, acetate, sulfate, tosylate, benezensulfonate, ammonium, lithium ion and sodium ion and the like.
  • heterocyclyl or “heterocyclic” or “heterocycle” refers to a saturated, unsaturated or partially saturated, monocyclic, bicyclic or tricyclic ring (unless otherwise stated) containing 3 to 20 atoms of which 1, 2, 3, 4 or 5 ring atoms are chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group is optionally be replaced by a -C(O)-; and where unless stated to the contrary a ring nitrogen or sulphur atom is optionally oxidised to form the N-oxide or S-oxide(s) or a ring nitrogen is optionally quarternized; wherein a ring -NH is optionally substituted with acetyl, formyl, methyl or mesyl; and a ring is optionally substituted with one or more halo.
  • heterocyclyl group is bi- or tricyclic then at least one of the rings may optionally be a heteroaromatic or aromatic ring provided that at least one of the rings is non-heteroaromatic. If the said heterocyclyl group is monocyclic then it must not be aromatic.
  • heterocyclyls include, but are not limited to, piperidinyl, N- acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2/f-pyranyl, tetrahydrofuranyl, tetrahydro-thiopyranyl, tetrahydro-thiopyran 1 -oxide, tetrahydro-thiopyran 1,1 -dioxide, IH- pyridin-2-one, and 2,5-dioxoimidazolidinyl.
  • heteroaryl refers to a heteroaromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (i.e.
  • furanyl quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, benzoxazolyl, aza-benzoxazolyl imidazothiazolyl, benzo[l,4]dioxinyl, benzo[l,3]dioxolyl and the like.
  • quinolyl isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzo
  • the heteroaryl group has from 1 to 20 carbon atoms, and in further embodiments from 3 to 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl group has 1 heteroatom.
  • haloalkyl used alone or as a suffix or prefix, is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups, having at least one halogen substituent and having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
  • C 0 - ohaloalkyl denotes alkyl having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.
  • Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl,
  • chlorofluoromethyl 1-fluoroethyl, 3-fluoropropyl, 2-chloropropyl, 3,4-difluorobutyl.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3 rd ed.; Wiley: New York, 1999).
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • non-toxic salts include those derived from inorganic acids such as hydrochloric acid.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • the present invention further includes all tautomeric forms of compounds of the invention.
  • tautomer means other structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom.
  • keto-enol tautomerism where the resulting compound has the properties of both a ketone and an unsaturated alcohol.
  • Other examples of tautomerism include 2H-imidazole-4-amine and its tautomer l,2-dihydroimidazol-5-imine, and 2H-imidazol-4-thiol and its tautomer 1,2- dihydroimidazol-5-thione. It is understood that in compound representations throughout this description, only one of the possible tautomers of the compound is drawn or named.
  • stable compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • Compounds of the invention further include hydrates and solvates.
  • the present invention further includes isotopically-labelled compounds of the invention.
  • An "isotopically" or “radio-labelled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 1, 124 1, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labelled compounds will depend on the specific application of that radio-labelled compound. For example, for in vitro receptor labelling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 1 , 131 1, 35 S or will generally be most useful. For radio- imaging applications 11 C, 18 F, 125 1, 123 1, 124 1, 131 1, 75 Br, 76 Br or 77 Br will generally be most useful.
  • a "radio-labelled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 1 , 35 S and 82 Br.
  • Compounds of the present invention may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
  • the dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient.
  • the quantity of the compound to be administered will vary for the patient being treated and will vary from about 100 ng/kg of body weight to 100 mg/kg of body weight per day.
  • dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art.
  • the skilled artisan can readily determine the amount of compound and optional additives, vehicles, and/or carrier in compositions and to be administered in methods of the invention.
  • the compounds of the invention, or a pharmaceutically acceptable salt thereof can be used as medicaments, e.g. to treat or prevent A ⁇ -related pathologies.
  • the compounds of the invention, or a pharmaceutically acceptable salt thereof can be used for the manufacture of a medicament to treat or prevent A ⁇ -related pathologies.
  • a method for the treatment of A ⁇ - related pathologies comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject, such as a mammal or a human being, in need thereof.
  • the compounds of the invention and their pharmaceutically acceptable salts thereby provides methods of treatment of A ⁇ -related pathologies, such as, but not limited to, Alzheimer's disease, Downs syndrome, ⁇ -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy traumatic brain injury and cortical basal degeneration.
  • a ⁇ -related pathologies such as, but not limited to, Alzheimer's disease, Downs syndrome, ⁇ -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI (“mild cognitive impairment"), memory loss, attention deficit symptoms associated with Alzheimer
  • a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according formula (I) in association with pharmaceutically acceptable excipients, carriers or diluents.
  • a method of treating or preventing an A ⁇ -related pathology in a mammal comprising administering to said patient a therapeutically effective amount of a compound according to formula (I), and at least one cognitive enhancing agent, memory enhancing agent, or choline esterase inhibitor, wherein said A ⁇ -related pathology is Alzheimer Disease.
  • the treatment of A ⁇ -related pathology defined herein may be applied as a mono therapy or may involve, in addition to the compound of the invention, conjoint treatment with conventional therapy of value in treating one or more disease conditions referred to herein.
  • Such conventional therapy may include one or more of the following categories of agents: acetyl cholinesterase inhibitors, anti-inflammatory agents, cognitive and/or memory enhancing agents or atypical antipsychotic agents.
  • Cognitive enhancing agents, memory enhancing agents and acetyl choline esterase inhibitors includes, but not limited to, donepezil (Aricept), galantamine (Reminyl or Razadyne), rivastigmine (Exelon), tacrine (Cognex) and memantine (Namenda, Axura or Ebixa).
  • Atypical antipsychotic agents includes, but not limited to, olanzapine (marketed as Zyprexa), aripiprazole (marketed as Abilify), risperidone (marketed as Risperdal), quetiapine (marketed as Seroquel), clozapine (marketed as Clozaril), ziprasidone (marketed as Geodon) and olanzapine/fluoxetine (marketed as Symbyax).
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of the invention.
  • Additional conventional therapy may include one or more of the following categories of agents:
  • antidepressants such as agomelatine, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, ramelteon, reboxetine, robalzotan, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • antidepressants such as agomelatine, amitriptyline, amoxapine, bupropion, citalopram, clomi
  • atypical antipsychotics including for example quetiapine and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • antipsychotics including for example amisulpride, aripiprazole, asenapine,
  • anxiolytics including for example alnespirone, azapirones,benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, zolazepam and equivalents and pharmaceutically active
  • anticonvulsants including for example carbamazepine, clonazepam, ethosuximide, felbamate, fosphenytoin, gabapentin, lacosamide, lamotrogine, levetiracetam,
  • oxcarbazepine phenobarbital, phenytoin, pregabaline, rufinamide, topiramate, valproate, vigabatrine, zonisamide and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Alzheimer's therapies including for example donepezil, rivastigmine, galantamine, memantine, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Parkinson's therapies including for example deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase and equivalents and
  • migraine therapies including for example almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, dihydroergotamine, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pizotiphen, pramipexole, rizatriptan, ropinirole,
  • (ix) stroke therapies including for example thrombolytic therapy with eg activase and desmoteplase, abciximab, citicoline, clopidogrel, eptifibatide, minocycline, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • urinary incontinence therapies including for example darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodine and and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • neuropathic pain therapies including for example lidocain, capsaicin, and
  • anticonvulsants such as gabapentin, pregabalin, and antidepressants such as duloxetine, venlafaxine, amitriptyline, klomipramine, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • nociceptive pain therapies such as paracetamol, NSAIDS and coxibs, such as celecoxib, etoricoxib, lumiracoxib, valdecoxib, parecoxib, diclofenac, loxoprofen, naproxen, ketoprofen, ibuprofen, nabumeton, meloxicam, piroxicam and opioids such as morphine, oxycodone, buprenorfin, tramadol, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • coxibs such as celecoxib, etoricoxib, lumiracoxib, valdecoxib, parecoxib, diclofenac, loxoprofen, naproxen, ketoprofen, ibuprofen, nabumeton, meloxicam, piroxicam and opioids such as morphine, oxycodone, buprenorfin
  • insomnia therapies including for example agomelatine, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine,
  • mood stabilizers including for example carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, verapamil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and/or the dosage described in the publication reference.
  • the present invention also relates to processes for preparing the compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof.
  • suitable protecting groups will be added to, and subsequently removed from the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis.
  • Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are for example described in Protective Groups in Organic Synthesis by T. W. Greene, P.G.M Wutz, 3 rd Edition, Wiley-Interscience, New York, 1999. It is understood that microwaves can alternatively be used for the heating of reaction mixtures.
  • Another aspect of the present invention provides a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein, unless specified otherwise, A, B and C are defined as in formula (I) above, R c is defined as for C in formula (I) above and R 1 is, unless specified otherwise, as defined in formula (I); R 10 and R 11 are defined as A or B above, or may be defined as groups that can be converted to A or B in subsequent transformations, R 12 may be defined as R 4 above, and LG represents a leaving group such as halogen (such as chlorine, bromine or iodine) or an alkyl-, aryl- or haloalkyl-sulfonate (such as triflate).
  • a compound of formula (VI) may be equivalent to a compound of formula (I).
  • Said process comprises of: (i) Formation of a corresponding compound of formula (W):
  • a ketone of formula (II), is reacted with ammonia to form intermediate (III), (Scheme 1).
  • the compound of formula (III) is further reacted with ethyl 2-oxopropanoate to form an imidazole compound of formula (FV).
  • Said reaction may be performed at a temperature range between +100 0 C and +160 0 C, in a suitable solvent, such as methanol, ethanol or isopropyl alcohol.
  • the amino imidazole compound (VI) may be obtained by an initial formation of intermediate (V), by reacting the alcohol of formula (IV), with a sulphurating reagent such as phosphorus pentasulfide in the presence of a base such as pyridine.
  • a sulphurating reagent such as phosphorus pentasulfide in the presence of a base such as pyridine.
  • the transformation to a compound of formula (VI) may be performed by reacting the intermediate of formula (V) with ammonia, optionally in the presence of an oxidation agent, such as tert-butyl hydroperoxide.
  • a compound of formula (III), may be obtained, as shown in (Scheme 3), by reacting compound of formula (VII), wherein LG is defined as above, with an organometallic reagent such as an alkyl lithium as for example butyl lithium, or with a metal such as magnesium, to form an intermediate compound of formula (VIII), wherein M is a metal, such as for example lithium or MgX, wherein X is a halide such as bromo or chloro.
  • the compound of formula (VIII) is further reacted with a nitrile of formula (IX). Said reaction may be performed at a temperature range between -78 0 C and room temperature, in a suitable solvent such as THF, 2-methyl-tetrahydrofuran or diethyl ether.
  • a catalyst such as CuBr may facilitate the reaction.
  • An alkylating agent such as methyl iodide and a thioimidazole of formula (X) are reacted to form a compound of formula (XI) ⁇ Scheme 5).
  • Said compound (XI) may be further transformed into a compound of formula (VI) by reacting it with an organometallic reagent, such as methylmagnesium bromide in the presence of a suitable catalyst, such as [l,3-bis(diphenylphosphino)propane]nickel(II) chloride.
  • the compound of formula (VI) may also be obtained by reacting compound of formula (XI) with a mixture of zinc iodide and methylmagnesium bromide in the presence of a suitable catalyst such as bis(triphenylphosphine)palladium(II) chloride in a suitable solvent such as THF, 2-methyl- tetrahydrofuran or toluene.
  • a suitable catalyst such as bis(triphenylphosphine)palladium(II) chloride
  • a suitable solvent such as THF, 2-methyl- tetrahydrofuran or toluene.
  • a compound of formula (VI) may be obtained from a compound of formula (III), wherein R 13 is hydrogen, S(O)alkyl, C(O)alkyl, S(O) 2 alkyl, OH or Oalkyl (Scheme 6).
  • Compound (III) may optionally be coordinated to a Lewis acid, as for example BF 3 , AlCl 3 , or TiCl 4 , to facilitate the reaction.
  • An imine of formula (III) is reacted with 2-oxopropane thioamide (described in Asinger et al. Justus Liebigs Annalen der Chemie 1971, vol 744, p.
  • a compound of formula (I) may be obtained (Scheme T) by starting from, for example, a compound of formula (XII), and reacting said compound of formula (XII) with a boronic acid or a boronic ester or a stannane of formula T-R c , wherein T is for example B(OH) 2 , B(Oalkyl) 2 , or SnR 3 , and R c is as defined above, in the presence of a transition metal catalyst such as a palladium catalyst, such as [ 1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride, tetrakis(triphenylphosphine)- palladium(O), palladium diphenylphosphineferrocene dichloride, palladium(II) acetate or bis(dibenzylideneacetone) palladium (0).
  • a suitable ligand such as
  • triphenylphosphine tri-ter?-butylphosphine or 2-(dicyclohexylphosphino)biphenyl, or zinc and sodium Mphenylphosphinetrimetasulfonate
  • a suitable base such as cesium fluoride, an alkyl amine, such as triethyl amine, or an alkali metal or alkaline earth metal carbonate or hydroxide such as potassium carbonate, sodium carbonate, cesium carbonate, or sodium hydroxide, may be used in the reaction.
  • Said reaction may be performed in a suitable solvent, such as toluene, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, dimethoxyethane, water, ethanol, N.iV-dimethylacetamide, acetonitrile or N 1 N- dimethylformamide, or mixtures thereof.
  • a suitable solvent such as toluene, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, dimethoxyethane, water, ethanol, N.iV-dimethylacetamide, acetonitrile or N 1 N- dimethylformamide, or mixtures thereof.
  • a compound of formula (I), wherein C is cyano may be obtained (Scheme 7) by starting from, for example, a compound of formula (XII), wherein LG is a leaving group such as a halogen, (such as iodide, bromide or chlorine), and reacting said compound of formula (XII) with a a metal cyano reagent such as copper(I) cyanide.
  • a compound of formula (XII) wherein C is cyano
  • LG is a leaving group such as a halogen, (such as iodide, bromide or chlorine)
  • a compound of formula (I), wherein C is an alkyl group such as methyl may be generated from compound of formula (XII) (Scheme 7), wherein LG represents a leaving group, such as a halogen, (such as iodide, bromide or chlorine), by reaction with an organometallic reagent generated from zinc iodide and methylmagnesium bromide under the influence of a transition metal catalyst such as for example bis(triphenylphosphine)palladium(II) chloride.
  • a transition metal catalyst such as for example bis(triphenylphosphine)palladium(II) chloride.
  • a compound of formula (I) wherein C is NHC(O)R 12 may be prepared according to
  • Scheme 7 by reacting a compound of formula (XII) with a compound R 12 C(O)NH 2 in the presence of a suitable palladium catalyst such as palladium(II) acetate, optionally in the presence of a suitable ligand such as Xantphos. Said reaction is preformed in the presence of a suitable base such as cesium carbonate in a suitable solvent such as THF or 2-methyl- tetrahydrofuran at a temperature between 100 0 C to 160 0 C.
  • a suitable palladium catalyst such as palladium(II) acetate
  • a suitable ligand such as Xantphos
  • Solvent mixture compositions are given as volume percentages or volume ratios.
  • Microwave heating was performed in a Biotage Creator, Initiator or Smith Synthesizer Single-mode microwave cavity producing continuous irradiation at 2450 MHz. It is understood that microwaves can be used for the heating of reaction mixtures.
  • TLC Thin layer chromatography
  • Merck TLC-plates Silica gel 60 F 254
  • Flash chromatography was performed on a Combi Flash® CompanionTM using RediSepTM normal-phase flash columns.
  • Straight phase flash column chromatography was manually performed on Merck Silica gel 60 (0.040- 0.063mm), or automatically using an ISCO Combiflash® CompanionTM system using the solvent system indicated. Phase separation was optionally performed on an Isolute® phase separator.
  • 1 H NMR spectra were recorded in the indicated deuterated solvent at 400 MHz unless otherwise indicated. Spectra were obtained using a Bruker av400 NMR spectrometer operating at 400 MHz for 1 H and 100 MHz for 13 C equipped with a 3 mm flow injection SEI 1 HZD- 13 C probe head with Z-gradients, using a BEST 215 liquid handler for sample injection, or using a Bruker DPX400 NMR spectrometer operating at 400 MHz for 1 H, 376 MHz for 19 F, and 100 MHz for 13 C, equipped with a 4-nucleus probehead with Z-gradients.
  • 500 MHz spectra were recorded using a Bruker 500MHz Avance III NMR spectrometer, operating at 500 MHz for 1 H, 125 MHz for 13 C, and 50 MHz for 15 N equipped with a 5mm TXI probehead with Z-gradients.
  • 600 MHz spectra were recorded using a Bruker DRX600 NMR spectrometer, operating at 600 MHz for 1 H, 150 MHz for 13 C, and 60 MHz for 15 N equipped with a 5mm TXI (or BBO) probehead with Z-gradients. Chemical shifts are given in ppm down- and upfield from TMS (0.00 ppm).
  • TMS ⁇ 0.00 or the residual solvent signal of DMSOd 6 ⁇ 2.49, CD 3 OD ⁇ 3.30, acetone-d ⁇ 2.04 or CDCI 3 ⁇ 7.25 (unless otherwise indicated).
  • Resonance multiplicities are denoted s, d, t, q, m, br and app for singlet, doublet, triplet, quartet, multiplet, broad and apparent, respectively. In some cases only diagnostic signals are reported.
  • HPLC analyses were performed on an Agilent HPl 100 system consisting of a G1322A Micro Vacuum Degasser, a Gl 311 A Quaternary Pump, a Gl 367 Well-Plate Autosampler, a G1316A Thermostatted Column Compartment and a G1315A Diode Array Detector.
  • the column used was an Xbridge C8 30x50mm, 3.5 ⁇ m or a Gemini C18, 3.0 x 50 mm, 3.0 ⁇ m, 110 A run at a flow rate of 1.0 ml/min.
  • HPLC analyses were performed on an Agilent HPl 100 system consisting of a G1379A Micro Vacuum Degasser, a Gl 312A Binary Pump, a Gl 367 Well-Plate Autosampler, a G1316A Column Compartment and a G1315B Diode Array Detector.
  • the column used was an Xbridge C8 30x50mm, 3.5 ⁇ m or a Gemini C18, 3.0 x 50 mm, 3.0 ⁇ m, 110 A run at a flow rate of 1.0 ml/min.
  • HPLC analyses were performed on an Agilent HPl 100 system consisting of a G1322A Micro Vacuum Degasser, a G1312A Binary Pump, a G1367 Well-Plate Autosampler, a G1316A Thermostatted Column Compartment and a G1315A Diode Array Detector.
  • the column used was an Xbridge C8 30x50mm, 3.5 ⁇ m or a Gemini C18, 3.0 x 50 mm, 3.0 ⁇ m, 110 A run at a flow rate of 1.0 ml/min.
  • GC analyses were performed on a HP 6890 GC equipped with a Gl 512AX flame ionization detector supplied by Agilent Technologies.
  • the column used was DB-5 MS, ID 0.18 mm x 10m, 0.18 ⁇ m (J&W Scientific). A linear temperature gradient was typically applied.
  • Chiral GC analyses were performed on an HP 6890 GC equipped with a flame ionization detector supplied by Agilent Technologies.
  • the column used was a Cyclodex B ID 0.25 mm x 30 m, 0.25 ⁇ m (Agilent Technologies).
  • the temperature of the GC oven was s typically held isocratically at for example 100 0 C for 30 minutes.
  • Mass spectra were run using an automated system with atmospheric pressure chemical (APCI or CI) or electrospray (+ESI) ionization. Generally, only spectra where parent masses are observed are reported. The lowest mass major ion is reported foro molecules where isotope splitting results in multiple mass spectral peaks (for example when chlorine is present).
  • UPLC-MS analyses were performed on a Waters Acquity UPLC system consisting of an Acquity Autosampler, Acquity Sample Organizer, Acquity Column Manager, Acquity Binary Solvent Manager, Acquity UPLC PDA detector and a Waters 3100 Mass Spectrometer. The mass spectrometer was equipped with an
  • s electrospray ion source operated in positive and negative ion mode. Separation was performed on an Acquity column, UPLC BEH, Cl 8 1.7 ⁇ M run at a flow rate of 0.5 ml/min.
  • UPLCMS analyses were performed on a Waters Acquity UPLC system consisting of an Acquity Solvent Manager, Acquity Sample Organizer, Acquity Column Manager, Acquity Binary Solvent Manager, Acquity PDA detector and a Waters0 SQ Detector. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode. Separation was performed on an Acquity column, UPLC BEH, Cl 8 1.7 ⁇ M run at a flow rate of 0.5 ml/min.
  • LC-MS analyses were performed on an LC-MS system consisting of a Waters Alliance5 2795 HPLC, a Waters PDA 2996 diode array detector, a Sedex 75 ELS detector and a ZQ 2000 single quadrupole mass spectrometer.
  • the mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode. Separation was performed on a Xbridge C18, 30x50mm, 3.5 ⁇ m column or on a Gemini C18 3.0 x 50, 3 ⁇ m (Phenomenex) column run at a flow rate of 1 ml/min.
  • ES electrospray ion source
  • LC-MS analyses0 were performed on an LC-MS consisting of a Waters sample manager 2777C, a Waters 1525 ⁇ binary pump, a Waters 1500 column oven, a Waters ZQ single quadrupole mass spectrometer, a Waters PDA2996 diode array detector and a Sedex 85 ELS detector.
  • the mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode.
  • ES electrospray ion source
  • the column used was a Xbridge C18, 30x50mm, 3.5 ⁇ m or a Gemini C 18, 3.0 mm x 50 mm, 3 ⁇ m, (Phenomenex) which was run at a flow rate of 1 ml/min.
  • LC-MS analyses were performed on a LC-MS consisting of a Waters sample manager 2777C, a Waters 1525 ⁇ binary pump, a Waters 1500 column oven, a Waters ZQ single quadrupole mass spectrometer, a Waters PDA2996 diode array detector and a Sedex 85 ELS detector.
  • the mass spectrometer was configured with an atmospheric pressure chemical ionisation (APCI) ion source which was further equipped with atmospheric pressure photo ionisation (APPI) device.
  • APCI atmospheric pressure chemical ionisation
  • APPI atmospheric pressure photo ionisation
  • the system consisted of a GC 6890N, G1530N, a G2614A Auto-sampler, G2613A injector and a G2589N mass spectrometer.
  • the mass spectrometer was equipped with a Direct Inlet Probe (DIP) interface manufactured by SIM GmbH.
  • the mass spectrometer was equipped with an electron impact (EI) ion source and the electron voltage was set to 70 eV.
  • the mass spectrometer scanned between m/z 50-550 and the scan speed was set to 2.91 scan/s.
  • the sample solution was either injected on the GC or introduced by direct inlet to the probe tip.
  • the GC column used was a DB-5 MS, ID 0.18 mm x 1 Om, 0.18 ⁇ m (J& W Scientific) or a VF-5 MS, ID 0.25 mm x 15m, 0.25 ⁇ m (Varian Inc.). A linear temperature gradient was typically applied.
  • GCMS analysis was performed on a GC-MS system supplied by Agilent Technologies, consisting of a 6890N G1530N GC, a G2614A Auto-sampler, G2613A injector and a G2589N mass spectrometer.
  • the column used was a DB-5 MS, ID 0.18 mm x 10m, 0.18 ⁇ m (J&W Scientific) or a VF-5 MS, ID 0.25 mm x 30m, 0.25 ⁇ m (Varian Inc.). Typically a linear temperature gradient was applied.
  • the mass spectrometer was equipped with a chemical ionisation (CI) ion source and the reactant gas was methane or the mass spectrometer was equipped with an electron impact (EI) ion source and the electron voltage was set to 70 eV.
  • the mass spectrometer scanned between m/z 50-500 and the scan speed was set to 3.21 scan/s.
  • Preparative HPLC was for example performed on a Waters Auto purification HPLC-UV system with a diode array detector using for example a Waters Xterra® MS Cg column (30x150 mm, 10 ⁇ m), a Phenomex Gemini-NX column (21x250 mm, 10 ⁇ m), a Waters XBridge C8 column (19x250 mm, 10 ⁇ m), or a Waters XBridgeTM C18 column (19x250 mm, 10 ⁇ m).
  • Mobile phase A 0.1 M ammonium acetate in water/mobile phase B (95:5).
  • Mobile phase B MeCN or MeOH. Typically a linear gradient of mobile phase B was applied.
  • 1,3-Dibromobenzene (3.04 mL, 25.2 mmol) was dissolved in Et 2 O (60 mL) and cooled to - 78 0 C. «-Butyllithium (10.1 mL, 25.25 mmol) was added and the the solution stirred for 30 min. Cyclohexanecarbonitrile (2.99 mL, 25.20 mmol) was added in Et 2 O (40 mL) at -78 0 C and the reaction was allowed to warm to room temperature over 30 min. MeOH (20 mL) containing ammonium acetate (2 g, 25.95 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water.
  • 1,3-Dibromobenzene (3.04 mL, 25.2 mmol) was dissolved in Et 2 O (60 mL) and cooled to - 78 0 C. «-Butyllithium (10.1 mL, 25.25 mmol) was added and the the solution stirred for 30 min. Tetrahydro-2H-pyran-4-carbonitrile (2.80 g, 25.20 mmol) was added in Et 2 O (20 mL) is at -78 0 C and the reaction was stirred for 30 min. The reaction was then allowed to warm to room temperature over 30 min. MeOH (20 mL) containing ammonium acetate (2 g, 25.95 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic phases were shaken with brine and dried over MgSO 4 . The mixture was
  • 1,3-Dibromobenzene (1.435 mL, 11.89 mmol) was dissolved in Et 2 O (90 mL) and cooled to -78 0 C.
  • n-Butyllithium (5 mL, 12.50 mmol) was added and the solution stirred for 30 min.
  • tert-Butyl 4-cyanopiperidine-l-carboxylate (2.5 g, 11.89 mmol) was added in Et 2 O (40 mL) at -78 0 C. The reaction was stirred for 30 min and was then allowed to warm to room temperature over 30 min. MeOH (20 mL) containing ammonium acetate (1 g, 13 mmol) was added.
  • Aqueous 2M HCl (15 mL) was added, the cooling bath removed and the mixture was stirred at rt for 1 h. The organics were removed under reduced pressure and the pH of the resulting aqueous residue was adjusted to 7-8 using an aqueous 20% NaOH solution. The aqueous mixture was diluted with brine (20 mL) and then saturated with solid NaCl and extracted with THF (3 x 25 mL). The combined organics were dried over MgSO 4 , filtered and concentrated.
  • Aqueous 3M HCl (7.95 mL, 23.86 mmol) was added to a stirred solution of 2-(3- bromophenyl)-2-(6-methoxy-5-methylpyridin-3-yl)-5-memyl-2H-imidazol-4-amine (424 mg, 1.14 mmol) in tetrahydrofuran (8 mL) in a microwave vial.
  • the vial was sealed and heated with microwaves at 100 0 C for 45 minutes.
  • the tetrahydrofuran was removed by evaporation, and the remaining aqueous phase basified with saturated aqueous NaHC ⁇ 3 and then extracted with EtOAc.
  • Example 48i The title compound was synthesized as described for Example 34i in 90% yield starting from (lR,2R,4S)-2-bromobicyclo[2.2.1]heptane (0.657 g, 3.76 mmol) and A- methoxybenzonitrile (0.5 g, 3.76 mmol): MS (EI) m/z 229 [M] + .
  • Example 48i The title compound was synthesized as described for Example 34i in 90% yield starting from (lR,2R,4S)-2-bromobicyclo[2.2.1]heptane (0.657 g, 3.76 mmol) and A- methoxybenzonitrile (0.5 g, 3.76 mmol): MS (EI) m/z 229 [M] + .
  • tetrakis(triphenylphosphine)palladium(0) (0.635 g, 0.55 mmol) were added and the reaction was stirred at 80 0 C over night under argon atmosphere. The mixture was cooled to room temperature and filtered through a pad of Celite and concentrated in vacuo.
  • tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.03 mmol) were dissolved in anhydrous DMF (2.00 mL) in a dry microwave vial under argon atmosphere. The mixture was irradiated in a microwave reactor for 30 min at 150 0 C.
  • 1,3-Dimethylbarbituric acid 0.580 g, 3.71 mmol
  • tetrakis(triphenylphosphine)palladium(0) 0.072 g, 0.06 mmol
  • 2-Cyclopropyl-2-(5-(diallylamino)-2-fluorophenyl)-5-methyl-2H- imidazol-4-amine (0.202 g, 0.62 mmol) in dichloromethane (5.00 mL) was added.
  • the resulting mixture was irradiated in a microwave reactor for 40 min at 100 0 C, and then concentrated in vacuo.
  • reaction mixture was stirred at 80 0 C for 3 h. MeOH was added to quench the reaction. Sat. aq. NH 4 Cl solution was added and the mixture was extracted with with DCM. The combined organic phases were dried over MgSO 4 , filtered and the solvent evaporated.
  • Example 11 The racemate of the title compounds were synthesized as described in Example 11 in 20% yield starting from 2-(3-bromophenyl)-5-memyl-2-(pyridin-3-yhnethyl)-2H-imidazol-4- amine and 5-chloropyridine-3-boronic acid.
  • the crude product was dissolved in MeOH and injected on a Chiralpak AD-H column (4.6 x 250 mm), using EtOH+DEA /CO 2 (40:60) as eluent at a flow rate of 2 mL/min.
  • the title compound was synthesized as described for Example 17, from 5-(4-amino-2-(3- bromophenyl)-5-methyl-2H-imidazol-2-yl)-l-ethyl-3-methylpyridin-2(lH)-one (75 mg, 0.19 mmol) and 3-methoxyphenylboronic acid (35.3 mg, 0.23 mmol), with the exception that to achieve full conversion another portion of 3-methoxyphenylboronic acid (14.71 mg, 0.10 mmol) and [l,r-bis(diphenylphosphino)ferrocene]palladium(II)chloride (3.98 mg, 4.84 ⁇ mol) was added and the reaction heated for another 10 minutes at 130 0 C.
  • the aqueous phase was extracted with ethyl acetate (three times).
  • the water mixture was poured onto a hydromatrix column and eluted with ethyl acetate, then acetonitrile.
  • the pH of the water phase was adjusted to ⁇ 8 with aqueous NaOH (5 M) and it was extracted with ethyl acetate.
  • the combined organic layers were passed through a phase separator and then concentrated in vacuo.
  • the product was purified by preparative HPLC. The desired fractions were pooled and concentrated in vacuo. The residue was partitioned between water (pH approximately 8) and dichloromethane (twice).
  • the mixture under an atmosphere of N 2 (g), was evacuated 3 times, then the procedure was repeated with carbon monoxide (excess) 3 times.
  • the pressure was adjusted to 4 bar of CO (g) and then the reactor was placed in an oil-bath set to 90 0 C. After 90 h, the reaction vessel was allowed to cool and removed from the carbon monoxide source.
  • the reaction mixture was diluted with MeOH/DCM and filtered through Celite, then concentrated..
  • the mixture under an atmosphere of N 2 (g), was evacuated 3 times, then the procedure was repeated with carbon monoxide (excess) 3 times.
  • the pressure was adjusted to 4 bar of CO (g) and then the reactor was placed in an oil-bath set to 90 0 C. After 71 h, the reaction vessel was allowed to cool and removed from the carbon monoxide source.
  • the reaction mixture was diluted with MeOH/DCM and filtered through Celite, then concentrated.
  • the title compound was synthesized as described for Example 17 starting from 5-(4- ammo-2-(3-bromophenyl)-5-memyl-2H-imidazol-2-yl)-l-ethyl-3-methylpyridin-2(lH)-one (71.0 mg, 0.18 mmol) and 3-(prop-l-ynyl)phenylboronic acid (88 mg, 0.55 mmol), with the following exceptions: The reaction time was 20 minutes and the reaction mixture was partitioned between saturated aqueous NaHCO 3 and DCM before purification. The DCM layer was passed through a phase separator and concentrated before the purification.
  • TR-FRET Assay The ⁇ -secretase enzyme used in the TR-FRET is prepared as follows:
  • the cDNA for the soluble part of the human ⁇ -Secretase (AA 1 - AA 460) was cloned using the ASP2-FclO-l-IRES-GFP-neoK mammalian expression vector.
  • the gene was fused to the Fc domain of IgGl (affinity tag) and stably cloned into HEK 293 cells.
  • Purified sBACE-Fc was stored in -80 0 C in Tris buffer, pH 9.2 and had a purity of 95%.
  • the enzyme (truncated form) was diluted to 6 ⁇ g/mL (stock 1.3 mg/mL) and the substrate (Europium)CEVNLDAEFK(Qsy7) to 200 nM (stock 120 ⁇ M) in reaction buffer
  • the assay was performed in a Costar 384 well round bottom, low volume, non-binding surface plate (Corning #3676).
  • the final concentration of the enzyme was 2.7 ⁇ g/ml; the final concentration of substrate was 100 nM (Km of -250 nM).
  • the dimethylsulphoxide control instead of test compound, defined the 100% activity level and 0% activity was defined by wells lacking enzyme (replaced with reaction buffer).
  • a control inhibitor was also used in dose response assays and had an IC50 of -575 nM.
  • SH-SY5Y cells were cultured in DMEM /F-12 with Glutamax, 10% FCS and 1% nonessential aminoacids and cryopreserved and stored at -14O 0 C at a concentration of 7.5x106 cells per vial. Thaw cells and seed at a cone, of 1.5x105/ml in DMEM /F-12 with Glutamax, 10% FCS and 1% non-essential aminoacids to a 96-well tissue culture treated plate, lOO ⁇ l cell susp/well. The cell plates were then incubated for 7 hours at 37 0 C, 5% CO2.
  • the cell medium was removed, followed by addition of 90 ⁇ l compound diluted in DMEM /F- 12 with Glutamax, 10% FCS, 1% non-essential aminoacids and 1% PeSt to a final cone, of 1% DMSO.
  • the compounds were incubated with the cells for 16h (over night) at 37 °C, 5% CO2.
  • Meso Scale Discovery (MSD) plates were used for the detection of sAPP ⁇ release. MSD sAPP ⁇ plates were blocked in 3% BSA in Tris wash buffer (150 ⁇ l/well) for 1 hour in RT and washed 4 times in Tris wash buffer (150 ⁇ l/well).
  • MSD sAPP ⁇ microplates 50 ⁇ l of medium was transferred to the pre-blocked and washed MSD sAPP ⁇ microplates, and the cell plates were further used in an ATP assay to measure cytotoxicity.
  • the MSD plates were incubated with shaking in RT for 1 hour followed by washing 4 times.
  • 25 ⁇ l detection antibody was added (InM) per well followed by incubation with shaking in RT for Ih and washing 4 times.
  • 150 ⁇ l Read Buffer was added per well and the plates were read in a SECTOR Imager.
  • ViaLightTM Plus cell proliferation/cytotoxicity kit from Cambrex BioScience that measures total cellular ATP.
  • the assay was performed according to the manufacture's protocol. Briefly, 25 ⁇ L cell lysis reagent was added per well. The plates were incubated at room temperature for 10 min. Two min after addition of 50 ⁇ L reconstituted ViaLightTM Plus ATP reagent, the luminescence was measured in a Wallac Victor2 1420 multilabel counter.
  • Typical IC50 values for the compounds of the present invention are in the range of about 1 to about 100,000 nM. Biological data is given below in Table I Table I.

Abstract

The present invention relates to novel compounds of formula (I) and their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention of Aβ-related pathologies such as Downs syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

Description

Novel compounds for treatment of neurodegeneration associated with diseases, such as Alzheimer's disease or dementia
The present invention relates to novel compounds and therapeutically acceptable salts thereof, their pharmaceutical compositions, processes for making them and their use as medicaments for treatment and/or prevention of various diseases. In particular the invention relates to compounds, which are inhibitors of β-secretase and hence inhibit the formation of amyloid β (Aβ) peptides and will be used for treatment and/or prevention of Aβ-related pathologies such as Alzheimer's disease, Downs syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
Background of the invention
The prime neuropathological event distinguishing Alzheimer's disease (AD) is deposition of the 40-42 residue amyloid β-peptide (Aβ) in brain parenchyma and cerebral vessels. A large body of genetic, biochemical and in vivo data support a pivotal role for Aβ in the pathological cascade that eventually leads to AD. Patients usually present early symptoms (commonly memory loss) in their sixth or seventh decades of life. The disease progresses with increasing dementia and elevated deposition of Aβ. In parallel, a hyperphosphorylated form of the microtubule-associated protein tau accumulates within neurons, leading to a plethora of deleterious effects on neuronal function. The prevailing working hypothesis regarding the temporal relationship between Aβ and tau pathologies states that Aβ deposition precedes tau aggregation in humans and animal models of the disease. Within this context, it is worth noting that the exact molecular nature of Aβ, mediating this pathological function is presently an issue under intense study. Most likely, there is a continuum of toxic species ranging from lower order Aβ oligomers to supramolecular assemblies such as Aβ fibrils. The Aβ peptide is an integral fragment of the Type I protein APP (Aβ amyloid precursor protein), a protein ubiquitously expressed in human tissues. Since soluble Aβ can be found in both plasma and cerebrospinal fluid (CSF), and in the medium from cultured cells, APP has to undergo proteolysis. There are three main cleavages of APP that are relevant to the paleobiology of AD, the so-called α-, β-, and γ-cleavages. The α-cleavage, which occurs roughly in the middle of the Aβ domain in APP is executed by the metalloproteases ADAMlO or ADAM 17 (the latter also known as TACE). The β-cleavage, occuring at the N terminus of Aβ, is generated by the transmembrane aspartyl protease Beta site APP Cleaving Enzymel (BACEl). The γ-cleavage, generating the Aβ C termini and subsequent release of the peptide, is effected by a multi-subunit aspartyl protease named γ-secretase. ADAM 10/ 17 cleavage followed by γ-secretase cleavage results in the release of the soluble p3 peptide, an N-terminally truncated Aβ fragment that fails to form amyloid deposits in humans. This proteolytic route is commonly referred to as the non-amyloidogenic pathway. Consecutive cleavages by BACEl and γ-secretase generates the intact Aβ peptide, hence this processing scheme has been termed the amyloidogenic pathway. With this knowledge at hand, it is possible to envision two possible avenues of lowering Aβ production: stimulating non-amyloidogenic processing, or inhibit or modulate
amyloidogenic processing. This application focuses on the latter strategy, inhibition or modulation of amyloidogenic processing.
Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of patients with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerative disorders. Neurofibrillary tangles also occur in other neurodegenerative disorders including dementia-inducing disorders (Varghese, J., et al, Journal of Medicinal Chemistry, 2003, 46, 4625-4630). β-amyloid deposits are predominately an aggregate of AB peptide, which in turn is a product of the proteolysis of amyloid precursor protein (APP). More specifically, AB peptide results from the cleavage of APP at the C-terminus by one or more γ- secretases, and at the N-terminus by B-secretase enzyme (BACE), also known as aspartyl protease or Asp2 or Beta site APP Cleaving Enzyme (BACE), as part of the B- amyloidogenic pathway. BACE activity is correlated directly to the generation of AB peptide from APP (Sinha, et al, Nature, 1999, 402, 537-540), and studies increasingly indicate that the inhibition of BACE inhibits the production of Aβpeptide (Roberds, S. L., et al, Human Molecular Genetics, 2001, 10, 1317-1324). BACE is a membrane bound type 1 protein that is synthesized as a partially active proenzyme, and is abundantly expressed in brain tissue. It is thought to represent the major β-secretase activity, and is considered to be the rate- limiting step in the production of amyloid-β-peptide (Aβ).
Drugs that reduce or block BACE activity should therefore reduce Aβ levels and levels of fragments of Aβ in the brain, or elsewhere where Aβ or fragments thereof deposit, and thus slow the formation of amyloid plaques and the progression of AD or other maladies involving deposition of Aβ or fragments thereof. BACE is therefore an important candidate for the development of drugs as a treatment and/or prophylaxis of Aβ-related pathologies such as Downs syndrome, β-amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
It would therefore be useful to inhibit the deposition of Aβ and portions thereof by inhibiting BACE through inhibitors such as the compounds provided herein. The therapeutic potential of inhibiting the deposition of Aβ has motivated many groups to isolate and characterize secretase enzymes and to identify their potential inhibitors.
Outline of the invention
Provided herein are novel compounds that are active BACE inhibitors. Thus, in one aspect of the invention, there is provided compounds according to formula (I):
Figure imgf000005_0001
O)
wherein
A is selected from
Figure imgf000005_0002
Q-όalkylheteroaryl, Co-6alkylC3-8cycloalkyl, C0^alkylC3.6cycloalkenyl, C0,6alkylC6cycloalkynyl or C0-6alkyl- C3-gheterocyclyl, wherein said A is optionally substituted with one or more R1;
B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R2;
C is selected from hydrogen,
Figure imgf000005_0003
C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co.6alkylC3-6cycloalkenyl, Co-όalkylCόcycloalkynyl, Co^alkylaryl, Co-6alkylheteroaryl, Co-ealkylheterocyclyl, C0-6alkylOR4, C0^alkylCO2R4, C0-6alkylN(R4)2, halogen,
C0-6alkylCN, C0-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, C0.6alkylOSO2R4, C0.6alkylSO3R4, C0-6alkylSO2R4, Co-6alkylSOR4, C0-6alkyl(SO2)N(R4)2, C0-6alkyl(SO)N(R4)2, C0-6alkylNR4(SO2)N(R4)2, C0-6alkylNR4(SO)R4, SF5, and OSF5, wherein said C^alkyl, C2-6alkenyl, C2.6alkynyl, Co-6alkylC3-6cycloalkyl, Co-όalkylaryl, Co-6alkylheteroaryl, or Co-όalkylheterocyclyl is optionally substituted with one or more R ;
R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl,
Co-6alkylC3-6cycloalkenyl, Co-δalkylCόCycloalkynyl, Co-βalkylaryl, C0-6alkylheteroaryl, Co-ealkylheterocyclyl, C0-6alkylCO2R4, C0-6alkylN(R4)2, C0.6alkylOR4, halogen,
Co_6alkylCN, C0.6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, C0^alkylOSO2R4, C0-6alkylSO3R4, C0^alkylSO2R4, Co^alkylSOR4, C0-6alkyl(SO2)N(R4)2, C0-6alkyl(SO)N(R4)2, CMalkylNR4(SO2)N(R4)2, C0-6alkylNR4(SO)R4, SF5, and OSF5, wherein said C^alkyl, C2-6alkenyl, C2_6alkynyl, Co-όalkylCs-βcycloalkyl, C0^alkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl or is optionally substituted with one or more R3; or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R2 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl,
Co-6alkylC3-6cycloalkenyl, C0_6alkylC6cycloalkynyl, C0-6alkylaryl, Co-βalkylheteroaryl, Co-δalkylheterocyclyl, Co-6alkylC02R4, C0-6alkylN(R4)2, halogen, C0-6alkylCN,
Co.6alkylCOR4 5 CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO> N(R4)2, C0-6alkylSR4, C0-6alkylOSO2R4, Co-6alkylS03R4, C0-6alkylSO2R4, C0.6alkylSOR4, C0-6alkyl(SO2)N(R4)2, C0.6alkyl(SO)N(R4)2, Co-6alkylNR4(S02)N(R4)2, C0-6alkylNR4(SO)- R4 and Co-6alkylOR4, wherein said Chalky!, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3.6cyclo- alkyl, Co-βalkylaryl, C0-6alkylheteroaryl or Co-ήalkylheterocyclyl is optionally substituted with one or more R3,
or two R2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R3 is selected from halogen, NO2, CHO, C0-6alkylCN, C0-6alkylOR4, C1-6haloalkyl, Co.6alkylN(R4)2, NR4C(O)R4, C0^alkylCO2R4, C0.6alkylCON(R4)2, C0-6alkylNR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, 0(CO)OR4, 0(CO)R4, C0-6alkylCOR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, C0-6alkyl(SO2)N(R4)2, OC2-6alkylN- R4(SO2)R4, C0^alkyl(SO)N(R4)2, OSO2R4, SO3R4, C0-6alkylNR4(SO2)N(R4)2, C0-6alkylN- R4(SO)R4, C0.6alkylSO2R4, C0-6alkylSOR4, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0.6alkyl- C3^cycloalkyl, CQ-6alkylC3.6cycloalkenyl, Co-βalkylCόCycloalkynyl, Co-6alkylaryl,
Co-6alkylheteroaryl, and Co-βalkyUieterocyclyl, wherein said Chalky!, C2_6alkenyl, C2^alkynyl, Co-6alkylC3-6cycloalkyl, Co-βahcylaryl, Co-όalkylheteroaryl, or Co-ealkylhetero- cyclyl is optionally substituted with one or more R6; R4 is selected from hydrogen, Cr6alkyl,
Figure imgf000007_0001
C2-6alkenyl, C2-6alkynyl, C0- 6alkylC3-6cycloalkyl, C0-6alkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, C0-6alkylaryl, CQ-6alkylheteroaryl, Co-όalkylheterocyclyl, Ci.6alkylOR5, and d-ealkylNQl5^, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-βalkyl- heteroaryl or Co-βalkylheterocyclyl is optionally substituted with one or more R6;
or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6; R5 is selected from hydrogen, d-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co.6alkylC6cycloalkynyl, Co-6alkylaryl, Co-όalkylheterocyclyl and Co-βalkylheteroaryl, wherein said Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkyl- C3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R6 is selected from oxo, halogen, nitro, CN, OR7, Ci.6alkyl, C2-6alkenyl, C2.6alkynyl, Co- 6alkylaryl, Co^alkylheteroaryl, Co-6alkylC3-6cycloalkyl, Co-όalkylheterocyclyl, C1-6IIaIo- alkyl, OC2-6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, O(CO)C1-6alkyl, (CO)OC ^alkyl, COR7, SON(R7)2, (SO2)N(R7)2, NR7SO2R7, NR7SOR7, SO2R7, SOR7, (CO)C1-6alkyl- N(R7)2, (SO2)C1-6alkylN(R7)2, OSO2R7 and SO3R7, wherein said C1-6alkyl, C2-6alkenyl, C2. όalkynyl, Co-6alkylaryl, Co-6alkylheteroaryl, Co-βalkylheterocyclyl, or Co-6alkylC3-6cyclo- alkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7, C1-6alkyl, or Ci-όhaloalkyl;
R7 is selected from hydrogen, Ct-όalkyl, d^haloalkyl, C2.6alkenyl, C2-6alkynyl, C3-6cyclo- alkyl, C3_6cycloalkenyl, C6cycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C1. βalkyl, C2-6alkenyl, C2-6alkynyl, C3^cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, cyano, halogen and OCualkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OC1-3alkyl, cyano and halogen; as a free base or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention, the molecular weight of the compound of formula (I) is more than 300 g/mol. In one embodiment of the present invention, the molecular weight of the compound of formula (I) is less than 600 g/mol.
In another embodiment of the present invention A is selected from C1-6alkyl, C2-6alkenyl, C^alkynyl, C1-6alkylaryl, C1-6alkylheteroaryl,
Co-6alkylC3-8cycloalkyl, Co-6alkylC3^cycloalkenyl, Co_6alkylC6cycloalkynyl or C0-6alkyl- C3.8heterocyclyl, wherein said A is optionally substituted with one or more R1;
B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R2;
C is selected from hydrogen, Chalky., C2.6alkenyl, C2-6alkynyl, Co-6alkylC3.6cycloalkyl, Co-6alkylC3.6cycloalkenyl, Co-βalkylCβcycloalkynyl, Co^alkylaryl, Co-6alkylheteroaryl, Co-ealkylheterocyclyl, C0-6alkylOR4, C0-6alkylCO2R4, C0-6alkylN(R4)2, halogen, Co-6alkyl- CN, Co-6alkylCOR4, CHO, NO2, C0.6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, C0-6alkyl(SO)N(R4)2, C0-6alkylNR4(SO2)N(R4)2, C0-6alkylNR4(SO)R4, SF5, and OSF5, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3.6cycloalkyl, Co.6alkylaryl, C0-6alkylheteroaryl, or Co-oalkymeterocyclyl is optionally substituted with one or more R3;
R1 is selected from C^alkyl, C2.6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl,
Co-6alkylC3-6cycloalkenyl, Co^alkylCόcycloalkynyl, Co-6alkylaryl, Co-όalkylheteroaryl, Co-βalkylheterocyclyl, C0-6alkylCO2R4, C0-6alkylN(R4)2, C0-6alkylOR4, halogen,
C0-6alkylCN, C0-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0.6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, Co.6alkylSR4, C0-6alkylOSO2R4, C0-6alkylSO3R4, C0.6alkylSO2R4, C0-6alkylSOR4, SF5, and OSF5, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl,
C0.6alkylC3-6cycloalkyl, Co.6alkylaryl, Co-όalkylheteroaryl, Co-βalkylheterocyclyl or is optionally substituted with one or more R3, or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R2 is selected from Ci_6alkyl, C2.6alkenyl, C^alkynyl, Co-6alkylC3-6cycloalkyl, Co_6alkyl- C3-6cycloalkenyl, C0_6alkylC6cycloalkynyl, C0^alkylaryl, C0-6alkylheteroaryl, Co-6alkyl- heterocyclyl, C0-6alkylCO2R4, C0-6alkylN(R4)2, halogen, C0.6alkylCN, C0-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0.6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkyl- (SO)N(R4)2, C0-6alkylNR4(SO2)N(R4)2, C0-6alkylNR4(SO)R4 and C0.6alkylOR4, wherein said Ci-βalkyl, C2-6alkenyl, C^alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-6alkyl- heteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3, or two R2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R3 is selected from halogen, NO2, CHO, C0_6alkylCN, C0.6alkylOR4, C1-6haloalkyl, Co-6alkylN(R4)2, NR4C(O)R4, C0^alkylCO2R4, C0.6alkylCON(R4)2, C0^alkylNR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, 0(CO)OR4, 0(CO)R4, C0-6alkylCOR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, C0-6alkyl(SO2)N(R4)2, OC2.6alkylN- R4(SO2)R4, C0-6alkyl(SO)N(R4)2, OSO2R4, SO3R4, C0.6alkylNR4(SO2)N(R4)2, Co-6alkylN- R4(SO)R4, Co-6alkylS02R4, Co-ealkylSOR4, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkyl- C3-6CyClOaIlCyI, Co-6alkylC3-6cycloalkenyl, C0.6alkylC6cycloalkynyl, C0-6alkylaryl,
Co-6alkylheteroaryl, and Co-δalkylheterocyclyl, wherein said C1-6alkyl, C^alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl, or Co-6alkyl- heterocyclyl is optionally substituted with one or more R6; R4 is selected from hydrogen, Cr6alkyl, C1-3haloalkyl, C2-6alkenyl, C2-6alkynyl, Co- 6alkylC3-6cycloalkyl, Co-6alkylC3^cycloalkenyl, Co.6alkylC6cycloalkynyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co-όalkylheterocyclyl,
Figure imgf000009_0001
and Ci-6alkylN(R5)2, wherein said Cr6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, Co-6alkylaryl, C0-6alkyl- heteroaryl or Co-όalkylheterocyclyl is optionally substituted with one or more R6;
or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R5 is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-όalkylCδcycloalkynyl, C0-6alkylaryl, Co^alkylheterocyclyl and Co-6alkylheteroaryl, wherein said Q-βalkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3~ όcycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl or Co-όalkylheterocyclyl is optionally substituted with one or more R6;
or two R5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R is selected from oxo, halogen, nitro, CN, OR , Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C0- όalkylaryl, Co-όalkylheteroaryl, C0.6alkylC3-6cycloalkyl, Chalky lheterocyclyl, C1-6halo- alkyl, OC2-6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, O(CO)C1-6alkyl, (CO)OC i.6alkyl, COR7, SON(R7)2, (SO2)N(R7)2, NR7SO2R7, NR7SOR7, SO2R7, SOR7, (CO)C 1-6alkyl- N(R7)2, (SO2)C1.6alkylN(R7)2, OSO2R7 and SO3R7, wherein said C1-6alkyl, C2-6alkenyl, C2- βalkynyl, Co-βalkylaryl, Co-βalkylheteroaryl, Co-όalkylheterocyclyl, or Co-6alkylC3-6cyclo- alkyl is optionally substituted with one or more substituents selected from halo, nitro, cyano, OR7, C^alkyl, or d-βhaloalkyl; R7 is selected from hydrogen, Chalky!, d-shaloalkyl, C2-6alkenyl, C2-6alkynyl, C3.6cyclo- alkyl, Cs^cycloalkenyl, Cόcycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C1- βalkyl, C2-6alkenyl, C2-6alkynyl, C3^cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to three substituents selected from hydroxy, cyano, halogen and 0Ci_3alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents selected from hydroxy,
Figure imgf000010_0001
cyano and halogen. In another embodiment of the present invention A is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, d-δalkylaryl, Q-ealkylheteroaryl, Co-ealkylCs-scycloalkyl, C0^alkylC3.
6cycloalkenyl, Co^alkylCecycloalkynyl or Co.6alkylC3-8heterocyclyl, wherein said A is optionally substituted with one or more R1 ;
B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R2; C is selected from hydrogen, C^alkyl, C2-6alkenyl, C^alkynyl, C0-6alkylC3-6cycloalkyl, Co-δalkylCs-όcycloalkenyl, Co-όalkylCβcycloalkynyl, Co^alkylaryl, Co-δalkylheteroaryl, Co-βalkylheterocyclyl, C0-6alkylOR4, C0-OaIlCyICO2R4, C0-6alkylN(R4)2, halogen, C0-6alkyl- CN, Co-6alkylCOR4, CHO, NO2, C0.6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, Co.6alkylNR4(CO)R4, Cwalkyl(SO)N(R4)2, C0-6alkylNR4(SO2)N(R4)2, Co-6alkylNR4(SO)R4, SF5, and OSF5, wherein said C^alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3.6cycloalkyl, C0-6alkylaryl, Co^alkylheteroaryl, or C0_6alkylheterocyclyl is optionally substituted with one or more R3;
R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3.6cycloalkyl, Co-βalkyl- C3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, Co-βalkylaryl, Co-6alkylheteroaryl, C0^alkyl- heterocyclyl, C0-6alkylCO2R4, C0-6alkylN(R4)2, Co-βalkylOR4, halogen, C0.6alkylCN, C0-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)- N(R4)2, C0-6alkylSR4, C0-6alkylOSO2R4, C0-6alkylSO3R4, C0-6alkylSO2R4, Co-ealkylSOR4, SF5, and OSF5, wherein said C^aUcyl, C2.6alkenyl, C2.6alkynyl, Co-6alkylC3.6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl or is optionally substituted with one or more R3;
R2 is selected from
Figure imgf000011_0001
C0-6alkyl- Cs-βcycloalkenyl, Co-6alkylC6cycloalkynyl, Co-βalkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl, C0-6alkylCO2R4, C0-6alkylN(R4)2, halogen, C0.6alkylCN, Co-ealkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, 0(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, Co-ealkyl- (SO)N(R4)2, C0-6alkylNR4(SO2)N(R4)2, C0-6alkylNR4(SO)R4 and C0-6alkylOR4, wherein said Q-βalkyl, C2-6alkenyl, C^alkynyl, C0-6alkylC3^cycloalkyl, Co-ealkylaryl, C0-6alkyl- heteroaryl or Co-βalkylheterocyclyl is optionally substituted with one or more R3;
R3 is selected from halogen, NO2, CHO, C0.6alkylCN, C0-6alkylOR4, C1-6haloalkyl, Co-6alkylN(R4)2, NR4C(O)R4, C0-6alkylCO2R4, C0.6alkylCON(R4)2, C0^alkylNR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, 0(CO)OR4, 0(CO)R4, C0-6alkylCOR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, C0-6alkyl(SO2)N(R4)2, OC^alkyl- NR4(SO2)R4, C0-6alkyl(SO)N(R4)2, OSO2R4, SO3R4, C0-6alkylNR4(SO2)N(R4)2, C0-6alkylN- R4(SO)R4, C0-6alkylSO2R4, Co-6alkylSOR4, C^alkyl, C2-6alkenyl, C2-6alkynyl, Co-ealkyl- C3^cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, Co-βalkylaryl,
Co-6alkylheteroaryl, and Co-βalkylheterocyclyl, wherein said C^alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, C0.6alkylheteroaryl, or C0-6alkyl- heterocyclyl is optionally substituted with one or more R6;
R4 is selected from hydrogen, C^aUcyl, C1-3haloalkyl, C2-6alkenyl, C2-6alkynyl, Co- 6alkylC3-6cycloalkyl, Co-6alkylC3^cycloalkenyl, Co-6alkylC6cycloalkynyl, Co-6alkylaryl, Co-6alkylheteroaryl, Co-βalkylheterocyclyl, Ci-βalkylOR5, and C!-6alkylN(R5)2, wherein said d-ealkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, C0-6alkyl- heteroaryl or Co-βalkylheterocyclyl is optionally substituted with one or more R6;
or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R5 is selected from hydrogen, Crβalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3.6cycloalkenyl, Co-6alkylC6cycloalkynyl, Co-6alkylaryl, Co-βalkylheterocyclyl and Co-6alkylheteroaryl, wherein said Crβalkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkyl- C3-6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6; R6 is selected from oxo, halogen, nitro, CN, OR7, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Co- όalkylaryl, Co-6alkylheteroaryl, Co-6alkylC3-6cycloalkyl, Co^alkylheterocyclyl, C1-6halo- alkyl, OC2-6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, 0(CO)C i-6alkyl,
Figure imgf000013_0001
COR7, SON(R7)2, (SO2)N(R7)2, NR7SO2R7, NR7SOR7, SO2R7, SOR7, (CO)C 1-6alkylN- (R7)2, (SO2)C1-6alkylN(R7)2, OSO2R7 and SO3R7, wherein said C1-6alkyl, C2-6alkenyl, C2. 6alkynyl, Co-ealkylaryl, Co.6alkylheteroaryl, Co-βalkylheterocyclyl, or C0.6alkylC3-6cyclo- alkyl is optionally substituted with one or more substituents selected from halo, nitro, cyano, OR7, d-δalkyl, or
Figure imgf000013_0002
R7 is selected from hydrogen, Ci-6alkyl, Ci-3haloalkyl, C2-6alkenyl, C2-6alkynyl, C3^cyclo- alkyl, Ca-όcycloalkenyl, Cecycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C^alkyl, C2-6alkenyl, C2-6alkynyl, C3^cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to three substituents selected from hydroxy, cyano, halogen and OC^alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OQ-salkyl, cyano and halogen.
In one embodiment of the present invention, A is selected from Ct-ealkyl, C2-6alkenyl, C2.6alkynyl, C^alkylaryl, Ci-όalkylheteroaryl,
Co-6alkylC3-8cycloalkyl, Co-δalkylCs-βcycloalkenyl, or C0-6alkyl-C3-8heterocyclyl, wherein said A is optionally substituted with one or more R1;
B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R2;
C is selected from hydrogen, C^alkyl, C2.6alkenyl, C2-6alkynyl, Co-6aIkylC3^cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co^alkylaryl, Co-ealkylheteroaryl, Co-όalkylheterocyclyl, C0-6alkylOR4, C0-6alkylCθ2R4, C0-6alkylN(R4)2, halogen, C0-6alkylCN, Co-ealkylCOR4, NO2, Co-6alkylCON(R4)2, 0(CO)R4, C0-6alkylNR4(CO)R4, Co-6alkylSR4, C0.6alkylSO2R4, Co-6alkylSOR4, wherein said Ct-βalkyl, C2.6alkenyl, C2.6alkynyl, Co-βalkylCs-ecycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl, or Co-βalkylheterocyclyl is optionally substituted with one or more R3;
R1 is selected from Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-ealkylCs-ecycloalkyl,
Co-6alkylC5-6cycloalkenyl, Co-6alkylaryl, C0-6alkylheteroaryl, Co-βalkylheterocyclyl, C0.6alkylCO2R4, Co-6alkylN(R4)2, C0.6alkylOR4, halogen, C0-6alkylCN, Co^alkylCOR4, NO2, C0^alkylCON(R4)2, 0(CO)R4, C0-6alkylNR4(CO)R4, Co-βalkylSR4, C0-6alkylSO2R4, Co-6alkylSOR4, wherein said
Figure imgf000014_0001
Co-6alkylaryl, Co-6alkylheteroaryl, Co-βalkylheterocyclyl or is optionally substituted with one or more R3; or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R2 is selected from Ci-6alkyl,
Figure imgf000014_0002
C0.6alkylaryl, C0-6alkylheteroaryl, Co-ealkylheterocyclyl, C0-6alkylCO2R4, Co_6alkylN(R4)2, halogen, C0-6alkylCN,
C0-6alkylCOR4, NO2, C0-6alkylCON(R4)2, 0(CO)R4, C0-6alkylSR4, C0.6alkylSO2R4, Co.6alkylSOR4, and Co-βalkylOR4, wherein said C1-6alkyl, Co-6alkylC3^cycloalkyl,
Co-6alkylaryl, C0-6alkylheteroaryl or Co-όalkylheterocyclyl is optionally substituted with one or more R3,
or two R2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R3 is selected from halogen, NO2, Co^alkylCN, C0.6alkylOR4, C1 Jialoalkyl,
C0-6alkylN(R4)2, NR4C(O)R4, C0-6alkylCO2R4, C0.6alkylCON(R4)2, C0-6alkylNR4(CO)R4, 0(CO)R4, Co-6alkylCOR4, C0-6alkylSR4, C0-6alkylSO2R4, C0.6alkylSOR4, C1-6alkyl, C2-6alkenyl, C2.6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-βalkylheteroaryl, and Co-βalkylheterocyclyl, wherein said
Figure imgf000014_0003
C2.6alkenyl, C2-6alkynyl,
Co-6alkylC3^cycloalkyl, Co-ealkylaryl, Co-βalkylheteroaryl, or Co-βalkylheterocyclyl is optionally substituted with one or more R6; R4 is selected from hydrogen, Ci-βalkyl, C^haloalkyl, C0-6alkylC3-6cycloalkyl, C0- βalkylaryl, C0-6alkylheteroaryl, Co-βalkyUieterocyclyl, Cϊ-όalkylOR5, and C1-6alkylN(R5)2, wherein said Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-βalkylaryl, Co-6alkylheteroaryl or Co-όalkylheterocyclyl is optionally substituted with one or more R6; or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R5 is selected from hydrogen, Ci-βalkyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl,
Co-βalkylheterocyclyl and Co-6alkylheteroaryl, wherein said d-βalkyl, Co-ealkyl- C3-6cycloalkyl, Co-βalkylaryl, Co-6alkylheteroaryl or Co^alkylheterocyclyl is optionally substituted with one or more R6;
or two R5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6; R6 is selected from oxo, halogen, nitro, CN, OR7, Ci^alkyl, C0.6alkylaryl, C0-
6alkylheteroaryl, Co-6alkylC3^cycloalkyl, Co-βalkylheterocyclyl, Ci-6haloalkyl, OC2- 6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, 0(CO)Ci -ealkyl, (CO)OC1.6alkyl, COR7, SO2R7, SOR7, wherein said C^alkyl, C0.6alkylaryl, C0-6alkylheteroaryl, C0.
όalkylheterocyclyl or Co-6alkylC3-6cycloalkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7, C^aUcyl, Ci-3haloalkyl, or OC^haloalkyl;
R7 is selected from hydrogen,
Figure imgf000015_0001
Cs-όcycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said
Figure imgf000015_0002
C3.6cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, cyano, halogen and OC^alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OCi^alkyl, cyano and halogen.
In another embodiment of the present invention B is phenyl or heteroaryl. In one embodiment, R2 is Ci-όalkyl, Co-6alkylC3_6cycloalkyl, halogen, Co.6alkylCN or Co-βalkylOR4.
In one embodiment, R2 is fluoro, OR4 or Ci-6alkyl.
In another embodiment of the present invention R2 is halogen, such as fluoro, cyano or Co-ealkylOR4.
2
In another embodiment of the present invention R is fluoro.
In one embodiment, R4 is hydrogen, Ci-βalkyl, C^haloalkyl, Co-6alkylC3-6cycloalkyl or Co-όalkyUieteroaryl.
In one embodiment, R4 is hydrogen, Crβalkyl or Ci-shaloalkyl.
In another embodiment of the present invention R4 is hydrogen.
In another embodiment of the present invention A is Ci^alkyl, Ci-oalkylaryl,
Ci_6alkylheteroaryl, C0-6alkylC3.8cycloalkyl, or Co-βalkylCs-gheterocyclyl.
In one embodiment, A is Co-6alkylC3.8cycloalkyl or Co-βalkyl-Cs-gheterocyclyl.
In another embodiment of the present invention R1 is C^alkyl, Co-6alkylC3^cycloalkyl, Co^alkylaryl, C0.6alkylheteroaryl, Co^alkylheterocyclyl, C0-6alkylN(R4)2, Co-βalkylOR4, halogen, C0-6alkylCN, C0-6alkylCOR4, C0-6alkylCON(R4)2, C0-6alkylNR4(CO)R4 5 C0-6alkylSR4, CMalkylSO2R4 or Co^alkylSOR4.
In one embodiment, R1 is Ci-βalkyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-βalkylOR4, halogen, C0-6alkylCN or C0-6alkylCOR4.
In one embodiment, R1 is
Figure imgf000016_0001
Co-6alkylC3_6cycloalkyl, Co-6alkylOR4, halogen or Co-βalkylCOR4. In another embodiment of the present invention C^alkyl is methyl or ethyl. In another embodiment of the present invention C^alkylaryl is CH2-phenyl.
In another embodiment of the present invention Co-6alkylC3.6cycloalkyl is cyclohexyl. In another embodiment of the present invention Co-βalkylCs-sheterocyclyl is piperidinyl. In another embodiment of the present invention Co-ealkylCs-sheterocycryl is
tetrahydropyranyl.
In another embodiment of the present invention A is piperidinyl or cyclohexyl. In one embodiment, C is hydrogen, C1-6alkyl, C2-6alkynyl, Co-ealkylCa-ecycloalkyl,
Co-6alkylaryl,
Figure imgf000017_0001
Co-βalkylheterocyclyl, C0-6alkylOR4, C0-6alkylCO2R4, C0-6alkylN(R4)2, halogen, C0.6alkylCN or C0-6alkylNR4(CO)R4.
In another embodiment of the present invention C is selected from hydrogen, Cι-6alkyl, Co- 6alkylaryl, C0-6alkylheteroaryl, Co-όalkylCN, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cyclo- alkyl, Co-βalkylheterocyclyl, C0-6alkylOR4, Co-6alkylN(R4)2, halogen, Co-6alkylCON(R4)2, C0-6alkylNR4(CO)R4.
In another embodiment of the present invention C is phenyl, pyridine or pyrimidine.
In another embodiment of the present invention R3 is halogen, C0-6alkylCN, Co^alkylOR4, C1-6haloalkyl, C^alkyl.
In one embodiment, R3 is halogen, NO2, C0-6alkylCN, Co-6alkylOR4, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-βalkylCs-ecycloalkyl or Co-βalkylheterocyclyl.
In one embodiment, R3 is halogen, C2-6alkynyl, CN or OR4. In one embodiment, R3 is halogen or C2-4alkynyl.
In one embodiment, R6 is oxo, halogen, CN, OR7, C1-6alkyl, C0-6alkylC3-6cycloalkyl or C1. βhaloalkyl.
In one embodiment, R6 is chloro.
In one embodiment of the present invention, A is Co-6alkylC3-8cycloalkyl or C0-6alkyl-C3. 8heterocyclyl, wherein said A is optionally substituted with one or more R1;
B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R2;
C is hydrogen, C^alkyl, C2.6alkynyl, Co-6alkylC3.6cycloalkyl, Co-6alkylaryl,
Co-6alkylheteroaryl, Co-όalkylheterocyclyl, C0-6alkylOR4, C0-6alkylCO2R4, C0-6alkylN(R4)2, halogen, C^alkylCN, C0-6alkylNR4(CO)R4;
R1 is Ci^alkyl, Co-ealkylCa-ecycloalkyl, C0-6alkylOR4, halogen or C0-6alkylCOR4;
R2 is C1-6alkyl, Co-6alkylC3^cycloalkyl, halogen, Co-ealkylCN or C0.6alkylOR4;
R3 is halogen, C2-6alkynyl, CN or OR4;
R4 is hydrogen, Ci-6alkyl, Ci.3haloalkyl, Co-6alkylC3-6cycloalkyl or Co-βalkylheteroaryl; R6 is oxo, halogen, CN, OR7,
Figure imgf000018_0001
Co-6alkylC3-6cycloalkyl or Ci-6haloalkyl.
In another embodiment of the present invention A is selected from
Figure imgf000018_0002
Q-ealkylaryl,
Co-6alkylC3-8cycloalkyl and Co.6alkylC3.8heterocyclyl, wherein said A is optionally substituted with one or more R1;
B is aryl;
C is Co-6alkylaryl or Co-6alkylheteroaryl, wherein said C0-6alkylaryl or Co-6alkylheteroaryl is optionally substituted with one or more R1;
R1 Co-βalkylCOR4;
R3 is C0-6alkylOR4; and
Figure imgf000018_0003
One embodiment of the present invention is a compound selected from 2-(3'-Methoxybiphenyl-3-yl)-2,5-dimethyl-2H-imidazol-4-amine;
(R)-2-(3 '-Methoxybiρhenyl-3 -yl)-2,5-dimethyl-2H-imidazol-4-amine;
2,5-Dimethyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
2-Ethyl-5-methyl-2-(3-(pyridin-3-yl)phenyl)-2H-imida2:ol-4-amine;
2-Cyclohexyl-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine;
2-Cyclohexyl-5-methyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
2-(3'-Methoxybiρhenyl-3-yl)-5-methyl-2-(tetrahydro-2H-pyran-4-yl)-2H-imidazol-4- amine;
l-(4-(4-Amino-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-2-yl)piperidin-l- yl)ethanone;
2-Benzyl-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine; and
(R)-2-Benzyl-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine;
(R)- and (S)- 2-(2'-fluoro-3'-methoxybiphenyl-3-yl)-5-methyl-2-(pyridin-3-ylmethyl)-2H- imidazol-4-amine;
(R)- and (S)- 2-(3-(5-Chloropyridin-3-yl)ρhenyl)-5-methyl-2-(ρyridin-3-ylmethyl)-2H- imidazol-4-amine;
2-(3-Bromophenyl)-2-cyclopropyl-5-methyl-2H-imidazol-4-amine;
2-(3-(5-Chloropyridin-3-yl)phenyl)-2-cyclopropyl-5-methyl-2H-imidazol-4-amme;
2-Cyclopropyl-5-methyl-2-(3-(5-(prop-l-ynyl)pyridin-3-yl)phenyl)-2H-imidazol-4-amine; 5-(4-Amino-2-(3-bromophenyl)-5-methyl-2H-imidazol-2-yl)-3-methylpyridin-2(lH)-one;
5-(4-Amino-2-(3-(5-cbJoropyridin-3-yl)ρhenyl)-5-melhyl-2H-imidazol-2-yl)-l-ethyl-3- methylpyridin-2(lH)-one;
5-(4-Amino-5-methyl-2-(3-(5-(prop- 1 -ynyl)pyridin-3-yl)phenyl)-2H-imidazol-2-yl)- 1 - ethyl-3-methylpyridin-2( 1 H)-one;
5-(4-Amino-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-2-yl)-l-ethyl-3- methylpyridin-2( 1 H)-one;
5-(4-Ammo-2-(3^5'-difluorobiphenyl-3-yl)-5-methyl-2H-imidazol-2-yl)-l-ethyl-3- methylpyridin-2(l H)~one;
2-(3 -(5 -Chloropyridin-3 -yl)-4-fluorophenyl)-2-cyclopropyl-5 -methyl-2H-imidazol-4- amine;
2-Cyclopropyl-2-(4-fluoro-3-(5-(prop-l-ynyl)pyridin-3-yl)phenyl)-5-methyl-2H-imidazol-
4-amine; 2-(3-(5-Cωoropyridin-3-yl)phenyl)-5-methyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H- imidazol-4-amine;
2-(3-(5-Fluoropyridin-3-yl)phenyl)-5-methyl-2-((tetrahydro-2H-pyraιi-4-yl)methyl)-2H- imidazol-4-amine;
2-(3-(5-Methoxypyridin-3-yl)phenyl)-5-methyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H- imidazol-4-amine;
2-(3l-Methoxybiphenyl-3-yl)-5-methyl-2-((tetrahydro-2H-ρyran-4-yl)methyl)-2H- imidazol-4-amine;
N-(3-(4-Ainino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)phenyl)pyrazine-2- carboxamide;
2-(3-(5-Chloropyridin-3-yl)phenyl)-2-cyclobutyl-5-methyl-2H-imidazol-4-amine;
2-Cyclobutyl-2-(3-(5-fluoropyridm-3-yl)phenyl)-5-memyl-2H-iniidazol-4-amine;
2-Cyclobutyl-5-methyl-2-(3-(5-(prop-l-ynyl)pyridm-3-yl)phenyl)-2H-iniidazol-4-a-nine;
2-(3-(5-Chloropyridin-3-yl)phenyl)-2-isopropyl-5-memyl-2H-imidazol-4-amine;
2-(3-(5-Fluoropyridin-3-yl)phenyl)-2-isopropyl-5-methyl-2H-imidazol-4-amine;
2-Isopropyl-5-methyl-2-(3-(5-(prop-l-ynyl)pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
2-Cyclohexyl-2-(4-methoxyphenyl)-5-methyl-2H-ύnidazol-4-amine;
2-Cycloheplyl-2-(4-methoxyphenyl)-5-methyl-2H-iinidazol-4-amine;
2-(Bicyclo[2.2.1]heptan-2-yl)-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine; 2-Cyclooctyl-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine;
2-(4-Methoxyphenyl)-5-methyl-2-(3-phenylpropyl)-2H-imidazol-4-amine;
2-(4-Methoxyphenyl)-2-(3 -(3 -methoxyphenyl)propyl)-5 -methyl-2H-imidazol-4-amine;
5-(4-Ammo-2-cyclopropyl-5-methyl-2H-iinidazol-2-yl)-2'-fluoro-5'-methoxybiphenyl-2- ol;
5-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-5'-chloro-2'-fluorobiphenyl-2-ol; 5l-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-6-fluoro-2'-hydroxybiphenyl-3- carbonitrile;
5-(4-Ammo-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2'-fluoro-3'-methoxybipb.enyl-2- ol;
4-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2-(5-(prop- 1 -ynyl)pyridin-3 - yl)phenol; 4-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2-(pyrazin-2-yl)phenol;
4-(4-Amino-2-cyclopropyl-5-meiliyl-2H-imidazol-2-yl)-2-(4-(prop-l-ynyl)pyridin-2- yl)phenol;
5-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2',5'-dichlorobiphenyl-2-ol;
5-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2'-chloro-5'-methoxybiplienyl-2- ol;
N-(3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-4-fluorophenyl)-5- chloropicolinamide;
3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-N-(3-chlorophenyl)benzamide; 3-(4-Amino-2-cyclopropyl-5-meώyl-2H-iniidazol-2-yl)-N-(4-chlorophenyl)benzarnide;
N-(3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)phenyl)-4-chloropicolinamide;
N-(3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)phenyl)-5-chloropicolinamide;
5-(4-Amino-5-methyl-2-(3'-(prop4-ynyl)biphenyl-3-yl)-2H-imidazol-2-yl)-l-ethyl-3- methylpyridin-2(l H)-one;
5<4-Amino-2-(2'-fluoro-5'-(proρ4-ynyl)biρhenyl-3-yl)-5-me%l-2H-imidazol-2-yl)-l- ethyl-3 -methylpyridin-2( 1 H)-one;
as a free base or a pharmaceutically acceptable salt thereof.
The present invention relates to the use of compounds of formula (I) as hereinbefore defined as well as to the salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I).
The compounds of the formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I).
Examples of prodrugs include in vivo hydrolysable esters of a compound of the formula (I). An in vivo hydrolysable (or cleavable) ester of a compound of the formula (I) that contains a carboxy or a hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Various forms of prodrugs are known in the art. The definitions set forth in this application are intended to clarify terms used throughout this application. The term "herein" means the entire application.
A variety of compounds in the present invention may exist in particular geometric or stereoisomeric forms. The present invention takes into account all such compounds, including tautomers, cis- and trans isomers, R- and S- enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or synthesis using optically active reagents. When required, separation of the racemic material can be achieved by methods known in the art. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents, positions of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used in this application, the term "optionally substituted," means that substitution is optional and therefore it is possible for the designated atom or moiety to be unsubstituted. As used herein, "alkyl", used alone or as a suffix or prefix, is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended. For example "Co-6 alkyl" denotes alkyl having 0, 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. In the case where a subscript is the integer 0 (zero) the group to which the subscript refers to indicates that the group may be absent, i.e. there is a direct bond between the groups.
As used herein, "alkenyl" used alone or as a suffix or prefix is intended to include both branched and straight-chain alkene or olefin containing aliphatic hydrocarbon groups having from 2 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended. For example "C2-6alkenyF' denotes alkenyl having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut- 1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
As used herein, "alkynyl" used alone or as a suffix or prefix is intended to include to include both branched and straight-chain alkynyl or olefin containing aliphatic
hydrocarbon groups having from 2 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended. For example ethynyl, propynyl (e.g. 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and l-methylpent-2- ynyl.
As used herein, "aromatic" refers to hydrocarbonyl groups having one or more unsaturated carbon ring(s) having aromatic characters, (e.g. 4n + 2 delocalized electrons) and comprising up to 14 carbon atoms. In addition "heteroaromatic" refers to groups having one or more unsaturated rings containing carbon and one or more heteroatoms such as nitrogen, oxygen or sulphur having aromatic character (e.g. 4n + 2 delocalized electrons). As used herein, the term "aryl" refers to an aromatic ring structure made up of from 5 to 14 carbon atoms. Ring structures containing 5, 6, 7 and 8 carbon atoms would be single-ring aromatic groups, for example, phenyl. Ring structures containing 8, 9, 10, 11, 12, 13, or 14 would be polycyclic, for example naphthyl. The aromatic ring can be substituted at one or
5 more ring positions with such substituents as described above. The term "aryl" also
includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls. Examples of polycyclic rings i o include, but are not limited to, 2,3 -dihydro- 1 ,4-benzodioxine and 2,3 -dihydro- 1 - benzofuran.
As used herein, the terms "cycloalkyl" or "carbocyclyl" are intended to include saturated ring groups, having the specified number of carbon atoms. These may include fused or is bridged polycyclic systems. Preferred cycloalkyls have from 3 to 10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, and 6 carbons in the ring structure. For example, "C3-6 cycloalkyl" denotes such groups as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
20 As used herein, the term "cycloalkenyl" is intended to include unsaturated ring groups, having the specified number of carbon atoms. These may include fused or bridged polycyclic systems. Preferred cycloalkenyls have from 3 to 10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, and 6 carbons in the ring structure. For example, "C3.6 cycloalkenyl" denotes such groups as cyclopropenyl, cyclobutenyl,
25 cyclopentenyl, or cyclohexenyl.
As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
"Counterion" is used to represent a small, negatively or positively charged species such as 30 chloride, bromide, hydroxide, acetate, sulfate, tosylate, benezensulfonate, ammonium, lithium ion and sodium ion and the like. As used herein, the term "heterocyclyl" or "heterocyclic" or "heterocycle" refers to a saturated, unsaturated or partially saturated, monocyclic, bicyclic or tricyclic ring (unless otherwise stated) containing 3 to 20 atoms of which 1, 2, 3, 4 or 5 ring atoms are chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH2- group is optionally be replaced by a -C(O)-; and where unless stated to the contrary a ring nitrogen or sulphur atom is optionally oxidised to form the N-oxide or S-oxide(s) or a ring nitrogen is optionally quarternized; wherein a ring -NH is optionally substituted with acetyl, formyl, methyl or mesyl; and a ring is optionally substituted with one or more halo. It is understood that when the total number of S and O atoms in the heterocyclyl exceeds 1, then these heteroatoms are not adjacent to one another. If the said heterocyclyl group is bi- or tricyclic then at least one of the rings may optionally be a heteroaromatic or aromatic ring provided that at least one of the rings is non-heteroaromatic. If the said heterocyclyl group is monocyclic then it must not be aromatic. Examples of heterocyclyls include, but are not limited to, piperidinyl, N- acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2/f-pyranyl, tetrahydrofuranyl, tetrahydro-thiopyranyl, tetrahydro-thiopyran 1 -oxide, tetrahydro-thiopyran 1,1 -dioxide, IH- pyridin-2-one, and 2,5-dioxoimidazolidinyl.
As used herein, "heteroaryl" refers to a heteroaromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (i.e. furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, benzoxazolyl, aza-benzoxazolyl imidazothiazolyl, benzo[l,4]dioxinyl, benzo[l,3]dioxolyl and the like. In some
embodiments, the heteroaryl group has from 1 to 20 carbon atoms, and in further embodiments from 3 to 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl group has 1 heteroatom.
As used herein, "haloalkyl", used alone or as a suffix or prefix, is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups, having at least one halogen substituent and having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended. For example "C0- ohaloalkyl" denotes alkyl having 0, 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl,
chlorofluoromethyl, 1-fluoroethyl, 3-fluoropropyl, 2-chloropropyl, 3,4-difluorobutyl.
As used herein, the phrase "protecting group" means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3rd ed.; Wiley: New York, 1999).
As used herein, "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such non-toxic salts include those derived from inorganic acids such as hydrochloric acid. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
The present invention further includes all tautomeric forms of compounds of the invention. As used herein, "tautomer" means other structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom. For example, keto-enol tautomerism where the resulting compound has the properties of both a ketone and an unsaturated alcohol. Other examples of tautomerism include 2H-imidazole-4-amine and its tautomer l,2-dihydroimidazol-5-imine, and 2H-imidazol-4-thiol and its tautomer 1,2- dihydroimidazol-5-thione. It is understood that in compound representations throughout this description, only one of the possible tautomers of the compound is drawn or named.
As used herein "stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
Compounds of the invention further include hydrates and solvates. The present invention further includes isotopically-labelled compounds of the invention. An "isotopically" or "radio-labelled" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 150, 170, 180, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 1231, 1241, 125I and 131I. The radionuclide that is incorporated in the instant radio-labelled compounds will depend on the specific application of that radio-labelled compound. For example, for in vitro receptor labelling and competition assays, compounds that incorporate 3H, 14C, 82Br, 1251 , 1311, 35S or will generally be most useful. For radio- imaging applications 11C, 18F, 1251, 1231, 1241, 1311, 75Br, 76Br or 77Br will generally be most useful.
It is understood that a "radio-labelled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of 3H, 14C, 1251 , 35S and 82Br.
Compounds of the present invention may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient.
The quantity of the compound to be administered will vary for the patient being treated and will vary from about 100 ng/kg of body weight to 100 mg/kg of body weight per day. For instance, dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art. Thus, the skilled artisan can readily determine the amount of compound and optional additives, vehicles, and/or carrier in compositions and to be administered in methods of the invention.
In another aspect of the invention, there is provided that the compounds of the invention, or a pharmaceutically acceptable salt thereof, can be used as medicaments, e.g. to treat or prevent Aβ-related pathologies. In another aspect of the invention, there is provided that the compounds of the invention, or a pharmaceutically acceptable salt thereof, can be used for the manufacture of a medicament to treat or prevent Aβ-related pathologies. In another aspect of the invention, there is provided a method for the treatment of Aβ- related pathologies, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject, such as a mammal or a human being, in need thereof. The compounds of the invention and their pharmaceutically acceptable salts thereby provides methods of treatment of Aβ-related pathologies, such as, but not limited to, Alzheimer's disease, Downs syndrome, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy traumatic brain injury and cortical basal degeneration. In another aspect of the invention, there is provided a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according formula (I) in association with pharmaceutically acceptable excipients, carriers or diluents. In another aspect of the invention, there is provided a method of inhibiting activity of BACE with a compound according to formula (I).
In another aspect of the invention, there is provided a method of treating or preventing an Aβ-related pathology in a mammal, such as a human being , comprising administering to said patient a therapeutically effective amount of a compound according to formula (I), and at least one cognitive enhancing agent, memory enhancing agent, or choline esterase inhibitor, wherein said Aβ-related pathology is Alzheimer Disease. The treatment of Aβ-related pathology defined herein may be applied as a mono therapy or may involve, in addition to the compound of the invention, conjoint treatment with conventional therapy of value in treating one or more disease conditions referred to herein. Such conventional therapy may include one or more of the following categories of agents: acetyl cholinesterase inhibitors, anti-inflammatory agents, cognitive and/or memory enhancing agents or atypical antipsychotic agents. Cognitive enhancing agents, memory enhancing agents and acetyl choline esterase inhibitors includes, but not limited to, donepezil (Aricept), galantamine (Reminyl or Razadyne), rivastigmine (Exelon), tacrine (Cognex) and memantine (Namenda, Axura or Ebixa). Atypical antipsychotic agents includes, but not limited to, olanzapine (marketed as Zyprexa), aripiprazole (marketed as Abilify), risperidone (marketed as Risperdal), quetiapine (marketed as Seroquel), clozapine (marketed as Clozaril), ziprasidone (marketed as Geodon) and olanzapine/fluoxetine (marketed as Symbyax).
Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of the invention. Additional conventional therapy may include one or more of the following categories of agents:
(i) antidepressants such as agomelatine, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, ramelteon, reboxetine, robalzotan, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(ii) atypical antipsychotics including for example quetiapine and pharmaceutically active isomer(s) and metabolite(s) thereof. (iii) antipsychotics including for example amisulpride, aripiprazole, asenapine,
benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, ziprasidone and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (iv) anxiolytics including for example alnespirone, azapirones,benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, zolazepam and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(v) anticonvulsants including for example carbamazepine, clonazepam, ethosuximide, felbamate, fosphenytoin, gabapentin, lacosamide, lamotrogine, levetiracetam,
oxcarbazepine, phenobarbital, phenytoin, pregabaline, rufinamide, topiramate, valproate, vigabatrine, zonisamide and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(vi) Alzheimer's therapies including for example donepezil, rivastigmine, galantamine, memantine, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(vii) Parkinson's therapies including for example deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase and equivalents and
pharmaceutically active isomer(s) and metabolite(s) thereof. (viii) migraine therapies including for example almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, dihydroergotamine, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pizotiphen, pramipexole, rizatriptan, ropinirole,
sumatriptan, zolmitriptan, zomitriptan, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(ix) stroke therapies including for example thrombolytic therapy with eg activase and desmoteplase, abciximab, citicoline, clopidogrel, eptifibatide, minocycline, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(x) urinary incontinence therapies including for example darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodine and and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(xi) neuropathic pain therapies including for example lidocain, capsaicin, and
anticonvulsants such as gabapentin, pregabalin, and antidepressants such as duloxetine, venlafaxine, amitriptyline, klomipramine, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(xii) nociceptive pain therapies such as paracetamol, NSAIDS and coxibs, such as celecoxib, etoricoxib, lumiracoxib, valdecoxib, parecoxib, diclofenac, loxoprofen, naproxen, ketoprofen, ibuprofen, nabumeton, meloxicam, piroxicam and opioids such as morphine, oxycodone, buprenorfin, tramadol, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
(xiii) insomnia therapies including for example agomelatine, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine,
mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, ramelteon, roletamide, triclofos, secobarbital, zaleplon, Zolpidem and equivalents and pharmaceutically active isomer(s) and
metabolite(s) thereof.
(xiv) mood stabilizers including for example carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, verapamil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and/or the dosage described in the publication reference.
Methods of preparation
The present invention also relates to processes for preparing the compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof. Throughout the following description of such processes it is understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are for example described in Protective Groups in Organic Synthesis by T. W. Greene, P.G.M Wutz, 3rd Edition, Wiley-Interscience, New York, 1999. It is understood that microwaves can alternatively be used for the heating of reaction mixtures.
Another aspect of the present invention provides a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein, unless specified otherwise, A, B and C are defined as in formula (I) above, Rc is defined as for C in formula (I) above and R1 is, unless specified otherwise, as defined in formula (I); R10 and R11 are defined as A or B above, or may be defined as groups that can be converted to A or B in subsequent transformations, R12 may be defined as R4 above, and LG represents a leaving group such as halogen (such as chlorine, bromine or iodine) or an alkyl-, aryl- or haloalkyl-sulfonate (such as triflate). A compound of formula (VI) may be equivalent to a compound of formula (I). Said process comprises of: (i) Formation of a corresponding compound of formula (W):
Figure imgf000034_0001
Scheme 1
A ketone of formula (II), is reacted with ammonia to form intermediate (III), (Scheme 1). The compound of formula (III) is further reacted with ethyl 2-oxopropanoate to form an imidazole compound of formula (FV). Said reaction may be performed at a temperature range between +100 0C and +160 0C, in a suitable solvent, such as methanol, ethanol or isopropyl alcohol.
(H) Formation of a corresponding compound of formula (VI):
Figure imgf000034_0002
(IV) (V) (VI)
Scheme 2
The amino imidazole compound (VI) may be obtained by an initial formation of intermediate (V), by reacting the alcohol of formula (IV), with a sulphurating reagent such as phosphorus pentasulfide in the presence of a base such as pyridine. The transformation to a compound of formula (VI) may be performed by reacting the intermediate of formula (V) with ammonia, optionally in the presence of an oxidation agent, such as tert-butyl hydroperoxide.
(Hi) Formation of a corresponding compound of formula (III): R11— CN
(IX) NH
R10-LG ~ R10-M - RioΛRii
K K
(VII) (VIII) (HI)
Scheme 3
A compound of formula (III), may be obtained, as shown in (Scheme 3), by reacting compound of formula (VII), wherein LG is defined as above, with an organometallic reagent such as an alkyl lithium as for example butyl lithium, or with a metal such as magnesium, to form an intermediate compound of formula (VIII), wherein M is a metal, such as for example lithium or MgX, wherein X is a halide such as bromo or chloro. The compound of formula (VIII) is further reacted with a nitrile of formula (IX). Said reaction may be performed at a temperature range between -78 0C and room temperature, in a suitable solvent such as THF, 2-methyl-tetrahydrofuran or diethyl ether. A catalyst such as CuBr may facilitate the reaction.
(iv) Formation of a corresponding compound of formula (X):
Figure imgf000035_0001
Scheme 4
An imine of formula (III), is reacted with ethanebis(thioamide) to form a compound of formula (X) (Scheme 4). Said reaction may be performed at a temperature range between +120 0C and +1800C, in a suitable solvent, such as methanol, ethanol or isopropyl alcohol. (v) Formation of a corresponding compound of formula (VI):
Figure imgf000036_0001
(X) (XI) (VI)
Scheme 5
An alkylating agent, such as methyl iodide and a thioimidazole of formula (X) are reacted to form a compound of formula (XI) {Scheme 5). Said compound (XI) may be further transformed into a compound of formula (VI) by reacting it with an organometallic reagent, such as methylmagnesium bromide in the presence of a suitable catalyst, such as [l,3-bis(diphenylphosphino)propane]nickel(II) chloride. Alternatively, the compound of formula (VI) may also be obtained by reacting compound of formula (XI) with a mixture of zinc iodide and methylmagnesium bromide in the presence of a suitable catalyst such as bis(triphenylphosphine)palladium(II) chloride in a suitable solvent such as THF, 2-methyl- tetrahydrofuran or toluene.
(vi) Formation of a corresponding compound of formula (VI): -
Figure imgf000036_0002
(IE) (V) (VI)
Scheme 6
A compound of formula (VI) may be obtained from a compound of formula (III), wherein R13 is hydrogen, S(O)alkyl, C(O)alkyl, S(O)2alkyl, OH or Oalkyl (Scheme 6). Compound (III) may optionally be coordinated to a Lewis acid, as for example BF3, AlCl3, or TiCl4, to facilitate the reaction. An imine of formula (III) is reacted with 2-oxopropane thioamide (described in Asinger et al. Justus Liebigs Annalen der Chemie 1971, vol 744, p. 51-64) in a solvent such as methanol at a temperature between room temperature and reflux temperature to yield a compound of formula (V). The compound of formula (V) is subsequently treated with ammonia, in a suitable solvent such as methanol, THF, or 2- memyl-tetrahydrofuran, optionally in the presence of an oxidation agent, such as tert-butyl hydroperoxide, at a temperature between room temeprature and 150 0C, optionally in a closed system, to yield the compound of formula (VI). (vii) Formation of a corresponding compound of formula (I):
Figure imgf000037_0001
Scheme 7
A compound of formula (I) may be obtained (Scheme T) by starting from, for example, a compound of formula (XII), and reacting said compound of formula (XII) with a boronic acid or a boronic ester or a stannane of formula T-Rc, wherein T is for example B(OH)2, B(Oalkyl)2, or SnR3, and Rc is as defined above, in the presence of a transition metal catalyst such as a palladium catalyst, such as [ 1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride, tetrakis(triphenylphosphine)- palladium(O), palladium diphenylphosphineferrocene dichloride, palladium(II) acetate or bis(dibenzylideneacetone) palladium (0). Optionally, a suitable ligand such as
triphenylphosphine, tri-ter?-butylphosphine or 2-(dicyclohexylphosphino)biphenyl, or zinc and sodium Mphenylphosphinetrimetasulfonate, is used. A suitable base, such as cesium fluoride, an alkyl amine, such as triethyl amine, or an alkali metal or alkaline earth metal carbonate or hydroxide such as potassium carbonate, sodium carbonate, cesium carbonate, or sodium hydroxide, may be used in the reaction. Said reaction may be performed in a suitable solvent, such as toluene, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, dimethoxyethane, water, ethanol, N.iV-dimethylacetamide, acetonitrile or N1N- dimethylformamide, or mixtures thereof. (viii) Formation of a corresponding compound of formula (I): A compound of formula (I), wherein C is cyano, may be obtained (Scheme 7) by starting from, for example, a compound of formula (XII), wherein LG is a leaving group such as a halogen, (such as iodide, bromide or chlorine), and reacting said compound of formula (XII) with a a metal cyano reagent such as copper(I) cyanide.
(ix) Formation of a corresponding compound of formula (I):
A compound of formula (I), wherein C is an alkyl group such as methyl may be generated from compound of formula (XII) (Scheme 7), wherein LG represents a leaving group, such as a halogen, (such as iodide, bromide or chlorine), by reaction with an organometallic reagent generated from zinc iodide and methylmagnesium bromide under the influence of a transition metal catalyst such as for example bis(triphenylphosphine)palladium(II) chloride.
(x) Formation of a corresponding compound of formula (I):
A compound of formula (I) wherein C is NHC(O)R12 may be prepared according to
Scheme 7 by reacting a compound of formula (XII) with a compound R12C(O)NH2 in the presence of a suitable palladium catalyst such as palladium(II) acetate, optionally in the presence of a suitable ligand such as Xantphos. Said reaction is preformed in the presence of a suitable base such as cesium carbonate in a suitable solvent such as THF or 2-methyl- tetrahydrofuran at a temperature between 100 0C to 160 0C.
Alternatively a compound of formula (I) wherein C is NHC(O)R12 may be obtained from a compound of formula (XII) as shown in Scheme 8.
Figure imgf000038_0001
Scheme 8 A compound of formula (XII) is reacted with ammonia in the presence of trans-4-hydroxy- L-proline, potassium carbonate and copper(I)iodide in a solvent such as DMSO at a temperature between room temperature and 150 0C to give a compound of formula (XIII). Said compound of formula (XIII) is further reacted with an acid of formula (XIV) in the presence of an amide coupling agent such as l-(3-dimethylaminopropyl)-3-ethyl- carbodiimide in a solvent such as DMF, optionally in the presence of hydrochloric acid.
Compounds of formula (II), (III), (VII), (DC), or (XTV) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.
General Methods
All solvents used were of analytical grade and commercially available anhydrous solvents were routinely used for reactions. Starting materials used were available from commercial sources, or prepared according to literature procedures. Room temperature refers to 20 - 25 0C. Solvent mixture compositions are given as volume percentages or volume ratios.
Microwave heating was performed in a Biotage Creator, Initiator or Smith Synthesizer Single-mode microwave cavity producing continuous irradiation at 2450 MHz. It is understood that microwaves can be used for the heating of reaction mixtures.
Thin layer chromatography (TLC) was performed on Merck TLC-plates (Silica gel 60 F254) and and spots were UV visualized. Flash chromatography was performed on a Combi Flash® Companion™ using RediSep™ normal-phase flash columns. Straight phase flash column chromatography was manually performed on Merck Silica gel 60 (0.040- 0.063mm), or automatically using an ISCO Combiflash® Companion™ system using the solvent system indicated. Phase separation was optionally performed on an Isolute® phase separator.
1H NMR spectra were recorded in the indicated deuterated solvent at 400 MHz unless otherwise indicated. Spectra were obtained using a Bruker av400 NMR spectrometer operating at 400 MHz for 1H and 100 MHz for 13C equipped with a 3 mm flow injection SEI 1HZD-13C probe head with Z-gradients, using a BEST 215 liquid handler for sample injection, or using a Bruker DPX400 NMR spectrometer operating at 400 MHz for 1H, 376 MHz for 19F, and 100 MHz for 13C, equipped with a 4-nucleus probehead with Z-gradients. 500 MHz spectra were recorded using a Bruker 500MHz Avance III NMR spectrometer, operating at 500 MHz for 1H, 125 MHz for 13C, and 50 MHz for 15N equipped with a 5mm TXI probehead with Z-gradients. 600 MHz spectra were recorded using a Bruker DRX600 NMR spectrometer, operating at 600 MHz for 1H, 150 MHz for 13C, and 60 MHz for 15N equipped with a 5mm TXI (or BBO) probehead with Z-gradients. Chemical shifts are given in ppm down- and upfield from TMS (0.00 ppm). The following reference signals were used: TMS δ 0.00, or the residual solvent signal of DMSOd6 δ 2.49, CD3OD δ 3.30, acetone-dβ 2.04 or CDCI3 δ 7.25 (unless otherwise indicated). Resonance multiplicities are denoted s, d, t, q, m, br and app for singlet, doublet, triplet, quartet, multiplet, broad and apparent, respectively. In some cases only diagnostic signals are reported.
HPLC analyses were performed on an Agilent HPl 100 system consisting of a G1322A Micro Vacuum Degasser, a Gl 311 A Quaternary Pump, a Gl 367 Well-Plate Autosampler, a G1316A Thermostatted Column Compartment and a G1315A Diode Array Detector. The column used was an Xbridge C8 30x50mm, 3.5μm or a Gemini C18, 3.0 x 50 mm, 3.0 μm, 110 A run at a flow rate of 1.0 ml/min. Alternatively, HPLC analyses were performed on an Agilent HPl 100 system consisting of a G1379A Micro Vacuum Degasser, a Gl 312A Binary Pump, a Gl 367 Well-Plate Autosampler, a G1316A Column Compartment and a G1315B Diode Array Detector. The column used was an Xbridge C8 30x50mm, 3.5μm or a Gemini C18, 3.0 x 50 mm, 3.0 μm, 110 A run at a flow rate of 1.0 ml/min. Alternatively, HPLC analyses were performed on an Agilent HPl 100 system consisting of a G1322A Micro Vacuum Degasser, a G1312A Binary Pump, a G1367 Well-Plate Autosampler, a G1316A Thermostatted Column Compartment and a G1315A Diode Array Detector. The column used was an Xbridge C8 30x50mm, 3.5μm or a Gemini C18, 3.0 x 50 mm, 3.0 μm, 110 A run at a flow rate of 1.0 ml/min.
GC analyses were performed on a HP 6890 GC equipped with a Gl 512AX flame ionization detector supplied by Agilent Technologies. The column used was DB-5 MS, ID 0.18 mm x 10m, 0.18 μm (J&W Scientific). A linear temperature gradient was typically applied. Chiral GC analyses were performed on an HP 6890 GC equipped with a flame ionization detector supplied by Agilent Technologies. The column used was a Cyclodex B ID 0.25 mm x 30 m, 0.25 μm (Agilent Technologies). The temperature of the GC oven was s typically held isocratically at for example 100 0C for 30 minutes.
Mass spectra (MS) were run using an automated system with atmospheric pressure chemical (APCI or CI) or electrospray (+ESI) ionization. Generally, only spectra where parent masses are observed are reported. The lowest mass major ion is reported foro molecules where isotope splitting results in multiple mass spectral peaks (for example when chlorine is present). UPLC-MS analyses were performed on a Waters Acquity UPLC system consisting of an Acquity Autosampler, Acquity Sample Organizer, Acquity Column Manager, Acquity Binary Solvent Manager, Acquity UPLC PDA detector and a Waters 3100 Mass Spectrometer. The mass spectrometer was equipped with an
s electrospray ion source (ES) operated in positive and negative ion mode. Separation was performed on an Acquity column, UPLC BEH, Cl 8 1.7 μM run at a flow rate of 0.5 ml/min. Alternatively, UPLCMS analyses were performed on a Waters Acquity UPLC system consisting of an Acquity Solvent Manager, Acquity Sample Organizer, Acquity Column Manager, Acquity Binary Solvent Manager, Acquity PDA detector and a Waters0 SQ Detector. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode. Separation was performed on an Acquity column, UPLC BEH, Cl 8 1.7 μM run at a flow rate of 0.5 ml/min.
LC-MS analyses were performed on an LC-MS system consisting of a Waters Alliance5 2795 HPLC, a Waters PDA 2996 diode array detector, a Sedex 75 ELS detector and a ZQ 2000 single quadrupole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode. Separation was performed on a Xbridge C18, 30x50mm, 3.5μm column or on a Gemini C18 3.0 x 50, 3 μm (Phenomenex) column run at a flow rate of 1 ml/min. Alternatively, LC-MS analyses0 were performed on an LC-MS consisting of a Waters sample manager 2777C, a Waters 1525μ binary pump, a Waters 1500 column oven, a Waters ZQ single quadrupole mass spectrometer, a Waters PDA2996 diode array detector and a Sedex 85 ELS detector. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive and negative ion mode. The column used was a Xbridge C18, 30x50mm, 3.5μm or a Gemini C 18, 3.0 mm x 50 mm, 3 μm, (Phenomenex) which was run at a flow rate of 1 ml/min. Alternatively, LC-MS analyses were performed on a LC-MS consisting of a Waters sample manager 2777C, a Waters 1525 μ binary pump, a Waters 1500 column oven, a Waters ZQ single quadrupole mass spectrometer, a Waters PDA2996 diode array detector and a Sedex 85 ELS detector. The mass spectrometer was configured with an atmospheric pressure chemical ionisation (APCI) ion source which was further equipped with atmospheric pressure photo ionisation (APPI) device. The mass spectrometer operated in positive and negative ion mode, switching between APCI and APPI mode. Separation was performed using a Gemini column C18, 3.0 mm x 50 mm, 3 μm, (Phenomenex) and run at a flow rate of 0.8 ml/min. Typical mobile phase systems for HPLC, UPLC-MS, and LCMS consisted of A: 1OmM NH4OAc (aq.) in 5% CH3OH) or 1OmM NH4OAc in 5% CH3CN and B: CH3OH or CH3CN and linear gradients from 100% A to 100% B was typically applied.
GCMS analysis was performed on a GC/DIP-MS system supplied by Agilent
Technologies. The system consisted of a GC 6890N, G1530N, a G2614A Auto-sampler, G2613A injector and a G2589N mass spectrometer. The mass spectrometer was equipped with a Direct Inlet Probe (DIP) interface manufactured by SIM GmbH. The mass spectrometer was equipped with an electron impact (EI) ion source and the electron voltage was set to 70 eV. The mass spectrometer scanned between m/z 50-550 and the scan speed was set to 2.91 scan/s. The sample solution was either injected on the GC or introduced by direct inlet to the probe tip. The GC column used was a DB-5 MS, ID 0.18 mm x 1 Om, 0.18 μm (J& W Scientific) or a VF-5 MS, ID 0.25 mm x 15m, 0.25 μm (Varian Inc.). A linear temperature gradient was typically applied. Alternatively, GCMS analysis was performed on a GC-MS system supplied by Agilent Technologies, consisting of a 6890N G1530N GC, a G2614A Auto-sampler, G2613A injector and a G2589N mass spectrometer. The column used was a DB-5 MS, ID 0.18 mm x 10m, 0.18 μm (J&W Scientific) or a VF-5 MS, ID 0.25 mm x 30m, 0.25 μm (Varian Inc.). Typically a linear temperature gradient was applied. The mass spectrometer was equipped with a chemical ionisation (CI) ion source and the reactant gas was methane or the mass spectrometer was equipped with an electron impact (EI) ion source and the electron voltage was set to 70 eV. The mass spectrometer scanned between m/z 50-500 and the scan speed was set to 3.21 scan/s.
Preparative HPLC was for example performed on a Waters Auto purification HPLC-UV system with a diode array detector using for example a Waters Xterra® MS Cg column (30x150 mm, 10 μm), a Phenomex Gemini-NX column (21x250 mm, 10 μm), a Waters XBridge C8 column (19x250 mm, 10 μm), or a Waters XBridge™ C18 column (19x250 mm, 10 μm). Mobile phase A: 0.1 M ammonium acetate in water/mobile phase B (95:5). Mobile phase B: MeCN or MeOH. Typically a linear gradient of mobile phase B was applied.
Preparative chiral chromatography for separation of enantiomers was run on a Berger Multigram II system (SFC) or a LaPrep® system (HPLC) using the specified column and mobile phase system.
Terms and abbreviations:
ACN acetomtπle
aq aqueous;
Atm atmospheric pressure;
Boc ?-butoxycarbonyl;
Cbz benzyloxycarbonyl;
dba dibenzylideneacetone
DCM dichloromethane;
DIBAL-H diisobutylaluminium hydride
DIPEA diisopropylethylamine;
DME 1 ,2-dimethoxyethane
DMF N,N-dimethyl formamide;
DMSO dimethyl sulfoxide;
Et2O diethyl ether;
EtOAc ethyl acetate;
equiv. equivalent
h hour(s); HPLC high performance liquid chromatography;
MeOH methanol;
min minute(s);
MS mass spectrometry
MW microwave(s)
NMR nuclear magnetic resonance;
Psi pounds per square inch;
sat saturated;
SFC supercritical fluid chromatography;
TFA trifluoroacetic acid;
THF tetrahydrofuran;
TLC thin layer chromatography
TMEDA tetramethylethylenediamine
UPLC ultra performance liquid chromatography
Compounds have been named using CambridgeSoft MedChem ELN v2.1 or ACD/Name, version 10.0, or 10.06, software from Advanced Chemistry Development, Inc.
(ACD/Labs), Toronto ON, Canada, www.acdlabs.com, or Lexichem, version 1.7, software from OpenEye.
EXAMPLES
Below follows a number of non-limiting examples of compounds of the invention.
Example Ii
2-(3-BromophenyI)-2,5-dimethyl-2H-imidazoI-4-oI
Figure imgf000044_0001
l-(3-Bromophenyl)ethanone (239 μL, 1.80 mmol) was dissolved in ammonia (7M in MeOH) (5.14 mL, 36 mmol). Ethyl 2-oxopropanoate (1 mL, 9 mmol) was added 1 equiv. at a time and the reaction was stirred at 150 0C for 1 h by microwave heating between each addition giving at total of 5 h. The solvent was evaporated and preparative HPLC yielded 76 mg (16% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 9.62 (br. s., 1 H) 7.65 (t, 1 H) 7.39 - 7.47 (m, 2 H) 7.24 (t, 1 H) 2.27 (s, 3 H) 1.80 (s, 3 H); MS (ES-) m/z 265, 267 [M-H]".
Example 2i
2-(3-Bromophenyl)-2,5-dimethyl-2H-imidazol-4-ainine
Figure imgf000045_0001
2-(3-Bromophenyl)-2,5-dimethyl-2H-imidazol-4-ol (76 mg, 0.28 mmol) was dissolved in pyridine (1.5 mL) and phosphorus pentasulfide (76 mg, 0.17 mmol) was added. The reaction was heated to 120 0C for 1 h. Ammonia (7M in MeOH) (4 mL, 28 mmol) and tert- butyl hydroperoxide (0.586 mL, 4.27 mmol) were added and the reaction was stirred at room temperature for 16 h. The solvents were evaporated and preparative HPLC yielded 41 mg (55% yield) of the title compound: MS (ES+) m/z 266, 268 [M+H]+. Example 3i
2-(3-Bromophenyl)-2-ethyl-5-methyl-2H-imidazol-4-ol
Figure imgf000045_0002
l-(3-Bromophenyl)propan-l-one (320 mg, 1.50 mmol) was dissolved in ammonia (7M in MeOH) (4 mL, 28 mmol). Ethyl 2-oxopropanoate (1 mL, 9 mmol) was added and the reaction was stirred at 150 0C for 3 h by microwave heating. The solvent was evaporated and preparative HPLC yielded 17 mg (4% yield) of the title compound: MS (ES-) m/z 279, 281 [M-H]". Example 4i
2-(3-Bromophenyl)-2-ethyl-5-methyI-2H-imidazol-4-amine
Figure imgf000046_0001
2-(3-Bromophenyl)-2-ethyl-5-methyl-2H-imidazol-4-ol (16.7 mg, 0.06 mmol) was dissolved in pyridine (1 mL) and phosphoras pentasulfide (50 mg, 0.11 mmol) was added. The reaction was heated to 120 °C for 1 h. Ammonia (33% in water) (0.25 mL, 4.26 mmol) and tert-butyl hydroperoxide (0.122 mL, 0.89 mmol) were added and the reaction was stirred at room temperature for 16 h. The solvent was evaporated and preparative HPLC yielded 9 mg (53% yield) of the title compound: MS (ES+) m/z 280, 282 [M+H]+.
Example 5i
(3-Bromophenyl)(cyclohexyl)methanimine
Figure imgf000046_0002
1,3-Dibromobenzene (3.04 mL, 25.2 mmol) was dissolved in Et2O (60 mL) and cooled to - 78 0C. «-Butyllithium (10.1 mL, 25.25 mmol) was added and the the solution stirred for 30 min. Cyclohexanecarbonitrile (2.99 mL, 25.20 mmol) was added in Et2O (40 mL) at -78 0C and the reaction was allowed to warm to room temperature over 30 min. MeOH (20 mL) containing ammonium acetate (2 g, 25.95 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic phases were shaken with brine and dried over MgSO4. The mixture was filtered and the solvent evaporated to yield 5.56 g (83% yield) of the title compound: MS (ES+) m/z 266, 268 [M+H]+. Example 6i
5-Amino-2-(3-bromophenyl)-2-cycIohexyl-2H-imidazole-4-thiol
Figure imgf000047_0001
(3-Bromophenyl)(cyclohexyl)methanimine (5.56 g, 7.73 mmol) and ethanebis(thioamide) (1.47 g, 12.23 mmol) were taken up in EtOH (10 mL). The reaction was heated to 165 0C for 2 h by microwave heating. The solvent was evaporated. Column chromatography using 0% to 100% EtOAc in heptane yielded 1.25 g (46% yield) of the title compound: MS (ES+) m/z 352, 354 [M+H]+. Example 7i
2-(3-Bromophenyl)-2-cyclohexyI-5-(methylthio)-2H-imidazol-4-amine
Figure imgf000047_0002
5-Amino-2-(3-bromophenyl)-2-cyclohexyl-2H-imidazole-4-thiol (1.25 g, 3.55 mmol) was taken up in THF (20 mL). Iodomethane (0.663 mL, 10.64 mmol) was added and the reaction was heated to 60 0C for 24 h. Column chromatography using 0% to 100% EtOAc in heptane yielded 925 mg (71% yield) of the title compound: MS (ES+) m/z 366, 368 [M+H]+.
Example 8i
2-(3-BromophenyI)-2-cycIohexyl-5-methyl-2H-imidazol-4-amine
Figure imgf000047_0003
To a solution of zinc iodide (5.0 g, 15.66 mmol) in THF (40 mL) at 0 0C was added methylmagnesium bromide (3M in diethyl ether) (5.22 mL, 15.66 mmol). To the formed slurry was then added 2-(3-bromophenyl)-2-cyclohexyl-5-(methyltWo)-2H-irnidazol-4- amine (925 mg, 2.53 mmol) in THF (20 mL), followed by bis(triphenylphosphine)- palladium(II) chloride (177 mg, 0.25 mmol). The reaction mixture was stirred at 50 0C for 3 h. MeOH was added to quench the reaction. The solvent was evaporated. Water was 5 added resulting in a thick slurry which was washed with DCM. The combined organic phases were dried over MgSO4, filtered and the solvent evaporated. Preparative HPLC yielded 120 mg (14% yield) of the title compound: MS (ES+) m/z 334, 336 [M+H]+.
Example 9i
i o (3-BromophenyI)(tetrahy dro-2H-pyran-4-yI)methanimine
Figure imgf000048_0001
1,3-Dibromobenzene (3.04 mL, 25.2 mmol) was dissolved in Et2O (60 mL) and cooled to - 78 0C. «-Butyllithium (10.1 mL, 25.25 mmol) was added and the the solution stirred for 30 min. Tetrahydro-2H-pyran-4-carbonitrile (2.80 g, 25.20 mmol) was added in Et2O (20 mL) is at -78 0C and the reaction was stirred for 30 min. The reaction was then allowed to warm to room temperature over 30 min. MeOH (20 mL) containing ammonium acetate (2 g, 25.95 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic phases were shaken with brine and dried over MgSO4. The mixture was
20 filtered and the solvent evaporated to yield 4.64 g (69% yield) of the title compound: MS (ES+) m/z 268, 270 [M+H]+.
Example 1Oi
5-Amino-2-(3-bromophenyI)-2-(tetrahydro-2H-pyran-4-yl)-2H-imidazole-4-thiol
Figure imgf000048_0002
(3-Bromophenyl)(tetrahydro-2H-pyran-4-yl)methanimine (4.64 g, 17.30 mmol) and ethanebis(thioamide) (2.496 g, 20.76 mmol) were taken up in EtOH (10 mL). The reaction was heated to 165 0C for 2 h by microwave heating. The reaction mixture was diluted with DCM and filtered. Column chromatography using EtOAc 0% to 100% in heptane yielded 3.7 g (60% yield) of the title compound: MS (ES+) m/z 354, 356 [M+H]+. Example Hi
2-(3-BromophenyI)-5-(methylthio)-2-(tetrahydro-2H-pyran-4-yl)-2H-imidazol-4- amine
Figure imgf000049_0001
5-Amino-2-(3-bromophenyl)-2-(tetrahydro-2H-pyran-4-yl)-2H-imidazole-4-thiol (3.7 g, 10.44 mmol) was taken up in THF (20 mL). Iodomethane (1.951 niL, 31.33 mmol) was added and the reaction was heated to 60 0C for 24 h. Column chromatography using EtOAc 0% to 100% in heptane yielded 2.2 g (57% yield) of the title compound: MS (ES+) m/z 368, 370 [M+H]+. Example 12i
2-(3'-MethoxybiphenyI-3-yl)-5-(methylthio)-2-(tetrahydro-2H-pyran-4-yI)-2H- imidazol-4-amine
Figure imgf000049_0002
2-(3-Bromophenyl)-5-(memyltWo)-2-(tetrahydro-2H-pyran-4-yl)-2H-imidazol-4-amine (625 mg, 1.70 mmol), 3-methoxyphenylboronic acid (258 mg, 1.70 mmol) and
bis(triphenylphosphine)palladium(II) chloride (119 mg, 0.17 mmol) were taken up in DME (20 mL) and water (10 mL). Sodium carbonate (IM in water) (4.24 mL, 4.24 mmol) was added and the reaction was heated to 80 0C for 2 h. The reaction mixture was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the solvents evaporated. Preparative HPLC yielded 80 mg (12% yield) of the title compound: MS (ES+) m/z 396 [M+H]+. Example 131
tert-Butyl 4-((3-bromophenyI)(imino)methyl)piperidine-l-carboxy late
Figure imgf000050_0001
1,3-Dibromobenzene (1.435 mL, 11.89 mmol) was dissolved in Et2O (90 mL) and cooled to -78 0C. n-Butyllithium (5 mL, 12.50 mmol) was added and the solution stirred for 30 min. tert-Butyl 4-cyanopiperidine-l-carboxylate (2.5 g, 11.89 mmol) was added in Et2O (40 mL) at -78 0C. The reaction was stirred for 30 min and was then allowed to warm to room temperature over 30 min. MeOH (20 mL) containing ammonium acetate (1 g, 13 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic phases were shaken with brine and dried over MgSO4, filtered and the solvent evaporated to yield 2.9 g (66% yield) of the title compound: MS (ES+) m/z 367, 369 [M+H]+.
Example 14i
tert-Butyl 4-(4-amino-2-(3-bromophenyI)-5-mercapto-2H-imidazol-2-yl)piperidine-l- carboxylate
Figure imgf000050_0002
tert-Butyl 4-((3-bromophenyl)(imino)methyl)piperidine-l-carboxylate (2.65 g, 7.22 mmol) and ethanebis(thioamide) (1 g, 8.32 mmol) were taken up in EtOH (10 mL). The reaction was heated to 180 0C for 30 min by microwave heating. The reaction mixture was diluted with DCM and filtered. Column chromatography using EtOAc 0% to 100% in heptane yielded 943 mg (29% yield) of the title compound: MS (ES+) m/z 453, 455 [M+H]+.
Example 15i
tert-Butyl 4-(4-amino-2-(3-bromophenyl)-5-(methylthio)-2H-imidazol-2-yl)piperidine- l-carboxylate
Figure imgf000051_0001
tert-Butyl 4-(4-amino-2-(3-bromophenyl)-5-mercapto-2H-imidazol-2-yl)piperidine- 1 - carboxylate (943 mg, 2.08 mmol) was taken up in THF (20 mL). Iodomethane (0.388 mL, 6.24 mmol) was added and the reaction was heated to 60 0C for 24 h. Column
chromatography using MeOH, with 0.1% NH3, 0% to 10% in DCM, yielded 0.57 g (59% yield) of the title compound: MS (ES+) m/z 467, 469 [M+H]+.
Example 16i
tert-ButyI 4-(4-amino-2-(3-bromophenyl)-5-methyl-2H-imidazol-2-yl)piperidine-l- carboxylate
Figure imgf000051_0002
To a solution of zinc iodide (3.41 g, 10.70 mmol) in THF (20 mL) at 0 0C was added methyhnagnesium bromide (3M in diethyl ether) (3.57 mL, 10.70 mmol). To the formed slurry was then added bis(triphenylphosphine)palladium(II) chloride (0.150 g, 0.21 mmol) followed by tert-butyl 4-(4-amino-2-(3-bromophenyl)-5-(methylthio)-2H-imidazol-2- yl)piperidine- l-carboxylate (0.5 g, 1.07 mmol) in THF (10 mL). The mixture was stirred at 50 0C for 3 h and then MeOH was added to quench the reaction. Saturated NH4Cl (aq.) solution was added and the mixture was extracted with diethyl ether. The combined organic phases were dried over MgSO4, filtered and the solvent evaporated. Preparative HPLC yielded 44.5 mg (9.5% yield) of the title compound: MS (ES+) m/z 435, 437
[M+H]+. s Example 17i
tert-Butyl 4-(4-amino-2-(3f-methoxybiphenyI-3-yl)-5-methyl-2H-imidazol-2- yl)piperidine-l-carboxylate
Figure imgf000052_0001
tert-Butyl 4-(4-amino-2-(3-bromophenyl)-5-methyl-2H-imidazol-2-yl)piperidine-l-o carboxylate (44.5 mg, 0.10 mmol), 3-methoxyphenylboronic acid (18.64 mg, 0.12 πrniol) and bis(triphenylphosphine)palladium(II) chloride (7.17 mg, 10.22 μmol) were taken up in DME (1 mL) and water (0.5 mL). Sodium carbonate (IM in water) (0.256 mL, 0.26 mmol) was added and the reaction was heated to 80 0C for 2 h. The reaction mixture was filtered and preparative HPLC yielded 15.7 mg (33% yield) of the title compound: MS (ES+) m/zs 463 [M+H]+.
Example 18i
5-Amino-2-ben2yl-2-(3-bromophenyl)-2H-imidazole-4-thiol
Figure imgf000052_0002
0 l-(3-bromophenyl)-2-phenylethanone (1 g, 3.63 mmol) and ethanebis(thioamide) (1.311 g, 10.9 mmol) were taken up in ammonia (7M in MeOH) (15 mL, 105 mmol). The reaction was heated to 150 0C for 1 h by microwave heating. The reaction mixture was diluted with DCM and filtered. Column chromatography using EtOAc 0% to 100% in heptane yielded 1.232 g (94% yield) of the title compound: MS (ES+) m/z 360, 362 [M+H]+.
Example 19i
2-Benzyl-2-(3-bromophenyl)-5-(methylthio)-2H-imidazol-4-amine
Figure imgf000053_0001
5-Amino-2-benzyl-2-(3-bromophenyl)-2H-imida2;ole-4-thiol (1.232 g, 3.42 mmol) was taken up in THF (30 mL). Iodomethane (0.639 mL, 10.26 mmol) was added and the reaction was heated to 60 0C for 4 h. Column chromatography using 0% to 100% EtOAc in heptane yielded 200 mg (16% yield) of the title compound: MS (ES+) m/z 374, 376
[M+H]+.
Example 2Oi
2-Benzyl-2-(3-bromophenyl)-5-methyl-2H-imidazoI-4-amine
Figure imgf000053_0002
2-Berizyl-2-(3-bromophenyl)-5-(memyltWo)-2H-imidazol-4-amine (200 mg, 0.53 mmol) and l,3-bis(diphenylphosphino)propane nickel (II) chloride (116 mg, 0.21 mmol) were dissolved in toluene (3 mL). Methylmagnesium bromide (3M in diethyl ether) (1.425 mL, 4.27 mmol) was added and the resulting suspension was stirred at room temperature. After 1 h, water was added and the phases were separated. The aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the solvents evaporated. Preparative HPLC yielded 66.5 mg (36% yield) of the title compound: MS (ES+) m/z 342, 344 [M+H]+. Example 21i
2-(3-BromophenyI)-4-methyI-2-(pyridin-3-ylmethyl)-lH-imidazole-5(2H)-thione
Figure imgf000054_0001
Lithium diisopropylamide (25.00 mL, 45.00 mmol) was added dropwise over 20 min to solution of 3-picoline (4.39 mL, 45.00 mmol) in THF (50 mL) under a nitrogen
atmosphere at -10 0C. The resulting mixture was stirred at -10 0C for 30 min and then a solution of 3-bromobenzonitrile (2.73 g, 15 mmol) in THF (10 mL) was added drowise over 5 min and the resulting mixture was stirred at -10 0C for 15 min. The cooling bath was removed and the mixture was stirred at rt for 2 h. A solution of ammonium acetate (3.23 mL, 45.00 mmol) in MeOH (20 mL) was added, the mixture stirred for 10 min and then the solvents were removed in vacuo. The resulting residue was taken up in DCM (50 mL) and water (30 mL) and poured into a phase separator. The organic phase was collected and concentrated. The resulting residue was taken up in MeOH (15 mL), 2- oxopropanethioamide (2.63 g, 25.50 mmol) was added and the mixture was stirred at 50 0C over night. When cooled to rt the mixture was concentrated onto silica and purified on a silica gel column eluted with 0-100% EtOAc in heptane to give 790 mg (15% yield) of the title compound: MS (ES-) m/z 358, 360 [M-I]'.
Example 22i
2-(3-Bromophenyl)-5-methyl-2-(pyridin-3-ylmethyl)-2H-imidazol-4-amme
Figure imgf000054_0002
2-(3-Bromophenyl)-4-methyl-2-(pyridin-3 -ylmethyl)- 1 H-imidazole-5 (2H)-thione (790 mg, 2.19 mmol) and 7M ammonia in MeOH (9.398 mL, 65.79 mmol) were mixed and heated in a microwave reactor at 100 0C for 1 h. The mixture was concentrated and the resulting residue was taken up in 1 :1 EtO Ac/toluene (10 mL) and IM aqueous citric acid (10 mL). The aqueous phase was separated and the organic phase was extracted with IM citric acid (10 mL). The combined aqueous phase was extracted with toluene (5 mL) and then made alkaline to pH~8 with 50% aqueous NaOH and extracted with DCM (3 x 5 mL). The combined organic phase was passed through a phase separator, concentrated and purified on a silica gel column eluted with 0-15% 0.1M NH3 in MeOH in DCM to give 205 mg (27% yield) of the title compound: MS (ES-) m/z 341, 343 [M-I]". Example 23i
(3-Bromophenyl)(cyclopropyI)methanimine
Figure imgf000055_0001
3-Bromobenzonitrile (1.1 g, 6.04 mmol) was dissolved in THF (3 mL) and
cyclopropylmagnesium bromide (0.5 M in THF, 13.30 mL, 6.65 mmol) was added dropwise. Copper(I) bromide (0.017 g, 0.12 mmol) was added immediately after. The mixture was heated to 40 0C for 18 h, cooled to rt and then ammonium acetate (0.699 g, 9.07 mmol) in methanol (5 mL) was added. The mixture was concentrated. DCM and water was added and the organic phase was collected, dried over MgSO^ and concentrated to give 1.3 g (96% yield). The compound was used directly in the next step: MS (CI) m/z 224, 226 [M+l]+.
Example 24i
2-(3-Bromophenyl)-2-cyclopropyl-4-methyl-lH-imidazole-5(2H)-thione
Figure imgf000055_0002
(3-Bromophenyl)(cyclopropyl)methanimine (1.900 g, 8.48 mmol) was dissolved in dry methanol (20 mL) under argon and 2-oxopropanethioamide (1.312 g, 12.72 mmol) was added in one portion. The solution was heated at 50 0C for 3.5 h. The reaction was allowed to cool to rt and the solvents were evaporated at reduced pressure. Chromatography using 5 0-30% EtOAc in n-heptane gave 2 g (76% yield) of the title compound: 1H NMR (500 MHz, DMSCMO δ ppm 12.57 (s, 1 H) 7.68 (t, 1 H) 7.54 - 7.61 (m, 1 H) 7.49 - 7.54 (m, 1 H) 7.37 (t, 1 H) 2.23 (s, 3 H) 1.60 (tt, 1 H) 0.43 - 0.57 (m, 2 H) 0.33 - 0.43 (m, 1 H) 0.15 - 0.27 (m, 1 H). MS (ES) m/z 309, 311 [M+l]+. o Example 25i
3-Bromo-5-(prop-l-ynyl)pyridine
Figure imgf000056_0001
To a solution of 3,5-dibromopyridine (5 g, 21.11 mmol), copper(I) iodide (0.238 mL, 6.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.220 g, 1.06 mmol) in toluene (250s mL) was added l-(trimethylsilyl)-l-propyne (3.16 mL, 21.11 mmol), triethylamine (9.71 mL, 69.65 mmol) and IM tetrabutylammonium fluoride in THF (21.11 mL, 21.11 mmol) and the resulting mixture was stirred under a nitrogen atmosphere at rt over night. The mixture was concentrated and the resulting residue was taken up in water (20 mL) and DCM (2OmL) and poured into a phase separator. The organic phase was collected and the0 aqueous phase was extracted once with DCM (20 mL). The combined organics were
concentrated and purified on a silica gel column eluted with 0-30% EtOAc in heptane to give 2.93 g (71% yield) of the title compound: 1H NMR (500 MHz, DMSO-J6) δ ppm 8.66 (d, 1 H) 8.58 (d, 1 H) 8.12 (t, 1 H) 2.10 (s, 3 H); MS (CI) m/z 196, 198 [M+H]+. s Example 26i
5-(Prop-l-ynyl)pyridin-3~yl boronic acid
HO^OH n-Butyllithium (7.17 mL, 17.93 mmol) was added dropwise over 10 min to a solution of 3- bromo-5-(prop-l-ynyl)pyridine (2.93 g, 14.95 mmol) and triisopropyl borate (4.14 mL, 17.93 mmol) in THF (6 mL) and toluene (24 mL) at -78 0C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 45 min. The cooling bath was removed and the mixture was stirred at rt for 30 min before being cooled to -10 0C. Aqueous 2M HCl (15 mL) was added, the cooling bath removed and the mixture was stirred at rt for 1 h. The organics were removed under reduced pressure and the pH of the resulting aqueous residue was adjusted to 7-8 using an aqueous 20% NaOH solution. The aqueous mixture was diluted with brine (20 mL) and then saturated with solid NaCl and extracted with THF (3 x 25 mL). The combined organics were dried over MgSO4, filtered and concentrated.
Recrystallization from MeOH gave 1.5 g (62% yield) of the title compound: MS (ES-) m/z 160 [M-I]-.
Example 27i
(3-Bromophenyl)(6-methoxy-5-methylpyridin-3-yl)methanimine
Figure imgf000057_0001
ft-Butyllithium was added drop wise to a solution of 5-bromo-2-methoxy-3-methylpyridine (0.502 g, 2.48 mmol) in dry Et2O (10 mL) cooled at -78 °C under an atmosphere of argon. The mixture was stirred at -78 0C for 20 minutes and then a solution of 3- bromobenzonitrile (0.452 g, 2.48 mmol) in dry Et2O (2.0 mL) was added dropwise. The reaction was stirred for 30 minutes at -78 0C and then dry MeOH (2 mL) was added dropwise to quench the reaction. The solvents were evaporated under reduced pressure at a heating bath temperature of 20 0C. The residue was dissolved in DCM, washed once with cold water, passed through a phase separator and the solvents were removed at reduced pressure to give the title compound that was used without purification directly in the next reaction: MS (CI+) m/z 305, 307 [M+H]+. Example 28i
2-(3-Bromophenyl)-2-(6-methoxy-5-methylpyridin-3-yl)-4-methyI-lH-imidazole-
5(2H)-thione
Figure imgf000058_0001
To a solution of crude (3-bromophenyl)(6-methoxy-5-methylpyridin-3-yl)methanimine (0.750 g, 2.46 mmol) in dry MeOH (10 mL) under argon was added 2- oxopropanethioamide (0.406 g, 3.93 mmol) in one portion. The mixture was stirred at rt for 60 minutes and then the reaction was heated at 50 0C for 17 hours and then 13 hours at 60 0C to achieve full conversion. The reaction was allowed to cool to rt and the solvents were evaporated to give the title compound that was used without purification in the next reaction: MS (ES+) m/z 390, 392 (M+H)+.
Example 29i
2-(3-BromophenyI)-2-(6-methoxy-5-methylpyridin-3-yl)-5-methyl-2H-imidazol-4- amine
Figure imgf000058_0002
2-(3-Bromophenyl)-2-(6-methoxy-5-methylpyridin-3-yl)-4-methyl-lH-imidazole-5(2H)- thione (0.950 g, 2.43 mmol) was dissolved in ammonia (7M in MeOH, 12.17 mL, 85.19 mmol) and heated with microwaves in a sealed vial at 100 °C for 1 h. The solvents were evaporated in vacuo, another portion of ammonia (7M in MeOH, 12.17 mL, 85.19 mmol) was added and the reaction was heated with microwaves in a sealed vial at 100 0C for 1 h. The solvent was evaporated in vacuo and the residue was partiotioned between EtOAc (50 mL) and aqueous IM HCl (15 mL). The layers were separated and the organics extracted with aqueous IM HCl (2 x 15 mL). The aqueous phases were combined, EtOAc (~20 mL) was added, and the mixture was made basic with saturated aqueous NaHCO3. The product was extracted with dichloromethane (2 x 100 mL), dried (Na2SO4), filtered and evaporated to give 2-(3-bromophenyl)-2-(6-methoxy-5-memylpyridin-3-yl)-5-methyl-2H-imidazol-4- amine (0.440 g, 48% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 8.09 (d, 1 H) 7.62 (t, 1 H) 7.59 (d, 1 H) 7.51 (d, 1 H) 7.39 (m, 1 H) 7.24 (m, 1 H) 6.73 (br. s., 2 H) 3.81 (s, 3 H) 2.24 (s, 3 H) 2.08 (s, 3 H); MS (ES+) m/z 373, 375 [M+H]+. Example 3Oi
5-(4-Amino-2-(3-bromophenyl)-5-methyl-2H-imidazoI-2-yl)-3-methylpyridin-2(lH)- one
Figure imgf000059_0001
Aqueous 3M HCl (7.95 mL, 23.86 mmol) was added to a stirred solution of 2-(3- bromophenyl)-2-(6-methoxy-5-methylpyridin-3-yl)-5-memyl-2H-imidazol-4-amine (424 mg, 1.14 mmol) in tetrahydrofuran (8 mL) in a microwave vial. The vial was sealed and heated with microwaves at 100 0C for 45 minutes. The tetrahydrofuran was removed by evaporation, and the remaining aqueous phase basified with saturated aqueous NaHCθ3 and then extracted with EtOAc. The organics were combined, dried (Na2SO4), filtered and evaporated to give 540 mg of the title compound that was used as such in the next step: MS (ES+) m/z 359, 361 [M+H]+. Example 31i
(3-Bromo-4-fluorophenyl)(cyclopropyl)raethanimine
Figure imgf000060_0001
3-Bromo-4-fluorobenzonitrile (1.0 g, 5.00 mmol) was dissolved in THF (3 mL) and cyclopropylmagnesium bromide (0.5 M in THF, 11.00 mL, 5.50 mmol) was added dropwise, directly followed by addition of copper(I) bromide (0.014 g, 0.10 mmol). The mixture was heated to 40 0C for 19 h, cooled to rt and then ammonium acetate (0.578 g, 7.50 mmol) in methanol (5 mL) was added. The mixture was concentrated and then partitioned between DCM and water. The organic phase was collected, dried over Na2SO4 and concentrated to give 1.20 g (99% yield) of the title compound that was used directly in next step: MS (EI) m/z 240, 242 [M]+.
Example 32i
2-(3-Bromo-4-fluorophenyl)-2-cyclopropyl-4-methyl-lH-imidazole-5(2H)-thione
Figure imgf000060_0002
(3-Bromo-4-fluorophenyl)(cyclopropyl)methanimine (1.200 g, 4.96 mmol) was dissolved in dry methanol (7 mL) under argon, and 2-oxopropanethioamide (0.869 g, 8.43 mmol) was added in one portion. The solution was heated at 50 0C for 17 h. The reaction was allowed to cool to rt and the solvents were evaporated at reduced pressure. Silica chromatography using 0-100% EtOAc in n-heptane gave 0.506 g (31% yield) of the title compound: MS (ES) m/z 327, 329 [M+l]+. Example 33i
2-(3-Bromo-4-fluorophenyl)-2-cyclopropyl-5-methyI-2H-imidazol-4-amine
Figure imgf000061_0001
2-(3-Bromo-4-fluorophenyl)-2-cyclopropyl-4-methyl-lH-imidazole-5(2H)-thione (0.506 g, 1.55 mmol) and 7N ammonia in MeOH (15.46 mL, 108.25 mmol) were heated to 45 0C overnight. The mixture was concentrated and another portion of 7N ammonia in MeOH (15.46 mL, 108.25 mmol) was added, followed by heating as above. This cycle was repeated twice more. The reaction mixture was concentrated and purified by column chromatography with a gradient of 0-100% EtOAc in heptane to give 250 mg (52% yield) of the title compound: IH NMR (500 MHz, DMSO-4) δ ppm 7.76 (dd, 1 H) 7.51 - 7.67 (m, 1 H) 7.29 (t, 1 H) 6.57 (br. s., 2 H) 2.15 (s, 3 H) 1.42 - 1.51 (m, 1 H) 0.24 - 0.36 (m, 2 H) 0.15 - 0.26 (m, 1 H), -0.10 - 0.06 (m, 1 H); MS (ES+) m/z 310, 312 [M+H]+. Example 34i
l-(3-Bromophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanimine
Figure imgf000061_0002
Magnesium (0.668 g, 27.47 mmol) and 2 small crystals of I2 was stirred under Ar(g) for 5 min. THF (5 mL) was added followed by dropwise addition of 4-(bromomethyl)tetrahydro- 2H-ρyran (2.95 g, 16.48 mmol) in THF (10 mL). The mixture was heated at 45 0C for 1.5 h and then transferred to a flask containing 3-bromobenzonitrile (2 g, 10.99 mmol) and coρper(I) bromide (0.032 g, 0.22 mmol) in THF (4 mL). The mixture was heated to 45 0C for 2 h. Ammonium acetate (1.270 g, 16.48 mmol) in methanol (7 mL) was added and after 10 min DCM and water was added. The organic phase was dried over MgSO4 and concentrated to give 3.05 g (98% yield) ot the title compound that was used directly in the next step: MS(CI) m/z 282, 284 [M+l]+. Example 35i
2-(3-Bromophenyl)-4-methyl-2-((tetrahydro-2H-pyran-4-yI)methyl)-lH-imidazoIe- 5(2H)-thione
Figure imgf000062_0001
The title compound was synthesized as described for Example 24i in 76% yield starting from l-(3-bromophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanimine (3.05 g, 10.81 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 12.73 (s, 1 H) 7.68 (s, 1 H) 7.50 - 7.57 (m, 2 H) 7.37 (t, 1 H) 3.71 (t, 2 H) 3.09 - 3.18 (m, 2 H) 2.25 (s, 3 H) 2.04 - 2.10 (m, 1 H) 1.85 - 1.91 (m, 1 H) 1.45 (d, 1 H) 1.33 (d, 1 H) 1.20 - 1.30 (m, 1 H) 1.09 - 1.19 (m, 2 H). MS (ES) m/z 367, 369 [M+l]+.
Example 36i
2-(3-BromophenyI)-5-methyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-imidazol-4-
Figure imgf000062_0002
The title compound was synthesized as described for Example 13 in 35% yield starting from 2-(3-bromophenyl)-4-memyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-lH-imidazole- 5(2H)-thione (3.01 g, 8.19 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.66 (t, 1 H) 7.53 - 7.58 (m, 1 H) 7.38 - 7.43 (m, 1 H) 7.25 (t, 1 H) 6.48 (s, 2 H) 3.64 - 3.72 (m, 2 H) 3.06 - 3.15 (m, 2 H) 2.15 (s, 3 H) 1.83 (dd, 1 H) 1.60 (dd, 1 H) 1.43 - 1.50 (m, 1 H) 1.34■ 1.41 (m, 1 H) 1.20 - 1.30 (m, 1 H) 0.98 - 1.11 (m, 2 H); MS (ES) m/z 350, 352 [M+l]+.
Example 37i
(3-Bromophenyl)(cycIobutyI)methanimine
Figure imgf000063_0001
The title compound was synthesized as described for Example 34i in 97% yield starting from bromocyclobutane (1.061 g, 7.86 mmol) and 3-bromobenzonitrile (1.1 g, 6.04 mmol): MS (CI) m/z 238, 240 [M+l]+.
Example 38i
2-(3-Bromophenyl)-2-cyclobutyl-4-methyl-lH-imidazoIe-5(2H)-thione
Figure imgf000063_0002
The title compound was synthesized as described for Example 24i in 65% yield starting from (3-bromophenyl)(cyclobutyl)methanimine (1.4 g, 5.88 mmol): 1H NMR (500 MHz, DMSCW6) δ ppm 12.77 (br. s., 1 H) 7.66 (t, 1 H) 7.53 - 7.56 (m, 1 H) 7.49 - 7.52 (m, 1 H) 7.34 - 7.39 (m, 1 H) 3.05 - 3.13 (m, 1 H) 2.27 (s, 3 H) 1.66 - 1.78 (m, 4 H) 1.53 - 1.66 (m, 2 H); MS (ES) m/z 323, 325 [M+l]+. Example 39i
2-(3-Bromophenyl)-2-cyclobutyl-5-methyl-2H-imidazol-4-amine
Figure imgf000063_0003
The title compound was synthesized as described for Example 13 in 38% yield starting from 2-(3-bromophenyl)-2-cyclobutyl-4-methyl-lH-imidazole-5(2H)-thione (1.24 g, 3.84 mmol): 1H NMR (500 MHz, DMSCW6) δ ppm 7.67 (t, 1 H) 7.53 - 7.58 (m, 1 H) 7.37 - 7.42 (m, 1 H) 7.24 (t, 1 H) 6.53 (s, 2 H) 2.88 - 2.97 (m, 1 H) 2.18 (s, 3 H) 1.47 - 1.70 (m, 6 H); MS (ES) m/z 306, 308 [M+l]+.
Example 4Oi
l-(3-Bromophenyl)-2-methyIpropan-l-imine
Figure imgf000064_0001
The title compound was synthesized as described for Example 23i in 90% yield starting from isopropylmagnesium bromide (15.28 mL, 15.28 mmol) and 3-bromobenzonitrile (2.14 g, 11.76 mmol): MS (CI) m/z 226, 228 [M+l]+.
Example 41i
2-(3-Bromophenyl)-2-isopropyl-4-methyl-lH-imidazole-5(2H)-thione
Figure imgf000064_0002
The title compound was synthesized as described for Example 24i in 52% yield starting from l-(3-bromophenyl)-2-methylpropan-l-imine (2.4 g, 10.61 mmol): 1HNMR (SOO MHz, DMSO-J6) δ ppm 12.72 (br. s., 1 H) 7.67 (t, 1 H) 7.53 - 7.57 (m, 1 H) 7.50 - 7.53 (m, 1 H) 7.35 - 7.39 (m, 1 H) 2.33 - 2.41 (m, 1 H) 2.25 (s, 3 H) 0.69 - 0.76 (m, 6 H); MS (ES) m/z 311, 313 [M+l]+.
Example 42i
2-(3-Bromophenyl)-2-isopropyl-5-methyl-2H-imidazol-4-amine
Figure imgf000065_0001
The title compound was synthesized as described for Example 13 in 41% yield starting from 2-(3-bromophenyl)-2-isopropyl-4-methyl-lH-imidazole-5(2H)-thione (1.7 g, 5.46 mmol): 1H NMR (500 MHz, DMS(W6) δppm 7.66 (t, 1 H) 7.52 - 7.57 (m, 1 H) 7.38 - 7.43 (m, 1 H) 7.25 (t, 1 H) 6.49 (br. s., 2 H) 2.16 (s, 3 H) 2.09 - 2.15 (m, 1 H) 0.72 (d, 3 H) 0.61 (d, 3 H); MS (ES) m/z 294, 296 [M+l]+.
Example 43i
Cyclohexyl(4-methox>phenyl)methanimine
Figure imgf000065_0002
The title compound was synthesized as described for Example 34i in 97% yield starting from bromocyclohexane (0.796 g, 4.88 mmol) and 4-methoxybenzonitrile (0.5 g, 3.76 mmol): MS (CI) m/z 218 [M+l]+.
Example 44i
2-Cyclohexyl-2-(4-methoxyphenyl)-4-methyl-lH-imidazole-5(2H)-tliione
Figure imgf000065_0003
The title compound was synthesized as described for Example 24i in 49% yield starting from cyclohexyl(4-memoxyphenyl)memanimine (0.8 g, 3.68 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 12.65 (s, 1 H) 7.32 - 7.40 (m, 2 H) 6.87 - 6.95 (m, 2 H) 3.72 (s, 3 H) 2.21 (s, 3 H) 1.88 - 1.95 (m, 1 H) 1.57 - 1.67 (m, 2 H) 1.50 - 1.57 (m, 1 H) 1.33 - 1.42 (m, 2 H) 1.01 - 1.14 (m, 2 H) 0.90 - 1.01 (m, 1 H) 0.77 - 0.89 (m, 2 H); MS (ES) m/z 303
[M+lf. Example 45i
Cycloheptyl(4-methoxyphenyl)methanimine
Figure imgf000066_0001
The title compound was synthesized as described for Example 34i in 90% yield starting from bromocycloheptane (0.864 g, 4.88 mmol) and 4-methoxybenzonitrile (0.5 g, 3.76 mmol): MS (CI) m/z 232 [M+l]+.
Example 46i
2-CycIoheptyI-2-(4-methoxyphenyl)-4-methyl-lH-imidazoIe-5(2H)-thione
Figure imgf000066_0002
The title compound was synthesized as described for Example 24i in 39% yield starting from cycloheptyl(4-memoxyphenyl)memanimine (0.78 g, 3.37 mmol): 1H NMR (500 MHz, DMSCW6) δ ppm 12.62 (br. s., 1 H) 7.33 - 7.40 (m, 2 H) 6.89 - 6.95 (m, 2 H) 3.74 (s, 3 H) 2.23 (s, 3 H) 2.17 - 2.22 (m, 1 H) 1.34 - 1.57 (m, 8 H) 1.26 - 1.31 (m, 2 H) 0.96 - 1.12 (m, 2 H); MS (ES) m/z 317 [M+l]+.
Example 47i
BicycIo[2.2.1|heptan-2-yl(4-methoxyphenyl)methanimine
Figure imgf000066_0003
The title compound was synthesized as described for Example 34i in 90% yield starting from (lR,2R,4S)-2-bromobicyclo[2.2.1]heptane (0.657 g, 3.76 mmol) and A- methoxybenzonitrile (0.5 g, 3.76 mmol): MS (EI) m/z 229 [M]+. Example 48i
2-(Bicyclo[2.2.1]heptan-2-yl)-2-(4-methoxyphenyI)-4-methyl-lH-imidazole-5(2H)- thione
Figure imgf000067_0001
The title compound was synthesized as described for Example 24i in 10% yield starting from (lS,2S,4R)-bicyclo[22J]heptoi-2-yl(4-methoxyphenyl)methanimine (0.9 g, 3.92 mmol): 1HNMR (500 MHz, DMS(W6) δ ppm 12.62 (br. s., 1 H) 7.39 - 7.45 (m, 2 H) 6.89 - 6.95 (m, 2 H) 3.73 - 3.75 (m, 3 H) 2.23 - 2.27 (m, 3 H) 2.15 - 2.22 (m, 1 H) 2.10 - 2.14 (m, 1 H) 1.77 - 1.85 (m, 1 H) 1.30 - 1.46 (m, 2 H) 1.21 - 1.30 (m, 2 H) 1.14 - 1.21 (m, 1 H) 1.00 - 1.10 (m, 2 H) 0.90 - 0.98 (m, 1 H); MS (ES) m/z 315 [M+l]+.
Example 49i
Cyclooctyl(4-methoxyphenyl)methanimine
Figure imgf000067_0002
The title compound was synthesized as described for Example 34i in 85% yield starting from bromocyclooctane (0.933 g, 4.88 mmol) and was used directly in the next step.
Example 5Oi
2-Cydooctyl-2-(4-methoxyphenyl)-4-methyl-lH-imidazoIe-5(2H)-thione
Figure imgf000067_0003
The title compound was synthesized as described for Example 24i in 4% yield starting from cyclooctyl(4-methoxyphenyl)meώanimine (0.9 g, 3.67 mmol): 1H NMR (500 MHz, DMSO-4) δ ppm 12.44 (br. s., 1 H) 7.21 - 7.26 (m, 2 H) 6.77 - 6.81 (m, 2 H) 3.60 (s, 3 H) 2.16 - 2.21 (m, 1 H) 2.09 (s, 3 H) 1.21 - 1.45 (m, 10 H) 1.03 - 1.19 (m, 4 H); MS (ES) m/z 331 [M+l]+. Example 511
l-(4-Methoxyphenyl)-4-phenylbutan-l-imine
Figure imgf000068_0001
The title compound was synthesized as described for Example 34i in 100% yield starting from (3-bromopropyl)benzene (1 g, 5,02 mmol) and 4-methoxybenzonitrile (0,669 g, 5,02 mmol): MS (CI) m/z 254 [M+l]+.
Example 52i
2-(4-Methoxyphenyl)-4-methyl-2-(3-phenylpropyl)-lH-imidazole-5(2H)-thione
Figure imgf000068_0002
The title compound was synthesized as described for Example 24i in 63% yield starting from l-(4-methoxyphenyl)-4-phenylbutan-l-imine (0.5 g, 1.97 mmol): 1H NMR (500 MHz, CDCl3) δ ppm 9.14 (br. s., 1 H) 7.24 - 7.29 (m, 4 H) 7.16 - 7.22 (m, 1 H) 7.08 - 7.13 (m, 2 H) 6.84 - 6.91 (m, 2 H) 3.80 (s, 3 H) 2.54 - 2.65 (m, 2 H) 2.38 (s, 3 H) 2.13 - 2.18 (m, 2 H) 1.43 - 1.60 (m, 2 H); MS (ES) m/z 339 [M+l]+.
Example 53i
4-(3-Methoxyphenyl)-l-(4-methoxyphenyl)butan-l-imine
Figure imgf000069_0001
The title compound was synthesized as described for Example 34i in 100% yield starting from l-(3-bromopropyl)-3-methoxybenzene (0.516 g, 2.25 mmol) and 4- methoxybenzonitrile (0.3 g, 2.25 mmol): MS (CI) m/z 284 [M+l]+.
Example 54i
2-(4-Methoxyphenyl)-2-(3-(3-methoxyphenyl)propyl)-4-methyl-lH-imidazole-5(2H)- thione
Figure imgf000069_0002
The title compound was synthesized as described for Example 24i in 32% yield starting from 4-(3-methoxyphenyl)-l-(4-methoxyphenyl)butan-l-imine (0.64 g, 2.26 mmol): 1H NMR (500 MHz, DMS(W6) δ ppm 12.69 (s, 1 H) 7.32 - 7.38 (m, 2 H) 7.16 (t, 1 H) 6.89 6.94 (m, 2 H) 6.70 - 6.74 (m, 1 H) 6.64 - 6.70 (m, 2 H) 3.73 (s, 3 H) 3.70 (s, 3 H) 2.45 - 2.49 (m, 2 H) 2.22 (s, 3 H) 1.93 - 2.01 (m, 2 H) 1.28 - 1.36 (m, 2 H); MS (ES) m/z 369 [M+l]+.
Example 55i
2-Bromo-4-(prop-l-ynyI)pyridine
Figure imgf000069_0003
To a solution of 2-bromo-4-iodopyridine (2 g, 7.04 mmol), copper(I) iodide (0.080 mL, 2.11 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.407 g, 0.35 mmol) in toluene (85 mL) was added l-(trimethylsilyl)-l-propyne (1.054 mL, 7.04 mmol), triethylamine (3.24 mL, 23.25 mmol) and tetrabutylammonium fluoride (1 M in THF, 7.04 mL, 7.04 mmol) and the resulting mixture was stirred under an argon atmosphere at room
temperature over night. The mixture was concentrated and the resulting residue was partitioned between water (10 mL) and dichloromethane (10 mL) and poured into a phase separator. The organic phase was collected and the aqueous phase was extracted once with dichloromethane (10 mL). The combined organics were concentrated and purified by silica gel chromatography using 0% to 30% ethyl acetate in heptane to give 2-bromo-4-(prop-l- ynyl)pyridine (1.195 g, 87% yield): 1H NMR (500 MHz, DMSCM5) δ ppm 8.35 (dd, 1 H) 7.65 (s, 1 H) 7.42 (dd, 1 H) 2.11 (s, 3 H); MS (ES+) m/z 196, 198 [M+H]+; MS (APCI+) m/z 196, 198 [M+H]+
Example 56i
4-(Prop-l-ynyI)-2-(trimethyIstannyI)pyridine
Figure imgf000070_0001
2-Bromo-4-(prop-l-ynyl)pyridine (1.077 g, 5.49 mmol) was dissolved in toluene (30 mL) and 1,1,1,2,2,2-hexamethyldistannane (2.278 mL, 10.99 mmol) and
tetrakis(triphenylphosphine)palladium(0) (0.635 g, 0.55 mmol) were added and the reaction was stirred at 80 0C over night under argon atmosphere. The mixture was cooled to room temperature and filtered through a pad of Celite and concentrated in vacuo.
Toluene (20 mL) was added and the mixture was concentrated in vacuo to yield the title comound that was used as such in the next step: MS (APCI+) m/z 282 (M+H)+.
Example 57i
(3-Bromo-4-methoxyphenyl)(cyclopropyl)methanimine
Figure imgf000070_0002
3-Bromo-4-methoxybenzonitrile (2.00 g, 9.43 mmol) and copper(I) bromide (0.068 g, 0.47 mmol) were dissolved in THF (15.0 mL) under argon and then heated to 40 0C.
Cyclopropylmagnesium bromide (0.5 M in THF) (20.75 mL, 10.38 mmol) was added. The resulting mixture was stirred at 40 0C for 3 h, then additional cyclopropylmagnesium bromide (0.5 M in THF) (9.43 mL, 4.72 mmol) was added and the resulting mixture was stirred at 40 °C for 2 h. The reaction was quenched by addition of ammonium acetate (1.091 g, 14.15 mmol) in methanol (30.0 mL). The mixture was partitioned between water and dichloromethane (twice). The organic layers were collected and concentrated in vacuo to give crude (3-bromo-4-methoxyphenyl)(cyclopropyl)methanimine (2.57 g,quantitative yield) That was used as such in the next step: MS (APCI+) m/z 254, 256 [M+H]+.
Example 58i
2-(3-Bromo-4-methoxyphenyl)-2-cycIopropyl-4-methyl-lH-imidazoIe-5(2H)-thione
Figure imgf000071_0001
(3-Bromo-4-methoxyphenyl)(cyclopropyl)memanimine (2.57 g, 10.11 mmol) and 2- oxopropanethioamide (1.773 g, 17.19 mmol) were stirred in MeOH (10 mL) at 50 °C for 4 h, then the mixture was concentrated in vacuo. Purification was achieved by silica chromatography using 0% to 20% ethyl acetate in heptane, then by silica chromatography using isocratic elution with dichloromethane to give 2-(3-bromo-4-methoxyphenyl)-2- cyclopropyl-4-methyl-lH-imidazole-5(2H)-thione (1.780 g, 52% yield) : 1H NMR (500 MHz, DMSCW6) δ ppm 12.53 (s, 1 H) 7.67 (d, 1 H) 7.48 (dd, 1 H) 7.14 (d, 1 H) 3.84 (s, 3 H) 2.23 (s, 3 H) 1.52 - 1.61 (m, 1 H) 0.43 - 0.55 (m, 2 H) 0.32 - 0.42 (m, 1 H) 0.15 - 0.24 (m, 1 H); MS (ES+) m/z 339, 341 [MH-H]+. Example 59i
2-(3-Bromo-4-methoxyphenyl)-2-cyclopropyl-5-methyl-2H-imidazol-4-amine
Figure imgf000072_0001
2-(3-Bromo-4-me1hoxyphenyl)-2-cyclopropyl-4-methyl-lH-imidazole-5(2H)-thione (0.780 g, 2.30 mmol) and ammonia (7 N in MeOH, 10 mL, 70.00 mmol) were added to a microwave vial and irradiated in a microwave reactor at 110 °C for 1 h. The solvent was evaporated, ammonia (7 N in MeOH, 10 mL, 70.00 mmol) was added and the mixture was irradiated in a microwave reactor at 110 0C for 2 h. The solvent was evaporated, ammonia (7 N in MeOH, 10 mL, 70.00 mmol) was added and the mixture was irradiated in a microwave reactor at 110 0C for 1 h. This cycle was repeated three more times, then the reaction mixture was concentrated in vacuo. The product was purified by silica
chromatography using 0% to 100% ethyl acetate in heptane to give 2-(3-bromo-4- methoxyphenyl)-2-cyclopropyl-5-methyl-2H-imidazol-4-amine (0.486 g, 66% yield): 1H NMR (500 MHz, DMSCW6) δ ppm 7.66 (d, 1 H) 7.52 (dd, 1 H) 7.02 (d, 1 H) 6.48 (s, 2 H) 3.81 (s, 3 H) 2.14 (s, 3 H) 1.43 (tt, 1 H) 0.23 - 0.33 (m, 2 H) 0.16 - 0.23 (m, 1 H) -0.07 - 0.01 (m, 1 H); MS (ES+) m/z 322, 324 [M+H]+.
Example 6Oi
4-(4-Amino-2-cyclopropyl-5-methyI-2H-imidazol-2-yl)-2-broiiiophenol
Figure imgf000072_0002
2-(3-Bromo-4-methoxyphenyl)-2-cyclopropyl-5-methyl-2H-imidazol-4-amine (0.07 g, 0.22 mmol) was dissolved in dichloromethane (3.00 mL) and boron tribromide (0.144 mL, 1.52 mmol) was added. The reaction mixture was stirred at room temperature over night. The reaction was quenched by dropwise addition of MeOH (2 mL). NH4OH (28-30 wt% NH3 in water, 1 mL) was added. The resulting mixture was stirred for 5 min. HCl was added dropwise until pH approximately 7. Additional dichloromethane was added and the organic layer was collected. The water phase was extracted with dichloromethane. NaCl was added and the water phase was extracted with acetonitrile (three times). The combined organic layers were dried (Na2SC>4), filtered and concentrated in vacuo to give crude 4-(4- amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2-bromophenol (0.154 g) that was used as such in the next step: MS (ES+) m/z 308, 310 [MH-H]+. Example 61i
2-Cyclopropyl-2-(4-methoxy-3-(pyrazin-2-yl)phenyl)-5-methyl-2H-imidazoI-4-amine
Figure imgf000073_0001
2-(Tributylstannyl)pyrazine (0.098 mL, 0.31 mmol), 2-(3-bromo-4-methoxyphenyl)-2- cyclopropyl-5-methyl-2H-imidazol-4-amine (0.100 g, 0.31 mmol) and
tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.03 mmol) were dissolved in anhydrous DMF (2.00 mL) in a dry microwave vial under argon atmosphere. The mixture was irradiated in a microwave reactor for 30 min at 150 0C. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC to give 2-cyclopropyl-2-(4- methoxy-3-(pyrazin-2-yl)phenyl)-5-methyl-2H-imidazol-4-amine (0.080 g, 46% yield): 1H NMR (500 MHz, DMSO-^6) δ ppm 9.07 (d, 1 H), 8.72 - 8.75 (m, 1 H), 8.54 (d, 1 H), 7.98 (d, 1 H), 7.67 (dd, 1 H), 7.12 (d, 1 H), 6.48 (br. s., 2 H), 3.85 (s, 3 H), 2.14 (s, 3 H), 1.43 - 1.50 (m, 1 H), 0.24 - 0.33 (m, 2 H), 0.17 - 0.24 (m, 1 H), -0.05 - 0.03 (m, 1 H) ; MS (ES+) m/z 322 [M+H]+. Example 62i
2-Cyclopropyl-2-(4-methoxy-3-(4-(prop-l-ynyl)pyridin-2-yl)phenyl)-5-methyl-2H- imidazoI-4-amine
Figure imgf000074_0001
4-(Prop-l-ynyl)-2-(trimethylstannyl)pyridine (0.313 g, 1.12 mmol), 2-(3-bromo-4- methoxyphenyl)-2-cyclopropyl-5-methyl-2H-imidazol-4-amine (0.120 g, 0.37 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.04 mmol) were dissolved in anhydrous DMF (2.00 mL) in a dry microwave vial under argon atmosphere. The reaction mixture was irradiated in a microwave reactor for 30 min at 150 0C. The mixture was then filtered through a syringe filter and purified by prep-HPLC, then by silica chromatography using 0% to 10% (3.5 M ammonia in methanol) in dichloromethane to give 2-cyclopropyl- 2-(4-memoxy-3-(4-(prop-l-ynyl)pyridin-2-yl)phenyl)-5-methyl-2H-imidazol-4-amine (0.016 g, 12 % yield) : 1H NMR (500 MHz, DMSO-<4) δ ppm 8.62 (dd, 1 H), 7.95 (d, 1 H), 7.75 (s, 1 H), 7.60 (dd, 1 H), 7.27 (dd, 1 H), 7.06 (d, 1 H), 6.43 (tar. s., 2 H), 3.82 (s, 3 H), 2.14 (s, 3 H), 2.11 (s, 3 H), 1.41 - 1.49 (m, 1 H), 0.24 - 0.32 (m, 2 H), 0.15 - 0.23 (m, 1 H), -0.05 - 0.02 (m, 1 H); MS (ES+) m/z 359 [M+H]+. Example 63i
2-CyclopropyI-2-(2',5t-dichloro-6-methoxybiphenyl-3-yI)-5-methyl-2H-imidazol-4- amine
Figure imgf000075_0001
2,5-Dichlorobenzeneboronic acid (62.2 mg, 0.33 mmol), 2-(3-bromo-4-methoxyphenyl)-2- cyclopropyl-5-methyl-2H-imidazol-4-amine (70 mg, 0.22 mmol), [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride (8.94 mg, 10.86 μmol), cesium carbonate (212 mg, 0.65 mmol) and DME:EtOH:Water 6:3:1 (3.00 mL) were put in a microwave vial and irradiated in a microwave reactor at 150 0C for 30 min. Additional 2,5- dichlorobenzeneboronic acid (41.5 mg, 0.22 mmol) was added and the resulting mixture was irradiated in a microwave reactor at 150 0C for 30 min. Additional [1,1*- bis(diphenylphosphino)ferrocene]palladium(II) chloride (8.94 mg, 10.86 μmol) was added and the resulting mixture was irradiated in a microwave reactor at 150 0C for 30 min. The reaction mixture was concentrated in vacuo. The residue was redissolved in
dichloromethane and methanol, filtered and concentrated in vacuo. The product was purified by silica chromatography using 0% to 10% (3.5 M ammonia in methanol) in dichloromethane. The desired fractions were pooled and concentrated in vacuo. Impure fractions of the title compound were pooled and concentrated in vacuo and then purified by silica chromatography using 0% to 10% (3.5 M ammonia in methanol) in dichloromethane. All fractions containing the title compound were pooled and concentrated in vacuo to give 2-cyclopropyl-2-(2^5'-dicriloro-6-memoxybiphenyl-3-yl)-5-methyl-2H-imidazol-4-amine (0.060 g, 72% yield, containing an unidentified biproduct): MS (ES-) m/z 387 [M-H]'.
Example 64i
5-(DiallyIamino)-2-fluorobenzonitriIe
Figure imgf000076_0001
Allyl bromide (4.66 mL, 55.10 mmol), 5-amino-2-fluorobenzonitrile (3.00 g, 22.04 mmol) and sodium carbonate (0.942 mL, 22.48 mmol) were dissolved in ethanol (70.00 mL) and water (20.00 mL) and refluxed over night. The reaction mixture was allowed to cool to room temperature and the ethanol was then evaporated in vacuo. The remaining water mixture was extracted with diethyl ether (twice). The combined organic layers were passed through a phase separator and concentrated in vacuo. The product was purified by silica chromatography using 0% to 50% ethyl acetate in heptane to give 5-(diallylamino)~ 2-fluorobenzonitrile (3.31 g, 70% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.22 - 7.32 (m, 1 H), 6.91 - 7.04 (m, 2 H), 5.76 - 5.88 (m, 2 H), 5.08 - 5.22 (m, 4 H), 3.95 (d, 4 H); MS (ES+) m/z 217 [M+H]+.
Example 65i
N,N-DiaIIyl-3-(cy clopropy l(imino)methyl)-4-fluoroaniline
Figure imgf000076_0002
5-(Diallylamino)-2-fluorobenzonitrile (3.311 g, 15.31 mmol) and copper(I) bromide (0.110 g, 0.77 mmol) were dissolved in THF (25.0 mL) under argon. Cyclopropylmagnesium bromide (0.5 M in THF, 33.7 mL, 16.84 mmol) was added dropwise. The mixture was heated to 50 0C and stirred for 6.5 h. Additional cyclopropylmagnesium bromide (0.5 M in THF) (30.6 mL, 15.31 mmol) was added and the resulting mixture was stirred at 50 °C over night. The reaction was quenched by addition of methanol (15.0 mL) and then stirred for 10 min, and then the solvents were removed in vacuo. The residue was partitioned between water and dichloromethane (twice). The combined organic layers were dried (Na2SC>4), filtered through a pad of Celite and concentrated in vacuo to give crude
NjN-diallyl-S-CcyclopropylOmino^ethy^^-fluoroaniline (4.04 g) that was used as such in the next step: MS (APCI+) m/z 259 [M+H]+. Example 66i
2-CyclopropyI-2-(5-(diallylamino)-2-jE[uorophenyl)-4-methyl-lH-imidazole-5(2H)- thione
Figure imgf000077_0001
N,N-Diallyl-3-(cyclopropyl(imino)methyl)-4-fluoroaniline (4 g, 15.48 mmol) and 2- oxopropanethioamide (2.71 g, 26.32 mmol) were stirred in MeOH (50.0 mL) at 40 0C over night, then the mixture was concentrated in vacuo. The product was purified by silica chromatography using 0% to 40% ethyl acetate in heptane to give 2-cyclopropyl-2-(5- (diallylamino)-2-fluorophenyl)-4-methyl-lH-imidazole-5(2H)-thione (3.02 g, 57% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 12.21 (s, 1 H), 6.90 - 7.01 (m, 2 H), 6.63 (dt, 1 H), 5.83 (ddt, 2 H), 5.10 - 5.23 (m, 4 H), 3.91 (d, 4 H), 2.20 (s, 3 H), 1.77 (tt, 1 H), 0.52 (dqd, 2 H), 0.40 (dq, 1 H), 0.13 - 0.21 (m, 1 H); MS (ES-) m/z 342 [M-H]".
Example 67i
2-Cyclopropyl-2-(5-(diallylamino)-2-fluorophenyl)-5-methyl-2H-iinidazol-4-amine
Figure imgf000078_0001
2-Cyclopropyl-2-(5-(diallylamino)-2-fluorophenyl)-4-methyl-lH-imidazole-5(2H)-thione (1.00 g, 2.91 mmol) and ammonia (7 N in MeOH, 13 mL, 91.00 mmol) were added to a microwave vial and irradiated in a microwave reactor at 110 0C for 1 h. The solvent was evaporated, ammonia (7 N in MeOH, 13 mL, 91.00 mmol) was added and the mixture irradiated in a microwave reactor at 110 0C for 1 h. This cycle (evaporation, addition of ammonia and irradiation) was repeated six more times, then the mixture was concentrated in vacuo. The produc twas purified by silica chromatography using 0% to 100% ethyl acetate in heptane to give 2-cyclopropyl-2-(5-(diallylamino)-2-fiuorophenyl)-5-methyl-2H- imidazol-4-amine (0.734 g, 77% yield): 1H NMR (500 MHz, DMSO-^6) δ ppm 6.90 - 6.95 (m, 1 H), 6.83 (dd, 1 H), 6.42 - 6.53 (m, 3 H), 5.80 (ddt, 2 H), 5.09 - 5.19 (m, 4 H), 3.83 (d, 4 H), 2.12 (s, 3 H), 1.70 - 1.81 (m, 1 H), 0.26 - 0.36 (m, 2 H), 0.12 - 0.20 (m, 1 H), -0.12 - - 0.04 (m, 1 H); MS (ES-) m/z 325 [M-H]".
Example 68i
2-(5-Amino-2-fluorophenyl)-2-cyclopropyl-5-methyl-2H-imidazol-4-amine
Figure imgf000078_0002
1,3-Dimethylbarbituric acid (0.580 g, 3.71 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.072 g, 0.06 mmol) were put in a microwave vial under argon. 2-Cyclopropyl-2-(5-(diallylamino)-2-fluorophenyl)-5-methyl-2H- imidazol-4-amine (0.202 g, 0.62 mmol) in dichloromethane (5.00 mL) was added. The resulting mixture was irradiated in a microwave reactor for 40 min at 100 0C, and then concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate (sat.) and ethyl acetate . NaCl was added to the water phase, that was extracted with ethyl acetate (three times), and then with acetonitrile (three times), the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The produc twas purified by silica chromatography using 0% to 10% (3.5 M ammonia in methanol) in
dichloromethane to give 2-(5-amino-2-fluorophenyl)-2-cyclopropyl-5-methyl-2H- imidazol-4-amine (0.044 g, 29% yield): 1H NMR (500 MHz, DMSO-^6) δ ppm 6.67 - 6.75 (m, 2 H), 6.42 (br. s., 2 H), 6.38 (dt, 1 H), 4.81 (s, 2 H), 2.12 (s, 3 H), 1.69 - 1.78 (m, 1 H), 0.24 - 0.36 (m, 2 H), 0.09 - 0.21 (m, 1 H), -0.16 - -0.03 (m, 1 H); MS (ES+)
m/z 247 [MH-H]+.
Example 69i
2-Oxopropanethioamide
Figure imgf000079_0001
A solution of acetyl cyanide (140 mL, 1764.24 mmol) in 2-methyltetrahydrofuran (850 mL) was stirred at -10 0C as hydrogen sulfide (Sigma- Aldrich lecture bottle) was bubbled through the solution. The addition of hydrogen sulfide was stopped after 15 min and to the stirred mixture, triethylamine (1.230 mL, 8.82 mmol) in 2-methyltetrahydrofuran (13 mL) was added slowly over 30 min (exothermic reaction). Hydrogen sulfide addition was continued for 3 h at 5 0C, 3 h at 10 0C and overnight at 15 0C. Nitrogen gas was bubbled though the solution for 30 min, followed by evaporation of the volatiles. To the residue was added a mixture of heptane (100 mL) and ethyl acetate (100 mL). A solid was filtered off (79 g, 43% yield) and the filtrate was purified by a short-plug silica gel
chromatography, eluting with 50% ethylacetate in heptane to give 79 g (43% yield) of the title compound. Both crops ( in total 158 g, 87% yield) contained the title product of adequate purity according to GC-MS: MS (ES+) m/z 104 [M+l]. Example 7Oi
2-(3-Aminophenyl)-2-cyclopropyl-5-methyI-2H-imidazol-4-amine
Figure imgf000080_0001
To a solution of 2-(3-bromophenyl)-2-cyclopropyl-5-methyl-2H-inύdazol-4-amine (248 mg, 0.85 mmol) in dry dimethylsulfoxide (4 mL) in a microwave vial was added copper(I) iodide (32.3 mg, 0.17 mmol), trans-4-hydroxy-L-proline (44.5 mg, 0.34 mmol) and potassium carbonate (0.145 mL, 2.55 mmol). The vial was filled with argon and then ammonia (25% aqueous solution, 0.979 mL, 12.73 mmol) was added. The vial was sealed and heated in an oil-bath at 60 0C for 21 hours. LCMS analysis indicated low conversion so dimethylsulfoxide (1.0 mL), copper(I) iodide (32.3 mg, 0.17 mmol), trans-4-hydroxy-L- proline (44.5 mg, 0.34 mmol) and ammonia (25% aqueous solution, 1.0 mL, 1.3 mmol) was added and the heating continued at 60 0C for another ~90 hours. The reaction mixture was diluted with water and brine and the product extracted with EtOAc. The product was extracted with aqueous 1 M HCl, the aqueous phase basified with saturated aqueous NaHCθ3 (pH ~9), the basic solution saturated with NaCl and the product extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated to give the title compound (157 mg, 81% yield): 1H NMR (500 MHz, DMSO-^6) δ ppm 6.87 (t, 1 H) 6.78 (t, 1 H) 6.72 (m, 1 H) 6.36 (m, 1 H) 6.32 (s, 2 H) 4.90 (s, 2 H) 2.11 (s, 3 H) 1.41 (m, 1 H) 0.26 (m, 2 H) 0.14 (m, 1 H) -0.07 (m, 1 H); MS (ES+) m/z 229 [MH-H]+.
Example 1
2-(3'-Methoxybiphenyl-3-yl)-2,5-dimethyl-2H-imidazoI-4-amine
Figure imgf000081_0001
2-(3-Bromophenyl)-2,5-dimethyl-2H-imida2ol-4-amine (41.4 mg, 0.16 mmol), 3- methoxyphenylboronic acid (28.4 mg, 0.19 mmol) and bis(triphenylphosphine)- palladium(II) chloride (10.92 mg, 0.02 mmol) were taken up in DME (2 mL) and water (1 mL). Sodium carbonate (IM in water) (0.389 mL, 0.39 mmol) was added and the reaction was heated to 80 °C for 2 h. Preparative HPLC yielded 21 mg (46.0% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (t, 1 H) 7.58 - 7.64 (m, 1 H) 7.46 - 7.51 (m, 1 H) 7.40 (t, 1 H) 7.35 (t, 1 H) 7.20 (ddd, 1 H) 7.15 (dd, 1 H) 6.89 (ddd, 1 H) 3.87 (s, 3 H) 2.29 (s, 3 H) 1.74 (s, 3 H); MS (ES+) m/z 294 [M+H]+.
Example 2
(R)-2-(3'-Methoxybiphenyl-3-yl)-2,5-dimetliyl-2H-imidazol-4-amine
Figure imgf000081_0002
Chromatographic separation of the enantiomers of 2-(3'-Methoxybiphenyl-3-yl)-2,5- dimemyl~2H-imidazol-4-amine. 2-(3'-Methoxybiphenyl-3-yl)-2,5-dimethyl-2H-imidazol- 4-amine (15 mg, 0.05 mmol) was dissolved in methanol (1 mL) and the resulting solution was injected on a Chiralpak AD column (21.2 x 250 mm), using methanol/Cθ2 (25:75) + 0.1% diethylamine as eluent at a flow rate of 50 mL/min. The title compound was the first to elute and was concentrated in vacuo to yield 5.1 mg (34% yield): 1H NMR (400 MHz, methanol-^) δ ppm 7.69 (s, 1 H) 7.45 (t, 2 H) 7.27 - 7.36 (m, 2 H) 7.13 (d, 1 H) 7.10 (d, 1 H) 6.87 (dd, 1 H) 3.81 (s, 3 H) 2.27 (s, 3 H) 1.66 (s, 3 H); MS (ES+) m/z 294 [M+H]+. Example 3
2,5-DimethyI-2-(3-(pyridin-3-yl)phenyL)-2H-imidazol-4-amine
Figure imgf000082_0001
2-(3-Bromophenyl)-2,5-dimethyl-2H-iniidaκol-4-amine (40 mg, 0.15 mmol), pyridin-3- ylboronic acid (36.9 mg, 0.30 mmol) and bis(triphenylphosphine)palladium(II) chloride (10.55 mg, 0.02 mmol) were taken up in DME (1 mL) and water (0.5 mL). Sodium carbonate (IM in water) (0.376 mL, 0.38 mmol) was added and the reaction was heated to 80 °C for 2 h. Preparative HPLC yielded 30.1 mg (61.7% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 8.85 (d, 1 H) 8.58 (d, 1 H) 7.92 (dd, 1 H) 7.81 (s, 1 H) 7.63 (d, 1 H) 7.47 (dt, 2 H) 7.37 (dd, 1 H) 2.32 (s, 3 H) 1.76 (s, 3 H); MS (ES+) m/z 265 [M+H]+.
Example 4
2-Ethyl-5-methyl-2-(3-(py ridin-3-yl)phenyl)-2H-imidazol-4-amine
Figure imgf000082_0002
2-(3-Bromophenyl)-2-ethyl-5-methyl-2H-imidazol-4-amine (8.8 mg, 0.03 mmol), pyridin- 3-ylboronic acid (7.72 mg, 0.06 mmol) and bis(triphenylphosphine)palladium(II) chloride (4.41 mg, 6.28 μmol) were taken up in DME (1 mL) and water (0.5 mL). Sodium carbonate (IM in water) (0.079 mL, 0.08 mmol) was added and the reaction was heated to 80 0C for 2 h. Preparative HPLC yielded 6 mg (56% yield) of the title compound: 1H NMR (500 MHz, CDCl3) δ ppm 8.88 (d, 1 H) 8.60 (dd, 1 H) 7.94 (dt, 1 H) 7.83 (s, 1 H) 7.63 (d, 1 H) 7.50 - 7.54 (m, 1 H) 7.43 - 7.49 (m, 1 H) 7.38 (dd, 1 H) 6.82 (jot. s., 2 H) 2.33 (s, 3 H) 2.13 - 2.23 (m, 1 H) 2.01 - 2.09 (m, 1 H) 0.79 (t, 3 H); MS (ES+) m/z 279 [M+H]+. Example 5
l-Cyclohexyl-S-methyl^-CS-φyrimidin-S-y^phenyO-lH-iinidazoW-amine
Figure imgf000083_0001
s 2-(3-Bromophenyl)-2-cyclohexyl-5-methyl-2H-imidazol-4-amine (60 mg, 0.18 mmol), pyrimidin-5-ylboronic acid (44.5 mg, 0.36 mmol) and bis(triphenylphosphine)- palladium(II) chloride (25.2 mg, 0.04 mmol) were taken up in DME (2 mL) and water (1 mL). Sodium carbonate (IM in water) (0.449 mL, 0.45 mmol) was added and the reaction was heated to 80 0C for 2 h. Preparative HPLC yielded 39.9 mg (67% yield) of the titleo compound: 1H NMR (400 MHz, CDCl3) δ ppm 9.20 (s, 1 H) 8.98 (s, 2 H) 7.84 (s, 1 H) 7.67 - 7.76 (m, 1 H) 7.48 (d, 2 H) 5.19 (br. s., 2 H) 2.31 (s, 3 H) 2.05 - 2.15 (m, 1 H) 1.42 - 1.76 (m, 5 H) 0.86 - 1.26 (m, 5 H); MS (ES+) m/z 334 [M+H]+.
Example 6
s 2-Cyclohexyl-5-methyl-2-(3-(pyridiii-3-yl)phenyl)-2H-imidazol-4-amine
Figure imgf000083_0002
2-(3-Bromophenyl)-2-cyclohexyl-5-methyl-2H-imidazol-4-amine (60 mg, 0.18 mmol), pyridin-3-ylboronic acid (44.1 mg, 0.36 mmol) and bis(triphenylphosphine)palladium(II) chloride (25.2 mg, 0.04 mmol) were taken up in DME (2 mL) and water (1 mL). Sodium0 carbonate (IM in water) (0.449 mL, 0.45 mmol) was added and the reaction was heated to 80 0C for 2 h. Preparative HPLC yielded 27.9 mg (47% yield) of the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 8.87 (d, 1 H) 8.58 (dd, 1 H) 7.92 (ddd, 1 H) 7.84 (s, 1 H) 7.66 (d, 1 H) 7.46 - 7.52 (m, 1 H) 7.40 - 7.46 (m, 1 H) 7.35 (dd, 1 H) 5.50 (br. s., 2 H) 2.30 (s, 3 H) 2.06 - 2.17 (m, 1 H) 1.42 - 1.77 (m, 5 H) 0.86 - 1.25 (m, 5 H); MS (ES+) m/z 3335 [M+H]+. Example 7
2-(3'-Methoxybiphenyl-3-yl)-5-methyl-2-(tetrahydro-2H-pyran-4-yl)-2H-imidazoI-4- amine
Figure imgf000084_0001
To a solution of zinc iodide (646 mg, 2.02 mmol) in THF (10 mL) at 0 0C was added methylmagnesium bromide (3M in diethyl ether) (0.674 mL, 2.02 mmol). To the formed slurry was then added bis(triphenylphosphine)palladium(II) chloride (28.4 mg, 0.04 mmol) followed by 2-(3!-methoxybiphenyl-3-yl)-5-(methylthio)-2-(tetrahydro-2H-pyran-4-yl)-2H- imidazol-4-amine (80 mg, 0.20 mmol) in THF (5 mL). The reaction mixture was stirred at 80 0C for 3 h. MeOH was added to quench the reaction. Sat. aq. NH4Cl solution was added and the mixture was extracted with with DCM. The combined organic phases were dried over MgSO4, filtered and the solvent evaporated. Preparative HPLC yielded 18.4 mg (25% yield) of the title compound: 1H NMR (400 MHz, MeOH) δ ppm 7.79 (s, 1 H) 7.59 - 7.68 (m, 1 H) 7.47 - 7.58 (m, 3 H) 7.38 (t, J=7.83 Hz, 1 H) 7.33 (t, J=7.83 Hz, 1 H) 7.18 (d, J=7.83 Hz, 1 H) 7.15 (d, J=2.02 Hz, 1 H) 6.90 (dd, J=8.08, 2.02 Hz, 1 H) 3.87 (d, J=I 1.37 Hz, 2 H) 3.84 (s, 3 H) 3.24 - 3.37 (m, 2 H) 2.35 - 2.47 (m, 1 H) 2.32 (s, 3 H) 1.22 - 1.43 (m, 4 H); MS (ES+) m/z 364 [M+H]+. Example 8
l-(4-(4-Amino-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-2-yl)piperidin-l- yl)ethanone
Figure imgf000084_0002
tert-Butyl 4-(4-amino-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-2-yl)piperidine- 1-carboxylate (15.7 mg, 0.03 mmol) was dissolved in DCM (2 mL). Trifluoroacetic acid (1 ml, 13 mmol) was added and the reaction was stirred at room temperature for 1 h. The solvent and excess reagent were evaporated. The residue was dissolved in DCM (2 mL) and triethylamine (11.35 μl, 0.08 mmol). Acetic anhydride (3.84 μl, 0.04 mmol) was added and the reaction was stirred for 16 h. The solvent was evaporated and preparative HPLC yielded 12.2 mg (77% yield) of the title compound: 1H NMR (400 MHz, methanol-^) δ ppm 7.80 (br. s., 1 H) 7.53 (d, 2 H) 7.39 (t, 1 H) 7.34 (t, 1 H) 7.18 (d, 1 H) 7.16 (s, 1 H) 6.91 (dd, 1 H) 4.49 (d, 1 H) 3.79 - 3.92 (m, 4 H) 2.90 - 3.06 (m, 1 H) 2.39 - 2.54 (m, 2 H) 2.33 (br. s., 3 H) 2.03 (s, 3 H) 1.36 - 1.62 (m, 2 H) 1.25 (d, 1 H) 0.99 - 1.17 (m, 1 H); MS (ES+) w/z 405 [M+H]+.
Example 9
2-BenzyI-5-methyI-2-(3-(pyrimidin-5-yI)phenyI)-2H-imidazoI-4-ainiiie
Figure imgf000085_0001
2-Benzyl-2-(3-bromophenyl)-5-methyl-2H-imidazol-4-amine (66.5 mg, 0.19 mmol), pyrimidin-5-ylboronic acid (48.2 mg, 0.39 mmol) and bis(triphenylphosphine)- palladium(II) chloride (27.3 mg, 0.04 mmol) were taken up in DME (1 mL) and water (0.5 mL). Sodium carbonate (IM in water) (0.486 mL, 0.49 mmol) was added and the reaction was heated to 80 °C for 2 h. The reaction mixture was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the solvent evaporated. Preparative HPLC yielded 30 mg (45% yield) of the title compound: MS (ES+) m/z 342 [M+H]+. Example 10
(R)- 2-BenzyI-5-methyl-2-(3-(pyrimidin-5-yI)pheiiyl)-2H-imidazol-4-aiiiine
Figure imgf000086_0001
Chromatographic separation of the enantiomers of 2-benzyl-5-methyl-2-(3-φyrimidin-5- yl)phenyl)-2H-imidazol-4-amine. 2-Benzyl-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H- imidazol-4-amine (29.6 mg, 0.087 mmol) was dissolved in methanol (2.7 mL) and the resulting solution was injected on a Chiralcel OJ column (21.2 x 250 mm), using methanol/CO2 (18:82) + 0.1% diethylamine as eluent at a flow rate of 50 mL/min. The title compound was the second to elute and was concentrated in vacuo to yield 7.5 mg (26% yield): 1H NMR (400 MHz, methanol-^) δ ppm 9.14 (s, 1 H) 9.05 (s, 2 H) 7.89 (t, 1 H) 7.76 (dt, 1 H) 7.62 - 7.67 (m, 1 H) 7.52 (t, 1 H) 7.11 - 7.20 (m, 3 H) 7.01 - 7.08 (m, 2 H) 3.40 - 3.49 (m, 1 H) 3.33 - 3.40 (m, 1 H) 2.07 (s, 3 H); MS (ES+) m/z 342 [M+H]+.
Example 11
(R)- and (S)- 2-(2'-fluoro-3'-methoxybiphenyl-3-yl)-5-methyl-2-(pyridin-3-yImethyI)-
2H-imidazol-4-amine
Figure imgf000086_0002
2-(3-Bromophenyl)-5-me%l-2-(pyridm-3-yhτiemyl)-2H-imidazol-4-aniine (100 mg, 0.29 mmol), 2-fluoro-3-methoxybenzeneboronic acid (54.5 mg, 0.32 mmol), [1,I1- bis(diphenylphosphino)ferrocene]palladium(II) chloride (11.98 mg, 0.01 mmol), potassium carbonate (2M aqueous solution, 0.364 mL, 0.73 mmol) and dioxane (1 mL) were mixed in a vial and heated in a microwave reactor at 130 0C for 15 min. The mixture was filtered and purified by preparative HPLC. The product was dissolved in MeOH and injected on a Chiralpak AD-H column (4.6 x 250 mm), using EtOH+DEA /CO2 (30:70) as eluent at a flow rate of 2 mL/min. Detection was monitored at 220 nm and the two isomers were collected and concentrated in vacuo to yield:
Isomer 1, example 1 Ia: 8 mg (7% yield) with unknown absolute configuration was collected: 1H NMR (500 MHz, OMSO-d6) δ ppm 8.30 (dd, 1 H) 8.14 (d, 1 H) 7.67 (s, 1 H)
7.57 - 7.65 (m, 1 H) 7.33 - 7.41 (m, 3 H) 7.12 - 7.24 (m, 3 H) 6.87 - 6.97 (m, 1 H) 6.38 (br. s., 2 H) 3.87 (s, 3 H) 3.10 - 3.25 (m, 2 H) 2.01 (s, 3 H); MS (ES+) m/z 389 [M+l]+.
Isomer 2, example 1 Ib: 8 mg (7% yield) with unknown absolute configuration was collected: 1HNMR (500 MHz, DMSO-^6) δ ppm 8.30 (dd, 1 H) 8.14 (d, 1 H) 7.67 (s, 1 H)
7.58 - 7.64 (m, 1 H) 7.32 - 7.41 (m, 3 H) 7.11 - 7.25 (m, 3 H) 6.86 - 6.97 (m, 1 H) 6.38 (br. s., 2 H) 3.87 (s, 3 H) 3.11 - 3.24 (m, 2 H) 2.01 (s, 3 H); MS (ES+) m/z 389 [M+l]+.
Example 12
(R)- and (S)- 2-(3-(5-ChIoropyridin-3-yl)phenyI)-5-methyI-2-(pyridin-3-ylmethyl)-2H- imidazoI-4-amine
Figure imgf000087_0001
The racemate of the title compounds were synthesized as described in Example 11 in 20% yield starting from 2-(3-bromophenyl)-5-memyl-2-(pyridin-3-yhnethyl)-2H-imidazol-4- amine and 5-chloropyridine-3-boronic acid. The crude product was dissolved in MeOH and injected on a Chiralpak AD-H column (4.6 x 250 mm), using EtOH+DEA /CO2 (40:60) as eluent at a flow rate of 2 mL/min. Detection was monitored at 220 nm and the two isomers were collected and concentrated in vacuo to yield: Isomer 1, example 12a: 15 mg with unknown absolute configuration was collected: 1H NMR (500 MHz, DMSO-flfe) δ ppm 8.76 (d, 1 H) 8.63 (d, 1 H) 8.31 (dd, 1 H) 8.11 - 8.19 (m, 2 H) 7.83 - 7.90 (m, 1 H) 7.62 (dd, 2 H) 7.35 - 7.45 (m, 2 H) 7.17 (dd, 1 H) 6.41 (br. s., 2 H) 3.17 - 3.29 (m, 2 H) 2.02 (s, 3 H); MS (ES+) m/z 376, 378 [M+l]+.
Isomer 2, example 12b: 15 mg with unknown absolute configuration was collected: 1H NMR (500 MHz, DMS(W6) δ ppm 8.76 (d, 1 H) 8.63 (d, 1 H) 8.31 (dd, 1 H) 8.10 - 8.20 (m, 2 H) 7.86 (t, 1 H) 7.62 (dd, 2 H) 7.35 - 7.45 (m, 2 H) 7.17 (dd, 1 H) 6.41 (br. s., 2 H) 3.16 - 3.29 (m, 2 H) 2.02 (s, 3 H); MS (ES+) m/z 376, 378 [M+l]+. Example 13
2-(3-Bromophenyl)-2-cycIopropyI-5-methyl-2H-imidazol-4-amine
Figure imgf000088_0001
2-(3-Bromoρhenyl)-2-cycloρropyl-4-methyl-lH-imidazole-5(2H)-thione (1.2 g, 3.88 mmol) and ammonia (7N in MeOH, 38.8 mL, 271.65 mmol) was heated to 45 0C o.n. The solvent was evaporated, ammonia (7N in MeOH, 38.8 mL, 271.65 mmol) was added and the mixture were heated to 45 0C for 8 h. This procedure were repeated 3 times and after final evaporation of the solvent, the title compound was isolated by chromatography (0- 60% EtOAc in n-heptane) to give 1.02 g (90% yield): 1H NMR (500 MHz, DMSO-^6) δ ppm 7.68 (s, 1 H) 7.56 - 7.61 (m, 1 H) 7.39 - 7.45 (m, 1 H) 7.26 (t, 1 H) 6.53 (br. s., 2 H) 2.15 (s, 3 H) 1.45 - 1.52 (m, 1 H) 0.26 - 0.35 (m, 2 H) 0.17 - 0.25 (m, 1 H) -0.06 - 0.02 (m, 1 H). MS (ES) m/z 292, 294 [M+l]+. Example 14
2-(3-(5-Chloropyridin-3-yl)phenyl)-2-cyclopropyI-5-methyl-2H-imidazol-4-amine
Figure imgf000089_0001
5-CMoropyridin-3-ylboronic acid (67.9 mg, 0.43 mmol), 2-(3-bromophenyl)-2- 5 cyclopropyl-5-methyl-2H-imidazol-4~amine (90 mg, 0.31 mmol), [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride (12.67 mg, 0.02 mmol) and potassium carbonate (2M in water, 0.385 mL, 0.77 mmol) were dissolved in dioxane (2 mL) and heated to 150 0C for 20 min using MW. After filtration and removal of solvents, the title compound was isolated using preparative HPLC to give 52 mg (52% yield): 1Ho NMR (500 MHz, DMSCW6) δ ppm 8.78 (s, 1 H) 8.62 - 8.65 (m, 1 H) 8.15 (s, 1 H) 7.88 (s, 1 H) 7.59 - 7.68 (m, 2 H) 7.43 (t, 1 H) 6.50 (br. s., 2 H) 2.16 (s, 3 H) 1.56 - 1.64 (m, 1 H) 0.27 - 0.39 (m, 2 H) 0.17 - 0.26 (m, 1 H) -0.01 - 0.07 (m, 1 H). MS (ES) m/z 325 [M+lf.
Example 15
s 2-Cyelopropyl-5-methyl-2-(3-(5-(prop-l-ynyl)pyridin-3-yl)plienyl)-2H-imidazol-4- amine
Figure imgf000089_0002
The title compound was synthesized as described for Example 14 in 40% yield starting from 5-(prop-l-ynyl)pyridin-3-ylboronic acid (86 mg, 0.53 mmol) and 2-(3-bromophenyl)-Q 2-cyclopropyl-5-methyl-2H-imidazol-4-amine (78 mg, 0.27 mmol): 1H NMR (500 MHz, DMSCW6) δ ppm 8.73 - 8.77 (m, 1 H) 8.58 (s, 1 H) 7.98 (s, 1 H) 7.85 (s, 1 H) 7.64 (d, 1 H) 7.59 (d, 1 H) 7.41 (t, 1 H) 6.50 (br. s., 2 H) 2.16 (s, 3 H) 2.12 (s, 3 H) 1.55 - 1.62 (m, 1 H) 0.27 - 0.39 (m, 2 H) 0.16 - 0.26 (m, 1 H) -0.02 - 0.07 (m, 1 H). MS (ES) mfz 329
[M+l]+.
Example 16
5-(4-Amino-2-(3-bromophenyI)-5-methyI-2H-imidazoI-2-yl)-3-methylpyridin-2(lH)- one
Figure imgf000090_0001
Sodium hydride (0.042 mL, 1.25 mmol) was added in one portion at 0 0C to a solution of 5-(4-amino-2-(3-bromophenyl)-5-methyl-2H-iniidazol-2-yl)-3-methylpyridin-2(lH)-one (450 mg, 1.25 mmol) in dry N,N-dimethylformamide (10 mL) under argon. The reaction was stirred at 0 0C for 5 minutes and then at rt for 20 minutes. The reaction was cooled to 0 0C and a solution of iodoethane (0.121 mL, 1.50 mmol) in dry N,N-dimethylformamide (3 mL) was added dropwise. LCMS indicated almost full conversion after 3.5 hours at 0 °C. The reaction was quenched by addition of MeOH (1.0 mL) and the reaction was stirred for 10 minutes at rt before evaporation of the solvents at reduced pressure. Remaining N,N- dimethylformamide was removed by co-evaporation with toluene. The residue was partitioned between DCM and saturated aqueous NaHCθ3, the phases were separated and the aqueous layer extracted with DCM. The organic phases were combined, dried
(Na2SO4), filtered and concentrated. Purification by flash chromatography on silica using a gradient from 0- 10% MeOH in DCM gave the title compound ( 172 mg, (36% yield) : 1H NMR (500 MHz, DMSO-^6) δ ppm 7.59 (t, 1 H) 7.50 (m, 2 H) 7.41 (ddd, 1 H) 7.35 (dd, 1 H) 7.25 (t, 1 H) 6.72 (br. s., 2 H) 3.88 (q, 2 H) 3.17 (d, 1 H) 2.23 (s, 2 H) 1.93 (s, 2 H) 1.16 (t, 3 H); MS (ES+) m/z 387, 389 [M+H]+. Example 17
5-(4-Amino-2-(3-(5-chIoropyridin-3-yl)phenyl)-5-methyl-2H-imidazol-2-yl)-l-ethyI-3- methylpyridin-2(lH)-one
Figure imgf000091_0001
A mixture of 5-(4-amino-2-(3-bromophenyl)-5-methyl-2H-imidazol-2-yl)-l-ethyl-3- methylpyridin-2(lH)-one (65.0 mg, 0.17 mmol), S-chloropyridme-S-boronic acid (31.7 mg, 0.20 mmol), [l,r-bis(diphenylphosphino)ferrocene]palladium(II)chloride (6.90 mg, 8.39 μmol), potassium carbonate (aqueous 2M) (0.168 mL, 0.34 mmol) and dioxane (2.0 mL) were heated in a microwave synthesizer at 130 0C for 15 minutes. The solvent was evaporated, the residue taken up in a MeOH/DMSO mixture and purified by preparative HPLC to give the title compound (20 mg, 28% yield): 1H NMR (500 MHz, DMS(W6) δ ppm 8.77 (d, 1 H) 8.63 (d, 1 H) 8.15 (t, 1 H) 7.81 (t, 1 H) 7.58-7.64 (m, 2 H) 7.56 (d, 1 H) 7.46 (dd, 1 H) 7.42 (m, 1 H) 6.68 (s, 2 H) 3.88 (q, 2 H) 2.25 (s, 3 H) 1.93 (s, 3 H) 1.16 (t, 3 H); MS (ES+) m/z 420 [M+H]+.
Example 18
5-(4-Amino-5-methyl-2-(3-(5-(prop-l-ynyl)pyridin-3-yl)phenyl)-2H-imidazol-2-yl)-l- ethyl-3-methylpy ridin-2(l H)-one
Figure imgf000091_0002
The title compound was synthesized as described for Example 17 starting from 5-(4- arnino-2-(3-bromophenyl)-5-methyl-2H-imidazol-2-yl)-l-ethyl-3-methylpyridin-2(lH)-one (65.0 mg, 0.17 mmol) and 5-(prop-l-ynyl)pyridin-3-ylboronic acid (40.5 mg, 0.25 mmol) to give the title compound (19 mg, 27% yield): 1H NMR (500 MHz, DMSO-Cf6) δ ppm 8.73 (d, 1 H) 8.57 (d, 1 H) 7.98 (t, 1 H) 7.78 (t, 1 H) 7.53 - 7.63 (m, 3 H) 7.46 (dd, 1 H) 7.36 - 7.43 (m, 1 H) 6.68 (s, 2 H) 3.88 (q, 2 H) 2.24 (s, 3 H) 2.11 (s, 3 H) 1.93 (s, 3 H) 1.16 (t, 3 H); MS (ES+) m/z 424 [M+H]+.
Example 19
5-(4-Ammo-2-(3*-methoxybiphenyl-3-yI)-5-methyl-2H-imidazoI-2-yl)-l-ethyl-3- methyIpyridin-2(lH)-one
Figure imgf000092_0001
The title compound was synthesized as described for Example 17, from 5-(4-amino-2-(3- bromophenyl)-5-methyl-2H-imidazol-2-yl)-l-ethyl-3-methylpyridin-2(lH)-one (75 mg, 0.19 mmol) and 3-methoxyphenylboronic acid (35.3 mg, 0.23 mmol), with the exception that to achieve full conversion another portion of 3-methoxyphenylboronic acid (14.71 mg, 0.10 mmol) and [l,r-bis(diphenylphosphino)ferrocene]palladium(II)chloride (3.98 mg, 4.84 μmol) was added and the reaction heated for another 10 minutes at 130 0C. The title compound was afforded (48 mg, 60% yield, containing 10mol% MeOH): 1H NMR (500 MHz, DMSO-4) δ ppm 7.71 (t, 1 H) 7.54 (d, 1 H) 7.49 (m, 2 H) 7.42 (dd, 1 H) 7.37 (dt, 2 H) 7.12 (m, 1 H) 7.07 (m, 1 H) 6.94 (m, 1 H) 6.67 (br. s, 2 H) 4.10 (q, 0.2 H. MeOH) 3.88 (q, 2 H) 3.81 (s, 3 H) 3.17 (d, 0.3 H, MeOH) 2.24 (s, 3 H) 1.93 (s, 3 H) 1.16 (t, 3 H); MS (ES+) m/z 415 [M+H]+.
Example 20
5-(4-Amino-2-(3',5'-difluorobiphenyI-3-yl)-5-methyl-2H-imidazol-2-yl)-l-ethyl-3- methylpyridin-2(lH)-one
Figure imgf000093_0001
The title compound was synthesized as described for Example 17 starting from
5-(4-ammo-2-(3-bromophenyl)-5-methyl-2H-imidazol-2-yl)-l-ethyl-3-methylpyridin- 2(lH)-one (75 mg, 0.19 mmol) and 3,5-difluorophenylboronic acid (36.7 mg, 0.23 mmol) to afford 57 mg (70 % yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.76 (t, 1 H) 7.53 - 7.61 (m, 3 H) 7.44 (dd, 1 H) 7.39 (t, 1 H) 7.33 (m, 2 H) 7.24 (tt, 1 H) 6.68 (br. s, 2 H) 3.88 (m, 2 H) 2.24 (s, 3 H) 1.93 (s, 3 H) 1.16 (t, 3 H); MS (ES+) m/z 421 [M+H]+.
Example 21
2-(3-(5-Chloropyridm-3-yI)-4-fluorophenyl)-2-cyclopropyl-5-methyI-2H-imidazoI-4- amine
Figure imgf000093_0002
To a microwave vial was added 5-chloropyridin-3-ylboronic acid (51.9 mg, 0.33 mmol), 1 , 1 l-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9.61 mg, 0.01 mmol) and potassium carbonate (2M in water, 0.294 mL, 0.59 mmol), and then 2-(3-bromo-4-fluorophenyl)-2-cyclopropyl-5-memyl-2H-miidazol-4-amine (73.0 mg, 0.24 mmol) in dioxane (2 mL). The reaction vessel was sealed and heated at 150 0C for 20 min in a microwave reactor. After cooling, the reaction mixture was filtered and concentrated. The residue was taken up in MeOH, filtered and purified by prep HPLC to yield 35 mg (43% yield) of the title compound: IH NMR (500 MHz, DMSO-J6) δ ppm 8.65 - 8.69 (m, 2 H) 8.08 - 8.12 (m, 1 H) 7.70 - 7.74 (m, 1 H) 7.64 - 7.70 (m, 1 H) 7.25 - 7.33 (m, 1 H) 6.52 (s, 2 H) 2.15 (s, 3 H) 1.57 (tt, 1 H) 0.28 - 0.37 (m, 2 H) 0.17 - 0.26 (m, 1 H) -0.04 - 0.06 (m, 1 H) ; MS (ES+) m/z 343 [M+H]+.
Example 22
2-CyclopropyI-2-(4-fluoro-3-(5-(prop-l-ynyl)pyridin-3-yl)phenyl)-5-methyl-2H- imidazol-4-amine
Figure imgf000094_0001
The title compound 24 mg (33% yield) was prepared from 2-(3-bromo-4-fluorophenyl)-2- cyclopropyl-5-methyl-2H-imidazol-4-amine (65.0 mg, 0.21 mmol), and 5-(prop-l- ynyl)pyridin-3-ylboronic acid (67.5 mg, 0.42 mmol), according to a similar procedure as that described for Example 21 : 1H NMR (500 MHz, DMSO-J6) δ ppm 8.64 (s, 1 H) 8.61 (d, 1 H) 7.91 (d, 1 H) 7.69 (dd, 1 H) 7.62 - 7.67 (m, 1 H) 7.28 (dd, 1 H) 6.51 (br. s., 2 H) 2.15 (s, 3 H) 2.11 (s, 3 H) 1.51 - 1.62 (m, 1 H) 0.27 - 0.41 (m, 2 H) 0.14 - 0.27 (m, 1 H) - 0.04 - 0.10 (m, 1 H); MS (ES+) m/z 347 [M+H]+.
Example 23
2-(3-(5-Chloropyridin-3-yl)phenyl)-5-methyl-2-((tetrahydro-2H-pyran-4-yl)methyl)- 2H-imidazoI-4-amine
Figure imgf000095_0001
The title compound was synthesized as described for Example 14 in 61% yield starting from 5-chloropyridin-3-ylboronic acid (46.7 mg, 0.30 mmol) and 2-(3-bromophenyl)-5- methyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-imidazol-4-amine (80 mg, 0.23 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 8.78 (d, 1 H) 8.63 (d, 1 H) 8.16 (t, 1 H) 7.86 (t, 1 H) 7.59 - 7.65 (m, 2 H) 7.42 (t, 1 H) 6.45 (br. s., 2 H) 3.63 - 3.73 (m, 2 H) 3.06 - 3.16 (m, 2 H) 2.16 (s, 3 H) 1.91 - 1.96 (m, 1 H) 1.67 - 1.74 (m, 1 H) 1.46 - 1.53 (m, 1 H) 1.37 - 1.44 (m, 1 H) 1.25 - 1.35 (m, 1 H) 1.00 - 1.14 (m, 2 H); MS (ES) m/z 383 [M+l]+. Example 24
2-(3-(5-Fluoropyridin-3-yI)phenyI)-5-methyl-2-((tetrahydro-2H-pyran-4-yl)methyl)- 2H-imidazol-4-amine
Figure imgf000095_0002
The title compound was synthesized as described for Example 14 in 38% yield starting from 5-fluoropyridin-3-ylboronic acid (41.8 mg, 0.30 mmol) and 2-(3-bromophenyl)-5- methyl-2-((te1xahydro-2H-pyran-4-yl)methyl)-2H-imidazol-4-amine (80mg, 0.23 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 8.71 (t, 1 H) 8.58 (d, 1 H) 7.96 - 8.01 (m, 1 H) 7.87 (t, 1 H) 7.59 - 7.65 (m, 2 H) 7.42 (t, 1 H) 6.45 (br. s., 2 H) 3.64 - 3.73 (m, 2 H) 3.07 - 3.16 (m, 2 H) 2.16 (s, 3 H) 1.91 - 1.96 (m, 1 H) 1.67 - 1.74 (m, 1 H) 1.46 - 1.53 (m, 1 H) 1.37 - 1.45 (m, 1 H) 1.25 - 1.36 (m, 1 H) 1.00 - 1.14 (m, 2 H); MS (ES) m/z 367 [M+l]+. Example 25
2-(3-(5-Methoxypyridin-3-yl)phenyl)-5-methyl-2-((tetrahydro-2H-pyran-4-yl)methyI)-
2H-imidazol-4~amine
Figure imgf000096_0001
The title compound was synthesized as described for Example 14 in 47% yield starting from 5-methoxypyridin~3-ylboronic acid (45.4 mg, 0.30 mmol) and 2-(3-bromophenyl)-5- methyl-2-((te1iahydro-2H-pyran-4-yl)methyl)-2H-imidazol-4-amine (80mg, 0.23 mmol): 1H NMR (500 MHz, DMSO-^6) δ ppm 8.32 (d, 1 H) 8.23 (d, 1 H) 7.76 (t, 1 H) 7.48 - 7.56 (m, 2 H) 7.43 - 7.47 (m, 1 H) 7.34 (t, 1 H) 6.38 (br. s., 2 H) 3.85 (s, 3 H) 3.56 - 3.67 (m, 2 H) 3.00 - 3.10 (m, 2 H) 2.10 (s, 3 H) 1.83 - 1.89 (m, 1 H) 1.59 - 1.66 (m, 1 H) 1.41 - 1.48 (m, 1 H) 1.31 - 1.38 (m, 1 H) 1.13 - 1.30 (m, 1 H) 0.94 - 1.07 (m, 2 H); MS (ES) m/z 379 [M+l]+.
Example 26
2-(3'-Methoxybiphenyl-3-yI)-5-methyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H- imidazoI-4-amine
Figure imgf000096_0002
The title compound was synthesized as described for Example 14 in 52% yield starting from 3-methoxyphenylboronic acid (45.1 mg, 0.30 mmol) and 2-(3-bromophenyl)-5- methyl-2-((tetrahydro-2H-pyran-4-yl)memyl)-2H-imidazol-4-arnine (80mg, 0.23 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.79 (t, 1 H) 7.55 (d, 1 H) 7.49 (d, 1 H) 7.32 - 7.41 (m, 2 H) 7.14 (d, 1 H) 7.07 - 7.11 (m, 1 H) 6.92 - 6.97 (m, 1 H) 6.43 (br. s., 2 H) 3.82 (s, 3 H) 3.63 - 3.72 (m, 2 H) 3.06 - 3.15 (m, 2 H) 2.16 (s, 3 H) 1.90 - 1.92 (m, 1 H) 1.63 - 1.69 (m, 1 H) 1.46 - 1.55 (m, 1 H) 1.38 - 1.44 (m, 1 H) 1.27 - 1.37 (m, 1 H) 0.99 - 1.14 (m, 2 H); MS (ES) m/z 378 [M+l]+.
Example 27
N-(3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)phenyl)pyrazine-2- carboxamide
Figure imgf000097_0001
Pyrazine-2-carboxamide (63.2 mg, 0.51 mmol), 2-(3-bromophenyl)-2-cyclopropyl-5- methyl-2H-imidazol-4-amine (50 mg, 0.17 mmol), palladium(II) acetate (3.84 mg, 0.02 mmol), cesium carbonate (112 mg, 0.34 mmol) and Xantphos (14.85 mg, 0.03 mmol) were dissolved in THF (2 mL) and heated to 150 0C for 1 h using MW. After filtration and removal of solvents in vacuo, were the title compound isolated using preparative HPLC to give 33mg (58% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 10.65 (s, 1 H), 9.29 (d, 1 H), 8.92 (d, 1 H), 8.81 (m, 1 H), 8.13 (t, 1 H), 7.69 (m, 1 H), 7.35 (m, 1 H), 7.26 (t, 1 H), 6.45 (br. s., 2 H), 2.16 (s, 3 H), 1.50 (m, 1 H), 0.33 (m, 2 H), 0.22 (m, 1 H), 0.02 (m, 1 H); MS (ES) rø/z 335 [M+l]+. Example 28
2-(3-(5-ChIoropyridin-3-yl)phenyI)-2-cyclobutyI-5-methyl-2H-imidazoI-4-amine
Figure imgf000098_0001
The title compound was synthesized as described for Example 14 in 29% yield starting from 5-chloropyridin~3-ylboronic acid (43.4 mg, 0.28 mmol) and 2-(3-bromophenyl)-2- cyclobutyl-5-methyl-2H-imidazol-4-amine (65 mg, 0.21 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 8.77 (d, 1 H), 8.63 (d, 1 H), 8.14 (t, 1 H), 7.86 (t, 1 H)5 7.62 (m, 2 H), 7.41 (t, 1 H), 6.50 (br. s., 2 H), 3.05 (m, 1 H), 2.19 (s, 3 H), 1.74 (m, 1 H), 1.59 (m, 5 H); MS (ES) m/z 339 [M+l]+.
Example 29
2-Cyclobutyl-2-(3-(5-fluoropyridin-3-yl)phenyl)-5-methyl-2H-imidazol-4-amine
Figure imgf000098_0002
The title compound was synthesized as described for Example 14 in 48% yield starting from 5-fluoropyridin-3-ylboronic acid (38.9 mg, 0.28 mmol) and 2-(3-bromophenyl)-2- cyclobutyl-5-methyl-2H-imidazol-4-amine (65 mg, 0.21 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 8.70 (t, 1 H), 8.58 (d, 1 H), 7.96 (m, 1 H), 7.86 (t, 1 H), 7.61 (m, 2 H), 7.41 (t, 1 H), 6.50 (br. s., 2 H), 3.05 (m, 1 H), 2.19 (m, 3 H), 1.73 (m, 1 H), 1.60 (m, 5 H); MS (ES) m/z 323 [M+l]+. Example 30
2-Cyclobutyl-5-methyl-2-(3-(5-(prop-l-ynyI)pyridin-3-yl)phenyl)-2H-imidazoI-4-
Figure imgf000099_0001
The title compound was synthesized as described for Example 14 in 25% yield starting from 5-(prop-l-ynyl)pyridin-3-ylboronic acid (51.3 mg, 0.32 mmol) and 2-(3- bromophenyl)-2-cyclobutyl-5-methyl-2H-imidazol-4-amine (65 mg, 0.21 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 8.74 (d, 1 H), 8.57 (d, 1 H), 7.97 (t, 1 H), 7.83 (t, 1 H), 7.60 (m, 2 H), 7.40 (t, 1 H), 6.49 (br. s., 2 H), 3.04 (m, 1 H), 2.19 (s, 3 H), 2.12 (s, 3 H), 1.73 (m, 1 H), 1.58 (m, 5 H); MS (ES) m/z 343 [M+l]+.
Example 31
2-(3-(5-Chloropyridin-3-yl)phenyl)-2-isopropyl-5-methyl-2H-imidazol-4-amine
Figure imgf000099_0002
The title compound was synthesized as described for Example 14 in 30% yield starting from 5-chloropyridin-3-ylboronic acid (45.2 mg, 0.29 mmol) and 2-(3-bromophenyl)-2- isopropyl-5-methyl-2H-imidazol-4-amine (65mg, 0.22 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 8.78 (d, 1 H), 8.62 (d, 1 H), 8.14 (t, 1 H), 7.85 (t, 1 H), 7.62 (m, 2 H), 7.42 (t, 1 H), 6.46 (br. s., 2 H), 2.26 (quin, 1 H), 2.17 (s, 3 H), 0.76 (d, 3 H), 0.65 (d, 3 H); MS (ES) m/.r 327 [M+l]+. Example 32
2-(3-(5-Fluoropyridin-3-yl)phenyI)-2-isopropyI-5-methyl-2H-imidazol-4-amine
Figure imgf000100_0001
The title compound was synthesized as described for Example 14 in 40% yield starting from 5-fluoropyridin-3-ylboronic acid (40.5 mg, 0.29 mmol) and 2~(3-bromophenyl)-2- isoρropyl-5-methyl-2H-imidazol-4-amine (65mg, 0.22 mmol): 1H NMR (500 MHz, DMSO-Cf6) δ ppm 8.68 - 8.74 (m, 1 H) 8.58 (d, 1 H) 7.94 - 8.01 (m, 1 H) 7.84 - 7.90 (m, 1 H) 7.59 - 7.66 (m, 2 H) 7.42 (t, 1 H) 6.46 (br. s., 2 H) 2.26 (quintet, 1 H) 2.17 (s, 3 H) 0.76 (d, 3 H) 0.65 (d, 3 H); MS (ES) m/z 311 [M+l]+.
Example 33
2-Isopropyl-5-methyl-2-(3-(5-(prop-l-ynyl)pyridin-3-yl)phenyl)-2H-imidazol-4-amine
Figure imgf000100_0002
The title compound was synthesized as described for Example 14 in 34% yield starting from 5-(prop-l-ynyl)pyridin-3-ylboronic acid (53.3 mg, 0.33 mmol) and 2-(3- bromophenyl)-2-isopropyl-5-methyl-2H-imidazol-4-amine (65mg, 0.22 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 8.75 (d, 1 H) 8.57 (d, 1 H) 7.97 (t, 1 H) 7.80 - 7.84 (m, 1 H) 7.56 - 7.63 (m, 2 H) 7.40 (t, 1 H) 6.46 (br. s., 2 H) 2.24 (quintet, 1 H) 2.17 (s, 3 H) 2.11 (s, 3 H) 0.76 (d, 3 H) 0.65 (d, 3 H); MS (ES) m/z 331 [M+l]+. Example 34
2-Cyclohexyl-2-(4-methoxyphenyl)-5-methyl-2H-imidazoI-4-amine
Figure imgf000101_0001
The title compound was synthesized as described for Example 13 in 40% yield starting from 2-cyclohexyl-2-(4-methoxyphenyl)-4-methyl-lH-imidazole-5(2H)-thione (0.55 g, 1.82 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.38 - 7.45 (m, 2 H) 6.76 - 6.83 (m, 2 H) 6.33 (br. s., 2 H) 3.70 (s, 3 H) 2.13 (s, 3 H) 1.63 - 1.73 (m, 1 H) 1.45 - 1.61 (m, 4 H) 1.33 - 1.42 (m, 1 H) 0.86 - 1.09 (m, 4 H) 0.69 - 0.81 (m, 1 H); MS (ES) m/z 286 [M+l]+.
Example 35
2-Cycloheptyl-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine
Figure imgf000101_0002
The title compound was synthesized as described for Example 13 in 29% yield starting from 2-cycloheptyl-2-(4-methoxyphenyl)-4-methyl-lH-imidazole-5(2H)-thione (0.42 g, 1.33 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.37 - 7.43 (m, 2 H) 6.76 - 6.82 (m, 2 H) 3.70 (s, 3 H) 2.13 (s, 3 H) 1.91 - 1.98 (m, 1 H) 1.30 - 1.54 (m, 8 H) 1.12 - 1.27 (m, 2 H) 1.01 - 1.11 (m, 1 H) 0.86 - 0.97 (m, 1 H); MS (ES) m/z 300 [M+l]+.
Example 36
2-(Bicydo[2.2.1]heptan-2-yl)-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine
Figure imgf000101_0003
The title compound was synthesized as described for Example 13 in 17% yield starting from 2-φicyclo[2.2.1]heρtan-2-yl)-2-(4-methoxyρhenyl)-4-methyl-lH-imidazole-5(2H)- thione (120mg, 0.38 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.41 - 7.48 (m, 2 H) 6.77 - 6.83 (m, 2 H) 6.21 - 6.37 (m, 2 H) 3.69 - 3.71 (m, 3 H) 2.10 - 2.17 (m, 3 H) 1.97 - 2.04 (m, 2 H) 1.67 - 1.72 (m, 1 H) 1.24 - 1.41 (m, 3 H) 1.03 - 1.11 (m, 1 H) 0.87 - 1.03 (m, 3 H) 0.71 - 0.83 (m, 1 H); MS (ES) m/z 298 [M+l]+.
Example 37
2-Cydooctyl-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine
Figure imgf000102_0001
The title compound was synthesized as described for Example 13 in 5% yield starting from i o 2-cyclooctyl-2-(4-methoxyphenyl)-4-methyl- 1 H-imidazole-5 (2H)-thione (43mg, 0.13 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.38 - 7.42 (m, 2 H) 6.77 - 6.82 (m, 2 H) 6.32 (br. s, 2 H) 3.70 (s, 3 H) 2.12 (s, 3 H) 1.32 - 1.55 (m, 10 H) 1.16 - 1.26 (m, 2 H) 1.03 - 1.16 (m, 2 H) 0.89 - 1.00 (m, 1 H); MS (ES) m/z 314 [M+l]+. is Example 38
2-(4-Methoxyphenyl)-5-methyl-2-(3-phenylpropyl)-2H-imidazol-4-amine
Figure imgf000102_0002
The title compound was synthesized as described for Example 13 in 41% yield starting from 2-(4-methoxyphenyl)-4-methyl-2-(3-phenylpropyl)- 1 H-imidazole-5 (2H)-thione 2Q (0.42g, 1.24 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.38 - 7.44 (m, 2 H) 7.22 (m, 2 H) 7.12 (m, 1 H) 7.06 (d, 2 H) 6.77 - 6.83 (m, 2 H) 6.34 (br. s., 2 H) 3.70 (s, 3 H) 2.43 (t, 2 H) 2.12 (s, 3 H) 1.83 (m, 1 H) 1.60 - 1.68 (m, 1 H) 1.24 - 1.36 (m, 2 H); MS (ES) m/z 322 [M+l]+.
25 Example 39
2-(4-MethoxyphenyI)-2-(3-(3-methoxyphenyl)propyl)-5-methyl-2H-imidazol-4-amine
Figure imgf000103_0001
The title compound was synthesized as described for Example 13 in 47% yield starting from 2-(4-methoxyphenyl)-2-(3-(3-methoxyphenyl)propyl)-4-methyl-lH-imidazole-5(2H)- thione (0.27 g, 0.73 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.38 - 7.44 (m, 2 H) 7.13 (t, 1 H) 6.77 - 6.84 (m, 2 H) 6.69 (m, 1 H) 6.60 - 6.66 (m, 2 H) 6.34 (br. s., 2 H) 3.70 (s, 3 H) 3.69 (s, 3 H) 2.41 (t, 2 H) 2.13 (s, 3 H) 1.83 (ddd, 1 H) 1.60 - 1.68 (m, 1 H) 1.23 - 1.35 (m, 2 H); MS (ES) m/z 352 [M+l]+.
Example 40
5-(4-Ammo-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2'-fluoro-5'-methoxybiphenyl-
2-ol
Figure imgf000103_0002
The title compound was synthesized as described for Example 14 in 30% yield starting from 4-(4-amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2-bromophenol (60mg, 0.19 mmol) and 2-fluoro-5-methoxyphenylboronic acid (39.7 mg, 0.23 mmol): 1H NMR (500 MHz, DMSO-40 δ ppm 9.42 (br. s., 1 H) 7.36 - 7.41 (m, 1 H) 7.30 - 7.34 (m, 1 H) 7.13 (t, 1 H) 6.87 - 6.92 (m, 1 H) 6.80 - 6.85 (m, 2 H) 6.37 (br. s., 2 H) 3.75 (s, 3 H) 2.12 (s, 3 H) 1.40 - 1.47 (m, 1 H) 0.24 - 0.32 (m, 2 H) 0.14 - 0.22 (m, 1 H) -0.08 - -0.01 (m, 1 H); MS (ES) m/z 354 [M+l]+. Example 41
5-(4-Amino-2-cyclopropyl-5-methyI-2H-imidazol-2-yI)-5'-chloro-2'-fluorobiphenyl-2- ol
Figure imgf000104_0001
The title compound was synthesized as described for Example 14 in 34% yield starting from 4-(4-amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2-bromophenol (60mg, 0.19 mmol) and S-chloro^-fluorophenylboronic acid (40.7 mg, 0.23 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 9.57 (s, 1 H) 7.40 - 7.46 (m, 2 H) 7.35 - 7.39 (m, 1 H) 7.32 - 7.35 (m, 1 H) 7.29 (t, 1 H) 6.85 (d, 1 H) 6.39 (br. s., 2 H) 2.13 (s, 3 H) 1.40 - 1.48 (m, 1 H) 0.24 - 0.32 (m, 2 H) 0.14 - 0.22 (m, 1 H) -0.08 - 0.00 (m, 1 H); MS (ES) m/z 358 [M+l]+.
Example 42
5'-(4-Amino-2-cyclopropyI-5-methyl-2H-imidazol-2-yl)-6-fluoro-2'-hydroxybiphenyl-
3-carbonitriIe
Figure imgf000104_0002
The title compound was synthesized as described for Example 14 in 11% yield starting from 4-(4-amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2-bromophenol (60mg, 0.19 mmol) and 5-cyano-2-fluorophenylboronic acid (38.5 mg, 0.23 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 9.67 (br. s., 1 H) 7.85 - 7.93 (m, 2 H) 7.43 - 7.51 (m, 2 H) 7.34 - 7.37 (m, 1 H) 6.87 (d, 1 H) 6.39 (br. s., 2 H) 2.13 (s, 3 H) 1.40 - 1.49 (m, 1 H) 0.25 - 0.32 (m, 2 H) 0.15 - 0.22 (m, 1 H) -0.07 - 0.01 (m, 1 H); MS (ES) m/z 349 [M+l]+. Example 43
5-(4-Amino-2-cycIopropyl-5-methyI-2H-imidazol-2-yI)-2'-fluoro-3'-methoxybiphenyI-
2-ol
Figure imgf000105_0001
The title compound was synthesized as described for Example 14 in 25% yield starting from 4-(4-amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2-bromophenol (60mg, 0.19 mmol) and 2~fluoro-3-methoxyphenylboronic acid (39.7 mg, 0.23 mmol): 1H NMR (500 MHz, DMSO-Cf6) δ ppm 9.38 (s, 1 H) 7.37 - 7.41 (m, 1 H) 7.29 (d, 1 H) 7.09 - 7.16 (m, 2 H) 6.79 - 6.86 (m, 2 H) 6.37 (tar. s., 2 H) 3.85 (s, 3 H) 2.12 (s, 3 H) 1.38 - 1.46 (m, 1 H) 0.23 - 0.31 (m, 2 H) 0.14 - 0.22 (m, 1 H) -0.08 - 0.00 (m, 1 H); MS (ES) m/z 354 [M+l]+.
Example 44
4-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2-(5-(prop-l-ynyl)pyridin-3- yl)phenol
Figure imgf000105_0002
The title compound was synthesized as described for Example 14 in 28% yield starting from 4-(4-ammo-2-cyclopropyl-5-methyl-2H-irnidazol-2-yl)-2-bromophenol (60mg, 0.19 mmol) and 5-(prop-l-ynyl)pyridin-3-ylboronic acid (47.0 mg, 0.29 mmol): 1H NMR (500 MHz, DMSO-J6) δ ppm 9.72 (tar. s., 1 H) 8.61 (d, 1 H) 8.50 (d, 1 H) 7.85 (t, 1 H) 7.44 - 7.49 (m, 1 H) 7.38 - 7.44 (m, 1 H) 6.88 (d, 1 H) 6.41 (tar. s., 2 H) 2.13 (s, 3 H) 2.10 (s, 3 H) 1.44 - 1.52 (m, 1 H) 0.24 - 0.33 (m, 2 H) 0.14 - 0.23 (m, 1 H) -0.07 - 0.03 (m, 1 H); MS (ES) m/z 345 [M+l]+.
Example 45
4-(4-Ammo-2-cyclopropyl-5-methyI-2H-imidazoI-2-yl)-2-(pyrazin-2-yl)phenol
Figure imgf000106_0001
2-Cyclopropyl-2-(4-methoxy-3-(pyrazin-2-yl)phenyl)-5-methyl-2H-imidazol-4-ainine (0.08 g, 0.25 mmol) was dissolved in dichloromethane (3.00 niL) and boron tribromide (0.165 mL, 1.74 mmol) was added. The mixture was stirred at room temperature for 30 min. The reaction was quenched by dropwise addition of MeOH (2 mL). NH4OH (28-30 wt% NH3 in water, 1 mL) was added. The resulting mixture was stirred for 5 min, then concentrated HCl was added dropwise until ~pH 7. Additional dichloromethane was added and the organic layer was collected. The water phase was extracted with dichloromethane. NaCl was added and the water phase was extracted with acetonitrile (three times). The combined organic layers were dried (TS^SC^), filtered and concentrated in vacuo. The residue was redissolved in dichloromethane and concentrated in vacuo. The produc twas purified by silica chromatography using 0% to 10% (3.5 M ammonia in methanol) in dichloromethane to give 4-(4-amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2- (pyrazin-2-yl)phenol (0.036 g, 47% yield): 1H NMR (500 MHz, DMSCM6) δ ppm 10.89 (br. s, 1 H), 9.26 (d, 1 H), 8.70 (dd, 1 H), 8.55 (d, 1 H), 8.08 (d, 1 H)5 7.51 (dd, 1 H), 6.91 (d, 1 H), 6.43 (br. s., 2 H), 2.14 (s, 3 H), 1.42 - 1.54 (m, 1 H), 0.24 - 0.36 (m, 2 H), 0.14 - 0.24 (m, 1 H), -0.06 - 0.04 (m, 1 H); MS (ES+) m/z 308 [M+H]+. Example 46
4-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazoI-2-yl)-2-(4-(prop-l-ynyl)pyridin-2- yl)phenol
Figure imgf000107_0001
2-Cyclopropyl-2-(4-methoxy-3-(4-(prop-l-ynyl)pyridin-2-yl)phenyl)-5-methyl-2H- imidazol-4-amine (0.016 g, 0.04 mmol) was dissolved in dichloromethane (1.00 mL) and cooled to -78 0C. Boron tribromide (0.015 mL, 0.16 mmol) was dropwise added. The reaction mixture was slowly warmed to room temperature over night. The reaction was quenched by dropwise addition of MeOH (0.5 mL). NH4OH (28-30 wt% NH3 in water)
(0.5 mL) was added and the mixture was stirred for 5 min. HCl was added dropwise until ~pH 7. The organic solvents were removed in vacuo. Dichloromethane was added and the organic layer was collected. The water phase was extracted with dichloromethane (three times). NaCl was added and the water phase was extracted with ethyl acetate (three times). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo.
The product was purified by prep-HPLC to give 4-(4-amino-2-cyclopropyl-5-methyl-2H- imidazol-2-yl)-2-(4-(prop-l-ynyl)pyridin-2-yl)phenol (2.1 mg, 14% yield) : 1H NMR (SOO MHz, DMSO-J6) δ ppm 13.21 (br. s, 1 H), 8.58 (d, 1 H), 8.07 (d, 1 H), 7.94 (s, 1 H), 7.50 (dd, 1 H), 7.37 (dd, 1 H), 6.85 (d, 1 H), 6.45 (br. s, 2 H), 2.16 (d, 6 H), 1.53 (tt, 1 H), 0.25 - 0.34 (m, 2 H), 0.16 - 0.23 (m, 1 H), -0.03 - 0.04 (m, 1 H); MS (ES-) m/z 343 [M-H]' ; MS (ES+) m/z 345 [M+H]+. Example 47
5-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazoI-2-yI)-2',5f-dichlorobiphenyl-2-ol
Figure imgf000108_0001
2-Cyclopropyl-2-(2^5'-dicMoro-6-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-4-amine (60.2 mg, 0.16 mmol) was dissolved in dichloromethane (3.00 mL) and boron tribromide (0.103 mL, 1.09 mmol) was added. The reaction mixture was stirred at room
temperature over night. The reaction was quenched by dropwise addition of MeOH (2 mL). NH4OH (28-30 wt% NH3 in water, 1 mL) was added And the mixture was stirred for
5 min. HCl was added dropwise until ~pH 7. Additional dichloromethane was added and the organic layer was collected. The water phase was extracted with dichloromethane (twice). The combined organic layers were passed through a phase separator and concentrated in vacuo. The product was purified by preparative HPLC. The desired fractions were pooled and concentrated in vacuo. The residue was redissolved in acetonitrile and methanol and water was added and the product was freeze-dried over night. The residue was partitioned between water (pH ~7) and dichloromethane (x5), the combined organic layers were passed through a phase separator and concentrated in vacuo to give 5-(4-amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2',5!-dichlorobiphenyl-2-ol (7.60 mg, 13% yield): 1H NMR (500 MHz5 DMSO-J6) δ ppm 9.53 (br. s., 1 H), 7.54 (d, 1 H), 7.42 (td, 2 H), 7.34 (d, 1 H), 7.25 (d, 1 H), 6.85 (d, 1 H), 6.38 (br. s., 2 H), 2.15 Qx. s., 3 H), 1.44 (br. s., 1 H), 0.12 - 0.43 (m, 3 H), 0.00 (br. s., 1 H); MS (ES+) m/z 374 [M+H]+ ; MS (ES-) m/z 372 [M-H]". Example 48
5-(4-Ammo-2-cyclopropyl-5-methyl-2H-imidazoI-2-yI)-2'-chloro-5'-methoxybiphenyI-
2-ol
Figure imgf000109_0001
2-Chloro-5-methoxyphenylboronic acid (93 mg, 0.50 mmol), 4-(4-amino-2-cyclopropyl-5- methyl-2H-imidazol-2-yl)-2-bromophenol (153.5 mg, 0.50 mmol), [1,1!- bis(diphenylphosphino)ferrocene]palladium(II) chloride (20.49 mg, 0.02 mmol), cesium carbonate (487 mg, 1.49 mmol) and DMErEtOH: Water 6:3:1 (4.00 mL) were put in a microwave vial and irradiated in a microwave reactor at 150 0C for 30 min, and then concentrated in vacuo. Dichloromethane and methanol were added to the residue and the resulting mixture was filtered through a syringe filter. The filtrate was concentrated in vacuo And the residue purified by silica chromatography using 0% to 10% (3.5 M ammonia in methanol) in dichloromethane. The desired fractions were pooled and concentrated in vacuo and purified by preparative HPLCto give 5-(4-amino-2-cyclopropyl- 5-methyl-2H-imidazol-2-yl)-2'-chloro-5!-methoxybiphenyl-2-ol (9.80 mg, 5% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 9.36 (br. s., 1 H), 7.34 - 7.41 (m, 2 H), 7.24 (d, 1 H), 6.92 (dd, 1 H), 6.80 (dd, 2 H), 6.36 (br. s., 2 H), 3.75 (s, 3 H), 2.12 (s, 3 H), 1.37 - 1.45 (m, 1 H), 0.24 - 0.33 (m, 2 H), 0.14 - 0.22 (m, 1 H), -0.07 - 0.00 (m, 1 H); MS (ES-) m/z 368 [M-H]"; MS (ES+) m/z 370 [MH-H]+.
Example 49
N-(3-(4-Amino-2-cyelopropyl-5-methyl-2H-imidazol-2-yl)-4-fluorophenyl)-5- chloropicolinamide
Figure imgf000110_0001
5-Chloro-2-pyridinecarboxylic acid (28.0 mg, 0.18 mmol), 2-(5-amino-2-fluorophenyl)-2- cyclopropyl-5-methyl-2H-imidazol-4-amine (43.7 mg, 0.18 mmol) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34.0 mg, 0.18 mmol) were dissolved in DMF and hydrochloric acid (2 M, 0.089 mL, 0.18 mmol) was added. The mixture was stirred at room temperature for 3 days, then quenched by addition of aqueous KHSO4 (1 M). The aqueous phase was extracted with ethyl acetate (three times). The water mixture was poured onto a hydromatrix column and eluted with ethyl acetate, then acetonitrile. The pH of the water phase was adjusted to ~8 with aqueous NaOH (5 M) and it was extracted with ethyl acetate. The combined organic layers were passed through a phase separator and then concentrated in vacuo. The product was purified by preparative HPLC. The desired fractions were pooled and concentrated in vacuo. The residue was partitioned between water (pH approximately 8) and dichloromethane (twice). Tthe combined organic layers were passed through a phase separator and concentrated in vacuo to give N-(3-(4-ammo-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-4-fluorophenyl)-5- chloropicolinamide (5.00 mg, 7% yield): 1H NMR (500 MHz, DMSO-^6) δ ppm 10.64 (s, 1 H), 8.77 (d, 1 H), 8.17 - 8.23 (m, 1 H), 8.12 - 8.17 (m, 1 H), 8.09 (dd, 1 H), 7.73 (dt, 1 H), 7.08 (dd, 1 H), 6.54 (br. s., 2 H), 2.16 (s, 3 H), 1.75 - 1.82 (m, 1 H), 0.30 - 0.41 (m, 2 H), 0.17 - 0.26 (m, 1 H), -0.08 - 0.00 (m, 1 H); MS (ES-) m/z 384 [M-H]" ; MS (ES+) m/z 386 [M+H]+.
Example 50
3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-N-(3-chlorophenyI)beiizainide
Figure imgf000111_0001
PalladiumQI) acetate (7.68 mg, 0.03 mmol) and l,3-bis(diphenylphosphino)propane (14.12 mg, 0.03 mmol) were added to a high pressure reactor (200 mL), then 2-(3-bromophenyl)- 2-cyclopropyl-5-methyl-2H-imidazol-4-amine (100 mg, 0.34 mmol) in dioxane (5 mL) was added, followed by 3-chloroaniline (0.362 mL, 3.42 mmol) and TEA (0.143 mL, 1.03 mmol). The reactor was connected to a carbon monoxide source, a nitrogen (g) source and a vacuum line. The mixture, under an atmosphere of N2 (g), was evacuated 3 times, then the procedure was repeated with carbon monoxide (excess) 3 times. The pressure was adjusted to 4 bar of CO (g) and then the reactor was placed in an oil-bath set to 90 0C. After 90 h, the reaction vessel was allowed to cool and removed from the carbon monoxide source. The reaction mixture was diluted with MeOH/DCM and filtered through Celite, then concentrated.. The product was purified by preparative chromatography to give the title compound in 37 mg (30 % yield): 1H NMR (500 MHz, DMSO-J6) δ ppm -0.03 - 0.08 (m, 1 H) 0.18 - 0.27 (m, 1 H) 0.27 - 0.38 (m, 2 H) 1.48 - 1.60 (m, 1 H) 2.17 (s, 3 H) 6.48 - 6.55 (m, 2 H) 7.13 - 7.19 (m, 1 H) 7.33 - 7.42 (m, 1 H) 7.42 - 7.47 (m, 1 H) 7.66 - 7.74 (m, 1 H) 7.75 - 7.85 (m, 2 H) 7.91 - 7.99 (m, 1 H) 8.08 - 8.17 (m, 1 H) 10.37 - 10.45 (m, 1 H) ; MS (APCI+) m/z 367 (M+H)+.
Example 51
3-(4-Amino-2-cyclopropyI-5-methyl-2H-imidazoI-2-yl)-N-(4-chlorophenyl)benzamide
Figure imgf000112_0001
Palladium(II) acetate (7.68 mg, 0.03 mmol) and l,3-bis(diphenylphosphino)propane (14.12 mg, 0.03 mmol) were added to a high pressure reactor (200 mL), then 2-(3-bromophenyl)- 2-cyclopropyl-5-methyl-2H-imidazol-4-amine (100 mg, 0.34 mmol) was added, followed by 4-chloroaniline (437 mg, 3.42 mmol), toluene (5 mL) and TEA (0.143 mL, 1.03 mmol). The reactor was connected to a carbon monoxide source, a nitrogen (g) source and a vacuum line. The mixture, under an atmosphere of N2 (g), was evacuated 3 times, then the procedure was repeated with carbon monoxide (excess) 3 times. The pressure was adjusted to 4 bar of CO (g) and then the reactor was placed in an oil-bath set to 90 0C. After 71 h, the reaction vessel was allowed to cool and removed from the carbon monoxide source. The reaction mixture was diluted with MeOH/DCM and filtered through Celite, then concentrated. The product was purified by preparative chromatography to give the title compound in 37mg (30% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm -0.02 - 0.08 (m, 1 H) 0.18 - 0.28 (m, 1 H) 0.29 - 0.39 (m, 2 H) 1.51 - 1.60 (m, 1 H) 2.18 (br. s., 3 H) 6.44 - 6.58 (m, 2 H) 7.38 - 7.43 (m, 2 H) 7.43 - 7.47 (m, 1 H) 7.76 - 7.83 (m, 4 H) 8.10 (s, 1 H) 10.37 (s, 1 H); MS (APCI+) m/z 367 (M+H)+.
Example 52
N-(3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yI)phenyl)-4- chloropicolinamide
Figure imgf000113_0001
4-Chloropicolinic acid (106 mg, 0.67 mmol) and l-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (129 mg, 0.67 mmol) was stirred in N,N- dimethylformamide (2 mL) at rt for 15 minutes. The solution was cooled to 0 0C (external temperature) in an ice- water bath and a solution of 2-(3-aminophenyl)-2~cyclopropyl-5- methyl-2H-imidazol-4-amine (128 mg, 0.56 mmol) and aqueous hydrochloric acid (3 M) (0.187 mL, 0.56 mmol) in N,N-dimethylformamide (2.000 mL) was added dropwise over 5 minutes. The reaction was stirred at 0 °C for 5 minutes and then at ambient temperature for 3 hours. MeOH (1 mL) was added to quench the reaction and the reaction was stirred over night. The mixture was purified by preparative HPLC to yield the title compound (24 mg, 12 % yield, containing 10% MeOH): 1H NMR (500 MHz, DMSO-J6) δ ppm 10.60 (s, 1 H) 8.72 (d, 1 H) 8.15 (d, 1 H) 8.12 (t, 1 H) 7.84 (dd, 1 H) 7.68 (m, 1 H) 7.34 (dt, 1 H) 7.25 (t, 1 H) 6.45 (s, 2 H) 4.10 (q, 0.1 H, MeOH) 3.17 (d, 0.3 H, MeOH) 2.16 (s, 3 H) 1.50 (m, 1 H) 0.32 (m, 2 H) 0.2 (m, 1 H) 0.00 (m, 1 H); MS (ES+) m/z 368 [M+H]+.
Example 53
N-(3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yI)phenyl)-5- chloropicolinamide
Figure imgf000113_0002
The title compound was synthesized as described for Example 52 starting from
5-chloro-2-pyridinecarboxylic acid (69.0 mg, 0.44 mmol) and 2-(3-aminophenyl)-2- cyclopropyl-5-methyl-2H-imidazol-4-amine (100 mg, 0.44 mmol), with the exception that the reaction time was 140 minutes, to give the title compound (22 mg, 14% yield): 1H NMR (500 MHz, DMSO-<&) δ ppm 10.55 (s, 1 H) 8.78 (m, 1 H) 8.20 (dd, 1 H) 8.15 (d, 1 H) 8.11 (t, 1 H) 7.68 (m, 1 H) 7.33 (dt, 1 H) 7.25 (t, 1 H) 6.44 (s, 2 H) 2.16 (s, 3 H) 1.50 (m, 1 H) 0.32 (m, 2 H) 0.21 (m, 1 H) 0.00 (m, 1 H); MS (ES+) m/z 368 [M+H]+.
Example 54
5-(4-Amino-5-methyl-2-(3'-(prop-l-ynyl)biphenyl-3-yl)-2H-imidazoI-2-yl)-l-ethyl-3- methylpyridin-2(lH)-one
Figure imgf000114_0001
The title compound was synthesized as described for Example 17 starting from 5-(4- ammo-2-(3-bromophenyl)-5-memyl-2H-imidazol-2-yl)-l-ethyl-3-methylpyridin-2(lH)-one (71.0 mg, 0.18 mmol) and 3-(prop-l-ynyl)phenylboronic acid (88 mg, 0.55 mmol), with the following exceptions: The reaction time was 20 minutes and the reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM before purification. The DCM layer was passed through a phase separator and concentrated before the purification.
Preparative HPLC gave 15 mg (19% yield) of the title compound: 1H NMR (500 MHz, DMSO-^6) δ ppm 7.73 (t, 1 H) 7.52 - 7.57 (m, 4 H) 7.50 (m, 1 H) 7.40 - 7.46 (m, 2 H) 7.32 - 7.40 (m, 2 H) 6.68 (s, 2 H) 3.88 (q, 2 H) 2.24 (s, 3 H) 2.07 (s, 3 H) 1.93 (s, 3 H) 1.16 (t, 3 H); MS (ES+) m/z 423 [M+H]+. Example 55
5-(4-Amino-2-(2'-fluoro-5'-(prop-l-ynyI)biphenyl-3-yl)-5-methyl-2H-iinidazol-2-yI)-l- ethyI-3-methylpyridin-2(lH)-one
Figure imgf000115_0001
The title compound was synthesized as described for Example 17 starting from 5-(4- amino-2-(3 -bromophenyl)-5 -methyl-2H-imidazol-2-yl)- 1 -ethyl-3 -methylpyridin-2( 1 H)-one (71.0 mg, 0.18 mmol) and 3-(prop-l-ynyl)phenylboronic acid (88 mg, 0.55 mmol), with the exception that it was purified twice by preparative HPLC to give the title compound, 27 mg (31% yield): 1H NMR (500 MHz, DMSO-J6) δ ppm 7.64 (s, 1 H) 7.53 - 7.57 (m, 1 H) 7.52 (d, 1 H) 7.37 - 7.46 (m, 5 H) 7.29 (dd, 1 H) 6.68 (br. s., 2 H) 3.88 (q, 2 H) 2.24 (s, 3 H) 2.05 (s, 3 H) 1.93 (s, 3 H) 1.16 (t, 3 H); MS (ES+) m/z 441 [M+H]+
The level of activity of the compounds was tested using the following methods: TR-FRET Assay The β-secretase enzyme used in the TR-FRET is prepared as follows:
The cDNA for the soluble part of the human β-Secretase (AA 1 - AA 460) was cloned using the ASP2-FclO-l-IRES-GFP-neoK mammalian expression vector. The gene was fused to the Fc domain of IgGl (affinity tag) and stably cloned into HEK 293 cells.
Purified sBACE-Fc was stored in -80 0C in Tris buffer, pH 9.2 and had a purity of 95%.
The enzyme (truncated form) was diluted to 6 μg/mL (stock 1.3 mg/mL) and the substrate (Europium)CEVNLDAEFK(Qsy7) to 200 nM (stock 120 μM) in reaction buffer
(NaAcetate, chaps, triton x-100, EDTA pH4.5). The robotic systems Biomek FX and Velocity 11 were used for all liquid handling and the enzyme and substrate solutions were kept on ice until they were placed in the robotic system. Enzyme (9 μl) was added to the plate then 1 μl of compound in dimethylsulphoxide was added, mixed and pre-incubated for 10 minutes. Substrate (10 μl) was then added, mixed and the reaction proceeded for 15 minutes at room temperature. The reaction was stopped with the addition of Stop solution (7 μl, NaAcetate, pH 9). The fluorescence of the product was measured on a Victor II plate reader with an excitation wavelength of 340nm and an emission wavelength of 615nm. The assay was performed in a Costar 384 well round bottom, low volume, non-binding surface plate (Corning #3676). The final concentration of the enzyme was 2.7 μg/ml; the final concentration of substrate was 100 nM (Km of -250 nM). The dimethylsulphoxide control, instead of test compound, defined the 100% activity level and 0% activity was defined by wells lacking enzyme (replaced with reaction buffer). A control inhibitor was also used in dose response assays and had an IC50 of -575 nM. sAPPβ release assay SH-SY5Y cells were cultured in DMEM /F-12 with Glutamax, 10% FCS and 1% nonessential aminoacids and cryopreserved and stored at -14O0C at a concentration of 7.5x106 cells per vial. Thaw cells and seed at a cone, of 1.5x105/ml in DMEM /F-12 with Glutamax, 10% FCS and 1% non-essential aminoacids to a 96-well tissue culture treated plate, lOOμl cell susp/well. The cell plates were then incubated for 7 hours at 37 0C, 5% CO2. The cell medium was removed, followed by addition of 90 μl compound diluted in DMEM /F- 12 with Glutamax, 10% FCS, 1% non-essential aminoacids and 1% PeSt to a final cone, of 1% DMSO. The compounds were incubated with the cells for 16h (over night) at 37 °C, 5% CO2. Meso Scale Discovery (MSD) plates were used for the detection of sAPPβ release. MSD sAPPβ plates were blocked in 3% BSA in Tris wash buffer (150μl/well) for 1 hour in RT and washed 4 times in Tris wash buffer (150μl/well). 50 μl of medium was transferred to the pre-blocked and washed MSD sAPPβ microplates, and the cell plates were further used in an ATP assay to measure cytotoxicity. The MSD plates were incubated with shaking in RT for 1 hour followed by washing 4 times. 25 μl detection antibody was added (InM) per well followed by incubation with shaking in RT for Ih and washing 4 times. 150 μl Read Buffer was added per well and the plates were read in a SECTOR Imager.
ATP assay
As indicated in the sAPPβ release assay, after transferring 50 μL medium from the cell plates for sAPPβ detection, the plates were used to analyse cytotoxicity using the
ViaLightTM Plus cell proliferation/cytotoxicity kit from Cambrex BioScience that measures total cellular ATP. The assay was performed according to the manufacture's protocol. Briefly, 25μL cell lysis reagent was added per well. The plates were incubated at room temperature for 10 min. Two min after addition of 50 μL reconstituted ViaLightTM Plus ATP reagent, the luminescence was measured in a Wallac Victor2 1420 multilabel counter.
Results
Typical IC50 values for the compounds of the present invention are in the range of about 1 to about 100,000 nM. Biological data is given below in Table I Table I.
Figure imgf000118_0001
Figure imgf000119_0001

Claims

1. A compound according to formula (I):
Figure imgf000120_0001
(I)
wherein
A is selected from Ci_6alkyl, C2^alkenyl, C2-6alkynyl, Cuβalkylaryl, C^alkylheteroaryl, Co-6alkylC3-8cycloalkyl,
Figure imgf000120_0002
C0-6alkylC6cycloalkynyl or Co-6alkyl- C3_8heterocyclyl, wherein said A is optionally substituted with one or more R1;
B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R2;
C is selected from hydrogen, C^aHcyl, C^alkenyl, C2-ealkynyl5 Co-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, C0.6alkylaryl, C0.6alkylheteroaryl, Co^alkylheterocyclyl, C0-6alkylOR4, C0^alkylCO2R4, C0-6alkylN(R4)2, halogen,
C0-6alkylCN, C^alkylCOR4, CHO, NO2, Co-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0.6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, C0-6alkylOSO2R4, Co-6alkylS03R4, C0^alkylSO2R4, Co-6alkylSOR4, C0-6alkyl(SO2)N(R4)2, C0-6alkyl(SO)N(R4)2, C0-6alkylNR4(SO2)N(R4)2, C0-6alkylNR4(SO)R4, SF5, and OSF5, wherein said C^alkyl, C2-6alkenyl, C2-6alkynyl, Co-βalkylCs-όCycloalkyl, Co-6alkylaryl, Co-βalkylheteroaryl, or Co-βalkylheterocyclyl is optionally substituted with one or more R3; R1 is selected from C1-6alkyl, C2^alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl,
Co-6alkylC3.6cycloalkenyl, Co-βalkylCecycloalkynyl, Co-βalkylaryl, C0-6alkylheteroaryl, Co-ealkyUieterocyclyl, C0-6alkylCO2R4, C0-6alkylN(R4)2, C0-6alkylOR4, halogen, Co-6alkylCN, C0-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0.6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, C0-6alkylOSO2R4, C0-6alkylSO3R4, C0-6alkylSO2R4, Co-6alkylSOR4, C0-6alkyl(SO2)N(R4)2, CMalkyl(SO)N(R4)2, C0-6alkylNR4(SO2)N(R4)2, Co-6alkylNR4(SO)R4, SF5, and OSF5, wherein said Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-βalkylheteroaryl, Co-όalkylheterocyclyl or is optionally substituted with one or more R3; or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R is selected from C^alkyl, C2.6alkenyl, C^alkynyl, C0-6alkylC3^cycloalkyl,
Co-6alkylC3-6cycloalkenyl, Co-όalkylCδcycloalkynyl, Co-βalkylaryl, Co-6alkylheteroaryl, Co-βalkylheterocyclyl, C0-6alkylCO2R4, C0-6alkylN(R4)2, halogen, C^alkylCN,
Co-ealkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, Co_6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO> N(R4)2, Co-ealkylSR4, C0-6alkylOSO2R4, C0-6alkylSO3R4, C0-6alkylSO2R4, C0.6alkylSOR4, Co.6alkyl(S02)N(R4)2, C0-6alkyl(SO)N(R4)2, C0.6alkylNR4(SO2)N(R4)2, C0.6alkylNR4(SO)- R4 and Co-6alkylOR4, wherein said C^alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3.6cyclo- alkyl, Co-6alkylaryl, Co-βalkylheteroaryl or Co-όalkylheterocyclyl is optionally substituted with one or more R3,
or two R2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R3 is selected from halogen, NO2, CHO, C0-6alkylCN, C0-6alkylOR4, C1-6haloalkyl, C0-6alkylN(R4)2, NR4C(O)R4, C0-6alkylCO2R4, C0-6alkylCON(R4)2, C0-6alkylNR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, 0(CO)OR4, 0(CO)R4, Co-ealkylCOR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, Co-6alkylSR4, C0.6alkyl(SO2)N(R4)2, OC2-6alkylN- R4(SO2)R4, C0-6alkyl(SO)N(R4)2, OSO2R4, SO3R4, C0-6alkylNR4(SO2)N(R4)2, C0-6alkylN- R4(SO)R4, C0-6alkylSO2R4, C0.6alkylSOR4, C1-6alkyl, C2-6alkenyl, C2.6alkynyl, C0.6alkyl-
Figure imgf000121_0001
Co-6alkylheteroaryl, and Co-βalkylheterocyclyl, wherein said Chalky!, C2-6alkenyl, C2-6alkynyl, Co^alkylCs-όcycloalkyl, Co-βalkylaryl, Co-6alkylheteroaryl, or Co-6alkylhetero- cyclyl is optionally substituted with one or more R6;
R4 is selected from hydrogen, Ci-βalkyl, Ci-3haloalkyl, C2-6alkenyl, C2-βalkynyl, C0- βalkylCs-βcycloalkyl, C0-6alkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co-δalkylheterocyclyl, Ci-6alkylOR5, and C1-6alkylN(R5)2, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-βalkylaryl, C0-6alkyl- heteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R5 is selected from hydrogen, Cpβalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3.6cycloalkenyl, C0.6alkylC6cycloalkynyl, C0-6alkylaryl, Co-βalkylheterocyclyl and Co-6alkylheteroaryl, wherein said Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkyl- C3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl or Co-όalkylheterocyclyl is optionally substituted with one or more R6;
or two R5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R6 is selected from oxo, halogen, nitro, CN, OR7,
Figure imgf000122_0001
C2-6alkenyl, C2-6alkynyl, Co- 6alkylaryl, C0-6alkylheteroaryl, C0.6alkylC3-6cycloalkyl, Co-βalkylheterocyclyl, d-βhalo- alkyl, OC2-6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, 0(CO)C 1-6alkyl, (CO)OC 1-6alkyl, COR7, SON(R7)2, (SO2)N(R7)2, NR7SO2R7, NR7SOR7, SO2R7, SOR7, (CO)C i-6alkyl-
N(R7)2, (SO2)C^alkylN(R7)2, OSO2R7 and SO3R7, wherein said C^alkyl, C2-6alkenyl, C2- δalkynyl, Co-6alkylaryl, Co-δalkylheteroaryl, Co-βalkylheterocyclyl, or Co-6alkylC3-6cyclo- ahcyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7,
Figure imgf000122_0002
R7 is selected from hydrogen,
Figure imgf000122_0003
Cj-shaloalkyl, C2-6alkenyl, C2-6alkynyl, C3.6cyclo- alkyl, C3-6cycloalkenyl, Cόcycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, Cs^cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, cyano, halogen and OCi-3alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OCi-3alkyl, cyano and halogen; as a free base or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein
A is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-βalkylaryl, Ct-ealkylheteroaryl, Co-6alkylC3_8cycloalkyl, Co-6alkylC3^cycloalkenyl, Co-δalkylCδcycloalkynyl or Co-6alkyl- C3_8heterocyclyl, wherein said A is optionally substituted with one or more R1;
B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R2;
C is selected from hydrogen, Chalky!, C2-6alkenyl, C2-6alkynyl, C0^alkylC3.6cycloalkyl, Co-6alkylC3^cycloalkenyl, C0^alkylC6cycloalkynyl, Co-όalkylaryl, Co-βalkylheteroaryl, Co-δalkylheterocyclyl, C0.6alkylOR4, C0-6alkylCO2R4, C0-6alkylN(R4)2, halogen, C0-6alkyl- CN, C0-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, Co.6alkylNR4(CO)R4, C0-6alkyl(SO)N(R4)2, C0.6alkylNR4(SO2)N(R4)2, Co-6alkylNR4(SO)R4, SF5, and OSF5, wherein said Ci^alkyl, C2-6alkenyl, C2.6alkynyl, Co-όalkylCs-όcycloalkyl, Co-6alkylaryl, Co-βalkylheteroaryl, or Co-βalkylheterocyclyl is optionally substituted with one or more R3;
R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl,
Co-6alkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, Co-6alkylaryl, C0^alkylheteroaryl, Co-θalkylheterocyclyl, Co-6alkylC02R4, C0-6alky]N(R4)2, Co-ealkylOR4, halogen,
Co-βalkylCN, Co-ealkylCOR4, CHO, NO2, C0.6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, C0-6alkylOSO2R4, C0-6alkylSO3R4, C0-6alkylSO2R4, Co-ealkylSOR4, SF5, and OSF5, wherein said C1-6alkyl, C2-6alkenyl, C2.6alkynyl,
Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-ealkylheteroaryl, Co-βalkylheterocyclyl or is optionally substituted with one or more R3, or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R2 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, C0-6alkyl- C3-6cycloalkenyl, Co-βalkylCβcycloalkynyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co-βalkyl- heterocyclyl, C0-6alkylCO2R4, C0-6alkylN(R4)2, halogen, C0.6alkylCN, Co-6alkylCOR4, CHO, NO2, Co-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, Co-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0^alkyl- (SO)N(R4)2, Co-6alkylNR4(S02)N(R4)2, C0-6alkylNR4(SO)R4 and C0.6alkylOR4, wherein said C^alkyl, C2-6alkenyl, C2^alkynyl, Co-ealkylCs-ecycloalkyl, C0-6alkylaryl, C0-6alkyl- heteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3, or two R may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R3 is selected from halogen, NO2, CHO, C0.6alkylCN, C0-6alkylOR4, C1-6haloalkyl, Co-6alkylN(R4)2, NR4C(O)R4, C0-6alkylCO2R4, CMalkylCON(R4)2, C0-6alkylNR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, 0(CO)OR4, 0(CO)R4, C0-6alkylCOR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, C0-6alkylSR4, C0.6alkyl(SO2)N(R4)2, OC2-6alkylN- R4(SO2)R4, C0-6alkyl(SO)N(R4)2, OSO2R4, SO3R4, C0.6alkylNR4(SO2)N(R4)2, C0-6alky]N- R4(SO)R4, C0-6alkylSO2R4, Co-6alkylSOR4, C1-6alkyl, C^alkenyl, C2.6alkynyl, Co-βalkyl- C3-6cycloalkyl, Co-ealkylCs-ecycloalkenyl, Co-6alkylC6cycloalkynyl, Co-6alkylaryl,
Co-βalkylheteroaryl, and Co-όalkylheterocyclyl, wherein said C^alkyl, C2.6alkenyl, C2-6alkynyl, Co-6alkylC3.6cycloalkyl, Co-6alkylaryl, C0.6alkylheteroaryl, or Co-ealkyl- heterocyclyl is optionally substituted with one or more R6; R4 is selected from hydrogen, Crβalkyl, Ci-3haloalkyl, C2-6alkenyl, C2-6alkynyl, C0- 6alkylC3-6cycloalkyl, C0-6alkylC3-6cycloalkenyl, Co^alkylC6cycloalkynyl, C0-6alkylaryl, Co-βalkylheteroaryl, Co-δalkylheterocyclyl, C1-6alkyl0R5, and Cr6alkylN(R5)2, wherein said Cϊ-βalkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-ealkyl- heteroaryl or Co-βalkylheterocyclyl is optionally substituted with one or more R6;
or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S; said heterocyclic ring optionally being substituted with one or more R6;
R5 is selected from hydrogen, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3_6cycloalkenyl, Co-6alkylC6cycloalkynyl, Co-6alkylaryl, Co-βalkylheterocyclyl and Co-βalkylheteroaryl, wherein said Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkylC3- βcycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl or Co-βalkylheterocyclyl is optionally substituted with one or more R6;
or two R5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6;
R6 is selected from oxo, halogen, nitro, CN, OR7, C^alkyl, C2-6alkenyl, C2-6alkynyl, C0- βalkylaryl, C0-6alkylheteroaryl, Co-δalkylCs-ecycloalkyl, Co-βalkylheterocyclyl, C1-6halo- alkyl, OC2-6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, O(CO)C1-6alkyl, (CO)OC1 ^alkyl, COR7, SON(R7)2, (SO2)N(R7)2, NR7SO2R7, NR7SOR7, SO2R7, SOR7, (CO)C1-6alkyl- N(R7)2, (SO2)C1.6alkylN(R7)2, OSO2R7 and SO3R7, wherein said C^alkyl, C2-6alkenyl, C2. βalkynyl, Co-βalkylaryl, C0-6alkylheteroaryl, Co^alkylheterocyclyl, or Co-βaU-ylCs-ecyclo- alkyl is optionally substituted with one or more substituents selected from halo, nitro, cyano, OR7, C^alkyl, or C^&haloalkyl; R7 is selected from hydrogen, C^alkyl, Ci-3haloalkyl, C2-βalkenyl, C2-6alkynyl, C3_6cyclo- alkyl, C3^cycloalkenyl, Cόcycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C1. δalkyl, C2-6alkenyl, C2-6alkynyl, C3^cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to three substituents selected from hydroxy, cyano, halogen and OQ.salkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents selected from hydroxy, 0Ci-3alkyl, cyano and halogen.
3. A compound according to claim 1, wherein
A is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkylaryl, d-βalkylheteroaryl, C0- βalkylCa-gcycloalkyl, C0-6alkylC3-6cycloalkenyl, Co-βalkylCόcycloalkynyl or Co-6alkylC3. sheterocyclyl, wherein said A is optionally substituted with one or more R1;
B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R2;
C is selected from hydrogen, d-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-όalkylCβcycloalkynyl, Co-6alkylaryl, C0^alkylheteroaryl, Co-ealkylheterocyclyl, C0.6alkylOR4, C0-6alkylCO2R4, Co-6alkylN(R4)2, halogen, C0-6alkyl- CN, Co-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, Co-6alkyl(SO)N(R4)2, C0^alkylNR4(SO2)N(R4)2, C0-6alkylNR4(SO)R4, SF5, and OSF5, wherein said C1-6alkyl, C2.6alkenyl, C2.6alkynyl, Co-6alkylC3_6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl, or Co^alkylheterocyclyl is optionally substituted with one or more R3; R1 is selected from Ci-6alkyl, C^alkenyl, C2-6alkynyl, Co-βalkylCs-ecycloalkyl, Co-δalkyl- C3-6cycloalkenyl, Co^alkylCecycloalkynyl, Co-6alkylaryl, C0-6alkylheteroaryl, Co-δalkyl- heterocyclyl, C0.6alkylCO2R4, C0-6alkylN(R4)2, Co^alkylOR4, halogen, C0.6alkylCN, C0-6alkylCOR4, CHO, NO2, C0-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, 0(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)- N(R4)2, C0-6alkylSR4, C0-6alkylOSO2R4, C0-6alkylSO3R4, Co-ealkylSO^4, C0-6alkylSOR4, SF5, and OSF5, wherein said
Figure imgf000126_0001
Co-6alkylC3-6cycloalkyl, Co-όalkylaryl, Co-6alkylheteroaryl, Co-βalkylheterocyclyl or is optionally substituted with one or more R3; R2 is selected from C1-6alkyl, C^alkenyl, C2^alkynyl, Co-6alkylC3.6cycloalkyl, Co-6alkyl- C3-6cycloalkenyl, C0-6alkylC6cycloalkynyl, Co.6alkylaryl, C0-6alkylheteroaryl, C0.6alkyl- heterocyclyl, Co-6alkylC02R4, C0-6alkylN(R4)2, halogen, C0-6alkylCN, C0^alkylCOR4, CHO, NO2, Co-6alkylCON(R4)2, 0(CO)OR4, 0(CO)R4, 0(CO)N(R4)2, NR4(CO)OR4, C0-6alkylNR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, Co-6alkyl- (SO)N(R4)2, C0-6alkylNR4(SO2)N(R4)2, C0-6alkylNR4(SO)R4 and C0-6alkylOR4, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-βalkyl- heteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R3;
R3 is selected from halogen, NO2, CHO, C^alkylCN, C0-6alkylOR4, C^haloalkyl, Co.6alkylN(R4)2, NR4C(O)R4, C0-6alkylCO2R4, C0-6alkylCON(R4)2, Co-6alkylNR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, 0(CO)OR4, 0(CO)R4, Co-βalkylCOR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, Co-βalkylSR4, C0.6alkyl(SO2)N(R4)2, OC2-6alkyl- NR4(SO2)R4, C0-6alkyl(SO)N(R4)2, OSO2R4, SO3R4, C0-6alkylNR4(SO2)N(R4)2, C0-6alkylN- R4(SO)R4,Co-6alkylS02R4, C0-6alkylSOR4, C^alkyl, C2.6alkenyl, C^alkynyl, Co-βalkyl- C3-6cycloalkyl, Co-δalkylC3-6cycloalkenyl, Co-6alkylC6cycloalkynyl, Co-6alkylaryl,
Co-6alkylheteroaryl, and Co-δalkylheterocyclyl, wherein said d-βalkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-βalkylaryl, Co-6alkylheteroaryl, or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
R4 is selected from hydrogen, Cι-6alkyl, C^haloalkyl, C2-6alkenyl, C2-δalkynyl, Co- 6alkylC3-6cycloalkyl, Co-6alkylC3-δcycloalkenyl, Co-δalkylC6cycloalkynyl, Co-6alkylaryl, Co-6alkylheteroaryl, Co-βalkylheterocyclyl, Cϊ-δalkylOR5, and C1-δalkylN(R5)2, wherein said Crδalkyl, C2-6alkenyl, C2-δalkynyl, Co-δalkylC3-δCycloalkyl, Co-δalkylaryl, Co-βalkyl- heteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S; said heterocyclic ring optionally being substituted with one or more R6;
R5 is selected from hydrogen, d-βalkyl, C2-δalkenyl, C2-6alkynyl, Co-δalkylC3-δCycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-βalkylCόcycloalkynyl, Co-δalkylaryl, Co-βalkylheterocyclyl and Co-δalkylheteroaryl, wherein said Q-βalkyl, C2-δalkenyl, Qrβalkynyl, Co-βalkyl- C3-δCycloalkyl, Co-δaUcylaryl, Co-δalkylheteroaryl or Co-δalkylheterocyclyl is optionally substituted with one or more R6; R is selected from oxo, halogen, nitro, CN, OR , C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0- 6alkylaryl, Co-6alkylheteroaryl, Co-6alkylC3-6cycloalkyl, Co-όalkylheterocyclyl, C1-6halo- alkyl, OC2-6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7,
Figure imgf000128_0001
^alkyl, COR7, SON(R7)2, (SO2)N(R7)2, NR7SO2R7, NR7SOR7, SO2R7, SOR7, (CO)C1-6alkylN- (R7)2, (SO2)C1-6alkylN(R7)2, OSO2R7 and SO3R7, wherein said C1-6alkyl, C^alkenyl, C2- 6alkynyl, C0-6alkylaryl, Co-6alkylheteroaryl, Co^alkylheterocyclyl, or Co-6alkylC3_6cyclo- alkyl is optionally substituted with one or more substituents selected from halo, nitro, cyano, OR7, d.6alkyl, or CJ-6haloalkyl; R7 is selected from hydrogen, Chalky!, Ci-3haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cyclo- alkyl, C3_ecycloalkenyl, C6cycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cy cloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to three substituents selected from hydroxy, cyano, halogen and OQ^alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OC1-3alkyl, cyano and halogen.
4. A compound according to claim 1, wherein
A is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, d-ealkylaryl, C1-6alkylheteroaryl, Co-6alkylC3_8cycloalkyl, Co^alkylCs-όcycloalkenyl, or Co-όalkyl-Cs-gheterocyclyl, wherein said A is optionally substituted with one or more R1;
B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R2;
C is selected from hydrogen, C^alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylC3-6cycloalkenyl, Co-βalkylaryl, Co-6alkylheteroaryl, Co-ealkylheterocyclyl, C0-6alkylOR4, C0-6alkylCO2R4, C0-6alkylN(R4)2, halogen, Co-δalkylCN, Co-βalkylCOR4, NO2,
Figure imgf000128_0002
Co-6alkylSOR4, wherein said
Figure imgf000128_0003
Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl, or Co-ealkylheterocyclyl is optionally substituted with one or more R3;
R1 is selected from Ci-6alkyl, C^alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl,
Co-όalkylCs-ecycloalkenyl, C0-6alkylaryl, Co-βalkylheteroaryl, Co-όalkylheterocyclyl, C0-6alkylCO2R4, C0-6alkylN(R4)2, Co-ealkylOR4, halogen, C0-6alkylCN, C0.6alkylCOR4, NO2, Co.6alkylCON(R4)2, 0(CO)R4, C0-6alkylNR4(CO)R4, C0-6alkylSR4, C0-«alkylSO2R4, C0-6alkylSOR4, wherein said C^alkyl, C2-6alkenyl, C2.6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl, Co-ealkylheterocyclyl or is optionally substituted with one or more R3; or two R1 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R2 is selected from C^aUcyl, C0-6alkylC3.6cycloalkyl, Co-όalkylaryl, Co-ealkylheteroaryl, Co-ealkylheterocyclyl, C0-6alkylCO2R4, C0^alkylN(R4)2, halogen, Co-6alkylCN,
C0-6alkylCOR4, NO2, C0-6alkylCON(R4)2, 0(CO)R4, C0.6alkylSR4, C0.6alkylSO2R4, C0.6alkylSOR4, and C0-6alkylOR4, wherein said C^alkyl, Co-6alkylC3-6cycloalkyl,
Co-6alkylaryl, Co-βalkylheteroaryl or Co-ealkylheterocyclyl is optionally substituted with one or more R3,
or two R2 may together with the atoms to which they are attached form a cyclic or heterocyclic ring optionally substituted with one or more R6;
R3 is selected from halogen, NO2, Co-ealkylCN, C0.6alkylOR4, d-βhaloalkyl,
Co-6alkylN(R4)2, NR4C(O)R4, C0-6alkylCO2R4, C0-6alkylCON(R4)2, CwalkylNR4(CO)R4, 0(CO)R4, Co-eaikylCOR4, C0.6alkylSR4, C0-6alkylSO2R4, C0-6alkylSOR4, C^alkyl, C2.6alkenyl, C2-6alkynyl, C0-6alkylC3^cycloalkyl, Co-βalkylaryl, Co-βalkylheteroaryl, and Co-δalkylheterocyclyl, wherein said C^alkyl, C2.6alkenyl, C2-6alkynyl,
Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl, or Co-βalkylheterocyclyl is optionally substituted with one or more R6; R4 is selected from hydrogen, Ct-ήalkyl, Ci.3haloalkyl, Co-6alkylC3-6cycloalkyl, Co-
6alkylaryl, C0-6alkylheteroaryl, Co-όalkylheterocyclyl, Ci.6alkyl0R5, and C1-6alkylN(R5)2, wherein said Q-ealkyl, C2-6alkenyl, C2-6alkynyl, Co-δalkylCs-ecycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl or Co-βalkylheterocyclyl is optionally substituted with one or more R6; or two R4 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S; said heterocyclic ring optionally being substituted with one or more R6;
R5 is selected from hydrogen, Ci-βalkyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl,
Co-6alkylheteroeyclyl and Co-6alkylheteroaryl, wherein said Cr6alkyl, C0-6alkyl- C3-6cycloalkyl, Co-6alkylaryl, C0-6alkylheteroaryl or CQ-δalkylheterocyclyl is optionally substituted with one or more R6;
or two R5 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring optionally being substituted with one or more R6; R6 is selected from oxo, halogen, nitro, CN, OR7, C^alkyl, Co-6alkylaryl, C0- όalkylheteroaryl, C0-6alkylC3-6cycloalkyl, Co-δalkylheterocyclyl, C1-6haloalkyl, OC2- 6alkylN(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, 0(CO)C j.6alkyl, (CO)Od.6alkyl, COR7, SO2R7, SOR7, wherein said C^alkyl, Co-6alkylaryl, Co-βalkylheteroaryl, Co- 6alkylheterocyclyl or C0-6alkylC3.6cycloalkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7, C^alkyl, C^shaloalkyl, or Odohaloalkyl;
R7 is selected from hydrogen, C^aUcyl, Ci.3haloalkyl, C3^cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said C^alkyl, C3.6cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, cyano, halogen and OCi^alkyl; or two R7 may together form a 4 to 6 membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from hydroxy, OC^alkyl, cyano and halogen; as a free base or a pharmaceutically acceptable salt thereof.
5. A compound according to any one of claims 1 to 4, wherein said B is phenyl or heteroaryl.
6. A compound according to any one of claims 1 to 5, wherein B is not substituted.
7. A compound according to any one of claims 1 to 5, wherein B is substituted.
8. A compound according to claim 7, wherein R2 is C^alkyl, Co-6alkylC3-6cycloalkyl, halogen, C0-6alkylCN or Co-βalkylOR4.
9. A compound according to claim 8, wherein R2 is fluoro, OR4 or
Figure imgf000131_0001
10. A compound according to any one of claims 1 to 9, wherein R4 is hydrogen, Ci-βalkyl, C^haloalkyl, Co-6alkylC3-6cycloalkyl or Co-6alkylheteroaryl.
11. A compound according to claim 11, wherein R4 is hydrogen, Q-δalkyl or d-shaloalkyl.
12. A compound according to any one of claims 1 to 11, wherein A is Chalky., C1.
δalkylaryl, d-ealkylheteroaryl, Co-6alkylC3.8cycloalkyl, or Co-δalkylCs-sheterocyclyl.
13. A compound according to claim 12, wherein A is Co-βalkylCs-gcycloalkyl or Co-6alkyl- C3_8heterocyclyl.
14. A compound according to any one of claims 1 to 13, wherein A is not substituted.
15. A compound according to any one of claims 1 to 13, wherein A is substituted.
16. A compound according to claim 15, wherein R1 is Ci^alkyl, C^alkynyl,
Co-6alkylC3-6cycloalkyl, C0-6alkylOR4 5 halogen, C0-6alkylCN or C0-6alkylCOR4.
17. A compound according to claim 16, wherein R1 is
Figure imgf000131_0002
C0-6alkylC3.6cycloalkyl, Co-6alkylOR4, halogen or C0-6alkylCOR4.
18. A compound according to any one of claims 14 to 17, wherein said C^alkyl is methyl or ethyl.
5 19. A compound according to any one of claims 1 to 18, wherein C is hydrogen,
Figure imgf000132_0001
C2-6alkynyl, C0-6alkylC3-6cycloalkyl, Co-6alkylaryl, C0.6alkylheteroaryl,
Co-ealkylheterocyclyl, C0-6alkylOR4, C0-6alkylCO2R4, C0_6alkylN(R4)2, halogen,
C0-6alkylCN or C0-6alkylNR4(CO)R4. o
20. A compound according to any one of claims 1 to 19, wherein R3 is halogen, NO2, Co-6alkylCN, C0.6alkylOR4, Ci-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0-6alkyl- C3-6cycloalkyl or Co^alkylheterocyclyl.
21. A compound according to claim 20, wherein R3 is halogen, C2-6alkynyl, CN or OR4.5
22. A compound according to claim 20, wherein R3 is halogen or C2-4alkynyl.
23. A compound according to any one of claims 1-22, wherein R6 is oxo, halogen, CN, OR7, Ci-βalkyl, C0-6alkylC3-6cycloalkyl or C1-6haloalkyl.
C
24. A compound according to claim 23, wherein R6 is chloro.
25. A compound according to claim 1, wherein
A is selected from C1-6alkyl, d-βalkylaryl, C0-6alkylC3.8cycloalkyl and Co-βalkylCs-shetero-5 cyclyl, wherein said A is optionally substituted with one or more R1 ;
B is aryl;
C is Co-ealkylaryl or C0.6alkylheteroaryl, wherein said C0-6alkylaryl or Co-βalkylheteroaryl is optionally substituted with one or more R1;
R1 Co.6alkylCOR4;
0 R3 is Co-ealkylOR4; and
R4 is Ci-βalkyl.
26. A compound according to claim 1, wherein
A is C0-6alkylC3.8cycloalkyl or C0-6alkyl-C3.8heterocyclyl, wherein said A is optionally substituted with one or more R1;
B is aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or more R2;
C is hydrogen, C^alkyl, C2-6alkynyl, Co-βalkylCs-όCycloalkyl, Co-6alkylaryl,
Co-ealkylheteroaryl, C0-6alkylheterocyclyl, C0-6alkylOR4, C0-6alkylCO2R4, Co-6alkylN(R4)2, halogen, C0-6alkylCN, Co-6alkylNR4(CO)R4;
R1 is C^alkyl, C0-6alkylC3-6cycloalkyl, C0-6alkylOR4, halogen or C0-6alkylCOR4;
R2 is C^alkyl, Co-6alkylC3-6cycloalkyl, halogen, Co-όalkylCN or Co-βalkylOR4;
R3 is halogen, C2-6alkynyl, CN or OR4;
R4 is hydrogen, Ci-6alkyl, Q^haloalkyl, C0-6alkylC3-6cycloalkyl or C0-6alkylheteroaryl;
R6 is oxo, halogen, CN, OR7, C^aHcyl, Co-6alkylC3_6cycloalkyl or Ci-βhaloalkyl.
27. A compound selected from
2-(3!-Methoxybiphenyl-3-yl)-2,5-dimethyl-2H-imidazol-4-amine;
(R)-2-(3'-Methoxybiphenyl-3-yl)-2,5-dimemyl-2H-imidazol-4-amine;
2,5-Dimethyl-2-(3-(pyridm-3-yl)phenyl)-2H-miidazol-4-amine;
2-Ethyl-5-methyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
2-Cyclohexyl-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)-2H-imidazol-4-amine;
2-Cyclohexyl-5-methyl-2-(3-(pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
2-(3l-Methoxybiphenyl-3-yl)-5-methyl-2-(tetrahydro-2H-ρyran-4-yl)-2H-imidazol-4- amine;
1 -(4-(4-Amino-2-(3 '-methoxybiphenyl-3 -yl)-5-methyl-2H-imidazol-2-yl)piperidin- 1 - yl)ethanone;
2-Berizyl-5-methyl-2-(3-(pyriniidm-5-yl)phenyl)-2H-imidazol-4-amine; and
(R)-2-Benzyl-5-methyl-2-(3-(jpyrmiidm-5-yl)phenyl)-2H-imidazol-4-aniine;
(R)- and (S)- 2-(2'-fluoro-3'-methoxybiphenyl-3-yl)-5-methyl-2-(pyridin-3-ylmethyl)-2H- imidazol-4-amine;
(R)- and (S)- 2-(3-(5-Chloroρyridin-3-yl)phenyl)-5-methyl-2-(pyridin-3-ylmethyl)-2H- imidazol-4-amine;
2-(3-Bromophenyl)-2-cyclopropyl-5-methyl-2H-imidazol-4-amine; 2-(3-(5-CMoropyridin-3-yl)phenyl)-2-cyclopropyl-5-methyl-2H-imidazol-4-amine;
2-Cyclopropyl-5-methyl-2-(3-(5-(prop-l-ynyl)pyridin-3-yl)phenyl)-2H-imidazol-4-amiiie;
5-(4- Amino-2-(3 -bromophenyl)-5 -methyl-2H-imidazol-2-yl)-3 -methylpyridin-2( 1 H)-one;
5-(4-Amino-2-(3-(5-cUoropyridin-3-yl)phenyl)-5-methyl-2H-imidazol-2-yl)-l-ethyl-3- methylpyridin-2( 1 H)-one;
5 -(4- Amino-5-methyl-2-(3 -(5 -(prop- 1 -ynyl)pyridin-3 -yl)phenyl)-2H-imidazol-2-yl)- 1 - ethyl-3-methylpyridin-2( 1 H)-one;
5-(4-Amino-2-(3'-methoxybiphenyl-3-yl)-5-methyl-2H-imidazol-2-yl)-l-ethyl-3- methylpyridin-2(lH)-one;
5-(4-Amino-2-(3',5'-difluorobiphenyl-3-yl)-5-methyl-2H-imidazol-2-yl)-l-ethyl-3- methylpyridin-2(lH)-one;
2-(3-(5-Chloropyridin-3-yl)-4-fluorophenyl)-2-cyclopropyl-5-methyl-2H-imidazol-4- amine;
2-Cyclopropyl-2-(4-fluoro-3-(5-(prop-l-ynyl)pyridin-3-yl)phenyl)-5-methyl-2H-imidazol- 4-amine;
2-(3<5-CWoropyridin-3-yl)phenyl)-5-methyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H- imidazol-4-amine;
2-(3-(5-Fluoropyridin-3-yl)phenyl)-5-methyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H- imidazol-4-amine;
2-(3-(5-Methoxypyridin-3-yl)phenyl)-5-methyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H- imidazol-4-amine;
2-(3'-Methoxybiphenyl-3-yl)-5-methyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H- imidazol-4-amine;
N-(3-(4-Ammo-2-cyclopropyl-5-memyl-2H-imidazol-2-yl)phenyl)pyrazine-2- carboxamide;
2-(3-(5-Chloropyridin-3-yl)phenyl)-2-cyclobutyl-5-methyl-2H-imidazol-4-amine;
2-Cyclobutyl-2-(3-(5-fluoropyridm-3-yl)phenyl)-5-memyl-2H-iπddazol-4-amine;
2-Cyclobutyl-5-methyl-2-(3-(5-(prop-l-ynyl)pyridm-3-yl)phenyl)-2H-imidazol-4-amine;
2-(3-(5-CMoropyridin-3-yl)phenyl)-2-isopropyl-5-memyl-2H-imidazol-4-amine;
2-(3-(5-Fluoropyridm-3-yl)phenyl)-24sopropyl-5-memyl-2H-imidazol-4-amine;
2-Isopropyl-5-methyl-2-(3-(5-(prop-l-ynyl)pyridin-3-yl)phenyl)-2H-imidazol-4-amine;
2-Cyclohexyl-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine; 2-Cycloheptyl-2-(4-methoxyphenyl)-5-methyl-2H-imidazol-4-amine;
2-(Bicyclo [2.2.1 ]heptan-2-yl)-2-(4-methoxyphenyl)-5-meώyl-2H-imidazol-4-amine;
2-Cyclooctyl-2-(4-metiboxyphenyl)-5-methyl-2H-imidazol-4-amine;
2-(4-Methoxyphenyl)-5-methyl-2-(3-phenylpropyl)-2H-imidazol-4-amine;
2-(4-Methoxyphenyl)-2-(3-(3-methoxyphenyl)propyl)-5-methyl-2H-imidazol-4-amine;
5-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2'-fluoro-5'-methoxybiphenyl-2- ol;
5-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-5l-chloro-2'-fluorobiphenyl-2-ol;
5'-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-6-fluoro-2l-hydroxybiphenyl-3- carbonitrile;
5-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2'-fluoro-3'-methoxybiphenyl-2- ol;
4-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2-(5-(prop-l-ynyl)pyridin-3- yl)phenol;
4-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2-(pyrazin-2-yl)phenol;
4-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2-(4-(prop-l-ynyl)pyridin-2- yl)phenol;
5-(4-Amino-2-cyclopropyl-5-metiiyl-2H-iniidazol-2-yl)-2',5!-dichlorobiphenyl-2-ol;
5-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-2'-chloro-5'-methoxybiphenyl-2- ol;
N-(3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-4-fluorophenyl)-5- chloropicolinamide;
3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-N-(3-chlorophenyl)benzamide;
3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)-N-(4-cUorophenyl)ben2amide; N-(3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)phenyl)-4-cWoropicolinamide;
N-(3-(4-Amino-2-cyclopropyl-5-methyl-2H-imidazol-2-yl)phenyl)-5-chloropicolinamide;
5-(4-Amino-5-methyl-2-(3'-(proρ-l-ynyl)biphenyl-3-yl)-2H-imidazol-2-yl)-l-ethyl-3- methylpyridin-2( 1 H)-one ;
5-(4-Amino-2-(2'-fluoro-5'-(prop-l-ynyl)biphenyl-3-yl)-5-methyl-2H-imidazol-2-yl)-l- ethyl-3 -methylpyridin-2( 1 H)-one;
as a free base or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 27, or a
pharmaceutically acceptable salt thereof, in association with pharmaceutically acceptable excipients, carriers or diluents.
29. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for use as a medicament.
30. A compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for treating or preventing an Aβ-related pathology.
31. A compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for treating or preventing an Aβ-related pathology, wherein said Aβ-related pathology is Downs syndrome, a β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer Disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
32. A compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for treating or preventing Alzheimer Disease.
33. A compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing an Aβ-related pathology.
34. Use of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing an Aβ-related pathology, wherein said Aβ-related pathology is Downs syndrome, a β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
35. Use of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing Alzheimer's Disease.
36. A method of inhibiting activity of BACE comprising contacting said BACE with a compound of any one of claims 1 to 27.
37. A method of treating or preventing an Aβ-related pathology in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.
38. The method of claim 37, wherein said Aβ-related pathology is Downs syndrome, a β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
39. A method of treating or preventing Alzheimer's Disease in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.
40. A method of treating or preventing an Aβ-related pathology in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, and at least one cognitive enhancing agent, memory enhancing agent, or choline esterase inhibitor.
5 41. A process for preparing a compound of formula (VI)
Figure imgf000138_0001
wherein R10 and R11 are defined as A and B in claim 1, or wherein R10 and R11 are defined as groups that can be converted to A and B in subsequent transformations;
comprising the steps of
i o a) reacting a compound of formula (III)
Figure imgf000138_0002
with 2-oxopropane thioarnide to yield a compound of formula (V)
Figure imgf000138_0003
and
15 b) treating a compound of formula (V) with ammonia, optionally in the presence of an oxidation agent.
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