WO2017127528A1

WO2017127528A1 - Peptoid agonists of fibroblast growth receptors

Info

Publication number: WO2017127528A1
Application number: PCT/US2017/014110
Authority: WO
Inventors: Xin Qi
Original assignee: University Of Florida Research Foundation, Inc.
Priority date: 2016-01-19
Filing date: 2017-01-19
Publication date: 2017-07-27

Abstract

Drug development targeting fibroblast growth factor receptors (FGFRs) represents an emerging theme in medicinal chemistry. Considering the fact that most of the currently identified FGFR agonists are long chain peptides with limited stability, discovery of novel non-peptide FGFR ligands is important. A linear one-bead-one-compound peptoid (oligomers of N-substituted glycine units) library with a theoretical diversity of 10⁶ was designed and synthesized. Microarray-based screening led to the identification of compounds of Formula (I) as FGFR ligands. Provided herein are novel peptoid agonists and antagonists, such as compounds of Formula (I), which can activate or inhibit FGFRs and are therefore useful in the treatment and/or prevention of disease.

Description

PEPTOID AGONISTS OF FIBROBLAST GROWTH RECEPTORS RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application, U.S.S.N.62/280,570, filed January 19, 2016, which is incorporated herein by reference. GOVERNMENT SUPPORT

[0002] This invention was made with government support under grant number UL1 TR0064 awarded by the National Institutes of Health and the National Center for Advancing

Translational Sciences. The government has certain rights in the invention. BACKGROUND OF THE INVENTION

[0003] Fibroblast growth factor receptors (FGFRs) consist of an extracellular ligand-binding region composed of three immunoglobulin (Ig)-like modules (IgI-III), a single

transmembrane (TM) domain, and a split tyrosine-kinase (TK) domain (see Figure 1). There are four FGFRs in mammals, and alternative splicing of FGFR 1, 2, and 3 in the third Ig-like loop domain further gives rise to IIIb and IIIc isoforms (see, e.g., Mohammadi et al.

“Structural basis for fibroblast growth factor receptor activation”, Cytokine Growth Factor Rev.2005, 16, 107-137). Binding of fibroblast growth factors (FGFs) to the FGFRs results in receptor dimerization, followed by kinase activation and autophosphorylation of tyrosine residues in the intracellular domain of FGFR. The phosphorylation of tyrosine residues activates FGFR substrate 2α (FRS2α), which further phosphorylates the mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K) pathways, leading to increased phosphorylation of ERK and Akt (see Figure 1). Other effector proteins including phospholipase-Cγ (PLCγ), Src homologous and collagen A (ShcA), and STAT transcription factors are also activated by FGFRs. (see, e.g., Eswarakumar et al.“Cellular signaling by fibroblast growth factor receptors”, Cytokine Growth Factor Rev.2005, 16, 139-149; Dailey et al.“Mechanisms underlying differential responses to FGF signaling”, Cytokine Growth Factor Rev.2005, 16, 233-247; Beenken, A., and Mohammadi, M.“The FGF family:

biology, pathophysiology and therapy”, Nat. Rev. Drug Discov.2009, 8, 235-253).

[0004] In humans, 22 members of the FGF family have been identified, all of which are structurally and functionally related polypeptide growth factors with the molecular mass ranges from 17 to 34 kDa. FGFs are involved in angiogenesis, wound healing, embryonic development, and various endocrine signaling pathways (see, e.g., Itoh, N., and Ornitz, D. M. “Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease”, J. Biochem.2011, 149, 121-130). In addition to the cognate FGFs, FGFRs also interact with a number of cell adhesion molecules, such as the neural cell adhesion molecule (NCAM), which plays multiple roles in nervous system development and maintenance, and modulates neuronal plasticity (see, e.g., Hinsby et al.“Molecular mechanisms of NCAM function”, Front. Biosci.2004, 9, 2227-2244; Cambon et al.“A synthetic neural cell adhesion molecule mimetic peptide promotes synaptogenesis, enhances presynaptic function, and facilitates memory consolidation”, J. Neurosci.2004, 24, 4197-4204).

[0005] Due to the essential roles of FGF/FGFR signaling in angiogenesis, wound healing, cell migration, neural outgrowth, embryonic development, and various other biological processes, drug development targeting FGFRs has become an emerging theme in the field of medicinal chemistry (see, e.g., Andre, F., and Cortes, J.“Rationale for targeting fibroblast growth factor receptor signaling in breast cancer”, Breast Cancer Res. Treat.2015, 150, 1-8; Hong et al.“Fibroblast growth factor receptor 2: a therapeutic target in gastric cancer”, Expert Rev. Gastroent.2013, 7, 759-765; Marek et al.“Fibroblast growth factor (FGF) and FGF receptor-mediated autocrine signaling in non-small-cell lung cancer cells”, Mol.

Pharmacol.2009, 75, 196-207). During the past few years, several peptide agonists of FGFRs have been identified, such as canofins, hexafins, and dekafins, all of which are based on the crystal structures of FGFs-FGFR complexes (see, e.g., Manfe et al.“Peptides derived from specific interaction sites of the fibroblast growth factor 2-FGF receptor complexes induce receptor activation and signaling”, J. Neurochem.2010, 114, 74-86; Li et al.

“Agonists of fibroblast growth factor receptor induce neurite outgrowth and survival of cerebellar granule neurons”, Dev. Neurobiol.2009, 69, 837-854; Li et al.“Fibroblast growth factor-derived peptides: functional agonists of the fibroblast growth factor receptor”, J.

Neurochem.2008, 104, 667-682). Upon binding to and activating FGFRs, these peptide agonists lead to induction of neurite outgrowth and protection against apoptosis in vitro (see, e.g., Li et al.“Neuritogenic and neuroprotective properties of peptide agonists of the fibroblast growth factor receptor”, Int. J. Mol. Sci.2010, 11, 2291-2305). Recently, FGF-P, a small peptide derived from FGF-2, was found to be a potential mitigator of acute

gastrointestinal syndrome (AGS) due to ionizing radiation (IR) (see, e.g., Zhang et al.

“Mitigation effect of an FGF-2 peptide on acute gastrointestinal syndrome after high-dose ionizing radiation”, Int. J. Radiat. Oncol. Biol. Phys.2010, 77, 261-268; Zhang et al.“FGF-P improves barrier function and proliferation in human keratinocytes after radiation”, Int. J. Radiat. Oncol. Biol. Phys.2011, 81, 248-254). In addition, peptide agonists of FGFR derived from NCAM have also been reported, such as Encamin, FGL peptide, BCL peptide (see, e.g., Hansen et al.“NCAM-derived peptides function as agonists for the fibroblast growth factor receptor”, J. Neurochem. 2008, 106, 2030-2041; Jacobsen et al.“A peptide motif from the second fibronectin module of the neural cell adhesion molecule, NCAM,

NLIKQDDGGSPIRHY, is a binding site for the FGF receptor”, Neurochem. Res.2008, 33, 2532-2539; Leong et al.“Radiation dermatitis following radioembolization for hepatocellular carcinoma: a case for prophylactic embolization of a patent falciform artery”, J. Vasc. Interv. Radiol.2009, 20, 833-836). However, the development of non-peptide ligands of FGFR remains largely unexplored. Considering the complexity and high cost of the synthesis of long-chain peptide ligands, as well as the instability of peptides toward proteolysis, the identification of novel non-peptide FGFR ligands is important in FGFR-targeted drug discovery. Novel non-peptide FGFR agonists and antagonists may be used in the treatment of various diseases associated with fibroblast growth factor receptors and in research to understand FGFR biology.

[0006] For example, drug development targeting acute radiation syndrome (ARS) using peptidomimetics of fibroblast growth factors (FGFs) represents an emerging theme in medicinal chemistry. Considering the fact that FGFs have been demonstrated as effective radiation mitigation agents against severe organ damages associated with irradiation, discovery of novel non-peptide FGFR agonists will provide anti-ARS drugs with improved stability. Acute radiation syndrome (ARS), induced by whole-body or significant partial-body irradiation, causes severe damage to a broad range of organ systems such as the

hematopoietic, cutaneous, gastrointestinal (GI) and cerebrovascular components. As a result, ARS leads to either near-term mortality or long-term adverse health effects. Therefore, the development of safe and effective medical radiation countermeasures to prevent and mitigate radiation damage is highly desirable. SUMMARY OF THE INVENTION

[0007] There is a need for new, non-peptidic activators and antagonists of fibroblast growth factor receptors (FGFRs). To this end, peptoids can be used. Peptoids are oligomers of N- substituted glycine (NSG) units (Figure 1), which represent a class of polymers which acts as peptide mimics. Compared with peptides, the side chains in peptoids are shifted from the chiral α-carbon atom to the achiral nitrogen (see, e.g., Zuckermann, R. N.“Peptoid origins.” Biopolymers 2011, 96, 545-555). As a result, peptoids are often incapable of forming hydrogen bonds characteristic of the secondary structures found in peptides. Distinctive advantages of peptoids over peptides include (1) enhanced stability toward proteolysis; (2) resistance to denaturation induced by solvent, temperature, or chemicals; (3) better cell penetration; and/or (4) low immunogenicity. Furthermore, peptoids can be easily synthesized based on a two-step solid-phase synthetic method including acylation and amination, using diverse primary amines as building blocks with high availability at low cost (see, e.g., Zuckermann et al.“Efficient method for the preparation of peptoids [oligo(N-substituted glycines)] by submonomer solid-phase synthesis”, J. Am. Chem. Soc.1992, 114, 10646- 10647). In addition, large, one-bead-one-compound (OBOC) peptoid libraries can be efficiently synthesized using the“split-and-pool” method, and the compatibility of OBOC libraries with existing screening methods makes peptoid libraries an ideal tool for identifying ligands toward various biological targets (see, e.g., Figliozzi et al.“Synthesis of N- substituted glycine peptoid libraries”, Methods Enzymol.1996, 267, 437-447; Fu et al.“The identification of high-affinity G protein-coupled receptor ligands from large combinatorial libraries using multicolor quantum dot-labeled cell-based screening”, Future Med. Chem. 2014, 6, 809-823). As described herein, chemical microarray screening has been used to discover novel peptoids that are agonists or antagonists of FGFR.

[0008] The present invention relates in part to novel compounds which are agonists or antagonists of FGFRs. Provided herein are novel compounds, such as compounds of Formula (I), which can activate or inhibit FGFRs, and therefore are useful in the treatment and/or prevention of disease. In one aspect, the present invention provides compounds of Formula (I):

and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R^N, and R^S are as described herein. [0009] Exemplary compounds of Formula (I) include, but are not limited to, the following compounds:

),

NH₂

and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0010] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein include a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. The pharmaceutical compositions described herein may be useful for treating and/or preventing a disease (e.g., a disease associated with FGFR or the FGFR signaling pathway) in a subject.

[0011] In another aspect, the present invention provides methods for treating and/or preventing a disease in a subject. The method may comprise administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the disease is associated with a FGFR or FGFR signaling. In certain embodiments, the disease is associated with decreased FGFR signaling. In certain embodiments, the disease is a disease associated with aberrant activity of a FGFR, such as decreased activity. In certain

embodiments, the disease to be treated and/or prevented is a proliferative disease, genetic disease, disease associated with angiogenesis, inflammatory disease, cardiovascular disease, hepatic disease, spleen disease, pulmonary disease, painful condition, hematological disease, neurological disease, psychiatric disorder, autoimmune disease, infectious disease, metabolic disease, gastrointestinal disorder, or endocrine disease. In certain embodiments, the disease is a disease associated with radiation exposure, such as acute radiation syndrome (ARS).

[0012] Yet another aspect of the present invention relates to a method of activating a FGFR with a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the method of activating a FGFR comprises contacting a FGFR with a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. The step of contacting may occur in vitro or in vivo. The step of contacting may occur in a cell in culture or in a subject.

[0013] The present invention also relates to a method of inhibiting a FGFR with a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the method of inhibiting a FGFR comprises contacting a FGFR with a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. The step of contacting may occur in vitro or in vivo. The step of contacting may occur in a cell in culture or in a subject.

[0014] Also provided herein is a method of mitigating the effects of radiation exposure in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a

pharmaceutical composition thereof.

[0015] Another aspect of the present invention relates to kits comprising a compound of Formula (I), or a salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or pharmaceutical composition of the invention. The kits described herein may include a single dose or multiple doses of the compound or pharmaceutical composition thereof. The provided kits may be useful in a method of the invention (e.g., a method of treating and/or preventing a disease in a subject). A kit of the invention may further include instructions for using the kit (e.g., instructions for using the compound or pharmaceutical composition included in the kit).

[0016] The details of certain embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed

Description, Figures, Examples, and Claims. DEFINITIONS

Chemical Definitions

[0017] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987.

[0018] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions, p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0019] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of ¹⁹F with ¹⁸F, or the replacement of ¹²C with ¹³C or ¹⁴C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0020] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example“C_1-6 alkyl” is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C_1-6, C_1-5, C_1-4, C_1-3, C_1-2, C_2-6, C_2-5, C_2-4, C_2-3, C_3-6, C_3-5, C_3-4, C_4-6, C_4-5, and C_5-6 alkyl.

[0021] The term“aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.

Likewise, the term“heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0022] The term“alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C_1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C_1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C_1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C_1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C_1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C_1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C_1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C_1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C_1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C_2-6 alkyl”). Examples of C_1-6 alkyl groups include methyl (C₁), ethyl (C₂), propyl (C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇), n- octyl (C₈), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an“unsubstituted alkyl”) or substituted (a“substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C_1-10 alkyl (such as unsubstituted C_1-6 alkyl, e.g.,−CH₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C_1-10 alkyl (such as substituted C_1-6 alkyl, e.g.,−CF₃, Bn).

[0023] The term“haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C_1-8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C_1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C_1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C_1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C_1-2 haloalkyl”). Examples of haloalkyl groups include−CF₃,−CF₂CF₃,−CF₂CF₂CF₃,−CCl₃,−CFCl₂,−CF₂Cl, and the like.

[0024] The term“heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain

(“heteroC_1-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC_1-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC_1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC_1-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC_1-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC₁ alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC_2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an“unsubstituted heteroalkyl”) or substituted (a“substituted heteroalkyl”) with one or more substituents. In certain

embodiments, the heteroalkyl group is an unsubstituted heteroC_1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC_1-10 alkyl.

[0025] The term“alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C_2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C_2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C_2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C_2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C_2-5 alkenyl”). In some

embodiments, an alkenyl group has 2 to 4 carbon atoms (“C_2-4 alkenyl”). In some

embodiments, an alkenyl group has 2 to 3 carbon atoms (“C_2-3 alkenyl”). In some

embodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C_2-4 alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1- butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C_2-6 alkenyl groups include the aforementioned C_2-4 alkenyl groups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additional examples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl (C₈), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an“unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C_2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C_2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g.,−CH=CHCH₃ or ) may be an (E)- or (Z)- double bond.

[0026] The term“heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-10 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1or 2

heteroatoms within the parent chain (“heteroC_2-4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC_2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an“unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC_2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC_2-10 alkenyl. [0027] The term“alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C_2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C_2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C_2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C_2- ₇ alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C_2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C_2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C_2-4 alkynyl”). In some

embodiments, an alkynyl group has 2 to 3 carbon atoms (“C_2-3 alkynyl”). In some

embodiments, an alkynyl group has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C_2-4 alkynyl groups include, without limitation, ethynyl (C₂), 1-propynyl (C₃), 2- propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), and the like. Examples of C_2-6 alkenyl groups include the aforementioned C_2-4 alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and the like. Additional examples of alkynyl include heptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an“unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C_2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C_2-10 alkynyl.

[0028] The term“heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-10 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_2- ₈ alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-6 alkynyl”). In some

embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC_2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC_2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an“unsubstituted heteroalkynyl”) or substituted (a“substituted

heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC_2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC_2-10 alkynyl.

[0029] The term“carbocyclyl” or“carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C_3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C_3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C_3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C_3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C_3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C_4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C_5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C_5-10 carbocyclyl”). Exemplary C_3-6 carbocyclyl groups include, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C_3-8 carbocyclyl groups include, without limitation, the aforementioned C_3-6 carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), and the like.

Exemplary C_3-10 carbocyclyl groups include, without limitation, the aforementioned C_3-8 carbocyclyl groups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀),

spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.“Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an“unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C_3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C_3-14 carbocyclyl.

[0030] In some embodiments,“carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C_3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C_3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C_3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C_3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C_4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C_5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C_5-10 cycloalkyl”). Examples of C_5-6 cycloalkyl groups include cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C_3-6 cycloalkyl groups include the aforementioned C_5-6 cycloalkyl groups as well as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C_3-8 cycloalkyl groups include the aforementioned C_3-6 cycloalkyl groups as well as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an“unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C_3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C_3-14 cycloalkyl.

[0031] The term“heterocyclyl” or“heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently

unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0032] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 3- membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl.

Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.

Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,

decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro- 5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3- b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4- tetrahydro-1,6-naphthyridinyl, and the like.

[0033] The term“aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C_6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl).“Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an“unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C_6-14 aryl. In certain embodiments, the aryl group is a substituted C_6-14 aryl.

[0034] The term“heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.“Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0035] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an“unsubstituted heteroaryl”) or substituted (a“substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl. Exemplary 5- membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6- membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl,

respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,

benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl,

benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

[0036]“Aralkyl” is a subset of“alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety (i.e.,–alkyl-aryl). The terms “aralkyl” and“arylalkyl” are used herein interchangeably. In certain embodiments, aralkyl is –C_1-10 alkyl-aryl. In certain embodiments, aralkyl is–C_1-6 alkyl-aryl. In certain embodiments, aralkyl is–C_1-3 alkyl-aryl. In certain embodiments, aralkyl is–CH(CH₃)-aryl. In certain embodiments, aralkyl is–CH₂CH₂-aryl. In certain embodiments, aralkyl is–CH₂-aryl. In certain embodiments, aralkyl is–alkyl-C_6-14 aryl. In certain embodiments, aralkyl is–alkyl-C₆ aryl. In certain embodiments, aralkyl is–C_1-10 alkyl-C₆ aryl. In certain embodiments, aralkyl is–C_1-6 alkyl-C₆ aryl. In certain embodiments, aralkyl is–C_1-3 alkyl-C₆ aryl. In certain embodiments, aralkyl is–CH(CH₃)-C₆ aryl. In certain embodiments, aralkyl is–CH₂CH₂-C₆ aryl. In certain embodiments, aralkyl is–CH₂-C₆ aryl. An example of an aralkyl group is benzyl (i.e.,–CH₂-phenyl).

[0037]“Heteroaralkyl” is a subset of“alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety (i.e.,–alkyl- heteroaryl). The terms“heteroaralkyl” and“heteroarylalkyl” are used herein interchangeably. In certain embodiments, heteroaralkyl is–C_1-10 alkyl-heteroaryl. In certain embodiments, heteroaralkyl is–C_1-6 alkyl-heteroaryl. In certain embodiments, heteroaralkyl is–C_1-3 alkyl- heteroaryl. In certain embodiments, heteroaralkyl is–CH₂-heteroaryl. In certain

embodiments, heteroaralkyl is–alkyl-heteroaryl, wherein the heteroaryl group is 5- to 14- membered heteroaryl. In certain embodiments, heteroaralkyl is–alkyl-heteroaryl, wherein the heteroaryl group is 5- to 6-membered heteroaryl. In certain embodiments, heteroaralkyl is– alkyl-heteroaryl, wherein the heteroaryl group is 5-membered heteroaryl. In certain embodiments, heteroaralkyl is–C_1-10 alkyl-heteroaryl, wherein the heteroaryl group is 5- to 6- membered heteroaryl. In certain embodiments, heteroaralkyl is–C_1-6 alkyl-heteroaryl, wherein the heteroaryl group is 5- to 6-membered heteroaryl. In certain embodiments, heteroaralkyl is–C_1-3 alkyl-heteroaryl, wherein the heteroaryl group is 5- to 6-membered heteroaryl. In certain embodiments, heteroaralkyl is–CH₂-heteroaryl, wherein the heteroaryl group is 5- to 6-membered heteroaryl.

[0038]“Carbocyclylalkyl” is a subset of“alkyl” and refers to an alkyl group substituted by a carbocyclyl group, wherein the point of attachment is on the alkyl moiety (i.e.,–alkyl- carbocyclyl). In certain embodiments, carbocyclylalkyl is–C_1-10 alkyl-carbocyclyl. In certain embodiments, carbocyclylalkyl is–C_1-6 alkyl-carbocyclyl. In certain embodiments, carbocyclylalkyl is–C_1-3 alkyl-carbocyclyl. In certain embodiments, carbocyclylalkyl is– CH₂-carbocyclyl. In certain embodiments, carbocyclylalkyl is–alkyl-C_3-14 carbocyclyl. In certain embodiments, carbocyclylalkyl is–alkyl-C_3-6 carbocyclyl. In certain embodiments, carbocyclylalkyl is–C_1-10 alkyl-C_3-6 carbocyclyl. In certain embodiments, carbocyclylalkyl is –C_1-6 alkyl-C_3-6 carbocyclyl. In certain embodiments, carbocyclylalkyl is–C_1-3 alkyl-C_3-6 carbocyclyl. In certain embodiments, carbocyclylalkyl is–CH₂-C_3-6 carbocyclyl

[0039]“Heterocyclylalkyl” is a subset of“alkyl” and refers to an alkyl group substituted by a carbocyclyl group, wherein the point of attachment is on the alkyl moiety (i.e.,–alkyl- heterocyclyl). In certain embodiments, heterocyclylalkyl is–C_1-10 alkyl-heterocyclyl. In certain embodiments, heterocyclylalkyl is–C_1-6 alkyl-heterocyclyl. In certain embodiments, heterocyclylalkyl is–C_1-3 alkyl-heterocyclyl. In certain embodiments, heterocyclylalkyl is– CH₂CH₂CH₂-heterocyclyl. In certain embodiments, heterocyclylalkyl is–CH₂-heterocyclyl. In certain embodiments, heterocyclylalkyl is–alkyl-heterocyclyl, wherein the heterocyclyl group is 3- to 14-membered heterocyclyl. In certain embodiments, heterocyclylalkyl is– alkyl-heterocyclyl, wherein the heterocyclyl group is 3- to 6-membered heterocyclyl. In certain embodiments, heterocyclylalkyl is–alkyl-heterocyclyl, wherein the heterocyclyl group is 5- to 10-membered heterocyclyl. In certain embodiments, heterocyclylalkyl is– alkyl-heterocyclyl, wherein the heterocyclyl group is 5- to 6-membered heterocyclyl. In certain embodiments, heterocyclylalkyl is–alkyl-heterocyclyl, wherein the heterocyclyl group is 5-membered heterocyclyl. In certain embodiments, heterocyclylalkyl is–C_1-10 alkyl- heterocyclyl, wherein the heterocyclyl group is 3- to 6-membered heterocyclyl. In certain embodiments, heterocyclylalkyl is–C_1-6 alkyl-heterocyclyl, wherein the heterocyclyl group is 3- to 6-membered heterocyclyl. In certain embodiments, heterocyclylalkyl is–C_1-3 alkyl- heterocyclyl, wherein the heterocyclyl group is 3- to 6-membered heterocyclyl. In certain embodiments, heterocyclylalkyl is–CH₂CH₂CH₂-heterocyclyl, wherein the heterocyclyl group is 3- to 6-membered heterocyclyl. In certain embodiments, heterocyclylalkyl is–CH₂- heterocyclyl, wherein the heterocyclyl group is 3- to 6-membered heterocyclyl.

[0040] The term“unsaturated bond” refers to a double or triple bond.

[0041] The term“unsaturated” or“partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0042] The term“saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0043] Affixing the suffix“-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0044] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.“Optionally substituted” refers to a group which may be substituted or unsubstituted (e.g.,“substituted” or“unsubstituted” alkyl, “substituted” or“unsubstituted” alkenyl,“substituted” or“unsubstituted” alkynyl, “substituted” or“unsubstituted” heteroalkyl,“substituted” or“unsubstituted” heteroalkenyl, “substituted” or“unsubstituted” heteroalkynyl,“substituted” or“unsubstituted” carbocyclyl, “substituted” or“unsubstituted” heterocyclyl,“substituted” or“unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term“substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a“substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents described herein.

[0045] Exemplary carbon atom substituents include, but are not limited to, halogen,−CN, −NO₂,−N₃,−SO₂H,−SO₃H,−OH,−OR^aa,−ON(R^bb)₂,−N(R^bb)₂,−N(R^bb) ⁺

3 X⁻,−N(OR^cc)R^bb, −SH,−SR^aa,−SSR^cc,−C(=O)R^aa,−CO₂H,−CHO,−C(OR^cc)₃,−CO₂R^aa,−OC(=O)R^aa, −OCO₂R^aa,−C(=O)N(R^bb)₂,−OC(=O)N(R^bb)₂,−NR^bbC(=O)R^aa,−NR^bbCO₂R^aa,

−NR^bbC(=O)N(R^bb)₂,−C(=NR^bb)R^aa,−C(=NR^bb)OR^aa,−OC(=NR^bb)R^aa,−OC(=NR^bb)OR^aa, −C(=NR^bb)N(R^bb)₂,−OC(=NR^bb)N(R^bb)₂,−NR^bbC(=NR^bb)N(R^bb)₂,−C(=O)NR^bbSO₂R^aa, −NR^bbSO₂R^aa,−SO₂N(R^bb)₂,−SO₂R^aa,−SO₂OR^aa,−OSO₂R^aa,−S(=O)R^aa,−OS(=O)R^aa, −Si(R^aa)₃,−OSi(R^aa)₃−C(=S)N(R^bb)₂,−C(=O)SR^aa,−C(=S)SR^aa,−SC(=S)SR^aa,

−SC(=O)SR^aa,−OC(=O)SR^aa,−SC(=O)OR^aa,−SC(=O)R^aa,−P(=O)(R^aa)₂,−P(=O)(OR^cc)₂, −OP(=O)(R^aa)₂,−OP(=O)(OR^cc)₂,−P(=O)(N(R^bb)₂)₂,−OP(=O)(N(R^bb)₂)₂,−NR^bbP(=O)(R^aa)₂, −NR^bbP(=O)(OR^cc)₂,−NR^bbP(=O)(N(R^bb)₂)₂,−P(R^cc)₂,−P(OR^cc)₂,−P(R^cc) ⁺

3 X⁻,

−P(OR^cc) ⁺

3 X⁻,−P(R^cc)₄,−P(OR^cc)₄,−OP(R^cc)₂,−OP(R^cc) ⁺

3 X⁻,−OP(OR^cc)₂,−OP(OR^cc) ⁺

3 X⁻, −OP(R^cc)₄,−OP(OR^cc)₄,−B(R^aa)₂,−B(OR^cc)₂,−BR^aa(OR^cc), C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, heteroC_1-10 alkyl, heteroC_2-10 alkenyl, heteroC_2-10 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups; wherein X⁻ is a counterion;

or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(R^bb)₂, =NNR^bbC(=O)R^aa, =NNR^bbC(=O)OR^aa, =NNR^bbS(=O)₂R^aa, =NR^bb, or =NOR^cc; each instance of R^aa is, independently, selected from C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, heteroC_1-10 alkyl, heteroC_2-10alkenyl, heteroC_2-10alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups;

each instance of R^bb is, independently, selected from hydrogen,−OH,−OR^aa, −N(R^cc)₂,−CN,−C(=O)R^aa,−C(=O)N(R^cc)₂,−CO₂R^aa,−SO₂R^aa,−C(=NR^cc)OR^aa,

−C(=NR^cc)N(R^cc)₂,−SO₂N(R^cc)₂,−SO₂R^cc,−SO₂OR^cc,−SOR^aa,−C(=S)N(R^cc)₂,−C(=O)SR^cc, −C(=S)SR^cc,−P(=O)(R^aa)₂,−P(=O)(OR^cc)₂,−P(=O)(N(R^cc)₂)₂, C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, heteroC_1-10alkyl, heteroC_2-10alkenyl, heteroC_2-10alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups; wherein X⁻ is a counterion;

each instance of R^cc is, independently, selected from hydrogen, C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, heteroC_1-10 alkyl, heteroC_2-10 alkenyl, heteroC_2-10 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups;

each instance of R^dd is, independently, selected from halogen,−CN,−NO₂,−N₃, −SO₂H,−SO₃H,−OH,−OR^ee,−ON(R^ff)₂,−N(R^ff)₂,−N(R^ff) ⁺

3 X⁻,−N(OR^ee)R^ff,−SH,−SR^ee, −SSR^ee,−C(=O)R^ee,−CO₂H,−CO₂R^ee,−OC(=O)R^ee,−OCO₂R^ee,−C(=O)N(R^ff)₂,

−OC(=O)N(R^ff)₂,−NR^ffC(=O)R^ee,−NR^ffCO₂R^ee,−NR^ffC(=O)N(R^ff)₂,−C(=NR^ff)OR^ee, −OC(=NR^ff)R^ee,−OC(=NR^ff)OR^ee,−C(=NR^ff)N(R^ff)₂,−OC(=NR^ff)N(R^ff)₂,

−NR^ffC(=NR^ff)N(R^ff)₂,−NR^ffSO₂R^ee,−SO₂N(R^ff)₂,−SO₂R^ee,−SO₂OR^ee,−OSO₂R^ee, −S(=O)R^ee,−Si(R^ee)₃,−OSi(R^ee)₃,−C(=S)N(R^ff)₂,−C(=O)SR^ee,−C(=S)SR^ee,−SC(=S)SR^ee, −P(=O)(OR^ee)₂,−P(=O)(R^ee)₂,−OP(=O)(R^ee)₂,−OP(=O)(OR^ee)₂, C_1-6 alkyl, C_1-6 perhaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, heteroC_1-6alkyl, heteroC_2-6alkenyl, heteroC_2-6alkynyl, C_3-10 carbocyclyl, 3-10 membered heterocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gg groups, or two geminal R^dd substituents can be joined to form =O or =S; wherein X⁻ is a counterion;

each instance of R^ee is, independently, selected from C_1-6 alkyl, C_1-6 perhaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, heteroC_1-6 alkyl, heteroC_2-6alkenyl, heteroC_2-6 alkynyl, C_3-10

carbocyclyl, C_6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gg groups;

each instance of R^ff is, independently, selected from hydrogen, C_1-6 alkyl, C_1-6 perhaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, heteroC_1-6alkyl, heteroC_2-6alkenyl, heteroC_2-6alkynyl, C_3-10 carbocyclyl, 3-10 membered heterocyclyl, C_6-10 aryl and 5-10 membered heteroaryl, or two R^ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,

heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gg groups; and

each instance of R^gg is, independently, halogen,−CN,−NO₂,−N₃,−SO₂H,−SO₃H, −OH,−OC_1-6 alkyl,−ON(C_1-6 alkyl)₂,−N(C_1-6 alkyl)₂,−N(C_1-6 alkyl) ⁺

3 X⁻,−NH(C_1-6 alkyl) ⁺

2 X⁻,−NH₂(C_1-6 alkyl) ⁺X⁻,−NH ⁺

3 X⁻,−N(OC_1-6 alkyl)(C_1-6 alkyl),−N(OH)(C_1-6 alkyl), −NH(OH),−SH,−SC_1-6 alkyl,−SS(C_1-6 alkyl),−C(=O)(C_1-6 alkyl),−CO₂H,−CO₂(C_1-6 alkyl),−OC(=O)(C_1-6 alkyl),−OCO₂(C_1-6 alkyl),−C(=O)NH₂,−C(=O)N(C_1-6 alkyl)₂, −OC(=O)NH(C_1-6 alkyl),−NHC(=O)( C_1-6 alkyl),−N(C_1-6 alkyl)C(=O)( C_1-6 alkyl), −NHCO₂(C_1-6 alkyl),−NHC(=O)N(C_1-6 alkyl)₂,−NHC(=O)NH(C_1-6 alkyl),−NHC(=O)NH₂, −C(=NH)O(C_1-6 alkyl),−OC(=NH)(C_1-6 alkyl),−OC(=NH)OC_1-6 alkyl,−C(=NH)N(C_1-6 alkyl)₂,−C(=NH)NH(C_1-6 alkyl),−C(=NH)NH₂,−OC(=NH)N(C_1-6 alkyl)₂,

−OC(=NH)NH(C_1-6 alkyl),−OC(=NH)NH₂,−NHC(=NH)N(C_1-6 alkyl)₂,−NHC(=NH)NH₂, −NHSO₂(C_1-6 alkyl),−SO₂N(C_1-6 alkyl)₂,−SO₂NH(C_1-6 alkyl),−SO₂NH₂,−SO₂(C_1-6 alkyl), −SO₂O(C_1-6 alkyl),−OSO₂(C_1-6 alkyl),−SO(C_1-6 alkyl),−Si(C_1-6 alkyl)₃,−OSi(C_1-6 alkyl)₃ −C(=S)N(C_1-6 alkyl)₂, C(=S)NH(C_1-6 alkyl), C(=S)NH₂,−C(=O)S(C_1-6 alkyl),−C(=S)SC_1-6 alkyl,−SC(=S)SC_1-6 alkyl,−P(=O)(OC_1-6 alkyl)₂,−P(=O)(C_1-6 alkyl)₂,−OP(=O)(C_1-6 alkyl)₂, −OP(=O)(OC_1-6 alkyl)₂, C_1-6 alkyl, C_1-6 perhaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, heteroC_1- ₆alkyl, heteroC_2-6alkenyl, heteroC_2-6alkynyl, C_3-10 carbocyclyl, C_6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R^gg substituents can be joined to form =O or =S; wherein X⁻ is a counterion. [0046] The term“halo” or“halogen” refers to fluorine (fluoro,−F), chlorine (chloro,−Cl), bromine (bromo,−Br), or iodine (iodo,−I).

[0047] The term“hydroxyl” or“hydroxy” refers to the group−OH. The term“substituted hydroxyl” or“substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from−OR^aa,−ON(R^bb)₂,−OC(=O)SR^aa,

−OC(=O)R^aa,−OCO₂R^aa,−OC(=O)N(R^bb)₂,−OC(=NR^bb)R^aa,−OC(=NR^bb)OR^aa,

−OC(=NR^bb)N(R^bb)₂,−OS(=O)R^aa,−OSO₂R^aa,−OSi(R^aa)₃,−OP(R^cc)₂,−OP(R^cc) ⁺

3 X⁻, −OP(OR^cc)₂,−OP(OR^cc) ⁺

3 X⁻,−OP(=O)(R^aa)₂,−OP(=O)(OR^cc)₂, and−OP(=O)(N(R^bb)₂)₂, wherein X⁻, R^aa, R^bb, and R^cc are as defined herein.

[0048] The term“amino” refers to the group−NH₂. The term“substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the“substituted amino” is a monosubstituted amino or a

disubstituted amino group.

[0049] The term“monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from−NH(R^bb),−NHC(=O)R^aa, −NHCO₂R^aa,−NHC(=O)N(R^bb)₂,−NHC(=NR^bb)N(R^bb)₂,−NHSO₂R^aa,−NHP(=O)(OR^cc)₂, and−NHP(=O)(N(R^bb)₂)₂, wherein R^aa, R^bb and R^cc are as defined herein, and wherein R^bb of the group−NH(R^bb) is not hydrogen.

[0050] The term“disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from−N(R^bb)₂,−NR^bbC(=O)R^aa,−NR^bbCO₂R^aa,

−NR^bbC(=O)N(R^bb)₂,−NR^bbC(=NR^bb)N(R^bb)₂,−NR^bbSO₂R^aa,−NR^bbP(=O)(OR^cc)₂, and −NR^bbP(=O)(N(R^bb)₂)₂, wherein R^aa, R^bb, and R^cc are as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0051] The term“trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from−N(R^bb)₃ and−N(R^bb) ⁺

3 X⁻, wherein R^bb and X⁻ are as defined herein.

[0052] The term“sulfonyl” refers to a group selected from–SO₂N(R^bb)₂,–SO₂R^aa, and– SO₂OR^aa, wherein R^aa and R^bb are as defined herein.

[0053] The term“sulfinyl” refers to the group–S(=O)R^aa, wherein R^aa is as defined herein.

[0054] The term“acyl” refers to a group having the general formula−C(=O)R^X1,

−C(=O)OR^X1,−C(=O)−O−C(=O)R^X1,−C(=O)SR^X1,−C(=O)N(R^X1)₂,−C(=S)R^X1, −C(=S)N(R^X1)₂,−C(=S)O(R^X1),−C(=S)S(R^X1),−C(=NR^X1)R^X1,−C(=NR^X1)OR^X1, −C(=NR^X1)SR^X1, and−C(=NR^X1)N(R^X1)₂, wherein R^X1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,

heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R^X1 groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO₂H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, aralkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0055] The term“carbonyl” refers a group wherein the carbon directly attached to the parent molecule is sp² hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (–C(=O)R^aa), carboxylic acids (–CO₂H), aldehydes (–CHO), esters (–CO₂R^aa,–C(=O)SR^aa,–C(=S)SR^aa), amides (–C(=O)N(R^bb)₂,–C(=O)NR^bbSO₂R^aa, −C(=S)N(R^bb)₂), and imines (–C(=NR^bb)R^aa,–C(=NR^bb)OR^aa),–C(=NR^bb)N(R^bb)₂), wherein R^aa and R^bb are as defined herein.

[0056] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen,−OH,−OR^aa,−N(R^cc)₂,−CN, −C(=O)R^aa,−C(=O)N(R^cc)₂,−CO₂R^aa,−SO₂R^aa,−C(=NR^bb)R^aa,−C(=NR^cc)OR^aa,

−C(=NR^cc)N(R^cc)₂,−SO₂N(R^cc)₂,−SO₂R^cc,−SO₂OR^cc,−SOR^aa,−C(=S)N(R^cc)₂,−C(=O)SR^cc, −C(=S)SR^cc,−P(=O)(OR^cc)₂,−P(=O)(R^aa)₂,−P(=O)(N(R^cc)₂)₂, C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, heteroC_1-10alkyl, heteroC_2-10alkenyl, heteroC_2-10alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^cc groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups, and wherein R^aa, R^bb, R^cc and R^dd are as defined above.

[0057] In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an“amino protecting group”). Nitrogen protecting groups include, but are not limited to,−OH,−OR^aa,−N(R^cc)₂,−C(=O)R^aa,−C(=O)N(R^cc)₂, −CO₂R^aa,−SO₂R^aa,−C(=NR^cc)R^aa,−C(=NR^cc)OR^aa,−C(=NR^cc)N(R^cc)₂,−SO₂N(R^cc)₂, −SO₂R^cc,−SO₂OR^cc,−SOR^aa,−C(=S)N(R^cc)₂,−C(=O)SR^cc,−C(=S)SR^cc, C_1-10 alkyl (e.g., aralkyl, heteroaralkyl), C_2-10 alkenyl, C_2-10 alkynyl, heteroC_1-10 alkyl, heteroC_2-10 alkenyl, heteroC_2-10 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,

heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups, and wherein R^aa, R^bb, R^cc and R^dd are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0058] For example, nitrogen protecting groups such as amide groups (e.g.,−C(=O)R^aa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o- nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide.

[0059] Nitrogen protecting groups such as carbamate groups (e.g.,−C(=O)OR^aa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t- butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1- methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate

(TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1- methylethyl carbamate (t-Bumeoc), 2-(2’- and 4’-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3- dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4- dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m- chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4- dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5- dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1- methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4- (trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate. [0060] Nitrogen protecting groups such as sulfonamide groups (e.g.,−S(=O)₂R^aa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4’,8’- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide,

trifluoromethylsulfonamide, and phenacylsulfonamide.

[0061] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)- acyl derivative, N’-p-toluenesulfonylaminoacyl derivative, N’-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3- oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl- 4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N- 2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2- picolylamino N’-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N-(N’,N’-dimethylaminomethylene)amine, N,N’- isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,

diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),

diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0062] In certain embodiments, the nitrogen protecting group is benzyl (Bn), tert- butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0063] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an“hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to,−R^aa,−N(R^bb)₂,−C(=O)SR^aa,−C(=O)R^aa, −CO₂R^aa,−C(=O)N(R^bb)₂,−C(=NR^bb)R^aa,−C(=NR^bb)OR^aa,−C(=NR^bb)N(R^bb)₂,−S(=O)R^aa, −SO₂R^aa,−Si(R^aa)₃,−P(R^cc)₂,−P(R^cc) ⁺

3 X⁻,−P(OR^cc)₂,−P(OR^cc) ⁺

3 X⁻,−P(=O)(R^aa)₂, −P(=O)(OR^cc)₂, and−P(=O)(N(R^bb) ₂)₂, wherein X⁻, R^aa, R^bb, and R^cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0064] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,

(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p- methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6- dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N- oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS),

diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,

diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p- nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4- ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4- nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0065] In certain embodiments, the oxygen protecting group is silyl. In certain embodiments, the oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2- trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1- ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2- methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0066] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a“thiol protecting group”). Sulfur protecting groups include, but are not limited to,−R^aa,−N(R^bb)₂,−C(=O)SR^aa,−C(=O)R^aa,−CO₂R^aa,−C(=O)N(R^bb)₂,

−P(=O)(N(R^bb) ₂)₂, wherein R^aa, R^bb, and R^cc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0067] A“counterion” or“anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions

sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p– toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like),

and carborane anion

Exemplary counterions which may be multivalent include

carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes. [0068] As used herein, a“leaving group” (LG) is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March’s Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g.,–OC(=O)SR^aa,–OC(=O)R^aa,–OCO₂R^aa,–OC(=O)N(R^bb)₂,–OC(=NR^bb)R^aa,– OC(=NR^bb)OR^aa,–OC(=NR^bb)N(R^bb)₂,–OS(=O)R^aa,–OSO₂R^aa,–OP(R^cc)₂,–OP(R^cc)₃,– OP(=O)₂R^aa,–OP(=O)(R^aa)₂,–OP(=O)(OR^cc)₂,–OP(=O)₂N(R^bb)₂, and–OP(=O)(NR^bb)₂, wherein R^aa, R^bb, and R^cc are as defined herein).

[0069] As used herein, use of the phrase“at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0070] A“non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0071] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. Other Definitions

[0072] The following definitions are more general terms used throughout the present application.

[0073] As used herein,“Fibroblast growth factors” (FGFs) refers to a family of growth factors involved in biological processes including, but not limited to, angiogenesis, embryonic development, woung healing, neural development, and various endocrine signaling pathways. In humans, 22 endogenous members of the FGF family are known, all of which are signaling proteins that play important roles in proliferation and differentiation of various different cells and tissues. Members of the FGF family found in humans include FGF1, FGF2, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGF10, FGF11, FGF12, FGF13, FGF14, FG1F6, FGF17, FGF18, FGF19, FGF20, FGF21, and FGF22. FGF15 is the mouse ortholog of human FGF19.

[0074] As used herein,“fibroblast growth factor receptors” (FGFRs) refers to the family of receptors that bind members of the fibroblast growth factor (FGF) family of proteins.

Examples of FGFRs include, but are not limited to, FGFR1, FGFR2, FGFR3, FGFR4, FGFRL1, and FGFR6. Over 48 different isoforms of FGFR exist due to natural alternate splicing of key FGFR genes, all of which are contemplated as being within the scope of the present invention.

[0075] As used herein,“peptoids” referes to the class of molecules comprising poly-N- substituted glycine units. Peptoids are similar in structure to peptides, except that the side chains of the amino acid subunits in peptoids are connected to the nitrogen atom, as opposed to the alpha-carbon as in peptides. In certain embodiments, peptoids lack (or have fewer of) the amide hydrogens typically found in peptides. Consequently, peptoids are often less likely to engage in the hydrogen bonding interactions that often give peptides and proteins secondary structure elements. As compared to peptides, peptoids are less likely to be denatured by solvent, temperature, or chemical denaturants. Additionally, peptoids are typically resistant to proteolysis, making them attractive therapeutic agents. The novel compounds provided herein (i.e., compounds of Formula (I)) are peptoids.

[0076] As used herein, the term“salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.

[0077] The term“pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate,

ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N⁺(C_1-4 alkyl)⁻

4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0078] The term“solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include

pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.“Solvate” encompasses both solution-phase and isolatable solvates.

Representative solvates include hydrates, ethanolates, and methanolates.

[0079] The term“hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R⋅x H₂O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R⋅0.5 H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R⋅2 H₂O) and hexahydrates (R⋅6 H₂O)).

[0080] The term“tautomers” or“tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations. [0081] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed“isomers”. Isomers that differ in the arrangement of their atoms in space are termed“stereoisomers”.

[0082] Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a“racemic mixture” or“racemate”.

[0083] The term“polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0084] The term“prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C₁-C₈ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 aralkyl esters of the compounds described herein may be preferred.

[0085] The terms“composition” and“formulation” are used interchangeably.

[0086] A“subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term“patient” refers to a human subject in need of treatment of a disease.

[0087] The term“biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.

[0088] The term“administer,”“administering,” or“administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0089] The terms“treatment,”“treat,” and“treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. [0090] The terms“condition,”“disease,” and“disorder” are used interchangeably.

[0091] An“effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses.

[0092] A“prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term“prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a

prophylactically effective amount is an amount sufficient for preventing any disease or condition decribed herein.

[0093] A“therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term“therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating in any disease or condition described herein.

[0094] As used herein,“activate”,“activator”, and the like, refer to the ability of a compound to increase, accelerate, or induce the activity of a biological process (e.g., a biological process in a cell).“Activator” and“agonist” are used interchangeably herein. A compound that“activates” a receptor protein is considered an agonist of said protein and induces or increases certain activities of the protein. In certain embodiments, such activation is of about 1% to 99.9%. In certain embodiments, the activation is about 1% to about 95%. In certain embodiments, the activation is about 5% to 90%. In certain embodiments, the activation is about 10% to 85%. In certain embodiments, the activation is about 15% to 80%. In certain embodiments, the activation is about 20% to 75%. In certain embodiments, the activation is about 25% to 70%. In certain embodiments, the activation is about 30% to 65%. In certain embodiments, the activation is about 35% to 60%. In certain embodiments, the activation is about 40% to 55%. In certain embodiments, the actrivation is about 45% to 50%. In certain embodiments, the activation is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99.9%.

[0095] As used herein,“inhibition”,“inhibiting”,“inhibit” and“inhibitor”, and the like, refer to the ability of a compound to reduce, slow, halt, or prevent the activity of a biological process (e.g., a biological process in a cell).“Inhibitor” and“antagonist” are used

interchangeably herein. In certain embodiments, such inhibition is of about 1% to 99.9%. In certain embodiments, the inhibition is about 1% to about 95%. In certain embodiments, the inhibition is about 5% to 90%. In certain embodiments, the inhibition is about 10% to 85%. In certain embodiments, the inhibition is about 15% to 80%. In certain embodiments, the inhibition is about 20% to 75%. In certain embodiments, the inhibition is about 25% to 70%. In certain embodiments, the inhibition is about 30% to 65%. In certain embodiments, the inhibition is about 35% to 60%. In certain embodiments, the inhibition is about 40% to 55%. In certain embodiments, the inhibition is about 45% to 50%. In certain embodiments, the inhibition is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99.9%.

[0096] The term“genetic disease” refers to a disease caused by one or more abnormalities in the genome of a subject, such as a disease that is present from birth of the subject. Genetic diseases may be heritable and may be passed down from the parents’ genes. A genetic disease may also be caused by mutations or changes of the DNAs and/or RNAs of the subject. In such cases, the genetic disease will be heritable if it occurs in the germline. Exemplary genetic diseases include, but are not limited to, Aarskog-Scott syndrome, Aase syndrome, achondroplasia, acrodysostosis, addiction, adreno-leukodystrophy, albinism, ablepharon- macrostomia syndrome, alagille syndrome, alkaptonuria, alpha-1 antitrypsin deficiency, Alport’s syndrome, Alzheimer’s disease, asthma, autoimmune polyglandular syndrome, androgen insensitivity syndrome, Angelman syndrome, ataxia, ataxia telangiectasia, atherosclerosis, attention deficit hyperactivity disorder (ADHD), autism, baldness, Batten disease, Beckwith-Wiedemann syndrome, Best disease, bipolar disorder, brachydactyl), breast cancer, Burkitt lymphoma, chronic myeloid leukemia, Charcot-Marie-Tooth disease, Crohn’s disease, cleft lip, Cockayne syndrome, Coffin Lowry syndrome, colon cancer, congenital adrenal hyperplasia, Cornelia de Lange syndrome, Costello syndrome, Cowden syndrome, craniofrontonasal dysplasia, Crigler-Najjar syndrome, Creutzfeldt-Jakob disease, cystic fibrosis, deafness, depression, diabetes, diastrophic dysplasia, DiGeorge syndrome, Down’s syndrome, dyslexia, Duchenne muscular dystrophy, Dubowitz syndrome, ectodermal dysplasia Ellis-van Creveld syndrome, Ehlers-Danlos, epidermolysis bullosa, epilepsy, essential tremor, familial hypercholesterolemia, familial Mediterranean fever, fragile X syndrome, Friedreich’s ataxia, Gaucher disease, glaucoma, glucose galactose malabsorption, glutaricaciduria, gyrate atrophy, Goldberg Shprintzen syndrome (velocardiofacial syndrome), Gorlin syndrome, Hailey-Hailey disease, hemihypertrophy, hemochromatosis, hemophilia, hereditary motor and sensory neuropathy (HMSN), hereditary non polyposis colorectal cancer (HNPCC), Huntington’s disease, immunodeficiency with hyper-IgM, juvenile onset diabetes, Klinefelter’s syndrome, Kabuki syndrome, Leigh’s disease, long QT syndrome, lung cancer, malignant melanoma, manic depression, Marfan syndrome, Menkes syndrome, miscarriage, mucopolysaccharide disease, multiple endocrine neoplasia, multiple sclerosis, muscular dystrophy, myotrophic lateral sclerosis, myotonic dystrophy, neurofibromatosis, Niemann-Pick disease, Noonan syndrome, obesity, ovarian cancer, pancreatic cancer, Parkinson’s disease, paroxysmal nocturnal hemoglobinuria, Pendred syndrome, peroneal muscular atrophy, phenylketonuria (PKU), polycystic kidney disease, Prader-Willi syndrome, primary biliary cirrhosis, prostate cancer, REAR syndrome, Refsum disease, retinitis pigmentosa, retinoblastoma, Rett syndrome, Sanfilippo syndrome, schizophrenia, severe combined immunodeficiency, sickle cell anemia, spina bifida, spinal muscular atrophy, spinocerebellar atrophy, sudden adult death syndrome, Tangier disease, Tay-Sachs disease, thrombocytopenia absent radius syndrome, Townes-Brocks syndrome, tuberous sclerosis, Turner syndrome, Usher syndrome, von Hippel-Lindau syndrome, Waardenburg syndrome, Weaver syndrome, Werner syndrome, Williams syndrome, Wilson’s disease, xeroderma piginentosum, and Zellweger syndrome.

[0097] A“proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology;

Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e.,“malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0098] The term“angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., FGF).“Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and/or is associated with a disease.

[0099] The terms“neoplasm” and“tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be“benign” or“malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A“benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain“benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as“pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a“malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term“metastasis,”“metastatic,” or“metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or“secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[00100] The term“cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma;

endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma);

endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B- cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL),

immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease);

hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer

(NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian

adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic

andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma;

testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[00101] The term“inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation. The term“inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis

(scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis,

chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[00102] An“autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis,

Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis/polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[00103] The term“liver disease” or“hepatic disease” refers to damage to or a disease of the liver. Non-limiting examples of liver disease include intrahepatic cholestasis (e.g., alagille syndrome, biliary liver cirrhosis), fatty liver (e.g., alcoholic fatty liver, Reye’s syndrome), hepatic vein thrombosis, hepatolenticular degeneration (i.e., Wilson's disease), hepatomegaly, liver abscess (e.g., amebic liver abscess), liver cirrhosis (e.g., alcoholic, biliary, and experimental liver cirrhosis), alcoholic liver diseases (e.g., fatty liver, hepatitis, cirrhosis), parasitic liver disease (e.g., hepatic echinococcosis, fascioliasis, amebic liver abscess), jaundice (e.g., hemolytic, hepatocellular, cholestatic jaundice), cholestasis, portal

hypertension, liver enlargement, ascites, hepatitis (e.g., alcoholic hepatitis, animal hepatitis, chronic hepatitis (e.g., autoimmune, hepatitis B, hepatitis C, hepatitis D, drug induced chronic hepatitis), toxic hepatitis, viral human hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E), granulomatous hepatitis, secondary biliary cirrhosis, hepatic encephalopathy, varices, primary biliary cirrhosis, primary sclerosing cholangitis, hepatocellular adenoma, hemangiomas, bile stones, liver failure (e.g., hepatic

encephalopathy, acute liver failure), angiomyolipoma, calcified liver metastases, cystic liver metastases, fibrolamellar hepatocarcinoma, hepatic adenoma, hepatoma, hepatic cysts (e.g., Simple cysts, Polycystic liver disease, hepatobiliary cystadenoma, choledochal cyst), mesenchymal tumors (mesenchymal hamartoma, infantile hemangioendothelioma, hemangioma, peliosis hepatis, lipomas, inflammatory pseudotumor), epithelial tumors (e.g., bile duct hamartoma, bile duct adenoma), focal nodular hyperplasia, nodular regenerative hyperplasia, hepatoblastoma, hepatocellular carcinoma, cholangiocarcinoma,

cystadenocarcinoma, tumors of blood vessels, angiosarcoma, Karposi's sarcoma,

hemangioendothelioma, embryonal sarcoma, fibrosarcoma, leiomyosarcoma,

rhabdomyosarcoma, carcinosarcoma, teratoma, carcinoid, squamous carcinoma, primary lymphoma, peliosis hepatis, erythrohepatic porphyria, hepatic porphyria (e.g., acute intermittent porphyria, porphyria cutanea tarda), and Zellweger syndrome.

[00104] The term“spleen disease” refers to a disease of the spleen. Example of spleen diseases include, but are not limited to, splenomegaly, spleen cancer, asplenia, spleen trauma, idiopathic purpura, Felty’s syndrome, Hodgkin’s disease, and immune-mediated destruction of the spleen.

[00105] The term“lung disease” or“pulmonary disease” refers to a disease of the lung.

Examples of lung diseases include, but are not limited to, bronchiectasis, bronchitis, bronchopulmonary dysplasia, interstitial lung disease, occupational lung disease, emphysema, cystic fibrosis, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), asthma (e.g., intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma), chronic bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, interstitial lung disease, sarcoidosis, asbestosis, aspergilloma, aspergillosis, pneumonia (e.g., lobar pneumonia, multilobar pneumonia, bronchial pneumonia, interstitial pneumonia), pulmonary fibrosis, pulmonary tuberculosis, rheumatoid lung disease, pulmonary embolism, and lung cancer (e.g., non-small-cell lung carcinoma (e.g., adenocarcinoma, squamous-cell lung carcinoma, large-cell lung carcinoma), small-cell lung carcinoma).

[00106] A“hematological disease” includes a disease which affects a hematopoietic cell or tissue. Hematological diseases include diseases associated with aberrant hematological content and/or function. Examples of hematological diseases include diseases resulting from bone marrow irradiation or chemotherapy treatments for cancer, diseases such as pernicious anemia, hemorrhagic anemia, hemolytic anemia, aplastic anemia, sickle cell anemia, sideroblastic anemia, anemia associated with chronic infections such as malaria,

trypanosomiasis, HTV, hepatitis virus or other viruses, myelophthisic anemias caused by marrow deficiencies, renal failure resulting from anemia, anemia, polycythemia, infectious mononucleosis (EVI), acute non-lymphocytic leukemia (ANLL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL), polycythemia vera, lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia, Wilm’s tumor, Ewing’s sarcoma, retinoblastoma, hemophilia, disorders associated with an increased risk of thrombosis, herpes, thalassemia, antibody-mediated disorders such as transfusion reactions and erythroblastosis, mechanical trauma to red blood cells such as micro-angiopathic hemolytic anemias, thrombotic thrombocytopenic purpura and

disseminated intravascular coagulation, infections by parasites such as Plasmodium, chemical injuries from, e.g., lead poisoning, and hypersplenism.

[00107] The term“neurological disease” refers to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease. Examples of neurological diseases include, but are not limited to, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illness, include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired

epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; bbrain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy- induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic

inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt- Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome;

Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune- mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile;

phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh’s disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis;

myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital;

narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome;

occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome;

olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain;

persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis;

porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic

encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury;

tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig-Hoffman disease; West syndrome;

whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome. [00108] A“painful condition” includes, but is not limited to, neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post–operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre–operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and/or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre–term labor, pain associated with withdrawl symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis,

osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter’s arthritis), lumbosacral pain, musculo–skeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache, dental/maxillofacial pain, visceral pain and the like. One or more of the painful conditions contemplated herein can comprise mixtures of various types of pain provided above and herein (e.g. nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular pain can dominate. In other embodiments, the painful condition comprises two or more types of pains without one dominating. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition.

[00109] The term“psychiatric disorder” refers to a disease of the mind and includes diseases and disorders listed in the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV), published by the American Psychiatric Association, Washington D. C. (1994). Psychiatric disorders include, but are not limited to, anxiety disorders (e.g., acute stress disorder agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, and specific phobia), childhood disorders, (e.g., attention-deficit/hyperactivity disorder, conduct disorder, and oppositional defiant disorder), eating disorders (e.g., anorexia nervosa and bulimia nervosa), mood disorders (e.g., depression, bipolar disorder, cyclothymic disorder, dysthymic disorder, and major depressive disorder), personality disorders (e.g., antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, schizoid personality disorder, and schizotypal personality disorder), psychotic disorders (e.g., brief psychotic disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, schizophrenia, and shared psychotic disorder), substance-related disorders (e.g., alcohol dependence, amphetamine dependence, cannabis dependence, cocaine dependence, hallucinogen dependence, inhalant dependence, nicotine dependence, opioid dependence, phencyclidine dependence, and sedative dependence), adjustment disorder, autism, delirium, dementia, multi-infarct dementia, learning and memory disorders (e.g., amnesia and age- related memory loss), and Tourette’s disorder.

[00110] The term "metabolic disorder" refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and/or

carbohydrates. Factors affecting metabolism include, and are not limited to, the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like. Examples of metabolic disorders include, but are not limited to, diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity.

[00111] A“diabetic condition” refers to diabetes and pre-diabetes. Diabetes refers to a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger). There are several types of diabetes. Type I diabetes results from the body's failure to produce insulin, and presently requires the person to inject insulin or wear an insulin pump. Type II diabetes results from insulin resistance a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency. Gestational diabetes occurs when pregnant women without a previous diagnosis of diabetes develop a high blood glucose level. Other forms of diabetes include congenital diabetes, which is due to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes, e.g., mature onset diabetes of the young (e.g., MODY 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Pre-diabetes indicates a condition that occurs when a person's blood glucose levels are higher than normal but not high enough for a diagnosis of diabetes. All forms of diabetes increase the risk of long-term complications. These typically develop after many years, but may be the first symptom in those who have otherwise not received a diagnosis before that time. The major long-term complications relate to damage to blood vessels. Diabetes doubles the risk of cardiovascular disease and macrovascular diseases such as ischemic heart disease (angina, myocardial infarction), stroke, and peripheral vascular disease. Diabetes also causes microvascular complications, e.g., damage to the small blood vessels. Diabetic retinopathy, which affects blood vessel formation in the retina of the eye, can lead to visual symptoms, reduced vision, and potentially blindness. Diabetic nephropathy, the impact of diabetes on the kidneys, can lead to scarring changes in the kidney tissue, loss of small or progressively larger amounts of protein in the urine, and eventually chronic kidney disease requiring dialysis. Diabetic neuropathy is the impact of diabetes on the nervous system, most commonly causing numbness, tingling and pain in the feet and also increasing the risk of skin damage due to altered sensation. Together with vascular disease in the legs, neuropathy contributes to the risk of diabetes-related foot problems, e.g., diabetic foot ulcers, that can be difficult to treat and occasionally require amputation.

[00112] A“cardiovascular disease” (CVD) refers to a disease that involves the heart or blood vessels. Cardiovascular disease includes coronary artery diseases (e.g., angina and

myocardial infarction (i.e., heart attack). Other types of cardiovascular disease include, but are not limited to, stroke, hypertensive heart disease, rheumatic heart disease,

cardiomyopathy, atrial fibrillation, congenital heart disease, endocarditis, aortic aneurysms, peripheral artery disease and venous thrombosis. CVDs that affect the blood vessels (i.e., “vascular diseases”) include, but are not limited to, coronary artery disease (i.e., coronary heart disease or ischemic heart disease), peripheral arterial disease, cerebrovascular disease (e.g., stroke), renal artery stenosis, and aortic aneurysm. CVDs that affect the heart include, but are not limited to, cardiomyopathy, hypertensive heart disease, heart failure, pulmonary heart disease, cardiac dysrhythmias, inflammatory heart disease (e.g., endocarditis, inflammatory cardiomegaly, myocarditis), valvular heart disease, congenital heart disease, and rheumatic heart disease.

[00113] An“infectious disease” refers to any disease caused by a pathogen (i.e., pathogenic microorganisms). An infectious disease may be caused by bacteria, viruses, parasites, or fungi. In certain embodiments, the infectious disease is a bacterial infection. In certain embodiments, the infectious disease is a viral infection.

[00114] A“gastrointestinal disorder” refers to a disease or disorder involving organs of the gastrointestinal tract (i.e., GI tract). Organs of the gastrointestinal tract include, but are not limited to, the esophagus, stomach, small intestine, large intestine, and rectum. [00115] An“endocrine disease” refers to a disease involving the endrocrine system.

Examples of endrocrine diseases include, but are not limited to, adrenal disorders (e.g., adrenal insufficiency (e.g., Addison's disease, mineralocorticoid deficiency), adrenal hormone excess (e.g., Conn's syndrome, Cushing's syndrome, glucocorticoid remediable aldosteronism (GRA), pheochromocytoma), congenital adrenal hyperplasia (i.e.,

adrenogenital syndrome), adrenocortical carcinoma)), glucose homeostasis disorders (e.g., diabetes mellitus, hypoglycemia, glucagonoma), thyroid disorders (e.g., goiter,

hyperthyroidism (e.g., Graves-Basedow disease, toxic multinodular goiter), hypothyroidism, thyroiditis (e.g., Hashimoto's thyroiditis), thyroid cancer, thyroid hormone resistance), calcium homeostasis disorders and Metabolic bone diseases (e.g., parathyroid gland disorders (e.g., primary hyperparathyroidism, secondary hyperparathyroidism, tertiary

hyperparathyroidism, hypoparathyroidism (e.g., pseudohypoparathyroidism)), osteoporosis, psteitis deformans (i.e., Paget's disease of bone), rickets, osteomalacia), pituitary gland disorders (e.g., diabetes insipidus, hypopituitarism (or panhypopituitarism), pituitary tumors (e.g., pituitary adenomas, prolactinoma (or hyperprolactinemia), acromegaly, gigantism, Cushing's disease))), sex hormone disorders (e.g., disorders of sex development or intersex disorders (e.g., hermaphroditism, gonadal dysgenesis, androgen insensitivity syndromes), hypogonadism (gonadotropin deficiency) (e.g., Kallmann syndrome, Klinefelter syndrome, Turner syndrome, ovarian failure (i.e., premature menopause), testicular failure), disorders of puberty (e.g., delayed puberty, precocious puberty), menstrual function or fertility disorders (e.g., amenorrhea, polycystic ovary syndrome)), and tumours of the endocrine glands.

[00116]“Acute radiation syndrome” (ARS), also known as radiation toxicity, raditation sickness, or radiation poisoning, is an illness caused by irradiation of the body (either the entire body or part(s) of the body). Acute radiation syndrome (ARS), induced by whole-body or significant partial-body irradiation, causes severe damage to a broad range of organ systems such as the hematopoietic, cutaneous, gastrointestinal (GI), and cerebrovascular systems. As a result, ARS leads to either near-term mortality or long-term adverse health effects. ARS includes, for example, radiation-induced gastrointestinal syndrome. In some instances, radiation-induced gastrointestinal syndrome is caused by ionizing radiation (IR). BRIEF DESCRIPTION OF THE DRAWINGS

[00117] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention. [00118] Figure 1 shows FGF-FGFR structure and downstream signaling pathway. The extracellular domain of FGFRs consist of three ligand binding Ig domains (IgI-III). Binding of FGFs to the FGFRs results in receptor dimerization and autophosphorylation of the tyrosine kinase (TK) domains. Upon phosphorylation, the major FGFR effector FRS2 acts as a docking site for GRB2, which then activates extracellular signal-regulated kinase (ERK) and Akt via SOS and GAB1.

[00119] Figure 2 shows the preparation of the one-bead-one-compound (OBOC) peptoid library. The diversity of the library: 10⁶ = 1,000,000 compounds. Beads: Rink-Amide aminomethyl polystyrene resins, particle size: 500 µm, capacity: 0.53 mmol/g.

[00120] Figure 3 shows the schematic representation of identifying FGFR ligands from peptoid OBOC library based on microarray technology.

[00121] Figure 4A shows a microarray scanner image of the peptoid-immobilized slide after incubation with Fc-modified FGFR1α and then FITC-labeled anti-Fc. Peptoids were printed onto the slide in triplicates. Four hit peptoids which showed stronger fluorescence compared with surrounding spots are framed in yellow rectangles. Figure 4B shows chemical structures of the four hit peptoids (1-4) as confirmed by MS/MS.

[00122] Figure 5 shows confirmation of the binding affinity of peptoids 1-4 toward FGFR1α. Hit peptoids 1-4 and two randomly selected negative peptoids were printed onto maleimide- modified slide in triplicates at three concentrations (100, 50, and 25 µM). The slide was visualized under GenePix Microarray Scanner before (left) and after (right) incubation with Fc-modified FGFR1α and Texas Red-labeled anti-Fc.

[00123] Figure 6 shows on-bead validation of the binding affinities of peptoids 2 and 4 toward FGFR1α. Peptoids were synthesized on TentalGel beads. Beads were washed with TBST, blocked with 5% BSA, and incubated with Fc-tagged FGFR1α and Texas Red-labeled anti-Fc sequentially. Another pool of beads bearing randomly selected peptoid was subjected to the same treatment as a negative control. Beads were observed under microscope (4X) using Texas Red filter.

[00124] Figure 7 shows effects of hit peptoids 1-4 on the expression levels of p-Akt and p- ERK in MCF-7 (Figure 7A), MDA-231 (Figure 7B), and NIH-3T3 (Figure 7C) cells. After serum starvation, all of the three cell lines were treated with peptoids 1-4 and a randomly selected peptoid control at a concentration of 15 µM for 10 min. The expression levels of p- Akt and p-ERK were detected by Western blot using specific antibodies.

[00125] Figure 8 shows the concentration- and time-dependent effects of peptoid 2 on the expression levels of p-Akt and p-ERK in NIH-3T3 cells. After serum starvation, NIH-3T3 cells were treated with different concentrations of peptoid 2 (0, 7.5, 15, and 30 µM) for 10 min (Figure 8A), or with 15 µM of peptoid 2 for different time periods (0, 5, 10, and 20 min) (Figure 8B). The expression levels of p-Akt and p-ERK were detected by Western blot using specific antibodies.

[00126] Figure 9 shows a flowchart of identifying FGFR ligands from peptoid OBOC library based on microarray technology for acute radiation syndrome drug discovery.

[00127] Figure 10 shows a general scheme outlining on-bead validation of the binding affinities of peptoids toward FGFR1α. Peptoids were synthesized on TentalGel beads. Beads were washed with TBST, blocked with 5% BSA, and incubated with Fc-tagged FGFR1α and Texas Red-labeled anti-Fc sequentially. Another pool of beads bearing randomly selected peptoid were subjected to the same treatment as a negative control. Beads were observed under microscope (4X) using Texas Red filter.

[00128] Figure 11 shows a survival curve for Swiss mice dosed intramuscularly with Peptoid 2, 1 mg/ml 24 hours post irradiation. Experimental groups contained 5 mice per group. Mice treated with peptoids have shown better survival rate at Day 8-10 before were all sacrificed at Day 11.

[00129] Figure 12 shows weight measurement for Swiss mice dosed intramuscularly with Peptoid 2, 1 mg/ml and 10 mg/ml. Experimental groups contained 5 mice per group. No obvious toxicity was observed for peptoid application to mice. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[00130] Fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling plays an important role in angiogenesis, wound healing, cell migration, neural outgrowth, embryonic development, and many other important biological processes linked to various diseases. Therefore, developing drugs that target FGFRs has become an emerging theme in the field of medicinal chemistry. As described herein, novel compounds which act as FGF mimics have been developed. The compounds of the present invention have been shown to activate FGFRs and therefore are useful in the treatment and/or prevention of various diseases. Provided herein are novel peptoids such as compounds of Formula (I), which are activators or inhibitors of FGFRs, and therefore may be used in the treatment and/or prevention of diseases. Also provided herein are pharmaceutical compositions and kits comprising the inventive compounds, or pharmaceutical compositions thereof. Also described herein are methods of treating diseases (e.g., diseases associated with FGFRs) using compounds of Formula (I), or pharmaceutical compositions thereof. Furthermore, provided herein are methods for activating or inhibiting an FGFR, the methods comprising contacting an FGFR with a compound described herein, or a composition thereof. Compounds

[00131] One aspect of the present invention relates to novel compounds, such as compounds of Formula (I). The novel peptoids described herein can act as FGFR activators or inhibitors, and are therefore useful in the treatment and/or prevention of diseases. In one aspect, the present invention provides compounds of Formula (I):

(I),

and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein:

each of R¹, R², R³, R⁴, R⁵, and R⁶ is independently optionally substituted aralkyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

each instance of R^N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group, or optionally two R^N are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; and

R^S is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group. [00132] In certain embodiments, one instance of R¹, R², R³, R⁴, R⁵, or R⁶ is optionally substituted alkenyl or optionally substituted alkynyl. In certain embodiments, one instance of R¹, R², R³, R⁴, R⁵, or R⁶ is optionally substituted alkenyl. In certain embodiments, exactly one instance of R¹, R², R³, R⁴, R⁵, or R⁶ is optionally substituted alkenyl or optionally substituted alkynyl. In certain embodiments, exactly one instance of R¹, R², R³, R⁴, R⁵, or R⁶ is optionally substituted alkenyl. In certain embodiments, no more than two instances of R¹, R², R³, R⁴, R⁵, or R⁶ are optionally substituted alkenyl or optionally substituted alkynyl. In certain embodiments, no more than two instances of R¹, R², R³, R⁴, R⁵, or R⁶ are optionally substituted alkenyl. In certain embodiments, no more than three instances of R¹, R², R³, R⁴, R⁵, or R⁶ are optionally substituted alkenyl or optionally substituted alkynyl. In certain embodiments, no more than three instances of R¹, R², R³, R⁴, R⁵, or R⁶ is optionally substituted alkenyl. In certain embodiments, no more than four instances of R¹, R², R³, R⁴, R⁵, or R⁶ are optionally substituted alkenyl or optionally substituted alkynyl. In certain embodiments, no more than four instances of R¹, R², R³, R⁴, R⁵, or R⁶ is optionally substituted alkenyl.

[00133] In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[00134] In certain embodiments, R^S is a sulfur protecting group. In other embodiments, R^S is hydrogen. In certain embodiments, R^S is hydrogen; and the compound of Formula (I) is of the formula:

[00135] In certain embodiments, at least one instance of R^N is hydrogen. In certain embodiments, one instance of R^N is hydrogen. In certain embodiments, two instances of R^N are hydrogen. In certain embodiments, three instances of R^N are hydrogen.

[00136] In certain embodiments, four instances of R^N are hydrogen. In certain embodiments, the compound of Formula (I) is of Formula (I-a):

(I-a),

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. [00137] In certain embodiments, five instances of R^N are hydrogen. In certain embodiments, six instances of R^N are hydrogen. In certain embodiments, seven instances of R^N are hydrogen. In certain embodiments, each instance of R^N is hydrogen. In certain embodiments, the compound of Formula (I) is of one of the following formulae:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. [00138] In certain embodiments, the compound of Formula (I) is of the formula:

, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0 In certain embodiments, the compound of Formula (I) is of Formula (I-c1):

(I-c1),

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:

each instance of n is independently 0, 1, 2, 3, 4, 5, or 6;

each instance of m is independently 0, 1, 2, 3, 4, or 5;

each instance of R⁷ is independently hydrogen, halogen,–CN,–SCN,–NO₂,–N₃, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl,–OR^a,–N(R^b)₂, or–SR^c;

each instance of R^a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R^b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;

each instance of R^c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; and

each instance of R^S is independently hydrogen or optionally substituted alkyl.

[00140] In certain embodiments, the compound of Formula (1-c1) is of the following formula:

[00141] In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; and the compound of Formula (I-c1) is of the formula:

, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. [00142] In certain embodiments, the compound of Formula (I-c1) is of Formula (I-d1):

( ),

[00143] In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; and the compound of Formula (I-d1) is of the following formula:

[00144] In certain embodiments, the compound of Formula (I-d1) is of Formula (I-e1):

( e ),

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. [00145] In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; and the compound of Formula (I-e1) is of the Formula (I-f1):

(I-f1),

[00146] In certain embodiments, the compound of Formula (I-f1) is Compound (1):

[00147] In certain embodiments, the compound of Formula (I-f1) is of the following formula:

[00148] In certain embodiments, the compound of Formula (I) is of Formula (I-c2):

(I-c2),

each instance of n is independently 0, 1, 2, 3, 4, 5, or 6;

each instance of m is independently 0, 1, 2, 3, 4, or 5;

each instance of R^b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R^b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; and

each instance of R^c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group. [00149] In certain embodiments, the compound of Formula (I-c2) is of the formula:

[00150] In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; and the compound of Formula (I-c2) is of the following formula:

[0 In certain embodiments, the compound of Formula (I-c2) is of Formula (I-d2):

(I-d2),

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. [00152] In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; and the compound of Formula (I-d2) is of the following formula:

[001 In certain embodiments, the compound of Formula (I-d2) is of Formula (I-e2):

(I-e2),

[00154] In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; and the compound of Formula (I-e2) is of Formula (I-f2):

(I-f2),

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. [00155] In certain embodiments, the compound of Formula (I-f2) is Compound (2):

(2),

[00156] In certain embodiments, the compound of Formula (I-f2) is of one of the following formulae:

[00157] In certain embodiments, the compound of Formula (I) is of Formula (I-c3):

(I-c3),

each instance of n is independently 0, 1, 2, 3, 4, 5, or 6;

each instance of m is independently 0, 1, 2, 3, 4, or 5;

each instance of R⁸ is independently hydrogen or optionally substituted alkyl.

[00158] In certain embodiments, the compound of Formula (I-c3) is of the formula:

[00159] In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; and the compound of Formula (I-c3) is of the formula:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. [00160] In certain embodiments, the compound of Formula (I-c3) is of Formula (I-d3):

(I-d3),

[00161] In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; and the compound of Formula (I-d3) is of the formula:

[00162] In certain embodiments, the compound of Formula (I-d3) is of Formula (I-e3):

(I-e3),

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. [00163] In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; and the compound of Formula (I-e3) is of Formula (I-f3):

(I-f3),

[00164] In certain embodiments, the compound of Formula (I-f3) is Compound (3):

(3),

[00165] In certain embodiments, the compound of Formula (I-f3) is of one of the following formulae:

[0 In certain embodiments, the compound of Formula (I) is of Formula (I-c4):

(I-c4),

each instance of n is independently 0, 1, 2, 3, 4, 5, or 6;

each instance of m is independently 0, 1, 2, 3, 4, or 5;

each instance of R⁷ is independently hydrogen, halogen,–CN,–SCN,–NO₂,–N₃, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl,–OR^a,–N(R^b)₂, or–SR^c; each instance of R^a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group;

[00167] In certain embodiments, the compound of Formula (I-c4) is of the formula:

[00168] In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; and the compound of Formula (I-c4) is of the formula:

[00169] In certain embodiments, the compound of Formula (I-c4) is of Formula (I-d4):

(I-d4),

[00170] In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; and the compound of Formula (I-d4) is of the formula:

,

[00171] In certain embodiments, the compound of Formula (I-d4) is of Formula (I-e4):

(I-e4),

[00172] In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; and the compound of Formula (I-e4) is of Formula (I-f4):

(I-f4),

[00173] In certain embodiments, the compound of Formula (I-f4) is Compound (4):

(4),

[00174] In certain embodiments, the compound of Formula (I-f4) is of one of the following formulae:

, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. Group R¹

[00175] As generally defined herein, R¹ is optionally substituted aralkyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In certain embodiments, R¹ is optionally substituted aralkyl. In certain embodiments, R¹ is optionally substituted carbocyclylalkyl. In certain

embodiments, R¹ is optionally substituted heteroaralkyl. In certain embodiments, R¹ is optionally substituted heterocyclylalkyl. In certain embodiments, R¹ is optionally substituted alkenyl. In certain embodiments, R¹ is optionally substituted alkynyl. In certain

embodiments, R¹ is optionally substituted carbocyclyl. In certain embodiments, R¹ is optionally substituted aryl. In certain embodiments, R¹ is optionally substituted heterocyclyl. In certain embodiments, R¹ is optionally substituted heteroaryl.

[00176] In certain embodiments, R¹ is optionally substituted heteroaralkyl. In certain embodiments, R¹ is optionally substituted–C_1-6alkyl-heteroaryl. In certain embodiments, R¹ is optionally substituted–C_1-6alkyl-heteroaryl, wherein the heteroaryl group is five-membered heteroaryl. In certain embodiments, R¹ is optionally substituted–C_1-6alkyl-furanyl. In certain embodiments, R¹ is unsubstituted–C_1-6alkyl-furanyl. In certain embodiments, R¹ is optionally substituted–C_1-3alkyl-heteroaryl. In certain embodiments, R¹ is optionally substituted–C_1- ₃alkyl-heteroaryl, wherein the heteroaryl group is five-membered heteroaryl. In certain embodiments, R¹ is optionally substituted–C_1-3alkyl-furanyl. In certain embodiments, R¹ is unsubstituted–C_1-3alkyl-furanyl. In certain embodiments, R¹ is optionally substituted–CH₂- heteroaryl. In certain embodiments, R¹ is optionally substituted–CH₂-heteroaryl, wherein the heteroaryl group is five-membered heteroaryl. In certain embodiments, R¹ is optionally substituted–CH₂-furanyl. In certain embodiments, R¹ is unsubstituted–CH₂-furanyl. In

certain embodiments, R¹ is of the formula:

wherein m, n, and R⁷ are as

defined herein. In certain embodiments, R¹ is of the formula:

, wherein m, n, R^N, and R⁷ are as defined herein. In certain embodiments, R¹ is of the formula:

, wherein m, n, and R⁷ are as defined herein. In certain embodiments, R¹ is of

the formula

, wherein m, n, and R⁷ are as defined herein. In certain

embodiments, R¹ is of the formula: In certain embodiments, R¹ is of the

formula:

. In certain embodiments, R¹ is of the formula: . In certain

embodiments, R¹ is of the formula:

[00177] In certain embodiments, R¹ is optionally substituted aralkyl. In certain embodiments, R¹ is optionally substituted–C_1-6alkyl-aryl. In certain embodiments, R¹ is optionally substituted–C_1-6alkyl-phenyl. In certain embodiments, R¹ is substituted–C_1-6alkyl-phenyl. In certain embodiments, R¹ is unsubstituted–C_1-6alkyl-phenyl. In certain embodiments, R¹ is optionally substituted–C_1-3alkyl-aryl. In certain embodiments, R¹ is optionally substituted– C_1-3alkyl-phenyl. In certain embodiments, R¹ is substituted–C_1-3alkyl-phenyl. In certain embodiments, R¹ is unsubstituted–C_1-3alkyl-phenyl. In certain embodiments, R¹ is optionally substituted–CH(CH₃)-aryl. In certain embodiments, R¹ is optionally substituted–CH(CH₃)- phenyl. In certain embodiments, R¹ is unsubstituted–CH(CH₃)-phenyl. In certain

embodiments, R¹ is of the formula:

wherein m, n, R⁷, and R⁸ are as

defined herein. In certain embodiments, R¹ is of the formula: . In certain

embodiments, R¹ is of the formula:

. In certain embodiments, R¹ is of the

formula: . In certain embodiments, R¹ is of the formula: . In certain

embodiments, R¹ is of the formula:

[00178] In certain embodiments, R¹ is optionally substituted alkenyl. In certain embodiments, R¹ is optionally substituted C_2-6alkenyl. In certain embodiments, R¹ is optionally substituted allyl. In certain embodiments, R¹ is unsubstituted allyl. In certain embodiments, R¹ is of the formula:

R¹ is of the formula: In certain embodiments, R¹ is of the formula:

unsubstituted allyl).

[00179] In certain embodiments, R¹ is optionally substituted heterocyclylalkyl. In certain embodiments, R¹ is optionally substituted–C_1-6alkyl-heterocyclyl. In certain embodiments, R¹ is optionally substituted–C_1-6alkyl-heterocyclyl, wherein the heterocyclyl group is five- membered heterocyclyl. In certain embodiments, R¹ is optionally substituted–C_1-6alkyl- lactam. In certain embodiments, R¹ is optionally substituted–C_1-6alkyl-γ-lactam. In certain embodiments, R¹ is unsubstituted–C_1-6alkyl-γ-lactam. In certain embodiments, R¹ is optionally substituted–C_1-3 alkyl-heterocyclyl. In certain embodiments, R¹ is optionally substituted–C_1-3 alkyl-heterocyclyl, wherein the heterocyclyl group is five-membered heterocyclyl. In certain embodiments, R¹ is optionally substituted–C_1-3 alkyl-lactam. In certain embodiments, R¹ is optionally substituted–C_1-3 alkyl-γ-lactam. In certain

embodiments, R¹ is unsubstituted–C_1-3 alkyl-γ-lactam. In certain embodiments, R¹ is optionally substituted–CH₂CH₂CH₂-heterocyclyl. In certain embodiments, R¹ is optionally substituted–CH₂CH₂CH₂-heterocyclyl, wherein the heterocyclyl group is five-membered heterocyclyl. In certain embodiments, R¹ is optionally substituted–CH₂CH₂CH₂-lactam. In certain embodiments, R¹ is optionally substituted–CH₂CH₂CH₂-γ-lactam. In certain embodiments, R¹ is unsubstituted–CH₂CH₂CH₂-γ-lactam. In certain embodiments, R¹ is of

the m, n, and R⁷ are as defined herein. In certain

embodiments, R¹ is of the formula:

, wherein m, n, R^N, and R⁷ are as defined

herein. In certain embodiments, R¹ is of the formula: . In certain embodiments, R¹ is of the formula:

. In certain embodiments, R¹ is of the

formula:

. In certain embodiments, R is of the formula: Group R²

[00180] As generally defined herein, R² is optionally substituted aralkyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In certain embodiments, R² is optionally substituted aralkyl. In certain embodiments, R² is optionally substituted carbocyclylalkyl. In certain

embodiments, R² is optionally substituted heteroaralkyl. In certain embodiments, R² is optionally substituted heterocyclylalkyl. In certain embodiments, R² is optionally substituted alkenyl. In certain embodiments, R² is optionally substituted alkynyl. In certain

embodiments, R² is optionally substituted carbocyclyl. In certain embodiments, R² is optionally substituted aryl. In certain embodiments, R² is optionally substituted heterocyclyl. In certain embodiments, R² is optionally substituted heteroaryl.

[00181] In certain embodiments, R² is optionally substituted alkenyl. In certain embodiments, R² is optionally substituted C_2-6 alkenyl. In certain embodiments, R² is optionally substituted allyl. In certain embodiments, R² is unsubstituted allyl. In certain embodiments, R² is of the

formula: , wherein m, n, and R⁷ are as defined herein. In certain embodiments,

R² is of the formula: . In certain embodiments, R² is of the formula:

unsubstituted allyl).

[00182] In certain embodiments, R² is optionally substituted aralkyl. In certain embodiments, R² is optionally substituted–C_1-6 alkyl-aryl. In certain embodiments, R² is optionally substituted–C_1-6 alkyl-phenyl. In certain embodiments, R² is substituted–C_1-6alkyl-phenyl. In certain embodiments, R² is unsubstituted–C_1-6 alkyl-phenyl. In certain embodiments, R² is optionally substituted–C_1-3 alkyl-aryl. In certain embodiments, R² is optionally substituted– C_1-3 alkyl-phenyl. In certain embodiments, R² is substituted–C_1-3 alkyl-phenyl. In certain embodiments, R² is unsubstituted–C_1-3 alkyl-phenyl. In certain embodiments, R² is optionally substituted–CH(CH₃)-aryl. In certain embodiments, R² is optionally substituted– CH(CH₃)-phenyl. In certain embodiments, R² is unsubstituted–CH(CH₃)-phenyl. In certain

embodiments, R² is of the formula:

wherein m, n, R⁷, and R⁸ are as

defined herein. In certain embodiments, R² is of the formula:

. In certain

embodiments, R² is of the formula:

. In certain embodiments, R² is of the

formula:

In certain embodiments, R² is of the formula: . In certain

embodiments, R² is of the formula:

[00183] In certain embodiments, R² is optionally substituted heterocyclylalkyl. In certain embodiments, R² is optionally substituted–C_1-6alkyl-heterocyclyl. In certain embodiments, R² is optionally substituted–C_1-6alkyl-heterocyclyl, wherein the heterocyclyl group is five- membered heterocyclyl. In certain embodiments, R² is optionally substituted–C_1-6alkyl- tetrahydrofuran. In certain embodiments, R² is unsubstituted–C_1-6alkyl-tetrahydrofuran. In certain embodiments, R² is optionally substituted–C_1-3alkyl-heterocyclyl. In certain embodiments, R² is optionally substituted–C_1-3alkyl-heterocyclyl, wherein the heterocyclyl group is five-membered heterocyclyl. In certain embodiments, R² is optionally substituted– C_1-3alkyl-tetrahydrofuran. In certain embodiments, R² is unsubstituted–C_1-3alkyl- tetrahydrofuran. In certain embodiments, R² is optionally substituted–CH₂-heterocyclyl. In certain embodiments, R² is optionally substituted–CH₂-heterocyclyl, wherein the heterocyclyl group is five-membered heterocyclyl. In certain embodiments, R² is optionally substituted–CH₂-tetrahydrofuran. In certain embodiments, R² is unsubstituted–CH₂-

tetrahydrofuran. In certain embodiments, R² is of the formula: , wherein m, n,

and R⁷ are as defined herein. In certain embodiments, R² is of the formula: , wherein m, n, and R⁷ are as defined herein. In certain embodiments, R² is of the formula:

, wherein m, n, and R⁷ are as defined herein. In certain embodiments, R² is of

the formula: , wherein m, n, and R⁷ are as defined herein. In certain

embodiments, R² is of the formula: . In certain embodiments, R² is of the

formula:

In certain embodiments, R is of the formula: In certain

embodiments, R² is of the formula: . Group R³

[00184] As generally defined herein, R³ is optionally substituted aralkyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In certain embodiments, R³ is optionally substituted aralkyl. In certain embodiments, R³ is optionally substituted carbocyclylalkyl. In certain

embodiments, R³ is optionally substituted heteroaralkyl. In certain embodiments, R³ is optionally substituted heterocyclylalkyl. In certain embodiments, R³ is optionally substituted alkenyl. In certain embodiments, R³ is optionally substituted alkynyl. In certain embodiments, R³ is optionally substituted carbocyclyl. In certain embodiments, R³ is optionally substituted aryl. In certain embodiments, R³ is optionally substituted heterocyclyl. In certain embodiments, R³ is optionally substituted heteroaryl.

[00185] In certain embodiments, R³ is optionally substituted heteroaralkyl. In certain embodiments, R³ is optionally substituted–C_1-6alkyl-heteroaryl. In certain embodiments, R³ is optionally substituted–C_1-6alkyl-heteroaryl, wherein the heteroaryl group is five-membered heteroaryl. In certain embodiments, R³ is optionally substituted–C_1-6alkyl-furanyl. In certain embodiments, R³ is unsubstituted–C_1-6alkyl-furanyl. In certain embodiments, R³ is optionally substituted–C_1-3alkyl-heteroaryl. In certain embodiments, R³ is optionally substituted–C_1- ₃alkyl-heteroaryl, wherein the heteroaryl group is five-membered heteroaryl. In certain embodiments, R³ is optionally substituted–C_1-3alkyl-furanyl. In certain embodiments, R³ is unsubstituted–C_1-3alkyl-furanyl. In certain embodiments, R³ is optionally substituted–CH₂- heteroaryl. In certain embodiments, R³ is optionally substituted–CH₂-heteroaryl, wherein the heteroaryl group is five-membered heteroaryl. In certain embodiments, R³ is optionally substituted–CH₂-furanyl. In certain embodiments, R³ is unsubstituted–CH₂-furanyl. In

certain embodiments, R³ is of the formula: , wherein m, n, and R⁷ are as

defined herein. In certain embodiments, R³ is of the formula: , wherein m, n, N, and R⁷ are as defined herein. In certain embodiments, R³ is of the formula:

, wherein m, n, and R⁷ are as defined herein. In certain embodiments, R³ is of

the formula: , wherein m, n, and R⁷ are as defined herein. In certain

embodiments, R³ is of the formula: . In certain embodiments, R³ is of the formula:

In certain embodiments, R is of the formula: In certain

embodiments, R³ is of the formula: .

[00186] In certain embodiments, R³ is optionally substituted aralkyl. In certain embodiments, R³ is optionally substituted–C_1-6 alkyl-aryl. In certain embodiments, R³ is optionally substituted–C_1-6 alkyl-phenyl. In certain embodiments, R³ is unsubstituted–C_1-6 alkyl- phenyl. In certain embodiments, R³ is optionally substituted–C_1-3 alkyl-aryl. In certain embodiments, R³ is optionally substituted–C_1-3 alkyl-phenyl. In certain embodiments, R³ is unsubstituted–C_1-3 alkyl-phenyl. In certain embodiments, R³ is optionally substituted–CH₂- aryl. In certain embodiments, R³ is optionally substituted–CH₂-phenyl (i.e., optionally substituted benzyl). In certain embodiments, R³ is unsubstituted–CH₂-phenyl (i.e.,

unsubstituted benzyl). In certain embodiments, R³ is of the formula: , wherein m, n, and R⁷ are as defined herein. In certain embodiments, R³ is of the formula:

. In certain embodiments, R³ is of the formula: (i.e., unsubstituted benzyl).

[00187] In certain embodiments, R³ is optionally substituted alkenyl. In certain embodiments, R³ is optionally substituted C_2-6 alkenyl. In certain embodiments, R³ is optionally substituted allyl. In certain embodiments, R³ is unsubstituted allyl. In certain embodiments, R³ is of the

R³ is of the formula: . In certain embodiments, R³ is of the formula:

unsubstituted allyl).

Group R⁴ [00188] As generally defined herein, R⁴ is optionally substituted aralkyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In certain embodiments, R⁴ is optionally substituted aralkyl. In certain embodiments, R⁴ is optionally substituted carbocyclylalkyl. In certain

embodiments, R⁴ is optionally substituted heteroaralkyl. In certain embodiments, R⁴ is optionally substituted heterocyclylalkyl. In certain embodiments, R⁴ is optionally substituted alkenyl. In certain embodiments, R⁴ is optionally substituted alkynyl. In certain

embodiments, R⁴ is optionally substituted carbocyclyl. In certain embodiments, R⁴ is optionally substituted aryl. In certain embodiments, R⁴ is optionally substituted heterocyclyl. In certain embodiments, R⁴ is optionally substituted heteroaryl.

[00189] In certain embodiments, R⁴ is optionally substituted heterocyclylalkyl. In certain embodiments, R⁴ is optionally substituted–C_1-6alkyl-heterocyclyl. In certain embodiments, R⁴ is optionally substituted–C_1-6alkyl-heterocyclyl, wherein the heterocyclyl group is five- membered heterocyclyl. In certain embodiments, R⁴ is optionally substituted–C_1-6alkyl- tetrahydrofuran. In certain embodiments, R⁴ is unsubstituted–C_1-6alkyl-tetrahydrofuran. In certain embodiments, R⁴ is optionally substituted–C_1-3alkyl-heterocyclyl. In certain embodiments, R⁴ is optionally substituted–C_1-3alkyl-heterocyclyl, wherein the heterocyclyl group is five-membered heterocyclyl. In certain embodiments, R⁴ is optionally substituted– C_1-3alkyl-tetrahydrofuran. In certain embodiments, R⁴ is unsubstituted–C_1-3alkyl- tetrahydrofuran. In certain embodiments, R⁴ is optionally substituted–CH₂-heterocyclyl. In certain embodiments, R⁴ is optionally substituted–CH₂-heterocyclyl, wherein the

heterocyclyl group is five-membered heterocyclyl. In certain embodiments, R⁴ is optionally substituted–CH₂-tetrahydrofuran. In certain embodiments, R⁴ is unsubstituted–CH₂-

tetrahydrofuran. In certain embodiments, R⁴ is of the formula: , wherein m, n,

and R⁷ are as defined herein. In certain embodiments, R⁴ is of the formula: , wherein m, n, and R⁷ are as defined herein. In certain embodiments, R⁴ is of the formula:

, wherein m, n, and R⁷ are as defined herein. In certain embodiments, R⁴ is of the formula:

, wherein m, n, and R⁷ are as defined herein. In certain

embodiments, R⁴ is of the formula: . In certain embodiments, R⁴ is of the

formula: . In certain embodiments, R⁴ is of the formula:

In certain

embodiments, R⁴ is of the formula: .

[00190] In certain embodiments, R⁴ is optionally substituted carbocyclyl. In certain embodiments, R⁴ is optionally substituted C_3-6 carbocyclyl. In certain embodiments, R⁴ is optionally substituted cyclopentyl. In certain embodiments, R⁴ is unsubstituted cyclopentyl.

In certain embodiments, R⁴ is of the formula: , wherein m, n, and R⁷ are as

defined herein. In certain embodiments, R⁴ is of the formula:

. In certain mbodiments R⁴ is of the formula: . In certain embodiments, R⁴ is of the formula:

. In certai embodiments R is of the formula: . In certain embodiments, R⁴

is of the formula:

. In certain embodiments, R is of the formula: .

[00191] In certain embodiments, R⁴ is optionally substituted aralkyl. In certain embodiments, R⁴ is optionally substituted–C_1-6alkyl-aryl. In certain embodiments, R⁴ is optionally substituted–C_1-6alkyl-phenyl. In certain embodiments, R⁴ is substituted–C_1-6alkyl-phenyl. In certain embodiments, R⁴ is unsubstituted–C_1-6 alkyl-phenyl. In certain embodiments, R⁴ is optionally substituted–C_1-3alkyl-aryl. In certain embodiments, R⁴ is optionally substituted– C_1-3alkyl-phenyl. In certain embodiments, R⁴ is substituted–C_1-3 alkyl-phenyl. In certain embodiments, R⁴ is unsubstituted–C_1-3 alkyl-phenyl. In certain embodiments, R⁴ is optionally substituted–CH(CH₃)-aryl. In certain embodiments, R⁴ is optionally substituted– CH(CH₃)-phenyl. In certain embodiments, R⁴ is unsubstituted–CH(CH₃)-phenyl. In certain

embodiments, R⁴ is of the formula: , wherein m, n, R⁷, and R⁸ are as

defined herein. In certain embodiments, R⁴ is of the formula: . In certain

embodiments, R⁴ is of the formula: In certain embodiments, R⁴ is of the

formula: . In certain embodiments, R⁴ is of the formula: . In certain

embodiments, R⁴ is of the formula:

Group R⁵

[00192] As generally defined herein, R⁵ is optionally substituted aralkyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In certain embodiments, R⁵ is optionally substituted aralkyl. In certain embodiments, R⁵ is optionally substituted carbocyclylalkyl. In certain

embodiments, R⁵ is optionally substituted heteroaralkyl. In certain embodiments, R⁵ is optionally substituted heterocyclylalkyl. In certain embodiments, R⁵ is optionally substituted alkenyl. In certain embodiments, R⁵ is optionally substituted alkynyl. In certain

embodiments, R⁵ is optionally substituted carbocyclyl. In certain embodiments, R⁵ is optionally substituted aryl. In certain embodiments, R⁵ is optionally substituted heterocyclyl. In certain embodiments, R⁵ is optionally substituted heteroaryl.

[00193] In certain embodiments, R⁵ is optionally substituted carbocyclyl. In certain embodiments, R⁵ is optionally substituted C_3-6 carbocyclyl. In certain embodiments, R⁵ is optionally substituted cyclopentyl. In certain embodiments, R⁵ is unsubstituted cyclopentyl. In certain embodiments, R⁵ is of the formula:

, wherein m, n, and R⁷ are as

defined herein. In certain embodiments, R⁵ is of the formula:

. In certain embodiments, R⁵ is of the formula:

In certain embodiments, R⁵ is of the formula:

. In certain embodiments, R⁵ is of the formula:

. In certain embodiments, R⁵ is

of the formula:

. In certain embodiments, R⁵ is of the formula: . In certain

embodiments, R⁵ is of the formula: .

[00194] In certain embodiments, R⁵ is optionally substituted aralkyl. In certain embodiments, R⁵ is optionally substituted–C_1-6alkyl-aryl. In certain embodiments, R⁵ is optionally substituted–C_1-6alkyl-phenyl. In certain embodiments, R⁵ is substituted–C_1-6alkyl-phenyl. In certain embodiments, R⁵ is unsubstituted–C_1-6alkyl-phenyl. In certain embodiments, R⁵ is optionally substituted–C_1-3alkyl-aryl. In certain embodiments, R⁵ is optionally substituted– C_1-3alkyl-phenyl. In certain embodiments, R⁵ is substituted–C_1-3alkyl-phenyl. In certain embodiments, R⁵ is unsubstituted–C_1-3alkyl-phenyl. In certain embodiments, R⁵ is optionally substituted–CH₂-aryl. In certain embodiments, R⁵ is optionally substituted–CH₂-phenyl (i.e., optionally substituted benzyl). In certain embodiments, R⁵ is substituted–CH₂-phenyl (i.e., substituted benzyl). In certain embodiments, R⁵ is unsubstituted–CH₂-phenyl (i.e.,

unsubstituted benzyl). In certain embodiments, R⁵ is of the formula: , wherein m, n, and R⁷ are as defined herein. In certain embodiments, R⁵ is of the formula:

. In certain embodiments, R⁵ is of the formula: (i.e., unsubstituted

benzyl). In certain embodiments, R⁵ is of the formula: . In certain embodiments, R⁵ is of the formula:

. In certain embodiments, R⁵ is of the

formula: . In certain embodiments, R⁵ is of the formula: In

certain embodiments, R⁵ is of the formula: . In certain embodiments, R⁵ is of

the formula: . In certain embodiments, R⁵ is of the formula: .

In certain embodiments, R⁵ is of the formula: . Group R⁶

[00195] As generally defined herein, R⁶ is optionally substituted aralkyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In certain embodiments, R⁶ is optionally substituted aralkyl. In certain embodiments, R⁶ is optionally substituted carbocyclylalkyl. In certain

embodiments, R⁶ is optionally substituted heteroaralkyl. In certain embodiments, R⁶ is optionally substituted heterocyclylalkyl. In certain embodiments, R⁶ is optionally substituted alkenyl. In certain embodiments, R⁶ is optionally substituted alkynyl. In certain

embodiments, R⁶ is optionally substituted carbocyclyl. In certain embodiments, R⁶ is optionally substituted aryl. In certain embodiments, R⁶ is optionally substituted heterocyclyl. In certain embodiments, R⁶ is optionally substituted heteroaryl.

[00196] In certain embodiments, R⁶ is optionally substituted aralkyl. In certain embodiments, R⁶ is optionally substituted–C_1-6alkyl-aryl. In certain embodiments, R⁶ is optionally substituted–C_1-6alkyl-phenyl. In certain embodiments, R⁶ is substituted–C_1-6alkyl-phenyl. In certain embodiments, R⁶ is unsubstituted–C_1-6alkyl-phenyl. In certain embodiments, R⁶ is optionally substituted–C_1-3alkyl-aryl. In certain embodiments, R⁶ is optionally substituted– C_1-3alkyl-phenyl. In certain embodiments, R⁶ is substituted–C_1-3alkyl-phenyl. In certain embodiments, R⁶ is unsubstituted–C_1-3alkyl-phenyl. In certain embodiments, R⁶ is optionally substituted–CH₂-aryl. In certain embodiments, R⁶ is optionally substituted–CH₂-phenyl (i.e., optionally substituted benzyl). In certain embodiments, R⁶ is unsubstituted–CH₂-phenyl (i.e., unsubstituted benzyl). In certain embodiments, R⁶ is optionally substituted–CH₂CH₂-aryl. In certain embodiments, R⁶ is optionally substituted–CH₂CH₂-phenyl. In certain embodiments, 6 is substituted–CH₂CH₂-phenyl. In certain embodiments, R⁶ is of the formula:

, wherein m, n, and R⁷ are as defined herein. In certain embodiments, R⁶ is

of the formula: . In certain embodiments, R⁶ is of the formula:

(i.e., unsubstituted benzyl). In certain embodiments, R⁶ is of the formula: . In

certain embodiments, R⁶ is of the formula: . In certain embodiments, R⁶ is of

the formula:

. In certain embodiments, R is of the formula: .

In certain embodiments, R⁶ is of the formula: . In certain embodiments, R⁶ is

of the formula: . In certain embodiments, R⁶ is of the formula: .

In certain embodiments R⁶ is of the formula: . In certain embodiments, R⁶ is of

the formula:

. In certain embodiments, R is of the formula: . In certain embodiments, R⁶ is of the formula:

. In certain embodiments, R⁶ is

of the formula: .

[00197] In certain embodiments, R⁶ is optionally substituted carbocyclyl. In certain embodiments, R⁶ is optionally substituted C_3-6 carbocyclyl. In certain embodiments, R⁶ is optionally substituted cyclopentyl. In certain embodiments, R⁶ is unsubstituted cyclopentyl.

In certain embodiments, R⁶ is of the formula: , wherein m, n, and R⁷ are as

defined herein. In certain embodiments, R⁶ is of the formula:

. In certain embodiments, R⁶ is of the formula:

. In cert in embodiments, R⁶ is of the formula:

. In certain embodiments, R⁶ is

of the formula:

. In certain embodiments, R⁶ is of the formula: . In certain

embodiments, R⁶ is of the formula:

[00198] In certain embodiments, R⁶ is optionally substituted heterocyclylalkyl. In certain embodiments, R⁶ is optionally substituted–C_1-6 alkyl-heterocyclyl. In certain embodiments, R⁶ is optionally substituted–C_1-6 alkyl-heterocyclyl, wherein the heterocyclyl group is five- membered heterocyclyl. In certain embodiments, R⁶ is optionally substituted–C_1-6 alkyl- lactam. In certain embodiments, R⁶ is optionally substituted–C_1-6 alkyl-γ-lactam. In certain embodiments, R⁶ is unsubstituted–C_1-6 alkyl-γ-lactam. In certain embodiments, R⁶ is optionally substituted–C_1-3 alkyl-heterocyclyl. In certain embodiments, R⁶ is optionally substituted–C_1-3 alkyl-heterocyclyl, wherein the heterocyclyl group is five-membered heterocyclyl. In certain embodiments, R⁶ is optionally substituted–C_1-3 alkyl-lactam. In certain embodiments, R⁶ is optionally substituted–C_1-3 alkyl-γ-lactam. In certain embodiments, R⁶ is unsubstituted–C_1-3 alkyl-γ-lactam. In certain embodiments, R⁶ is optionally substituted–CH₂CH₂CH₂-heterocyclyl. In certain embodiments, R⁶ is optionally substituted–CH₂CH₂CH₂-heterocyclyl, wherein the heterocyclyl group is five-membered heterocyclyl. In certain embodiments, R⁶ is optionally substituted–CH₂CH₂CH₂-lactam. In certain embodiments, R⁶ is optionally substituted–CH₂CH₂CH₂-γ-lactam. In certain embodiment R⁶ is unsubstituted–CH₂CH₂CH₂-γ-lactam. In certain embodiments, R⁶ is of

the formula:

, wherein m, n, and R⁷ are as defined herein. In certain

embodiments, R⁶ is of the formula:

, wherein m, n, R^N, and R⁷ are as defined

herein. In certain embodiments, R⁶ is of the formula: . In certain

embodiments, R⁶ is of the formula: . In certain embodiments, R⁶ is of the

formula:

In certain embodiments, R is of the formula: Group R⁷, R⁸, m, and n

[00199] As generally defined herein, each instance of R⁷ is independently each instance of R⁷ is independently hydrogen, halogen,–CN,–SCN,–NO₂,–N₃, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl,–OR^a,–N(R^b)₂, or–SR^c, wherein R^a, R^b, and R^c are as defined herein. In certain embodiments, at least one instance of R⁷ is hydrogen. In certain embodiments, at least one instance of R⁷ halogen. In certain embodiments, at least one instance of R⁷ is–CN. In certain embodiments, at least one instance of R⁷ is–SCN. In certain embodiments, at least one instance of R⁷ is–NO₂. In certain embodiments, at least one instance of R⁷ is–N₃. In certain embodiments, at least one instance of R⁷ is optionally substituted alkyl. In certain embodiments, at least one instance of R⁷ is optionally substituted alkenyl. In certain embodiments, at least one instance of R⁷ is optionally substituted alkynyl. In certain embodiments, at least one instance of R⁷ is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R⁷ is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R⁷ is optionally substituted aryl. In certain embodiments, at least one instance of R⁷ is optionally substituted heteroaryl. In certain embodiments, at least one instance of R⁷ is optionally substituted acyl. In certain

embodiments, at least one instance of R⁷ is–OR^a. In certain embodiments, at least one instance of R⁷ is–N(R^b)₂. In certain embodiments, at least one instance of R⁷ is–SR^c.

[00200] As generally defined herein, each instance of R^a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group;

[00201] As generally defined herein, each instance of R^b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R^b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl.As generally defined herein, each instance of R^c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group.

[00202] In certain embodiments, at least one instance of R⁷ is optionally substituted alkyl. In certain embodiments, R⁷ is optionally substituted C_1-6 alkyl. In certain embodiments, R⁷ is substituted C_1-6 alkyl. In certain embodiments, R⁷ is optionally substituted C_1-3 alkyl. In certain embodiments, R⁷ is substituted C_1-3 alkyl. In certain embodiments, R⁷ is perhaloalkyl. In certain embodiments, R⁷ is perfluoroalkyl. In certain embodiments, R⁷ is trihalomethyl. In certain embodiments, R⁷ is trifluoromethyl. In certain embodiments, R⁷ is–CF₃.

[00203] In certain embodiments, at least one instance of R⁷ is halogen. In certain

embodiments, R⁷ is–F. In certain embodiments, R⁷ is–Br. In certain embodiments, R⁷ is–I. In certain embodiments, R⁷ is–Cl.

[00204] As generally defined herein, each instance of R⁸ is independently hydrogen or optionally substituted alkyl. In certain embodiments, R⁸ is hydrogen. In certain embodiments, R⁸ is optionally substituted C_1-6 alkyl. In certain embodiments, R⁸ is unsubstituted C_1-6 alkyl. In certain embodiments, R⁸ is optionally substituted C_1-3 alkyl. In certain embodiments, R⁸ is unsubstituted C_1-3 alkyl. In certain embodiments, R⁸ is methyl.

[00205] As generally defined herein, each instance of n is independently 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6.

[00206] As generally defined herein, each instance of m is independently 0, 1, 2, 3, 4, or 5. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. Groups R^N and R^S

[00207] As generally defined herein, each instance of R^N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group, or optionally two R^N are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain

embodiments, at least one instance of R^N is hydrogen. In certain embodiments, at least one instance of R^N is optionally substituted alkyl. In certain embodiments, at least one instance of R^N is optionally substituted alkenyl. In certain embodiments, at least one instance of R^N is optionally substituted alkynyl. In certain embodiments, at least one instance of R^N is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R^N is optionally substituted aryl. In certain embodiments, at least one instance of R^N is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R^N is optionally substituted heteroaryl. In certain embodiments, at least one instance of R^N is optionally substituted acyl. In certain embodiments, at least one instance of R^N is a nitrogen protecting group. In certain embodiments, two R^N are taken together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, two R^N are taken together with the intervening atoms to form optionally substituted heteroaryl. In certain embodiments, each instance of R^N is hydrogen. In certain embodiments, at least one instance of R^N is Boc (tert- butyloxycarbonyl).

[00208] As generally defined herein, R^S is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group. In certain

embodiments, R^S is hydrogen. In certain embodiments, R^S is optionally substituted alkyl. In certain embodiments, R^S is optionally substituted alkenyl. In certain embodiments, R^S is optionally substituted alkynyl. In certain embodiments, R^S is optionally substituted carbocyclyl. In certain embodiments, R^S is optionally substituted aryl. In certain

embodiments, R^S is optionally substituted heterocyclyl. In certain embodiments, R^S is optionally substituted heterocyclyl. In certain embodiments, R^S is optionally substituted acyl. In certain embodiments, R^S is a sulfur protecting group. In certain embodiments, R^S is trityl (Trt) (i.e., triphenylmethyl or–CPh₃). [00209] Compounds of Formula (I) include the groups R^S, R^N, R¹, R², R³, R⁴, R⁵, and R⁶. In certain embodiments, R^S and R^N are as defined herein; R¹ is optionally substituted

heteroaralkyl; R² is optionally substituted alkenyl; R³ is optionally substituted heteroaralkyl; R⁴ is optionally substituted heterocyclylalkyl; R⁵ is optionally substituted carbocyclyl; and R⁶ is optionally substituted aralkyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted heteroaralkyl; R² is optionally substituted alkenyl; R³ is optionally substituted heteroaralkyl; R⁴ is optionally substituted heterocyclylalkyl; R⁵ is optionally substituted carbocyclyl; and R⁶ is optionally substituted aralkyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted– C_1-6 alkyl-heteroaryl; R² is optionally substituted C_2-6 alkenyl; R³ is optionally substituted– C_1-6 alkyl-heteroaryl; R⁴ is optionally substituted–C_1-6 alkyl-heterocyclyl; R⁵ is optionally substituted C_3-6 carbocyclyl; and R⁶ is optionally substituted–C_1-6 alkyl-aryl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted– C_1-6 alkyl-C_5-6 heteroaryl; R² is optionally substituted C_2-6 alkenyl; R³ is optionally substituted–C_1-6 alkyl-C_5-6 heteroaryl; R⁴ is optionally substituted–C_1-6 alkyl-heterocyclyl, wherein the heterocyclyl group is 3-6 membered heterocyclyl; R⁵ is optionally substituted C_3- ₆ carbocyclyl; and R⁶ is optionally substituted–C_1-6 alkyl-C₆ aryl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–C_1-3 alkyl-C₅ heteroaryl; R² is optionally substituted C_2-4 alkenyl; R³ is optionally substituted–C_1-3 alkyl-C₅ heteroaryl; R⁴ is optionally substituted–C_1-3 alkyl-heterocyclyl, wherein the heterocyclyl group is 5-membered heterocyclyl; R⁵ is optionally substituted C_5-6 carbocyclyl; and R⁶ is optionally substituted–C_1-3 alkyl-C₆ aryl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–C_1-3 alkyl-furanyl; R² is optionally substituted C_2-4 alkenyl; R³ is optionally substituted–C_1-3 alkyl-furanyl; R⁴ is optionally substituted–C_1-3 alkyl-heterocyclyl, wherein the heterocyclyl group is tetrahydrofuran; R⁵ is optionally substituted cyclopentyl; and R⁶ is optionally substituted–C_1-3 alkyl-phenyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–CH₂-furanyl; R² is optionally substituted allyl; R³ is optionally substituted–CH₂- furanyl; R⁴ is optionally substituted–CH₂-tetrahydrofuranyl; R⁵ is optionally substituted cyclopentyl; and R⁶ is optionally substituted–CH₂CH₂-phenyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is unsubstituted–CH₂-furanyl; R² is unsubstituted allyl; R³ is unsubstituted–CH₂-furanyl; R⁴ is unsubstituted–CH₂- tetrahydrofuranyl; R⁵ is unsubstituted cyclopentyl; and R⁶ is–CH₂CH₂-phenyl, wherein the phenyl group is substituted with a halogen (e.g., chlorine).

[00210] In certain embodiments, R^S and R^N are as defined herein; R¹ is optionally substituted aralkyl; R² is optionally substituted alkenyl; R³ is optionally substituted heteroaralkyl; R⁴ is optionally substituted carbocyclyl; R⁵ is optionally substituted aralkyl; and R⁶ is optionally substituted aralkyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted aralkyl; R² is optionally substituted alkenyl; R³ is optionally substituted heteroaralkyl; R⁴ is optionally substituted carbocyclyl; R⁵ is optionally substituted aralkyl; and R⁶ is optionally substituted aralkyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–C_1-6 alkyl-aryl; R² is optionally substituted C_2-6 alkenyl; R³ is optionally substituted–C_1-6 alkyl-heteroaryl; R⁴ is optionally substituted C_3-6 carbocyclyl; R⁵ is optionally substituted–C_1-6 alkyl-aryl; and R⁶ is optionally substituted–C_1-6 alkyl-aryl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–C_1-6 alkyl-C₆ aryl; R² is optionally substituted C_2-6 alkenyl; R³ is optionally substituted–C_1-6 alkyl-C_5-6 heteroaryl; R⁴ is optionally substituted C_3-6 carbocyclyl; R⁵ is optionally substituted–C_1-6 alkyl-C₆ aryl; and R⁶ is optionally substituted–C_1-6 alkyl-C₆ aryl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–C_1-3 alkyl-phenyl; R² is optionally substituted C_2-4 alkenyl; R³ is optionally substituted–C_1-3 alkyl-C₅ heteroaryl; R⁴ is optionally substituted C_5-6 carbocyclyl; R⁵ is optionally substituted–C_1-3 alkyl-phenyl; and R⁶ is optionally substituted– C_1-3 alkyl-phenyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–C_1-3 alkyl-phenyl; R² is optionally substituted C_2-4 alkenyl; R³ is optionally substituted–C_1-3 alkyl-furanyl; R⁴ is optionally substituted C_5-6 carbocyclyl; R⁵ is optionally substituted–C_1-3 alkyl-phenyl; and R⁶ is optionally substituted–C_1-3 alkyl-phenyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–CH(CH₃)-phenyl; R² is optionally substituted allyl; R³ is optionally substituted– CH₂-furanyl; R⁴ is optionally substituted cyclopentyl; R⁵ is optionally substituted–CH₂- phenyl (i.e., optionally substituted benzyl); and R⁶ is optionally substituted–CH₂-phenyl (i.e., optionally substituted benzyl). In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is unsubstituted–CH(CH₃)-phenyl; R² is unsubstituted allyl; R³ is unsubstituted –CH₂-furanyl; R⁴ is unsubstituted cyclopentyl; R⁵ is substituted–CH₂-phenyl (i.e., substituted benzyl), wherein the phenyl group is substituted with trihalomethyl (e.g.,–CF₃); and R⁶ is unsubstituted–CH₂-phenyl (i.e., unsubstituted benzyl).

[00211] In certain embodiments, R^S and R^N are as defined herein; R¹ is optionally substituted alkenyl; R² is optionally substituted aralkyl; R³ is optionally substituted aralkyl; R⁴ is optionally substituted carbocyclyl; R⁵ is optionally substituted aralkyl; and R⁶ is optionally substituted carbocyclyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted alkenyl; R² is optionally substituted aralkyl; R³ is optionally substituted aralkyl; R⁴ is optionally substituted carbocyclyl; R⁵ is optionally substituted aralkyl; and R⁶ is optionally substituted carbocyclyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted C_2-6 alkenyl; R² is optionally substituted–C_1-6 alkyl-aryl; R³ is optionally substituted–C_1-6 alkyl-aryl; R⁴ is optionally substituted C_3-6 carbocyclyl; R⁵ is optionally substituted–C_1-6 alkyl-aryl; and R⁶ is optionally substituted C_3-6 carbocyclyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted C_2-6 alkenyl; R² is optionally substituted–C_1-6 alkyl-C₆ aryl; R³ is optionally substituted–C_1-6 alkyl-C₆ aryl; R⁴ is optionally substituted C_3-6 carbocyclyl; R⁵ is optionally substituted–C_1-6 alkyl-C₆ aryl; and R⁶ is optionally substituted C_3-6 carbocyclyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted C_2-4 alkenyl; R² is optionally substituted–C_1-3 alkyl-phenyl; R³ is optionally substituted–C_1-3 alkyl-phenyl; R⁴ is optionally substituted C_5-6 carbocyclyl; R⁵ is optionally substituted–C_1-3 alkyl-phenyl; and R⁶ is optionally substituted C_5-6 carbocyclyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted allyl; R² is optionally substituted– CH(CH₃)-phenyl; R³ is optionally substituted–CH₂-phenyl (i.e., optionally substituted benzyl); R⁴ is optionally substituted cyclopentyl; R⁵ is optionally substituted–CH₂-phenyl (i.e., optionally substituted benzyl); and R⁶ is optionally substituted cyclopentyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is unsubstituted allyl; R² is unsubstituted–CH(CH₃)-phenyl; R³ is unsubstituted–CH₂-phenyl (i.e., unsubstituted benzyl); R⁴ is unsubstituted cyclopentyl; R⁵ is unsubstituted–CH₂-phenyl (i.e., unsubstituted benzyl); and R⁶ is unsubstituted cyclopentyl.

[00212] Compounds of Formula (I) include the groups R^S, R^N, R¹, R², R³, R⁴, R⁵, and R⁶. In certain embodiments, R^S and R^N are as defined herein; R¹ is optionally substituted

heterocyclylalkyl; R² is optionally substituted heterocyclylalkyl; R³ is optionally substituted alkenyl; R⁴ is optionally substituted aralkyl; R⁵ is optionally substituted aralkyl; and R⁶ is optionally substituted heterocyclylalkyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted heterocyclylalkyl; R² is optionally substituted heterocyclylalkyl; R³ is optionally substituted alkenyl; R⁴ is optionally substituted aralkyl; R⁵ is optionally substituted aralkyl; and R⁶ is optionally substituted heterocyclylalkyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–C_1-6 alkyl-heterocyclyl; R² is optionally substituted–C_1-6 alkyl-heterocyclyl; R³ is optionally substituted C_2-6 alkenyl; R⁴ is optionally substituted–C_1-6 alkyl-aryl; R⁵ is optionally substituted–C_1-6 alkyl-aryl; and R⁶ is optionally substituted–C_1-6 alkyl- heterocyclyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–C_1-6 alkyl-heterocyclyl, wherein the heterocyclyl group is 3- to 6- membered heterocyclyl; R² is optionally substituted–C_1-6 alkyl-heterocyclyl, wherein the heterocyclyl group is 3- to 6-membered heterocyclyl; R³ is optionally substituted C_2-6 alkenyl; R⁴ is optionally substituted–C_1-6 alkyl-C₆ aryl; R⁵ is optionally substituted–C_1-6 alkyl-C₆ aryl; and R⁶ is optionally substituted–C_1-6 alkyl-heterocyclyl, wherein the heterocyclyl group is 3- to 6-membered heterocyclyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–C_1-3 alkyl- heterocyclyl, wherein the heterocyclyl group is 5- to 6-membered heterocyclyl; R² is optionally substituted–C_1-3 alkyl-heterocyclyl, wherein the heterocyclyl group is 5- to 6- membered heterocyclyl; R³ is optionally substituted C_2-4 alkenyl; R⁴ is optionally substituted –C_1-3 alkyl-phenyl; R⁵ is optionally substituted–C_1-3 alkyl-phenyl; and R⁶ is optionally substituted–C_1-3 alkyl-heterocyclyl, wherein the heterocyclyl group is 5- to 6-membered heterocyclyl. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–C_1-3 alkyl-heterocyclyl, wherein the heterocyclyl group is a lactam; R² is optionally substituted–C_1-3 alkyl-heterocyclyl, wherein the heterocyclyl group is tetrahydrofuran; R³ is optionally substituted C_2-4 alkenyl; R⁴ is optionally substituted–C_1-3 alkyl-phenyl; R⁵ is optionally substituted–C_1-3 alkyl-phenyl; and R⁶ is optionally substituted –C_1-3 alkyl-heterocyclyl, wherein the heterocyclyl group is a lactam. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–C_1-3 alkyl-γ- lactam; R² is optionally substituted–C_1-3 alkyl-tetrahydrofuranyl; R³ is optionally substituted C_2-4 alkenyl; R⁴ is optionally substituted–C_1-3 alkyl-phenyl; R⁵ is optionally substituted–C_1-3 alkyl-phenyl; and R⁶ is optionally substituted–C_1-3 alkyl-γ-lactam. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is optionally substituted–CH₂CH₂CH₂- γ-lactam; R² is optionally substituted–CH₂-tetrahydrofuranyl; R³ is optionally substituted allyl; R⁴ is optionally substituted–CH(CH₃)-phenyl; R⁵ is optionally substituted–CH₂-phenyl (i.e., optionally substituted benzyl); and R⁶ is optionally substituted–CH₂CH₂CH₂-γ-lactam. In certain embodiments, R^S is hydrogen; each instance of R^N is hydrogen; R¹ is unsubstituted –CH₂CH₂CH₂-γ-lactam; R² is unsubstituted–CH₂-tetrahydrofuranyl; R³ is unsubstituted allyl; R⁴ is unsubstituted–CH(CH₃)-phenyl; R⁵ is substituted–CH₂-phenyl (i.e., substituted benzyl), wherein the phenyl group is substituted with trihalomethyl (e.g.,–CF₃); and R⁶ is unsubstituted–CH₂CH₂CH₂-γ-lactam. Pharmaceutical Compositions, Kits, and Administration

[00213] The present invention provides pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, a pharmaceutical composition described herein comprises a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.

[00214] In certain embodiments, a compound described herein, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, is provided in an effective amount in the

pharmaceutical composition. In certain embodiments, the effective amount is a

therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. [00215] In certain embodiments, the effective amount is an amount effective for treating a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a genetic disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a genetic disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a disease associated with angiogenesis in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a disease associated with angiogenesis in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating an inflammatory disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing an inflammatory disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a cardiovascular disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a cardiovascular disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a liver disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a liver disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a spleen disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a spleen disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a pulmonary disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a pulmonary disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a painful condition subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a painful condition in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a psychiatric disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a psychiatric disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating an autoimmune disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing an autoimmune disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating an infectious disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing an infectious disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a gastrointestinal disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a gastrointestinal disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating an endocrine disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing an endocrine disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease (e.g., proliferative disease, neurological disease, gastrointestinal disorder) in a subject in need thereof.

[00216] In certain embodiments, the effective amount is an amount effective for treating acute radiation syndrome (ARS) in a subject in need thereof. In certain embodiments, the effective amount is effective for treating radiation-induced gastrointestinal syndrome in a subject in need thereof.

[00217] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the“active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.

[00218] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A“unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage. [00219] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.

[00220] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[00221] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[00222] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[00223] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween^® 20), polyoxyethylene sorbitan (Tween^® 60), polyoxyethylene sorbitan monooleate (Tween^® 80), sorbitan monopalmitate (Span^® 40), sorbitan monostearate (Span^® 60), sorbitan tristearate (Span^® 65), glyceryl monooleate, sorbitan monooleate (Span^® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj^® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol^®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor^®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij^® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic^® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

[00224] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,

ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl

methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum^®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

[00225] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[00226] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium

metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[00227] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[00228] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[00229] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[00230] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[00231] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT),

ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant^® Plus, Phenonip^®, methylparaben, Germall^® 115, Germaben^® II, Neolone^®, Kathon^®, and Euxyl^®.

[00232] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[00233] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[00234] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[00235] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor^®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[00236] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[00237] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[00238] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[00239] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d)

disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[00240] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[00241] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.

Examples of encapsulating agents which can be used include polymeric substances and waxes.

[00242] Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

[00243] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[00244] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[00245] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for

administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling

solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[00246] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[00247] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[00248] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[00249] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

[00250] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical

compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

[00251] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[00252] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial,

intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct

administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[00253] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of

administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 µg and 1 µg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[00254] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[00255] A compound or composition, as described herein, can be administered in

combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in activating a FGFR in a subject or a cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.

[00256] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents.

Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., proliferative disease, neurological disease, gastrointestinal disease). Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[00257] The additional pharmaceutical agents include, but are not limited to, anti- proliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, and pain-relieving agents. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative or anti-cancer agent.

[00258] As generally defined herein,“anti-proliferative agents” and“anti-cancer agents” encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents. Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g. HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)). Exemplary

chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine

(CCNU)), alkylsulphonates (e.g. busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide), platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g.

paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel

(ABRAXANE), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate;

docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), anti- metabolites, DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g.5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g. cytarabine (ara C), cytosine arabinoside, and

fludarabine), purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g.1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca²⁺ ATPase inhibitors (e.g. thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN^TM, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib

(TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab

(CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK^TM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,, aminopterin, and hexamethyl melamine.

[00259] In certain embodiments, the compounds or pharmaceutical compositions described herein can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.

[00260] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a

pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[00261] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, the kits are useful for activating a FGFR in a subject in need thereof.

[00262] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease or condition in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease or condition in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease or condition in a subject in need thereof. In certain embodiments, the kits and instructions provide for activing a FGFR in a subject or a cell. In certain embodiments, the kits and instructions provide for treating acute radiation syndrome (ARS) in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition. Methods of Treatment and Use

[00263] The novel compounds disclosed herein act as agonists or antagonists of fibroblast growth family receptors (FGFRs), and are therefore useful in the treatment and/or prevention of diseases. Thus, the present invention provides methods of using the compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co- crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the treatment and/or prevention of diseases or conditions.

[00264] In one aspect, the present invention provides a method for treating a disease or condition in a subject in need thereof, the method comprising: administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[00265] Any disease or condition can be treated and/or prevented with a compound or composition provided herein. In certain embodiments, the disease or conditions is a proliferative disease, genetic disease, disease associated with angiogenesis, inflammatory disease, cardiovascular disease, hepatic disease, spleen disease, pulmonary disease, painful condition, hematological disease, neurological disease, psychiatric disorder, autoimmune disease, infectious disease, metabolic disease, gastrointestinal disorder, or endocrine disease. In certain embodiments, the disease is a genetic disease. In certain embodiments, the disease is a disease associated with angiogenesis. In certain embodiments, the disease is a

inflammatory disease. In certain embodiments, the disease is a cardiovascular disease. In certain embodiments, the disease is a hepatic disease. In certain embodiments, the disease is a spleen disease. In certain embodiments, the disease is a pulmonary disease. In certain embodiments, the disorder is a painful condition. In certain embodiments, the disease is a hematological disease. In certain embodiments, the disease is a neurological disease. In certain embodiments, the disorder is a psychiatric disorder. In certain embodiments, the disease is a autoimmune disease. In certain embodiments, the disease is a infectious disease. In certain embodiments, the disease is a metabolic disease. In certain embodiments, the disorder is a gastrointestinal disorder. In certain embodiments, the gastrointestinal disorder is acute gastrointestinal syndrome (AGS). In certain embodiments the disease is a endocrine disease. In certain embodiments, the disease is a proliferative disease. In certain

embodiments, the disease is cancer. In certain embodiments, the disease is breast cancer. In certain embodiments, the disease is lung cancer.

[00266] In certain embodiments, the disease is a condition associated with radiation exposure. In certain embodiments, the disease is acute radiation syndrome (ARS). In certain embodiments, the disease is radiation-induced gastrointestinal syndrome. In certain embodiments, the ARS is due to ionizing radiation (IR).

[00267] In certain embodiments, the disease or condition to be treated and/or prevented is disease associated with a fibroblast growth factor receptor (FGFR). In certain embodiments, the disease or condition is associated with abberant activity of an FGFR. In certain embodiments, the abberant activity is decreased activity. In certain embodiments, the abberant activity is increased activity. In certain embodiments, the disease is associated with FGFR signaling or an FGFR pathway. In certain embodiments, the FGFR is selected from the group consisting of FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, FGFRL1, and FGFR6. In certain embodiments, the FGFR is FGFR1. In certain embodiments, the FGFR is FGFR1α. In certain embodiments, the disease to be treated and/or prevented is a disease associated with decreased activity of a FGFR. In certain embodiments, the disease to be treated and/or prevented is a disease associated with decreased activity of FGFR1. In certain embodiments, the disease to be treated and/or prevented is a disease associated with decreased activity of FGFR1α. In certain embodiments, the disease is a disease for which activating FGFR is beneficial for treatment (e.g., proliferative diseases such as cancer, acute radiation syndrome (ARS)).

[00268] Also provided herein is a method for mitigating the effects of radiation exposure (e.g., radiation damage) in a subject, the method comprising administering to the subject an effective amount compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[00269] In certain embodiments, the methods described herein comprise administering to a subject a therapeutically effective amount compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, a therapeutically effective amount is an amount sufficient for activating a FGFR in a subject. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting a FGFR in a subject. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease associated with a FGFR in a subject. In certain embodiments, the disease is associated with FGFR signaling. In certain embodiments, the disease is associated with a FGFR pathway. In certain embodiments, a therapeutically effective amount is an amount sufficient for activating a FGFR and treating a disease associated with decreased activity of the FGFR. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting a FGFR and treating a disease associated with increased activity of the FGFR. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating acute radiation syndrome (ARS) in a subject. In certain embodiments, the therapeutically effective amount is an amount sufficient for treating radiation-induced gastrointestinal syndrome.

[00270] In certain embodiments, the methods described herein comprise administering to a subject a prophylactically effective amount compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, a prophylactically effective amount is an amount sufficient for activating a FGFR. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting a FGFR. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease or conditions associated with a FGFR. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease or conditions associated with FGFR signaling. In certain embodiments, a

prophylactically effective amount is an amount sufficient for preventing a disease or conditions associated with a FGFR pathway. In certain embodiments, a prophylactically effective amount is an amount sufficient for activating a FGFR and for preventing a diease or condition associated with a FGFR.

[00271] In certain embodiments, the subject being treated is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent, dog, or non-human primate. In certain embodiments, the subject is a non-human transgenic animal, such as a transgenic mouse or transgenic pig.

[00272] In yet another aspect, the present invention provides uses of compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrug thereofs, or pharmaceutical compositions thereof, in the manufacture of medicaments for the treatment and/or prevention of diseases.

[00273] In yet another aspect, the present invention provides uses of compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrug thereofs, or pharmaceutical compositions thereof, in the manufacture of medicaments for the mitigation of effects of radiation exposure (e.g., radiation damage) in a subject.

[00274] The novel compounds provided herein are effective agonists of fibroblast growth factor receptors. Therefore, the present invention provides methods for activating a fibroblast growth factor receptor using a compound or composition described herein. In certain embodiments, the method for activating a FGFR comprises contacting the FGFR with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the FGFR to be actrvated is exhibiting aberrant activity. In certain embodiments, the activity is decreased activity. In certain embodiments, the FGFR is selected from the group consisting of FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, FGFRL1, and FGFR6. In certain embodiments, the FGFR is FGFR1. In certain embodiments, the FGFR is FGFR1α. In certain embodiments, the present invention provides a method for activating FGFR1α, the method comprising contacting FGFR1α with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, activationg of FGFR without a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, leads to activation of downstream signaling pathways such as increased phosphorylation of Akt and ERK proteins. In certain embodiments, the method of activating an FGFR as described herein results in elevated expression levels of p-Akt and p-ERK. [00275] The novel compounds provided herein can be effective antagonists of fibroblast growth factor receptors. Therefore, the present invention provides methods for inhibiting a fibroblast growth factor receptor using a compound or composition described herein. In certain embodiments, the method for inhibiting a FGFR comprises contacting the FGFR with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the FGFR to be inhibited is exhibiting aberrant activity (i.e., increased activity). In certain embodiments, the FGFR is selected from the group consisting of FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, FGFRL1, and FGFR6. In certain embodiments, the FGFR is FGFR1. In certain embodiments, the FGFR is FGFR1α.

[00276] The invention also provides uses of compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrug thereofs, and pharmaceutical composition thereof, for the manufacture of medicaments for activating or inhibiting an FGFR in a subject.

[00277] In certain embodiments, the provided methods and uses comprise contacting a cell with an effective amount of a compound of Formula (I), or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition, as described herein. The cell may be contacted in vitro or in vivo. In certain embodiments, the contacting is in vivo. In certain embodiments, the contacting is in vitro. In certain embodiments, the cell is a cancer cell. In certain

embodiments, the cell is a human cancer cell. In certain embodiments, the cell is a breast cancer cell. In certain embodiments, the cell is a lung cancer cell.

[00278] In certain embodiments, the methods and uses described herein include contacting a biological sample with an effective amount of a compound of Formula (I), or a

pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the step of contacting the biological sample occurs in vitro. In certain embodiments, the step of contacting the biological sample occurs in vivo. EXAMPLES

[00279] These and other aspects of the present invention will be further appreciated upon consideration of the following Examples, which are intended to illustrate certain particular embodiments of the invention but are not intended to limit its scope. Discovery of Peptoid Agonists of Fibroblast Growth Factor Receptors

Preparation of OBOC peptoid library

[00280] For the discovery of novel peptoid agonists of FGFR, a linear one-bead-one- compound (OBOC) peptoid library was constructed on 500 µm Rink Amide beads (see Figure 2). Briefly, Rink Amide beads were first attached with a triphenylmethyl (Trt)- protected cysteine residue, which was utilized to spot the peptoids onto maleimide-modified glass slides in the following procedure (see, e.g., Astle et al.“Seamless bead to microarray screening: rapid identification of the highest affinity protein ligands from large combinatorial libraries”, Chem. Biol.2010, 17, 38-45). Next, an N-lysine-N-lysine (Nlys-Nlys) linker was introduced as the invariant region, which provides a positive charge to aid in ionization in the mass spectrometer. Following the invariant linker, split-and-pool synthesis using the standard sub-monomer method for peptoids was employed to construct the variable region of the OBOC library (see, e.g., Alluri et al.“Isolation of protein ligands from large peptoid libraries”, J. Am. Chem. Soc.2003, 125, 13995-14004). The split-and-pool protocol ensures that each bead expresses only one compound and each compound exhibits equal distribution in the library. The variable region was diversified at six positions using random substitutes (R groups, i.e., R¹, R², R³, R⁴, R⁵, and R⁶ of Formula (I)) derived from 10 different primary amines (see Figure 2), affording a library with a theoretical diversity of one million (10⁶) compounds. The quality of the constructed library was tested by cleaving 30 beads randomly selected from the library and sequencing the cleaved products using mass spectrometry (MS/MS). In each case, a single and strong molecular ion was observed, and the molecules could be sequenced unambiguously by MS/MS. For compound 1 (Hit 1): Exact mass: 1208.6; [M + H]⁺ found: 1209.6. For compound 2 (Hit 2): Exact mass: 1258.6; [M + H]⁺ found:

1259.5. For compound 3 (Hit 3): Exact mass: 1178.7; [M + H]⁺ found: 1179.7. For compound 4 (Hit 4): Exact mass: 1354.7; [M + H]⁺ found: 1355.7. Microarray-based screening targeting FGFR

[00281] The procedure of microarray-based screening of the OBOC library targeting FGFR is illustrated in Figure 3. Each bead in the library was isolated into a single well of a 96-well plate and treated with cleavage cocktail to release the peptoid from each bead. Both the triphenylmethyl (Trt) and tert-butoxycarbonyl (Boc) protecting groups were also removed simultaneously under these conditions. The cleavage mixture was evaporated and redissolved in dimethyl sulfoxide (DMSO). Half of the solution in each well was transferred into 384- well master plates, and the remaining solution in 96-well plates was kept for structure decoding after screening.

[00282] The most commonly used solid support for microarray printing is a standard microscope glass slide, and automatic arrays have been developed to print chemical microarrays through the surface contact between the solid support and the tip of the needle or pin. In this study, using the Arrayit SpotBot® Extreme Microarray Spotters, peptoids in 384- well master plates were immobilized onto a maleimide-modified glass slide through Michael reaction between the thiol group on the C-terminal cysteine of the peptoid and the maleimide residue on the slide (see, e.g., MacBeath et al.“Printing small molecules as microarrays and detecting protein-ligand interactions en masse”, J. Am. Chem. Soc.1999, 121, 7967-7968). Each peptoid was printed onto the slide in triplicate.

[00283] FGFR1α, which plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing, was employed as the target for subsequent screening as a proof of concept (see, e.g., Groth et al.“The structure and function of vertebrate fibroblast growth factor receptor 1”, Int. J. Dev. Biol.2002, 46, 393-400). After washing with tris-buffered saline/0.1% Tween 20 (TBST) buffer and blocked with 5% bovine serum albumin (BSA), the glass slide immobilized with peptoid array was incubated with Fc- modified FGFR1α (1 µg/mL in TBST) at 4 °C for 1 hour with gentle shaking. The slide was thoroughly rinsed with TBST to wash off any unbound FGFR1α. Then the slide was further incubated with fluorescein isothiocyanate (FITC)-labeled anti-Fc (3 µg/mL in TBST) at 4 °C for 1 hour. Thus, positive peptoids showing FGFR1α binding affinities were labeled with FITC through the Fc/anti-Fc interaction (see Figure 3).

[00284] After the slide was prepared, high-throughput screening was conducted using GenePix Microarray Scanner according to the intensity of the spots’ fluorescence on the slide. As shown in Figure 4A, four peptoids (1-4) displayed significantly more prominent fluorescence compared with others, and the fluorescence intensity of each of these peptoids showed good consistency among the triplicate spots, indicating the molecules attached at these spots as hit peptoids toward FGFR1α. Thus, the stock solutions of these four hit peptoids were subjected to MS/MS spectrometry to elucidate their chemical structures. The sequence of all the four peptoids were unambiguously interpreted, and their structures are shown in Figure 4B. Validation of the binding ability of hit peptoids

[00285] In order to confirm the binding affinity of the four hit peptoids toward FGFR1α, peptoids 1-4 as well as two randomly selected negative peptoids (see supporting information) were reprinted onto maleimide-modified glass slide at three concentrations (100, 50, and 25 µM) in triplicates. The slide was visualized under GenePix Microarray Scanner, and the image was shown in Figure 5 (left). The green color indicated the intrinsic florescence from peptoids, and equal intensity was observed for both hit peptoids and peptoid controls at all the three concentrations. The same incubation procedure as shown in Figure 3 was then applied to the slide, except that Texas Red-labeled anti-Fc was used instead of FITC-labeled anti-Fc. The slide was re-visualized and the image was shown on the right panel of Figure 5.

Apparently, the spots representing the four hit peptoids exhibited much stronger florescence than the two peptoid controls at all the three concentrations, demonstrating the high affinity of peptoids 1-4 toward FGFR1α.

[00286] To further validate the binding ability of the hit peptoids toward FGFR1α, on-bead binding assay was conducted after peptoids 1-4 were resynthesized on TentalGel beads (150 µM). Beads bearing one of the four hit peptoids were washed with TBST, blocked with 5% BSA, and incubated with Fc-tagged FGFR1α (1 µg/mL in TBST) and Texas Red-labeled anti-Fc (2 µg/mL in TBST) sequentially. Meanwhile beads bearing a randomly selected peptoid were subjected to the same treatment as above as a control. Beads were then observed directly under fluorescence microscope using Texas Red filter, and the image was shown in Figure 6 using 2 and 4 as an example. It is evident that beads bearing peptoid 2 or 4 are much brighter than the control under the same condition, further confirming the binding affinity of the hit peptoids toward FGFR1α. Effects of hit peptoids on FGFR signaling pathways

[00287] After the binding affinity of the four hit peptoids was confirmed by both solution- phase (see Figure 5) and solid-phase (see Figure 6) assays, we next aimed to investigate whether the binding of the peptoids to FGFR were able to activate the receptor. As is introduced above, FGFR agonists lead to the activation of various intracellular signaling pathways, resulting in the phosphorylation of several downstream protein targets, such as Akt and ERK (see Figure 1). Therefore, we examined the expression levels of p-Akt and p-ERK upon peptoids treatment using Western blot.

[00288] Three cell lines were selected including human breast cancer cell lines MCF-7 and MDA-231 and mouse embryonic fibroblast cell NIH-3T3. It was previously reported that MCF-7 cells have greater levels of FGFR1 and that MDA-231 cells have greater relative levels of FGFR2 (see, e.g., Nurcombe et al.“The proliferative and migratory activities of breast cancer cells can be differentially regulated by heparan sulfates”, J. Biol. Chem.2000, 275, 30009-30018). In addition, NIH-3T3 cells are known to express predominantly FGFR1, and are commonly used in studying FGFR signaling pathways (see, e.g., Maher, P. A.

“Nuclear translocation of fibroblast growth factor (FGF) receptors in response to FGF-2”, J. Cell Biol.1996, 134, 529-536; Zhen et al.“Indirubin-3'-monoxime inhibits

autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK”, Oncogene 2007, 26, 6372-6385; Ren et al.“Src activation plays an important key role in

lymphomagenesis induced by FGFR1 fusion kinases”, Cancer Res.2011, 71, 7312-7322; Jones et al.“Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma”, Nat. Genet.2013, 45, 927-932). After serum starvation, all the three cell lines were treated with peptoids 1-4 and a randomly selected peptoid (peptoid control 1, supporting

information) at a concentration of 15 µM for 10 min. Cell lysates were then prepared, and the expression levels of p-Akt and p-ERK were detected using Western blot. Generally speaking, the effects of 1-4 on p-Akt and p-ERK were consistent among the three cell lines. As shown in Figure 7, peptoid 1 exhibited negligible effects on the expression levels of p-Akt and p- ERK in all of the three cell lines. However, treatment with peptoids 2-4 resulted in apparently increased phosphorylation of Akt and ERK to different extents in different cells. The most prominent effects of 2-4 on the levels of p-Akt and p-ERK were observed in MCF-7 cells (see Figure 7A). In addition, peptoid 2 led to a significantly increased phosphorylation of Akt in MDA-231 cells, (see Figure 7B).

[00289] Next, the concentration- and time-dependent effects of peptoid 2, the most potent activator of FGFR as revealed in Figure 7, on p-Akt and p-ERK were further assessed in NIH-3T3 cells. As shown in Figure 8, treating NIH-3T3 cells with peptoid 2 led to increased expression of p-Akt and p-ERK in both a dose- (see Figure 8A) and time- (see Figure 8B) dependent manner. Taken together, the Western blot results demonstrated that peptoids 2-4 acted as FGFR agonists, and 2 showed the most potent FGFR-activating effects.

[00290] Mounting evidence nowadays suggests the potential role of FGF/FGFR signaling pathway as an attractive target in drug discovery. The involvement of FGF/FGFR in angiogenesis, wound healing, embryonic development, and various endocrine signaling pathways highlights the necessity of discovering novel FGFR ligands with diverse chemical structures, although numerous FGFR peptide ligands have been documented. Against this backdrop, and as a continuing exploration to identify peptoid ligands toward biologically significant targets, a linear OBOC peptoid library was designed and synthesized with high efficiency using combinatorial chemistry method (see Figure 2). Microarray-assisted high- throughput screening (see Figure 3) led to the rapid identification of four peptoids (1-4) which were able to bind to FGFR1α (see Figure 4). The binding affinity of the hit peptoids were further validated in both solution-phase (see Figure 5) and solid-phase (see Figure 6) assays. The effects of the hit peptoids on FGFR signaling pathways were investigated in different cell lines using Western blot. It was found that peptoids 2-4 activated FGFR, leading to increased phosphorylation of Akt and ERK (see Figure 7). Particularly, peptoid 2 proved to be apotent FGFR agonist, which elevated the expression of p-Akt and p-ERK in both a dose- and time-dependent manner (see Figure 8). Radiomitigative effects of peptoids in animal models of ARS (in vivo)

[00291] Peptoid 2, when administered to mice with post-irradiation reduced mortality, increased animal survival rate (see Figure 11) without significant toxicity (Figure 12). Drugs that attenuate radiation injury under such conditions are qualified as radiomitigators and constitute a class of medical countermeasures against radiation. Methods

Peptoid library design and synthesis

[00292] A one-bead-one-compound peptoid library was constructed by split-and-pool synthesis on Rink-Amide beads. An invariable sequence (Met-Nlys-Nlys), which precedes the variable region, was linked to the bead. The thiol residue in Met was utilized to spot the peptoids onto maleimide-modified glass slides; the Nlys-Nlys linker provides a positive charge to aid in ionization in the mass spectrometer. Ten amines were used to construct the variable region. The theoretical diversity of the library was 10⁶.

[00293] The peptoid library was synthesized starting from Rink-Amide aminomethyl polystyrene resins (H50056023, particle size: 500 µm, capacity: 0.53 mmol/g, Rapp

Polymere, Germany). Rink-Amide beads were swelled in dimethylformamide (DMF) for 1 h, and were treated twice with 20% piperidine in DMF for 1 h to remove the Fmoc group.

Fmoc-Met(Trt)-OH was coupled with 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1-hydroxybenzotriazole (HOBT), N-methylmorpholine (NMM) in DMF, and the Fmoc group was removed with 20% piperidine in DMF. The two Nlys sequences were attached using traditional peptoid synthetic method assisted by microwave. The beads were treated with 2 M bromoacetic acid and 2 M

diisopropylcarbodiimide (DIC) in DMF, and the reaction was performed in a microwave oven set to 10% power for a total of 30 s. After thoroughly washed with DMF, the beads were then treated with Nlys solution (2 M in anhydrous DMF) in microwave oven as described above. The variable peptoid region was constructed using split-and-pool protocol and the same acylation and amination procedures as Nlys were used and repeated until the desired length was achieved.

[00294] To test the quality of the library, 30 beads were randomly selected. Each bead was treated with 20 µL of cleavage cocktail containing 95% trifluoroacetic acid (TFA), 2.5% triisopropylsilane, and 2.5% water for 1 hour to cleave peptoids from the resins as well as remove all the side chain protecting groups. The cleavage mixture was evaporated, and the resulting residue was dissolved in acetonitrile/water (80:20). The structure of each peptoid was decoded using the 3200 QTRAP^® System (AB Sciex, Redwood City, CA, USA). The parent peak was identified using Q1 mode, and the sequence of each peptoid was elucidated using Enhanced Product Ion (MS/MS) mode. Immobilization of peptoid library to glass slides

[00295] The above prepared peptoid library was thoroughly washed with dichloromethane to remove any DMF, and each bead was isolated into a single well of 96-well plates. Each well was then treated with 95% TFA cleavage cocktail as described above. The cleavage mixture was dried, and the resulting residue in each well was dissolved in 20 µL of DMSO. After that, 10 µL of the DMSO solution in each well of the 96-well plates was transferred into 384-well master plates using multichannel pipettes. Peptoid arrays were then prepared by immobilizing each peptoid in the 384-well plates onto maleimide-modified glass slide using Arrayit SpotBot^® Extreme Microarray Spotters (Arrayit Corporation, Sunnyvale, CA, USA). Each peptoid was spotted onto the slide in triplicates using 946MP4 pins, and the glass slide was allowed to dry overnight after printing. Screening for FGFR1α ligands

[00296] The glass slide was washed with 1X TBST buffer and blocked with 5% bovine serum albumin (BSA) in TBST for 1 h at room temperature. The slide was then incubated with 1 µg/mL of recombinant human FGFR1α (IIIc) Fc chimera (658-FR-050, R&D, Minneapolis, MN, USA) in TBST at 4 °C for 1 hour with gentle shake. Unbound FGFR was thoroughly washed off with TBST (3 × 15 min). The slide was further incubated with 3 µg/mL of FITC-labeled anti-Fc (F9512, Sigma) at 4 °C for 1 hour. After that, the slide was washed with TBST (3 × 15 min), dried, and visualized using GenePix 4000B Microarray Scanner (Molecular Devices, Sunnyvale, CA, USA). Hit peptoids were selected according to the intensity of the spots’ fluorescence. The structures of selected peptoids were elucidated by MS/MS spectrometry using their corresponding stock solutions. On-bead validation of binding affinity

[00297] Hit peptoids and two randomly-selected control peptoids were resynthesized on TentaGel beads (MB160002, particle size: 150 µm, capacity: 0.3 mmol/g, Rapp Polymere, Germany) using the same method as described above. The beads were washed with

DMF/H₂O with a successive ratio of 90:10, 50:50, 0:100 and then with TBST. The beads were blocked with 5% BSA in TBST at 4 °C overnight with gentle shake. After blockade, the beads were incubated with 1 µg/mL of recombinant human FGFR1α (IIIc) Fc chimera (658- FR-050, R&D, Minneapolis, MN, USA) in TBST at 4 °C for 1 hour, washed with TBST, and treated with 2 µg/mL of Texas Red-labeled anti-Fc (SAB3701287, Sigma) in TBST at 4 °C for 1 h. After washing with TBST, beads were visualized using the Olympus IX73 inverted microscope system with a Texas Red filter. Resynthesized of soluble peptoids

[00298] Resynthesis of hit peptoids and two randomly-selected control peptoids was conducted on Rink-Amide AM resin (855004, 200-400 mesh, Novabiochem, Germany). The general peptoid synthesis protocol as described in the library synthesis section was used to build the peptoid portion. After the synthesis, peptoids were cleaved off the resin using a 95% TFA, 2.5% triisopropylsilane, and 2.5% water mixture for 2 h at room temperature, and the crude product was purified by reverse-phase preparative HPLC using acetonitrile-water (0.1% TFA) as the eluents. Cell culture

[00299] MCF-7, MDA-231, and NIH3T3 cell lines were purchased from ATCC (Manassas, VA, USA). Dulbecco’s Modified Eagle Medium (DMEM), and fetal bovine serum (FBS) were purchased from Gibco (Grand Island, NE, USA). All the three cell lines were cultured in DMEM medium supplied with 10% FBS and 1% antibiotic in a humidified atmosphere at 37 °C with 5% CO₂. Cell lysates preparation

[00300] Cells were plated in 100-mm dishes with 10 mL DMEM containing 10% FBS and 1% antibiotic. After growing to a confluence of around 80%, cells were subjected to serum deprivation with 9 mL DMEM containing 1% antibiotic overnight. Cells were then treated with 1 mL of DMEM with or without peptoids for indicated time. Cells were washed PBS and lysed in 400 µL lysis buffer containing 50 mM Tris-HCl (pH 8.0), 137 mM NaCl, 1 mM EDTA, 50 mM NaF, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 1% Triton X-100, and 10% glycerl. Lysates were collected and centrifuged for 15 min at 25,000 × g at 4 °C. The protein concentrations were measured using Bradford assay. All the cell lysates were stored at -80 °C. Western blot

[00301] Cell lysates containing 20-40 µg total protein were mixed with protein loading buffer, heated for 5 min at 95 °C, and subjected to SDS-polyacrylamide (12%) gel electrophoresis. Proteins were transferred onto nitrocellulose mini membrane using Trans- Blot^® Turbo™ Transfer System (Bio-Rad, CA, USA). Membranes were blocked with 5% BSA in TBST for 1 h at room temperature, incubated with specific primary antibody (concentrations according to suppliers) at 4 °C overnight, washed with TBST (3 × 15 min), incubated with horseradish peroxidase (HRP)-linked secondary antibody for 1 h at room temperature, and washed with TBST (3 × 15 min). Enhanced chemiluminescence detection was carried out using Supersignal^® West Pico Chemiluminescent Substrate Kits (1856135, 1856136, Thermo Scientific), and the blots were visualized using ChemiDoc™ MP Imaging System (Bio-Rad, CA, USA). The following primary antibodies were used: Phospho-p44/42 MAPK XP^® Rabbit mAb (#4370, Cell Signaling, Danvers, MA, USA), phosphor-Akt XP^® Rabbit mAb (#4060, Cell Signaling, Danvers, MA, USA), and β-Actin Mouse mAb (#3700, Cell Signaling, Danvers, MA, USA). Animals Studies Design

[00302] Fifteen mice (8 weeks old, 20-30 mg) were purchased from Charles River (Maryland – Frederick). All animals’ procedures were performed in accordance with protocols approved by University of Florida Institutional Animal Care and Use Committee. Mice were separated by 5 per cage. One dose I.P. injection was taken place 24 hours after irradiation. Peptoid administration

[00303] Peptoid 2 was administered once intramuscularly, at a concentration of 1 mg/ml and 10 mg/ml, at 24 hours after irradiation. Irradiation and weight measurement. Animals were irradiated using a Gammacell 40 Exactor Low-Dose Research Irradiator (Best Theratronics, Ottawa, Ontario, Canada) housing two 137Cs sources in parallel and opposed geometry to deliver isotropic radiation with dose uniformity within ± 3%. All mice were subjected to total body irradiation (TBI) at 10.5 Gy. Five mice were secured in a plastic jig in the center of the irradiation chamber and were simultaneously irradiated at a dose rate of 0.9 Gy/min to achieve a single fraction. Body weight was recorded daily. E^{QUIVALENTS AND} S^COPE

[00304] Text here. In the claims articles such as“a,”“an,” and“the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include“or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[00305] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. [00306] It is also noted that the terms“comprising,”“comprises,”“contains,”“containing,” “includes” and“including” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub–range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[00307] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[00308] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMS What is claimed is: 1. A compound of Formula (I):

(I),

or a pharmaceutically acceptable salt thereof, wherein:

R^S is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.

2. The compound of claim 1, wherein R^S is hydrogen.

3. The compound of claim 1, wherein R^S is a sulfur protecting group.

4. The compound of claim 1, wherein at least one instance of R^N is hydrogen.

5. The compound of claim 1, wherein all occurrences of R^N are hydrogen.

6. The compound of claim 1, wherein the compound is of Formula (I-a):

(I-a),

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound is of Formula (I-b):

(I-b),

or a pharmaceutically acceptable salt thereof.

8. The compound of any of claims 1-7, wherein R¹ is optionally substituted aralkyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.

9. The compound of claim 8, wherein R¹ is optionally substituted heteroaralkyl.

10. The compound of claim 8, wherein R¹ is optionally substituted alkenyl.

11. The compound of claim 8, wherein R¹ is optionally substituted aralkyl.

12. The compound of claim 8, wherein R¹ is optionally substituted heterocyclylalkyl.

13. The compound of any one of claims 1-12, wherein R² is optionally substituted aralkyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.

14. The compound of claim 13, wherein R² is optionally substituted alkenyl.

15. The compound of claim 13, wherein R² is optionally substituted aralkyl.

16. The compound of claim 13, wherein R² is optionally substituted heterocyclylalkyl.

17. The compound of any one of claims 1-16, wherein R³ is optionally substituted aralkyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.

18. The compound of claim 17, wherein R³ is optionally substituted heteroaralkyl.

19. The compound of claim 17, wherein R³ is optionally substituted aralkyl.

20. The compound of claim 17, wherein R³ is optionally substituted alkenyl.

21. The compound of any one of claims 1-20, wherein R⁴ is optionally substituted aralkyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.

22. The compound of claim 21, wherein R⁴ is optionally substituted heterocyclylalkyl.

23. The compound of claim 21, wherein R⁴ is optionally substituted carbocyclyl.

24. The compound of claim 21, wherein R⁴ is optionally substituted aralkyl.

25. The compound of any one of claims 1-24, wherein R⁵ is optionally substituted aralkyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.

26. The compound of claim 25, wherein R⁵ is optionally substituted carbocyclyl.

27. The compound of claim 25, wherein R⁵ is optionally substituted aralkyl.

28. The compound of any one of claims 1-27, wherein R⁶ is optionally substituted aralkyl, optionally substituted carbocyclylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.

29. The compound of claim 28, wherein R⁶ is optionally substituted aralkyl.

30. The compound of claim 28, wherein R⁶ is optionally substituted carbocyclyl.

31. The compound of claim 28, wherein R⁶ is optionally substituted heterocyclylalkyl.

32. The compound of any one of claims 1-5, wherein R¹, R², R³, R⁴, R⁵, and R⁶ are each independently selected from the group consisting of:

wherein:

each instance of n is independently 0, 1, 2, 3, 4, 5, or 6;

each instance of m is independently 0, 1, 2, 3, 4, or 5;

33. The compound of claim 32, wherein R¹ is of the formula:

.

34. The compound of claim 33, wherein R¹ is of the formula:

35. The compound of claim 34, wherein R¹ is of the formula:

.

36. The compound of claim 32, wherein R¹ is of the formula:

.

37. The compound of claim 36, wherein R¹ is of the formula:

.

38. The compound of claim 37, wherein R⁸ is optionally substituted alkyl.

39. The compound of claim 38, wherein R⁸ is optionally substituted C_1-3alkyl.

40. The compound of claim 39, wherein R⁸ is methyl.

41. The compound of claim 37, wherein R¹ is of the formula:

42. The compound of claim 32, wherein R¹ is of the formula:

.

43. The compound of claim 42, wherein R¹ is of the formula:

.

44. The compound of claim 43, wherein R¹ is of the formula:

45. The compound of claim 32, wherein R¹ is of the formula:

.

46. The compound of claim 45, wherein R¹ is of the formula:

47. The compound of claim 46, wherein R¹ is of the formula:

48. The compound of claim 32, wherein R² is of the formula:

.

49. The compound of claim 48, wherein R² is of the formula:

.

50. The compound of claim 49, wherein R² is of the formula:

51. The compound of claim 32, wherein R² is of the formula:

.

52. The compound of claim 51, wherein R² is of the formula:

.

53. The compound of claim 52, wherein R⁸ is optionally substituted alkyl.

54. The compound of claim 53, wherein R⁸ is optionally substituted C_1-3alkyl.

55. The compound of claim 54, wherein R⁸ is methyl.

56. The compound of claim 52, wherein R² is of the formula:

57. The compound of claim 32, wherein R² is of the formula:

.

58. The compound of claim 57, wherein R² is of the formula:

59. The compound of claim 58, wherein R² is of the formula:

.

60. The compound of claim 32, wherein R³ is of the formula:

.

61. The compound of claim 60, wherein R³ is of the formula:

62. The compound of claim 61, wherein R³ is of the formula:

.

63. The compound of claim 32, wherein R³ is of the formula:

.

64. The compound of claim 63, wherein R³ is of the formula:

.

65. The compound of claim 64, wherein R³ is of the formula:

.

66. The compound of claim 32, wherein R³ is of the formula:

.

67. The compound of claim 66, wherein R³ is of the formula:

.

68. The compound of claim 67, wherein R³ is of the formula:

69. The compound of claim 32, wherein R⁴ is of the formula:

.

70. The compound of claim 69, wherein R⁴ is of the formula:

71. The compound of claim 70, wherein R⁴ is of the formula:

.

72. The compound of claim 32, wherein R⁴ is of the formula:

.

73. The compound of claim 72, wherein R⁴ is of the formula:

.

74. The compound of claim 73, wherein R⁴ is of the formula:

.

75. The compound of claim 32, wherein R⁴ is of the formula:

.

76. The compound of claim 75, wherein R⁴ is of the formula:

.

77. The compound of claim 76, wherein R⁸ is optionally substituted alkyl.

78. The compound of claim 77, wherein R⁸ is optionally substituted C_1-3alkyl.

79. The compound of claim 78, wherein R⁸ is methyl.

80. The compound of claim 76, wherein R⁴ is of the formula:

81. The compound of claim 32, wherein R⁵ is of the formula:

.

82. The compound of claim 81, wherein R⁵ is of the formula:

.

83. The compound of claim 82, wherein R⁵ is of the formula:

.

84. The compound of claim 32, wherein R⁵ is of the formula:

.

85. The compound of claim 84, wherein R⁵ is of the formula:

.

86. The compound of claim 85, wherein R⁵ is of the formula:

.

87. The compound of claim 84 or 85, wherein m is 1.

88. The compound of claim 84 or 85, wherein R⁷ is optionally substituted alkyl.

89. The compound of claim 88, wherein R⁷ is substituted alkyl.

90. The compound of claim 89, wherein R⁷ is trihalomethyl.

91. The compound of claim 90, wherein R⁷ is–CF₃.

92. The compound of claim 91, wherein R⁵ is of the formula:

.

93. The compound of claim 32, wherein R⁶ is of the formula:

.

94. The compound of claim 93, wherein R⁶ is of the formula:

.

95. The compound of claim 93 or 94, wherein m is 1.

96. The compound of claim 93 or 94, wherein R⁷ is halogen.

97. The compound of claim 96, wherein R⁷ is–Cl.

98. The compound of claim 97, wherein R⁶ is of the formula:

.

99. The compound of claim 93, wherein R⁶ is of the formula:

.

100. The compound of claim 99, wherein R⁶ is of the formula:

.

101. The compound of claim 32, wherein R⁶ is of the formula:

.

102. The compound of claim 101, wherein R⁶ is of the formula:

.

103. The compound of claim 102, wherein R⁶ is of the formula:

.

104. The compound of claim 32, wherein R⁶ is of the formula:

.

105. The compound of claim 104, wherein R⁶ is of the formula:

.

106. The compound of claim 105, wherein R⁶ is of the formula:

107. The compound of any one of claims 1-31, wherein exactly one of R¹, R², R³, R⁴, R⁵, or R⁶ is optionally substituted alkenyl.

108. The compound of claim 1, wherein the compound is of one of the following formulae:

-c3), or

(I-c4),

or a pharmaceutically acceptable salt thereof, wherein:

each instance of n is independently 0, 1, 2, 3, 4, 5, or 6;

each instance of m is independently 0, 1, 2, 3, 4, or 5;

each instance of R⁸ is independently optionally substituted alkyl.

109. The compound of claim 108, wherein the compound is of one of the following

formulae:

-d1),

(I-d2),

-d3),

or a pharmaceutically acceptable salt thereof.

110. The compound of claim 109, wherein the compound is of one of the following formulae:

(I-e1),

(I-e3),

(I-e4), or a pharmaceutically acceptable salt thereof.

111. The compound of claim 110, wherein the compound is of one of the following formulae:

(I-f1),

(I-f2),

(I-f4), or a pharmaceutically acceptable salt thereof.

112. The compound of any one of claims 1-111, wherein the compound is one of the following:

,

or a pharmaceutically acceptable salt thereof.

113. A pharmaceutical composition comprising a compound of any one of claims 1-112, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

114. The pharmaceutical composition of claim 113, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound.

115. The pharmaceutical composition of claim 113 or 114, wherein the pharmaceutical composition comprises one or more additional therapeutic agents.

116. A method of treating a disease in a subject, the method comprising: administering to a subject a therapeutically effective amount of a compound of any one of claims 1-112, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 113-115.

117. The method of claim 116, wherein the disease is a proliferative disease, genetic disease, disease associated with angiogenesis, inflammatory disease, cardiovascular disease, hepatic disease, spleen disease, pulmonary disease, painful condition, hematological disease, neurological disease, psychiatric disorder, autoimmune disease, infectious disease, metabolic disease, gastrointestinal disorder, or endocrine disease.

118. The method of claim 117, wherein the disease is a proliferative disease.

119. The method of claim 118, wherein the proliferative disease is cancer.

120. The method of claim 117, wherein the disease is a disease associated with

angiogenesis.

121. The method of claim 117, wherein the disease is a neurological disease.

122. The method of claim 117, wherein the disease is a gastrointestinal disorder.

123. The method of claim 122, wherein the gastrointestinal disorder is acute

gastrointestinal syndrome (AGS).

124. The method of claim 116, wherein the disease is a condition associated with radiation exposure.

125. The method of claim 124, wherein the disease is acute radiation syndrome (ARS).

126. The method of claim 124, wherein the disease is radiation-induced gastrointestinal syndrome.

127. The method of any one of claims 116-126, wherein the subject is an animal.

128. The method of claim 127, wherein the subject is a mammal.

129. The method of claim 128, wherein the subject is a human.

130. The method of claim 116, wherein the disease is associated with the fibroblast growth factor receptor (FGFR).

131. The method of claim 130, wherein the disease is associated with aberrant activity of the fibroblast growth factor receptor (FGFR).

132. The method of claim 131, wherein the aberrant activity is decreased activity.

133. A method of activating a fibroblast growth factor receptor (FGFR), the method comprising: contacting the FGFR with a compound of any one of claims 1-112, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 113-115.

134. The method of claim 133, wherein the step of contacting occurs in vitro.

135. The method of claim 133, wherein the step of contacting occurs in vivo.

136. The method of any one of claims 130-135, wherein the FGFR is selected from the group consisting of FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, FGFRL1, and FGFR6.

137. The method of claim 136, wherein the FGFR is FGFR1.

138. The method of claim 137, wherein the FGFR is FGFR1α.

139. A method for mitigating the effects of radiation exposure in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1-112, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 113-115.

140. Use of a compound of any one of claims 1-112, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 113-115, for treating a disease in a subject in need thereof.

141. Use of a compound of any one of claims 1-112, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 113-115, for the manufacture of a medicament for treating a disease.

142. Use of a compound of any one of claims 1-112, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 113-115, for mitigating the effects of radiation exposure in a subject.

143. Use of a compound of any one of claims 1-112, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 113-115, for the manufacture of a medicament for mitigating the effects of radiaton exposure in a subject.

144. A kit comprising a compound of any of claims 1-112, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 113-115; and optionally instructions for administering the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition.