Rev-erb antagonists

Abstract

The present disclosure provides compounds of the formulae herein (e.g., Formula (I), Formula (I')), and pharmaceutically acceptable salts thereof, which bind REV-ERB. The present disclosure also provides pharmaceutical compositions and kits comprising the compounds, or pharmaceutically acceptable salts thereof, and methods of treating or preventing diseases by administering to a subject in need thereof the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

Description

REV-ERB ANTAGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 63 / 515,565, filed July 25, 2023, titled REV-ERB ANTAGONISTS, the contents of which are incorporated herewith by reference in their entirety. BACKGROUND OF THE INVENTION

[0002] Unlike the majority of nuclear receptors, REV-ERB is a ligand-dependent repressor of gene transcription, for which the natural ligand is heme. REV-ERB agonists can induce recruitment of a coactivator, leading to repression of basal transcription. REV-ERB antagonists can inhibit the recruitment of a corepressor, leading to basal transcription of the target gene. Since the endogenous ligand, heme, is present in all cells, there is a degree of corepressor recruitment during most conditions, so addition of an antagonist will, in most cases, relieve the repression and appear as activation of transcription.

[0003] Reduced expression of the genes REV-ERBα and REV-ERBβ has been shown to increase expression of markers of myogenesis. Reduced expression of REV-ERBα results in increased muscle mass and grip strength in mouse models, and allows for more rapid recovery from a muscle injury. SUMMARY OF THE INVENTION

[0004] Pharmacological inhibition of REV-ERB (e.g., REV-ERBα and REV-ERBβ) may therefore have similar effects, increasing expression of markers of myogenesis, resulting in increased muscle mass and grip strength in mouse models, and allowing for more rapid recovery from a muscle injury. These effects may be useful in accelerating muscle development after an injury, and compounds capable of inhibiting REV-ERB may be useful for the treatment of diseases such as sarcopenia and Duchenne muscular dystrophy (DMD). Additionally, such compounds may have the ability to increase interleukin 17 (IL-17) secretion, which may modulate Th17 or Tc17 cell differentiation and offer utility in cancer immunotherapies.

[0005] Accordingly, in one aspect, the present disclosure provides compounds of Formula (I):, or pharmaceutically acceptable salts thereof, wherein:,each of R2aand R2bis independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to formR3is hydrogen, -CH3, -Cl, or -Br;provided that: if R3is -Cl or -CH3, and R4, R5, and R6are each hydrogen, then R1is notif R4is -CH3, and R3, R5, and R6are each hydrogen, then R1is notif R4is -OCH3 or -F, and R3, R5, and R6are each hydrogen, then R1is notif R4is -Cl or -I, and R3, R5, and R6are each hydrogen, then R1is notif R4is -Br, and R3, R5, and R6are each hydrogen, then R1is notif R5is -CH3, and R3, R4, and R6are each hydrogen, then R1is notif R5is -CF3, and R3, R4, and R6are each hydrogen, then R1is notif R5is -F, and R3, R4, and R6are each hydrogen, then R1is notif R5is -Br, and R3, R4, and R6are each hydrogen, then R1is notif R6is -OCH3, and R3, R4, and R5are each hydrogen, then R1is notif R6is -Cl or -Br, and R3, R4, and R5are each hydrogen, then R1is notif R3, R4, R5, and R6are each hydrogen, then R1is notif R4and R5are each -F, and R3and R6are each hydrogen, then R1is notif R4and R5are each -OCH3, and R3and R6are each hydrogen, then R1is notif R4and R6are each -Br, and R3and R5are each hydrogen, then R1is not

[0006] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein. In some embodiments, the pharmaceutical composition comprises an excipient.

[0007] In another aspect, the present disclosure provides methods of treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof a provided compound or pharmaceutical composition. In certain embodiments, the disease is associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma))).

[0008] In another aspect, the present disclosure provides methods of inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition. In certain embodiments, the cell, tissue, or biological sample is in vivo. In certain embodiments, the cell, tissue, or biologicalsample is in vitro. In certain embodiments, the method comprises binding REV-ERB (e.g., REV- ERBa, REV-ERBP).

[0009] In another aspect, the present disclosure provides kits comprising a provided compound or pharmaceutical composition disclosed herein and instructions for its use.

[0010] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIGs. 1A-1F show that novel REV-ERB agonist compound 19 induces myogenesis in mouse primary skeletal muscle myoblasts in culture. FIGs. 1A-1C show percentage of MyoG expressing cells (FIG. 1A), differentiation index (FIG. IB), and the fusion index (FIG. 1C) for cells treated with a control REV-ERB antagonist. FIGs. 1D-1F show percentage of MyoG expressing cells (FIG. ID), differentiation index (FIG. IE), and the fusion index (FIG. IF) for cells treated with compound 19.

[0012] FIGs. 2A-2B show REV-ERB antagonist compound 19 is therapeutic in the CTX model of muscle injury, using muscle cross-sectional area as a marker of myogenesis and accelerated muscle recovery after injury. FIG. 2A shows treatment with a positive control SR8278. FIG. 2B shows treatment with compound 19. *p<0.05. Individual vehicle controls were run for the two drugs as one vehicle was administered s.c. and the other i.p.DEFINITIONS

[0013] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0014] 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, 75thEd., 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 Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’ s AdvancedOrganic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0015] 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. The term “isomers” is intended to include diastereoisomers, enantiomers, regioisomers, structural isomers, rotational isomers, tautomers, and the like. All such isomers of such compounds herein are expressly included in the present invention.

[0016] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “C1-6 alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2– 4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl.

[0017] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0018] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1–6alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl,tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2- butanyl, tert-amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n- heptyl (C7), n-octyl (C8), n-dodecyl (C12), 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 C1–12alkyl (such as unsubstituted C1–6alkyl, 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 or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1–12 alkyl (such as substituted C1–6 alkyl, e.g., –CH2F, –CHF2, –CF3, – CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)).

[0019] 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. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all 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 20 carbon atoms (“C1–20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C1–10 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1–9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1–8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1–7 haloalkyl”).In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1–6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1–5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1–4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1–3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1–2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include –CHF2, −CH2F, −CF3, −CH2CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like.

[0020] 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 (e.g., 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 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–20alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–12alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–11alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–10alkyl”). 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 (“heteroC1–9alkyl”). 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 (“heteroC1–8 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 (“heteroC1–7alkyl”). 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 (“heteroC1–6 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 (“heteroC1–5 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 (“heteroC1–4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–2 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 (“heteroC2-6 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 heteroC1–12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–12 alkyl.

[0021] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 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 20 carbon atoms (“C2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C2–12 alkenyl”). In some embodiments, an alkenyl group has 2 to 11 carbon atoms (“C2–11 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2–6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2–5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2–3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). 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 C2–4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2-4alkenyl 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 C2-20alkenyl. In certain embodiments, the alkenyl group is a substituted C2-20 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3 ormay be in the (E)- or (Z)-configuration.

[0022] 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 (e.g., 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 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–20 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–11 alkenyl”). 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 (“heteroC2–10 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 (“heteroC2–9 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 (“heteroC2–8alkenyl”). 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 (“heteroC2–7alkenyl”). 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 (“heteroC2–6alkenyl”). 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 (“heteroC2–5alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2–4alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2–3alkenyl”). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2alkenyl”). 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 (“heteroC2–6alkenyl”). 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 unsubstitutedheteroC2–20alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2–20alkenyl.

[0023] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 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 C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 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 C2-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-20 alkynyl.

[0024] 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 (e.g., 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 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2– 20 alkynyl”). 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 (“heteroC2–10alkynyl”). 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 (“heteroC2–9alkynyl”). 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 (“heteroC2–8alkynyl”). 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 (“heteroC2–7alkynyl”). 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 (“heteroC2–6alkynyl”). 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 (“heteroC2–5alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain(“heteroC2–4alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2–3alkynyl”). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2alkynyl”). 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 (“heteroC2–6 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 heteroC2–20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2–20 alkynyl.

[0025] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 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 C3-10carbocyclyl groups include the aforementioned C3-8carbocyclyl 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. Exemplary C3-8carbocyclyl groups include the aforementioned C3-10carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), 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 orcan 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 C3-14carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0026] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 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 C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0027] 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 memberscontinue 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. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0028] 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.

[0029] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6- membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8- membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include 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.

[0030] 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 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; 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 C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.

[0031] “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.

[0032] 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 pi 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 beon either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0033] 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.

[0034] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6- membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include 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 naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl,and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0035] “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.

[0036] The term “unsaturated bond” refers to a double or triple bond.

[0037] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0038] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds.

[0039] 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.

[0040] 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 is 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 valenciesof the heteroatoms and results in the formation of a stable moiety. The invention is not limited in any manner by the exemplary substituents described herein.

[0041] Exemplary carbon atom substituents include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)2, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −OSi(Raa)3 −C(=S)N(Rbb)2, −C(=O)SRaa, −C(=S)SRaa, −SC(=S)SRaa, −SC(=O)SRaa, −OC(=O)SRaa, −SC(=O)ORaa, −SC(=O)Raa, −P(=O)(Raa)2, −P(=O)(ORcc)2, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, −P(=O)(N(Rbb)2)2, −OP(=O)(N(Rbb)2)2, −NRbbP(=O)(Raa)2, −NRbbP(=O)(ORcc)2, −NRbbP(=O)(N(Rbb)2)2, −P(Rcc)2, −P(ORcc)2, −P(Rcc)3+X−, −P(ORcc)3+X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, C6-14 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 Rddgroups; wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; wherein: each instance of Raais, independently, selected from C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1– 20 alkynyl, heteroC1–20 alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups 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 Rddgroups;each instance of Rccis, independently, selected from hydrogen, C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3- 14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups 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 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3- 10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 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 Rgggroups, or two geminal Rddsubstituents are joined to form =O or =S; wherein X−is a counterion; each instance of Reeis, independently, selected from C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1– 10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, C6-10 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 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, 3- 10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, or two Rffgroups 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 Rgggroups; each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1–6alkyl, −ON(C1–6alkyl)2, −N(C1–6alkyl)2, −N(C1–6alkyl)3+X−, −NH(C1–6alkyl)2+X−, −NH2(C1–6alkyl)+X−, −NH3+X−, −N(OC1–6alkyl)(C1–6alkyl), −N(OH)(C1–6alkyl), −NH(OH), −SH, −SC1–6alkyl, −SS(C1–6alkyl), −C(=O)(C1–6alkyl), −CO2H, −CO2(C1–6alkyl), −OC(=O)(C1–6alkyl), −OCO2(C1–6alkyl), −C(=O)NH2, −C(=O)N(C1–6alkyl)2, −OC(=O)NH(C1–6alkyl), −NHC(=O)( C1–6alkyl), −N(C1–6alkyl)C(=O)( C1–6alkyl), −NHCO2(C1–6alkyl), −NHC(=O)N(C1–6alkyl)2, −NHC(=O)NH(C1–6alkyl), −NHC(=O)NH2, −C(=NH)O(C1–6alkyl), −OC(=NH)(C1–6alkyl), −OC(=NH)OC1–6alkyl, −C(=NH)N(C1–6alkyl)2, −C(=NH)NH(C1–6alkyl), −C(=NH)NH2, −OC(=NH)N(C1–6alkyl)2,−OC(NH)NH(C1–6alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6alkyl), −SO2N(C1–6alkyl)2, −SO2NH(C1–6alkyl), −SO2NH2, −SO2C1–6alkyl, −SO2OC1–6alkyl, −OSO2C1–6alkyl, −SOC1–6alkyl, −Si(C1–6alkyl)3, −OSi(C1–6alkyl)3−C(=S)N(C1–6alkyl)2, C(=S)NH(C1–6alkyl), C(=S)NH2, −C(=O)S(C1–6alkyl), −C(=S)SC1–6alkyl, −SC(=S)SC1–6alkyl, −P(=O)(OC1–6 alkyl)2, −P(=O)(C1–6 alkyl)2, −OP(=O)(C1–6 alkyl)2, −OP(=O)(OC1–6 alkyl)2, C1–10 alkyl, C1–10perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; and each X−is a counterion.

[0042] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, –NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, –NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine- sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1–10 alkyl, −ORaa, −SRaa, −N(Rbb)2, – CN, –SCN, or –NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine- sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0043] In certain embodiments, the molecular weight of a carbon atom substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen,sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0044] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0045] 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 −ORaa, −ON(Rbb)2, −OC(=O)SRaa, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −OC(=NRbb)N(Rbb)2, −OS(=O)Raa, −OSO2Raa, −OSi(Raa)3, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, and −OP(=O)(N(Rbb))2, wherein X−, Raa, Rbb, and Rccare as defined herein.

[0046] The term “thiol” or “thio” refers to the group –SH. The term “substituted thiol” or “substituted thio,” by extension, refers to a thiol group wherein the sulfur atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from – SRaa, –S=SRcc, –SC(=S)SRaa, –SC(=S)ORaa, –SC(=S) N(Rbb)2, –SC(=O)SRaa, –SC(=O)ORaa, – SC(=O)N(Rbb)2, and –SC(=O)Raa, wherein Raaand Rccare as defined herein.

[0047] 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.

[0048] 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(Rbb), −NHC(=O)Raa, −NHCO2Raa, −NHC(=O)N(Rbb)2, −NHC(=NRbb)N(Rbb)2, −NHSO2Raa, −NHP(=O)(ORcc)2, and −NHP(=O)(N(Rbb)2)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group −NH(Rbb) is not hydrogen.

[0049] 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(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −NRbbSO2Raa, −NRbbP(=O)(ORcc)2, and −NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0050] 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(Rbb)3and −N(Rbb)3+X−, wherein Rbband X−are as defined herein.

[0051] The term “sulfonyl” refers to a group selected from –SO2N(Rbb)2, –SO2Raa, and –SO2ORaa, wherein Raaand Rbbare as defined herein.

[0052] The term “sulfinyl” refers to the group –S(=O)Raa, wherein Raais as defined herein.

[0053] The term “acyl” refers to a group having the general formula −C(=O)RX1, −C(=O)ORX1,wherein RX1is 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 RX1groups 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, arylalkyl, 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).

[0054] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (–C(=O)Raa), carboxylic acids (–CO2H), aldehydes (–CHO), esters (–CO2Raa, – C(=O)SRaa, –C(=S)SRaa), amides (–C(=O)N(Rbb)2, –C(=O)NRbbSO2Raa, −C(=S)N(Rbb)2), and imines (–C(=NRbb)Raa, –C(=NRbb)ORaa), –C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0055] The term “silyl” refers to the group –Si(Raa)3, wherein Raais as defined herein.

[0056] The term “phosphino” refers to the group –P(Rcc)2, wherein Rccis as defined herein.

[0057] The term “phosphono” refers to the group – (P=O)(ORcc)2, wherein Raaand Rccare as defined herein.

[0058] The term “phosphoramido” refers to the group –O(P=O)(N(Rbb)2)2, wherein each Rbbis as defined herein.

[0059] The term “oxo” refers to the group =O, and the term “thiooxo” refers to the group =S.

[0060] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRbb)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(ORcc)2, −P(=O)(Raa)2, −P(=O)(N(Rcc)2)2, C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, hetero C1–20alkyl, hetero C1–20alkenyl, hetero C1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups 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 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0061] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a nitrogen protecting group.

[0062] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1–10 alkyl (e.g., aralkyl, heteroaralkyl), C1–20 alkenyl, C1–20 alkynyl, hetero C1–20alkyl, hetero C1–20alkenyl, hetero C1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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 Rddgroups, and wherein Raa, Rbb, Rccand Rddare 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, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0063] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group,together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N- benzoylphenylalanyl derivatives, 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 derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0064] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of 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-dimethoxyacylvinylcarbamate, 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.

[0065] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of 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.

[0066] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N’-p-toluenesulfonylaminoacyl derivatives, N’- phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 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-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 derivatives, N- diphenylborinic acid derivatives, 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). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine.

[0067] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0068] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or an oxygen protecting group.

[0069] 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 −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb) 2)2, wherein X−, Raa, Rbb, and Rccare 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, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0070] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methyl, methoxymethyl (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 (PMB), 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, 4,4'-Dimethoxy-3"'- [N-(imidazolylmethyl) ]trityl Ether (IDTr-OR), 4,4'-Dimethoxy-3"'-[N- (imidazolylethyl)carbamoyl]trityl Ether (IETr-OR), 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 carbonate (MTMEC-OR), 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).

[0071] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0072] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a sulfur protecting group.

[0073] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb) 2)2, wherein Raa, Rbb, and Rccare 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, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0074] In certain embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0075] 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 (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3−,HSO4–, 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), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−,B4O72−, SO42−, S2O32−, 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.

[0076] A “leaving group” (LG) is an art-understood term referring to an atomic or 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 e.g., Smith, March Advanced Organic Chemistry 6th ed. (501–502). Exemplary leaving groups include, but are not limited to, halo (e.g., fluoro, chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., –OC(=O)SRaa, –OC(=O)Raa, –OCO2Raa, –OC(=O)N(Rbb)2, –OC(=NRbb)Raa, –OC(=NRbb)ORaa, –OC(=NRbb)N(Rbb)2, –OS(=O)Raa, –OSO2Raa, – OP(Rcc)2, –OP(Rcc)3, –OP(=O)2Raa, –OP(=O)(Raa)2, –OP(=O)(ORcc)2, –OP(=O)2N(Rbb)2, and – OP(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein). Additional examples of suitable leaving groups include, but are not limited to, halogen alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some embodiments, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, –OTs), methanesulfonate (mesylate, –OMs), p-bromobenzenesulfonyloxy (brosylate, –OBs), –OS(=O)2(CF2)3CF3 (nonaflate, –ONf), or trifluoromethanesulfonate (triflate, –OTf). In some embodiments, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some embodiments, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. In some embodiments, the leaving group is a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0077] 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.

[0078] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0079] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not limited in any manner by the above exemplary listing of substituents.

[0080] As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts. The term “salt” refers to ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this disclosure include those derived from inorganic and organic acids and bases. Examples of 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 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, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1–4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0081] 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 disclosure 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+(C1–4alkyl)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.

[0082] 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.

[0083] 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)).

[0084] 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.

[0085] The term “co-crystal” refers to a crystalline structure comprising at least two different components (e.g., a compound and an acid), wherein each of the components is independently anatom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound and an acid is different from a salt formed from a compound and the acid. In the salt, a compound is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound easily occurs at room temperature. In the co-crystal, however, a compound is complexed with the acid in a way that proton transfer from the acid to a herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is substantially no proton transfer from the acid to a compound. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound. Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound.

[0086] 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.

[0087] 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.”

[0088] 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.”

[0089] The term “isotopically labeled compound” refers to a derivative of a compound that only structurally differs from the compound in that at least one atom of the derivative includes at least one isotope enriched above (e.g., enriched 3-, 10-, 30-, 100-, 300-, 1,000-, 3,000- or 10,000-fold above) its natural abundance, whereas each atom of the compound includes isotopes at their natural abundances. In certain embodiments, the isotope enriched above its natural abundance is2H. In certain embodiments, the isotope enriched above its natural abundance is13C,15N, or18O.

[0090] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which arepharmaceutically active in vivo. Such examples include 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, Bundgaard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include, 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.

[0091] The terms “pharmaceutical composition,” “composition,” and “formulation” are used interchangeably.

[0092] 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.

[0093] 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.

[0094] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a pharmaceutical composition thereof, in or on a subject.

[0095] 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.

[0096] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population. In some embodiments, the subject is at risk of developing a disease or condition due to environmental factors (e.g., exposure to the sun).

[0097] 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, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition 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. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0098] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0099] It will be appreciated that 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.

[0100] 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” canencompass 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 a disease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof. In certain embodiments, a therapeutically effective amount is an amount effective for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, a therapeutically effective amount is an amount effective for binding REV-ERB (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, at least 98%, at least 99%, or at least about 100%). In certain embodiments, a therapeutically effective amount is an amount effective for inhibiting REV-ERB (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, at least 98%, at least 99%, or at least about 100%). In certain embodiments, inhibiting REV-ERB comprises inhibiting at least one of REV-ERBα and REV-ERBβ.

[0101] A “prophylactically effective amount” of a compound is an amount sufficient to prevent a condition, or one or more signs and / or symptoms associated with the condition or prevent its recurrence. In certain embodiments, the prophylactically effective amount is an amount that improves overall prophylaxis and / or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount effective for preventing a disease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof. In certain embodiments, a prophylactically effective amount is an amount effective for reducing the risk of developing a disease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof. In certain embodiments, a prophylactically effective amount is an amount effective for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, a prophylactically effective amount is an amount effective for binding REV-ERB (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, at least 98%, at least 99%, or at least about 100%). In certain embodiments, a prophylactically effective amount is an amount effective for inhibiting REV-ERB (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, at least 98%, at least 99%, or at least about 100%). In certain embodiments, inhibiting REV-ERB comprises inhibiting at least one of REV-ERBα and REV- ERBβ.

[0102] 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 andprimary 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).

[0103] 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) thepathological 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.

[0104] 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., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and / or is associated with a disease.

[0105] 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.

[0106] 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 inflammatoryreaction 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.

[0107] 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. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0108] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, and as such can, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting. Compounds

[0109] In one aspect, the present disclosure provides a compound of Formula (I):each of R2aand R2bis independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to formR3is hydrogen, -CH3, -Cl, or -Br;provided that: if R3is -Cl or -CH3, and R4, R5, and R6are each hydrogen, then R1is notif R4is -CH3, and R3, R5, and R6are each hydrogen, then R1is notif R4is -OCH3 or -F, and R3, R5, and R6are each hydrogen, then R1is notif R4is -Cl or -I, and R3, R5, and R6are each hydrogen, then R1is notif R4is -Br, and R3, R5, and R6are each hydrogen, then R1is notif R5is -CH3, and R3, R4, and R6are each hydrogen, then R1is notif R5is -CF3, and R3, R4, and R6are each hydrogen, then R1is notif R5is -F, and R3, R4, and R6are each hydrogen, then R1is notif R5is -Br, and R3, R4, and R6are each hydrogen, then R1is notif R6is -OCH3, and R3, R4, and R5are each hydrogen, then R1is notif R6is -Cl or -Br, and R3, R4, and R5are each hydrogen, then R1is notif R3, R4, R5, and R6are each hydrogen, then R1is notif R4and R5are each -F, and R3and R6are each hydrogen, then R1is notif R4and R5are each -OCH3, and R3and R6are each hydrogen, then R1is notif R4and R6are each -Br, and R3and R5are each hydrogen, then R1is not

[0110] In another aspect, the present disclosure provides a compound of Formula (I'):each of R2aand R2bis independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to formR3is hydrogen, -CH3, -Cl, or -Br;, . In certain embodiments, R1iscertain embodiments,certain embodiments, R1isembodiments,embodiments,embodiments,embodiments,certain embodiments, R1is. In certain embodiments, R1is. In certain embodiments,certain embodiments,certain embodiments,certain embodiments,certain embodiments,embodiments, R1is. In certain embodiments, R1embodiments,certain embodiments, R1icertain embodiments,

[0114] In certain embodiments, R1is not. In certain embodiments, R1is notcertain embodiments, R1is not. In certain embodiments, R1is notembodiments,embodiments,embodiments,. In certain embodiments, R1is notcertain embodiments, R1is not

[0115] In certain embodiments, each of R2aand R2bis independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to form

[0116] In certain embodiments, at least one of R2aand R2bis hydrogen. In certain embodiments, each of R2aand R2bis hydrogen. In certain embodiments, at least one of R2aand R2bis p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to form. In certain embodiments, at least one of R2aand R2bis p-toluenesulfonyl. In certain embodiments, at least one of R2aand R2bis acetyl. In certain embodiments, at least one of R2aand R2bis benzoyl. In certain embodiments, R2aand R2bare joined together with their intervening nitrogen atom to form. In certain embodiments, at least one of R2aand R2bis hydrogen, and at least one of R2aand R2bis p-toluenesulfonyl. In certain embodiments, each of R2aand R2bis acetyl. In certain embodiments, at least one of R2aand R2bis hydrogen, and at least one of R2aand R2bis benzoyl.

[0118] The compound of any one of claims X, wherein the compound is of Formula (I-a):or a pharmaceutically acceptable salt thereof.

[0119] In certain embodiments, R3is hydrogen, -CH3, -Cl, or -Br. In certain embodiments, R3is hydrogen. In certain embodiments, R3is -CH3. In certain embodiments, R3is -Cl or -Br. In certain embodiments, R3is -Cl. In certain embodiments, R3is -Br. In certain embodiments, R3is hydrogen, - CH3, or -Cl. In certain embodiments, R3is hydrogen or -CH3. In certain embodiments, R3is -CH3 - Cl. In certain embodiments, R3is hydrogen or -Cl.

[0120] In certain embodiments, R3is not hydrogen. In certain embodiments, R3is not -CH3. In certain embodiments, R3is not -Cl. In certain embodiments, R3is not -Br.

[0121] In certain embodiments, R4is hydrogen, -CH3, -CF3, -OCH3, -OCF3, -F, -Cl, -Br, -I,

[0122] In certain embodiments, R4is hydrogen. In certain embodiments, R4is -CH3, -CF3, -OCH3, or -OCF3. In certain embodiments, R4is -CH3. In certain embodiments, R4is -CF3. In certainembodiments, R4is -OCH3. In certain embodiments, R4is -OCF3. In certain embodiments, R4is -F, - Cl, -Br, or -I. In certain embodiments, R4is -F. In certain embodiments, R4is -Cl. In certain, certain embodiments, R4iscertain embodiments, R4is. In certain embodiments,. In certain embodiments, R4is hydrogen.

[0124] In certain embodiments, R4is not hydrogen. In certain embodiments, R4is not -CH3. In certain embodiments, R4is not -CF3. In certain embodiments, R4is not -OCH3. In certain embodiments, R4is not -OCF3. In certain embodiments, R4is not -F. In certain embodiments, R4is not -Cl. In certain embodiments, R4is not -Br. In certain embodiments, R4is not -I. In certain embodiments, R4is not. In certain embodiments, R4is notcertain embodiments, R4is notcertain embodiments, R4is notcertain embodiments, R4is notcertain embodiments, R4is not in embodiments, R4is notcertain embodiments, R4is not in embodiments, R4is not. In certain embodiments, R4is. In certain embodiments, R4is notembodiments, R4certain embodiments, R4is not. In certain embodiments, R4is not

[0125] In certain embodiments, R5is hydrogen, -CH3, -CF3, -OCH3, -NH2, -NHNH2, -F, -Br,

[0126] In certain embodiments, R5is hydrogen. In certain embodiments, R5is -CH3 or -CF3. Incertain embodiments, R5is -CH3. In certain embodiments, R5is -CF3. In certain embodiments, R5is - OCH3, -NH2, or -NHNH2. In certain embodiments, R5is -OCH3. In certain embodiments, R5is - NH2. In certain embodiments, R5is -NHNH2. In certain embodiments, R5is -F or -Br. In certain embodiments, R5is -F. In certain embodiments, R5is -Br. In certain embodiments, R5is

[0127] In certain embodiments, R5is hydrogen,In certain embodiments, R5is hydrogen or -OCH3. In certain embodiments, R5is hydrogen.

[0128] In certain embodiments, R5is not hydrogen. In certain embodiments, R5is not -CH3. In certain embodiments, R5is not -CF3. In certain embodiments, R5is not -OCH3. In certain embodiments, R5is not -NH2. In certain embodiments, R5is not -NHNH2. In certain embodiments,R5is not -F. In certain embodiments, R5is not -Br. In certain embodiments, R5is notcertain embodiments, R5is not F

[0129] In certain embodiments, R6is hydrogen,

[0130] In certain embodiments, R6is hydrogen. In certain embodiments, R6is -CH3 or -CF3. In certain embodiments, R6is -CH3. In certain embodiments, R6is -CF3. In certain embodiments, R6is - OCH3. In certain embodiments, R6is -Cl or -Br. In certain embodiments, R6is -Cl. In certainembodiments, R6is -Br. In certain embodiments,. In certain embodiments, R6is, certain embodiments, R6is,

[0131] In certain embodiments, R6is -CH3, -OCH3, -Cl, or -Br. In certain embodiments, R6is hydrogen, -OCH3, or -Cl. In certain embodiments, R6is hydrogen.

[0132] In certain embodiments, R6is not hydrogen. In certain embodiments, R6is not -CH3. In certain embodiments, R6is not -CF3. In certain embodiments, R6is not -OCH3. In certain embodiments, R6is not -Cl. In certain embodiments, R6is not -Br. In certain embodiments, R6is not. In certain embodiments, R6is notcertain embodiments, R6is not certain embodiments, R6is notcertain embodiments, R6is not

[0133] In certain embodiments, each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; R4is hydrogen,R6is hydrogen, -CH3, -OCH3, -Cl, or -Br.

[0134] In certain embodiments, each of R3, R4, R5, and R6is hydrogen. In certain embodiments, eachR4, R5, and R6is hydrogen. In certain embodiments, R1isR3, R4, R5, and R6is hydrogen.

[0135] In certain embodiments, the compound is of Formula (I-b):or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is of Formula (I-each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; R4is hydrogen, -CH3, -CF3, -OCH3, -

[0137] In certain embodiments, each of R2aand R2bis hydrogen; R3is hydrogen; R4is hydrogen, -hydrogen, -CH3, -OCH3, -Cl, or -Br.

[0138] In certain embodiments, R3is hydrogen, -CH3, or -Cl; and each of R4, R5, and R6is hydrogen. In certain embodiments, R3is hydrogen, -CH3, or -Cl; and each of R2aand R2bis hydrogen. In certain embodiments, R3is hydrogen, -CH3, or -Cl; and each of R2a, R2b, R4, R5, and R6isis hydrogen, -CH3, or -Cl; and each of R4, R5, and R6is hydrogen. In certain embodiments, R1isis hydrogen, -CH3, or -Cl; and each of R4, R5, and R6is hydrogen. In certain embodiments, R1is

[0140] In certain embodiments, the compound is of Formula (I-c):or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is of Formula (I- c), wherein R3is hydrogen, -CH3, or -Cl. In certain embodiments, the compound is of Formula (I-c),certain embodiments, the compound is ofhydrogen, -CH3, or -Cl.

[0141] In certain embodiments, each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; R4iseach of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; R4is hydrogen, -CH3, -OCH3, -Cl, -I,s hydrogen, -CH3, -OCH3, -Cl, or -Br.

[0142] In certain embodiments, each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; R4ishydrogen; R3is hydrogen, -CH3, or -Cl; R4is hydrogen, -CH3, -CF3, -OCH3, -F, -Cl, -Br, -I, orhydrogen, -CH3, -OCH3, -Cl, or -Br.

[0143] In certain embodiments, each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; R4is

[0144] In certain embodiments, each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; R4is hydrogen; R5is hydrogen,s hydrogen, -; each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; R4is hydrogen; R5is hydrogen,s hydrogen, -CH3, -OCH3,-Cl, or -Br.each of R2a, R2b, R3, R5, and R6is hydrogen. In certain embodiments, R1iseach of R2a, R2b, R3, R5, and R6is hydrogen.each of R2aand R2bis hydrogen. In certain embodiments, R4is hydrogen, -CH3, -OCH3, -Cl, -I,is hydrogen.

[0147] In certain embodiments, R4is hydrogen, -CH3, -CF3, -OCH3, -F, -Cl, -Br, -I, orembodiments, R4is hydrogen, -CH3, -CF3, -OCH3, -F, -Cl, -Br, -I, or; and each ofeach of R3, R5, and R6is hydrogen. In certain embodiments, R1isof R2aand R2bis hydrogen. In certain embodiments, R1isof R2a, R2b, R3, R5, and R6is hydrogen.

[0148] In certain embodiments, R4is hydrogen, -CH3, -OCH3, -Cl, -I, or; and each ofR3, R5, and R6is hydrogen. In certain embodiments, R4is hydrogen, -CH3, -OCH3, -Cl, -I, orembodiments,and each of R2a, R2b, R3, R5, and R6is hydrogen.R6is hydrogen. In certain embodiments, R1iseach of R2aand R2bis hydrogen. In certain embodiments, R1iseach of R2a, R2b, R3, R5, and R6is hydrogen.

[0150] In certain embodiments,each of R3, R5, and R6is hydrogen. In certain embodiments, R1iseach of R2aand R2bis hydrogen. In certaineach of R2a, R2b, R3, R5, and R6is hydrogen.

[0151] In certain embodiments,is hydrogen,each of R3, R5, and R6is hydrogen. In certain embodiments,R4is hydrogen,each of R2aand R2bis hydrogen. In certain embodiments,R4is hydrogen,each of R2a, R2b, R3, R5, and R6is hydrogen.hydrogen, -CH3, -OCH3, -Cl, -I, or; and each of R2aand R2bis hydrogen. In certain embodiments,each of R2a, R2b, R3, R5, and R6is hydrogen.

[0153] In certain embodiments, the compound is of Formula (I-d):or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is of Formula (I-certain embodiments, the compound is of Formula (I-d), wherein R4is hydrogen, -CH3, -OCH3, -Cl,certain embodiments, thecompound is of Formula (I-d), wherein R4is hydrogen, -CH3, -CF3, -OCH3, -F, -Cl, -Br, -I, or. In certain embodiments, the compound is of Formula (I-d), wherein R4is hydrogen, -CH3, -OCH3, -Cl, -I, or. in certain embodiments, the compound is of Formula (I-d),compound is of Formula (I-d), wherein R1isor. In certain embodiments, the compound is of Formula (I-d), wherein R1is

[0154] In certain embodiments, the compound is of Formula (I-d), wherein R1iscertain embodiments, the compound is of Formula (I-d),OCH3, -F, -Cl, -Br, -I, or. In certain embodiments, the compound is of Formula (I-d),

[0155] In certain embodiments, each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; R4ishydrogen or -OCH3; and R6is hydrogen, -CH3, -OCH3, -Cl, or -Br. In certain embodiments, R1is

[0156] In certain embodiments, each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; R4ishydrogen; and R6is hydrogen, -CH3, -OCH3, -Cl, or -Br.

[0157] In certain embodiments, R5is hydrogen,and each of R3, R4, and R6is hydrogen. In certain embodiments, R5is hydrogen, -CH3, -CF3, -OCH3,each of R2aand R2bis hydrogen. In certain embodiments, R5is jQ hydrogen, -CH3, -CF3, -OCH3, -NH2, -F, or F ; and each of R2a, R2b, R3, R4, and R6is hydrogen. In certain embodiments, R1isis hydrogen,each of R3, R4, and R6isis hydrogen,each of R2aand R2bis hydrogen.

[0158] In certain embodiments, R5is hydrogen or -OCH3; and each of R3, R4, and R6is hydrogen. In certain embodiments, R5is hydrogen or -OCH3; and each of R2aand R2bis hydrogen. In certain embodiments, R5is hydrogen or -OCH3; and each of R2a, R2b, R3, R4, and R6is hydrogen. In certainis hydrogen or -OCH3; and each of R2a, R2b, R3, R4, and R6is hydrogen.

[0159] In certain embodiments,R5is hydrogen,each of R3, R4, and R6is hydrogen. In certain embodiments,; R5is hydrogen,each of R2aand R2bis hydrogen. In certain embodiments,; R5is hydrogen,each of R2a, R2b, R3, R4, andR6is hydrogen.

[0160] In certain embodiments,R5is hydrogen or -OCH3; and each of R3, R4, and R6is hydrogen. In certain embodiments, R1iss hydrogen or -OCH3; and each of R2a, R2b, R3, R4, and R6is hydrogen.

[0161] In certain embodiments, the compound is of Formula (I-e):or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is of Formula (Ie), wherein R5is hydrogen, -CH3, -CF3, -OCH3, -NH2, -F, or F . In certain embodiments, the compound is of Formula (I-e), wherein R5is hydrogen or -OCH3. In certain. , p ,

[0162] In certain embodiments, the compound is of Formula (I-e), wherein R1iscertain embodiments, the compound is of Formula (I-e),CH3, -CF3, -OCH3, -NH2, -F, or F . in certain embodiments, the compound is ofFormula (I-e), whereinhydrogen or -OCH3.

[0163] In certain embodiments, each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; R4ishydrogen; R3is hydrogen, -CH3, or -Cl; R4is hydrogen, -CH3, -CF3, -OCH3, -F, -Cl, -Br, -I,R6is hydrogen, -OCH3, or -Cl.

[0164] In certain embodiments, each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; R4isR6is hydrogen.

[0165] In certain embodiments, R6is hydrogen, -CH3, -OCH3, -Cl, or -Br; and each of R3, R4, and R5is hydrogen. In certain embodiments, R6is hydrogen, -CH3, -OCH3, -Cl, or -Br; and each of R2aand R2bis hydrogen. In certain embodiments, R6is hydrogen, -CH3, -OCH3, -Cl, or -Br; and each ofis hydrogen, -CH3, -OCH3, -Cl, or -Br; and each of R2aand R2bis hydrogen. In certain embodiments,Br; and each of R2a, R2b, R3, R4, and R5is hydrogen.

[0166] In certain embodiments, R6is hydrogen, -OCH3, or -Cl; and each of R3, R4, and R5is hydrogen. In certain embodiments, R6is hydrogen, -OCH3, or -Cl; and each of R1' and R2bis hydrogen. In certain embodiments, R6is hydrogen, -OCH3, or -Cl; and each of R2'1. R2b, R3, R4, andis hydrogen, -OCH3, or -Cl; and each of R3, R4, and R5is hydrogen. In certain embodiments, R1is; R6is hydrogen, -OCH3, or -Cl; and each of R2a, R2b, R3, R4, and R5is hydrogen.

[0167] In certain embodiments,R6is hydrogen, -CH3, -OCH3, -Cl, or -Br; and each of R3, R4, and R5is hydrogen. In certain embodiments,CH3, -OCH3, -Cl, or -Br; and each of R2aand R2bis hydrogen. In certain embodiments, R1iss hydrogen, -CH3, -OCH3, -Cl, or -Br; and each of R2a, R2b, R3, R4, and R5is hydrogen.

[0168] In certain embodiments,R6is hydrogen, -OCH3, or -Cl; and each of R3, R4, and R5is hydrogen. In certain embodiments, R1iss hydrogen, -OCH3, or -Cl; and each of R2a, R2b, R3, R4, and R5is hydrogen.

[0169] In certain embodiments, the compound is of Formula (I-f) :or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is of Formula (I- f), wherein R6is hydrogen, -CH3, -OCH3, -Cl, or -Br. In certain embodiments, the compound is of Formula (I-f), wherein R6is hydrogen, -OCH3, or -Cl. In certain embodiments, the compound is of; and R6is hydrogen, -CH3, -OCH3, -Cl, or -Br. In certain embodiments, theR6is hydrogen, -OCH3, or -Cl.

[0170] In certain embodiments, the compound is of Formula (I-f), wherein R1iscertain embodiments, the compound is of Formula (I-f), whereinCH3, -OCH3, -Cl, or -Br. In certain embodiments, the compound is of Formula (I-f), wherein R1is

[0171] In certain embodiments, each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; eachof R4and R5is -OCH3; and R6is hydrogen, -CH3, -OCH3, -Cl, or -Br. In certain embodiments, each of R2a, R2b, R3, and R6is hydrogen; and each of R4and R5is -OCH3. In certain embodiments, R1ishydrogen, -CH3, or -Cl; each of R4and R5is -OCH3; and R6is hydrogen, -CH3, -OCH3, -Cl, or -Br.and R6is hydrogen; and each of R4and R5is -OCH3.

[0172] In certain embodiments,each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; each of R4and R5is -OCH3; and R6is hydrogen, -CH3, -OCH3, -Cl, or -Br. In certain embodiments, R1iseach of R2a, R2b, R3, and R6is hydrogen; and each of R4andR5is -OCH3.

[0173] In certain embodiments, each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; each of R4and R5is -F; and R6is hydrogen, -CH3, -OCH3, -Cl, or -Br. In certain embodiments, each ofR2a, R2b, R3, and R6is hydrogen; and each of R4and R5is -F. In certain embodiments, R1is; each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or-Cl; each of R4and R5is -F; and R6is hydrogen, -CH3, -OCH3, -Cl, or -Br. In certain embodiments,and each of R4and R5is -F.

[0174] In certain embodiments,each of R2aand R2bis hydrogen; R3is hydrogen, -CH3, or -Cl; each of R4and R5is -F; and R6is hydrogen, -CH3, -OCH3, -Cl, or -Br. In certain embodiments, R1iseach of R2a, R2b, R3, and R6is hydrogen; and each of R4andR5is -F.

[0175] In certain embodiments, the compound is of Formula (I-g):or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is of Formula (I- g), wherein each of R4and R5is -OCH3. In certain embodiments, the compound is of Formula (I-g), wherein each of R4and R5is -F. In certain embodiments, the compound is of Formula (I-g), whereinis -OCH3. In certain embodiments, the compound is of Formula (I-g), wherein R1iscompound is of Formula (I-g), wherein R1isembodiments, the compound is of Formula (I-g), wherein R1is

[0176] In certain embodiments, the compound of Formula (I) is of formula:or a pharmaceutically acceptable salt thereof.

[0177] In certain embodiments, the compound of Formula (I) is not of formula:or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certainembodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formulapharmaceutically acceptable salt thereof.

[0178] In certain embodiments, the compound of Formula (I') is of formula:or a pharmaceutically acceptable salt thereof.

[0179] In certain embodiments, a provided compound (a compound described herein, a compound of the present disclosure) is a compound of any of the formulae herein (e.g., Formula (I), Formula (I')), or pharmaceutically acceptable salt thereof. In certain embodiments, a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, a provided compound is a compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In certain embodiments, a provided compound is a compound of any of the formulae herein (e.g., Formula (I), Formula (I')), or a salt thereof.Pharmaceutical Compositions and Kits

[0180] In one aspect, the present disclosure provides pharmaceutical compositions comprising a provided compound. In some embodiments, the pharmaceutical composition comprises one or more excipients. In certain embodiments, the pharmaceutical compositions described herein comprise a provided compound and an excipient.

[0181] In certain embodiments, the pharmaceutical composition comprises an effective amount of the provided compound. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophy tactically effective amount.

[0182] In certain embodiments, the effective amount is an amount effective for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the effective amount is an amount effective for binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the effective amount is an amount effective for inhibiting REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the amount effective for inhibiting REVERB is effective for inhibiting at least one of REV-ERBa and REV-ERBp. In certain embodiments, the effective amount is an amount effective for treating a disease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a disease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non- small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof.

[0183] In certain embodiments, the subject is an animal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human aged 18 years or older. In certain embodiments, the subject is a human aged 12-18 years, exclusive. In certain embodiments, the subject is a human aged 2-12 years, inclusive. In certain embodiments, the subject is a human younger than 2 years. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. 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 (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a geneticallyengineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0184] In certain embodiments, the effective amount is an amount effective for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample.

[0185] In certain embodiments, the effective amount is an amount effective for binding REV-ERB (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, at least 98%, at least 99%, or at least about 100%). In certain embodiments, the effective amount is an amount effective for binding REV-ERB by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive. In certain embodiments, the effective amount is an amount effective for inhibiting REV-ERB (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, at least 98%, at least 99%, or at least about 100%). In certain embodiments, the effective amount is an amount effective for inhibiting REV-ERB by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive. In certain embodiments, the amount effective for inhibiting REV-ERB is effective for inhibiting at least one of REV-ERBa and REV-ERBp.

[0186] In certain embodiments, the pharmaceutical composition is for use in treating a disease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof. In certain embodiments, the pharmaceutical composition is for use in preventing a disease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof. In certain embodiments, the pharmaceutical composition is for use in inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the pharmaceutical composition is for use in binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the pharmaceutical composition is for use in inhibiting REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the pharmaceutical composition is for use in inhibiting at least one of REV-ERBa and REV-ERBp.

[0187] A provided compound or pharmaceutical composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeuticallyand / or prophylactically active agents). The provided compounds or pharmaceutical 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 or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof, in preventing a disease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof, and / or in reducing the risk of developing a disease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof), 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 additional pharmaceutical agents 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 provided compound described herein and an additional pharmaceutical agent exhibit a synergistic effect that is absent in a pharmaceutical composition including one of the provided compounds and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.

[0188] The provided compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which are different from the compound or pharmaceutical composition and 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, synthetic 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 adisease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))).

[0189] 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 pharmaceutical 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.

[0190] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol- lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti-pyretics, hormones, and prostaglandins.

[0191] In certain embodiments, the provided compound or pharmaceutical composition is a solid. In certain embodiments, the provided compound or pharmaceutical composition is a powder. In certain embodiments, the provided compound or pharmaceutical composition can be dissolved in a liquid to make a solution. In certain embodiments, the provided compound or pharmaceutical composition is dissolved in water to make an aqueous solution. In certain embodiments, the pharmaceutical composition is a liquid for parental injection. In certain embodiments, the pharmaceutical composition is a liquid for oral administration (e.g., ingestion). In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for intravenous injection. In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for subcutaneous injection.

[0192] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the composition comprising a provided compound (i.e., the “active ingredient”) into association with a carrier 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.

[0193] 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.

[0194] Relative amounts of the provided compound, pharmaceutically acceptable excipient, agent, 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 pharmaceutical composition is to be administered. The pharmaceutical composition may comprise between 0.1% and 100% (w / w) agent, inclusive.

[0195] Pharmaceutically acceptable excipients used in 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 and accessory ingredients, such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents, may also be present in the pharmaceutical composition.

[0196] 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.

[0197] 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.

[0198] 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 monostearate (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.

[0199] 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, hydroxy ethylcellulose, 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.

[0200] 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.

[0201] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxy anisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0202] 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.

[0203] 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.

[0204] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0205] 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.

[0206] 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, NeoIone®, Kathon®, and Euxyl®.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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 pharmaceutical 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.

[0211] 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.

[0212] 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 pharmaceutical compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0213] 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.

[0214] Pharmaceutical 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 solidat ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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 pharmaceuticallyacceptable 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.

[0219] 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.

[0220] Suitable devices for use in delivering injectable pharmaceutical compositions described herein include short needle devices. Injectable pharmaceutical 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 administration. Jet injection devices which deliver liquid formulations via a liquid jet injector and / or via a needle. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound in powder form are suitable.

[0221] 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 pharmaceutical 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 pharmaceutical compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0222] 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 pharmaceutical composition, and the active ingredient may constitute 0.1 to 20% (w / w) of thepharmaceutical 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).

[0223] 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 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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 pharmaceutical 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 pharmaceutical 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.

[0228] Provided compounds 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 pharmaceutical 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.

[0229] The provided compounds and pharmaceutical compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarticular, 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 intraarticular administration, 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).

[0230] The exact amount of a provided 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 of the disclosure, 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 biological sample, tissue, or cell, any two doses of the multiple doses include different or substantially the same amounts of an agent described herein.

[0231] In certain embodiments, a pharmaceutical composition comprising a provided compound is administered, orally or parenterally, at dosage levels of each pharmaceutical composition sufficient to deliver from about 0.001 mg / kg to about 200 mg / kg in one or more dose administrations for one or several days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and / or prophylactic effect. In certain embodiments, the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg / kg to about 200 mg / kg, from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and / or prophylactic effect. The desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). In certain embodiments, the pharmaceutical composition described herein is administered at a dose that is below the dose at which the agent causes nonspecific effects.

[0232] In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.

[0233] Dose ranges as described herein provide guidance for the administration of provided compounds or 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. In certain embodiments, a dose described herein is a dose to an adult human whose body weight is 70 kg.

[0234] 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 multipledoses to the tissue or cell may be, in non-limiting examples, 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, or even slow dose controlled delivery over a selected period of time using a drug delivery device. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, 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.

[0235] Also encompassed by the present disclosure are kits (e.g., pharmaceutical packs). In certain embodiments, the kit comprises a provided compound or pharmaceutical composition described herein, and instructions for using the compound or pharmaceutical composition. In certain embodiments, the kit comprises a first container, wherein the first container includes the compound or pharmaceutical composition. In some embodiments, the kit further comprises a second container. In certain embodiments, the second container includes an excipient (e.g., an excipient for dilution or suspension of the compound or pharmaceutical composition). In certain embodiments, the second container includes an additional pharmaceutical agent. In some embodiments, the kit further comprises a third container. In certain embodiments, the third container includes an additional pharmaceutical agent. In some embodiments, the provided compound or pharmaceutical composition included in the first container and the excipient or additional pharmaceutical agent included in the second container are combined to form one unit dosage form. In some embodiments, the provided compound or pharmaceutical composition included in the first container, the excipient included in the second container, and the additional pharmaceutical agent included in the third container are combined to form one unit dosage form. In certain embodiments, each of the first, second, and third containers is independently a vial, ampule, bottle, syringe, dispenser package, tube, or inhaler.

[0236] In certain embodiments, the instructions are for administering the provided compound or pharmaceutical composition to a subject (e.g., a subject in need of treatment or prevention of a disease described herein). In certain embodiments, the instructions are for contacting a biological sample or cell with the provided compound or pharmaceutical composition. In certain embodiments, the instructions comprise information required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or the European Agency for the Evaluation of Medicinal Products (EMA). In certain embodiments, the instructions comprise prescribing information.

[0237] In certain embodiments, the kits and instructions provide for treating a disease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchennemuscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease or disorder (e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)))) in a subject in need thereof. In certain embodiments, the kits and instructions provide for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the kits and instructions provide for binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the kits and instructions provide for inhibiting REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the kits and instructions provide for inhibiting at least one of REV-ERBa and REV-ERBP in a subject in need thereof or in a cell, tissue, or biological sample.

[0238] A kit described herein may include one or more additional pharmaceutical agents described herein as a separate pharmaceutical composition.

[0239] Another object of the present disclosure is the use of a compound as described herein in the manufacture of a medicament for use in the treatment of a disorder or disease described herein.Another object of the present disclosure is the use of a compound as described herein for use in the treatment of a disorder or disease described herein.Methods of Treatment and Prevention

[0240] In another aspect, the present disclosure provides methods of treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I):or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein:each of R2aand R2bis independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to formR3is hydrogen, -CH3, -Cl, or -Br;provided that: if R3is -Cl or -CH3, and R4, R5, and R6are each hydrogen, then R1is notif R4is -CH3, and R3, R5, and R6are each hydrogen, then R1is notif R4is -OCH3 or -F, and R3, R5, and R6are each hydrogen, then R1is notif R4is -Cl or -I, and R3, R5, and R6are each hydrogen, then R1is notif R4is -Br, and R3, R5, and R6are each hydrogen, then R1is notif R5is -CH3, and R3, R4, and R6are each hydrogen, then R1is notif R5is -CF3, and R3, R4, and R6are each hydrogen, then R1is notif R5is -F, and R3, R4, and R6are each hydrogen, then R1is notorif R5is -Br, and R3, R4, and R6are each hydrogen, then R1is notif R6is -OCH3, and R3, R4, and R5are each hydrogen, then R1is notif R6is -Cl or -Br, and R3, R4, and R5are each hydrogen, then R1is notif R3, R4, R5, and R6are each hydrogen, then R1is notif R4and R5are each -F, and R3and R6are each hydrogen, then R1is notif R4and R5are each -OCH3, and R3and R6are each hydrogen, then R1is notif R4, R5, and R6are each -OCH3, and R3is hydrogen, then R1is notor. In certain embodiments, the present disclosure provides methods of treating a disease in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides methods of preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof. In certain embodiments, the disease is associated with REVERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g.,glioblastoma), adrenocortical carcinoma))).

[0241] In another aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof, for use in treating or preventing a disease in a subject in need thereof. In another aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof, for use in treating a disease in a subject in need thereof. In another aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof, for use in preventing a disease in a subject in need thereof. In certain embodiments, the disease is associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma))).

[0242] In another aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treatment or prevention of a disease in a subject in need thereof. In another aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treatment of a disease in a subject in need thereof. In another aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for prevention of a disease in a subject in need thereof. In certain embodiments, the disease is associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma))).

[0243] In another aspect, the present disclosure provides methods of treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I'):or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formulaeach of R2aand R2bis independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to formR3is hydrogen, -CH3, -Cl, or -Br;of treating a disease in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides methods of preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'),or pharmaceutically acceptable salt thereof. In certain embodiments, the disease is associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma))).

[0244] In another aspect, the present disclosure provides a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof, for use in treating or preventing a disease in a subject in need thereof. In another aspect, the present disclosure provides a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof, for use in treating a disease in a subject in need thereof. In another aspect, the present disclosure provides a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof, for use in preventing a disease in a subject in need thereof. In certain embodiments, the disease is associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCEC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma))).

[0245] In another aspect, the present disclosure provides a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treatment or prevention of a disease in a subject in need thereof. In another aspect, the present disclosure provides a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treatment of a disease in a subject in need thereof. In another aspect, the present disclosure provides a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for prevention of a disease in a subject in need thereof. In certain embodiments, the disease is associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCEC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma))).

[0246] In certain embodiments, the disease is associated with REV-ERB (e.g., a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)), a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervicalcancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma))).

[0247] In certain embodiments, the disease is a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)). In certain embodiments, the muscular disease is sarcopenia. In certain embodiments, the muscular disease is Duchenne muscular dystrophy (DMD).

[0248] In certain embodiments, the disease is a proliferative disease (e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma)). In certain embodiments, the proliferative disease is cancer (e.g., adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (NSCLC)), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer (e.g., glioblastoma), adrenocortical carcinoma). In certain embodiments, the cancer is adenocarcinoma. In certain embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC)). In certain embodiments, the cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is esophageal cancer. In certain embodiments, the cancer is cervical cancer. In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is brain cancer (e.g., glioblastoma). In certain embodiments, the cancer is glioblastoma. In certain embodiments, the cancer is adrenocortical carcinoma.

[0249] In certain embodiments, the method comprises increasing a number of satellite cells in dystrophic muscle in the subject (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%). In certain embodiments, the method comprises reducing fibrosis in dystrophic muscle in the subject (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In certain embodiments, the method comprises increasing a muscle fiber cross-sectional area in the subject (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%).

[0250] In certain embodiments, the subject has suffered an injury to one or more muscles. In certain embodiments, the method comprises improving muscle regeneration in the subject. In certain embodiments, the method comprises inducing muscle hypertrophy in the subject.

[0251] In certain embodiments, the method comprises increasing a rate of muscle regeneration in the subject (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%). In certain embodiments, the method comprises increasing grip strength in the subject (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%). In certain embodiments, the method comprises increasing lean mass in the subject (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%).Methods of Binding REV-ERB and Inhibiting Cell Proliferation or Promoting Apoptosis

[0252] In another aspect, the present disclosure provides methods of binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formulaeach of R2aand R2bis independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to formR3is hydrogen, -CH3, -Cl, or -Br;provided that: if R3is -Cl or -CH3, and R4, R5, and R6are each hydrogen, then R1is notif R4is -CH3, and R3, R5, and R6are each hydrogen, then R1is notif R4is -OCH3 or -F, and R3, R5, and R6are each hydrogen, then R1is notif R4is -Cl or -I, and R3, R5, and R6are each hydrogen, then R1is notif R4is -Br, and R3, R5, and R6are each hydrogen, then R1is notif R5is -CH3, and R3, R4, and R6are each hydrogen, then R1is notif R5is -CF3, and R3, R4, and R6are each hydrogen, then R1is notif R5is -F, and R3, R4, and R6are each hydrogen, then R1is notif R5is -Br, and R3, R4, and R6are each hydrogen, then R1is notif R6is -OCH3, and R3, R4, and R5are each hydrogen, then R1is notif R6is -Cl or -Br, and R3, R4, and R5are each hydrogen, then R1is notif R3, R4, R5, and R6are each hydrogen, then R1is notif R4and R5are each -F, and R3and R6are each hydrogen, then R1is notif R4and R5are each -OCH3, and R3and R6are each hydrogen, then R1is notif R4and R6are each -Br, and R3and R5are each hydrogen, then R1is notif R4, R5, and R6are each -OCH3, and R3is hydrogen, then R1is notor. In certain embodiments, the present disclosure provides methods of binding REV¬ERB in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides methods of binding REV-ERB in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof for use in binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample.

[0253] In another aspect, the present disclosure provides methods of binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I'):or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formulaeach of R2aand R2bis independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to formR3is hydrogen, -CH3, -Cl, or -Br;binding REV-ERB in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides methods of binding REV-ERB in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or acomposition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof for use in binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the present disclosure provides a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample.

[0254] In certain embodiments, binding REV-ERB comprises binding at least one of REV-ERBa and REV-ERBp. In certain embodiments, binding REV-ERB comprises binding REV-ERBa. In certain embodiments, binding REV-ERB comprises binding REV-ERBp. In certain embodiments, binding REV-ERB comprises binding REV-ERBa and REV-ERBp.

[0255] In another aspect, the present disclosure provides methods of inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein:each of R2aand R2bis independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to formR3is hydrogen, -CH3, -Cl, or -Br;provided that: if R3is -Cl or -CH3, and R4, R5, and R6are each hydrogen, then R1is notif R4is -CH3, and R3, R5, and R6are each hydrogen, then R1is notif R4is -OCH3 or -F, and R3, R5, and R6are each hydrogen, then R1is notif R4is -Cl or -I, and R3, R5, and R6are each hydrogen, then R1is notif R4is -Br, and R3, R5, and R6are each hydrogen, then R1is notif R5is -CH3, and R3, R4, and R6are each hydrogen, then R1is notif R5is -CF3, and R3, R4, and R6are each hydrogen, then R1is notif R5is -F, and R3, R4, and R6are each hydrogen, then R1is notif R5is -Br, and R3, R4, and R6are each hydrogen, then R1is notif R6is -OCH3, and R3, R4, and R5are each hydrogen, then R1is notif R6is -Cl or -Br, and R3, R4, and R5are each hydrogen, then R1is notif R3, R4, R5, and R6are each hydrogen, then R1is notif R4and R5are each -F, and R3and R6are each hydrogen, then R1is notif R4and R5are each -OCH3, and R3and R6are each hydrogen, then R1is notif R4and R6are each -Br, and R3and R5are each hydrogen, then R1is notif R4, R5, and R6are each -OCH3, and R3is hydrogen, then R1is not. In certain embodiments, the present disclosure provides methods of inhibiting cell proliferation or promoting apoptosis in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides methods of inhibiting cell proliferation or promoting apoptosis in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof for use in inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample.

[0256] In another aspect, the present disclosure provides methods of inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I'):or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula(I'), or pharmaceutically acceptable salt thereof, wherein:each of R2aand R2bis independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to formR3is hydrogen, -CH3, -Cl, or -Br;of inhibiting cell proliferation or promoting apoptosis in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides methods of inhibiting cell proliferation or promoting apoptosis in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with an effective amount of a compoundof Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof for use in inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the present disclosure provides a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (I'), or pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample.

[0257] In certain embodiments, binding REV-ERB comprises inhibiting REV-ERB. In certain embodiments, inhibiting REV-ERB comprises inhibiting at least one of REV-ERBa and REV-ERBp. In certain embodiments, inhibiting REV-ERB comprises inhibiting REV-ERBa. In certain embodiments, inhibiting REV-ERB comprises inhibiting REV-ERBp. In certain embodiments, inhibiting REV-ERB comprises inhibiting REV-ERBa and REV-ERBp.

[0258] In certain embodiments, the method comprises inducing myogenesis in the subject or in the cell, tissue, or biological sample. In certain embodiments, the method comprises increasing an amount of one or more myogenesis gene markers (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%). In certain embodiments, the method comprises increasing an amount of one or more myogenesis gene markers by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive. In certain embodiments, the one or more myogenesis gene markers are Myod, Myodl, Myf5, Myog, Myog5, p21, Mhcl, Mhc2, Mhc2b, Mhc2x, Mhc3, or a combination thereof. In certain embodiments, the myogenesis gene marker is Myod. In certain embodiments, the myogenesis gene marker is Myodl. In certain embodiments, the myogenesis gene marker is Myf5. In certain embodiments, the myogenesis gene marker is Myog. In certain embodiments, the myogenesis gene marker is Myog5. In certain embodiments, the myogenesis gene marker is p21. In certain embodiments, the myogenesis gene marker is Mhcl. In certain embodiments, the myogenesis gene marker is Mhc2. In certain embodiments, the myogenesis gene marker is Mhc2b. In certain embodiments, the myogenesis gene marker is Mhc2x. In certain embodiments, the myogenesis gene marker is Mhc3.

[0259] In certain embodiments, the method comprises increasing an amount of one or more mitochondrial biogenesis gene markers (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 200%, at least about 300%, at least about400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%). In certain embodiments, the method comprises increasing an amount of one or more mitochondrial biogenesis gene markers by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive. In certain embodiments, the one or more mitochondrial biogenesis gene markers are Tfam, Pgcla, Nampt, Sirt3, Nrfl, or a combination thereof. In certain embodiments, the mitochondrial biogenesis gene marker is Tfam. In certain embodiments, the mitochondrial biogenesis gene marker is Pgcla. In certain embodiments, the mitochondrial biogenesis gene marker is Nampt. In certain embodiments, the mitochondrial biogenesis gene marker is Sirt3. In certain embodiments, the mitochondrial biogenesis gene marker is Nrfl.

[0260] In certain embodiments, the method comprises increasing an amount of one or more myogenic regulatory factors (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%). In certain embodiments, the method comprises increasing an amount of one or more myogenic regulatory factors by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive. In certain embodiments, the one or more myogenic regulatory factors are MYOD, MYOG, MYF5, or a combination thereof. In certain embodiments, the myogenic regulatory factor is MYOD. In certain embodiments, the myogenic regulatory factor is MYOG. In certain embodiments, the myogenic regulatory factor is MYF5.

[0261] In certain embodiments, the method comprises increasing IL17 secretion. In certain embodiments, the increased IL17 secretion modulates at least one of Thl7 or Tcl7 cell differentiation. In certain embodiments, the increased IL17 secretion modulates Thl7 cell differentiation. In certain embodiments, the increased IL17 secretion modulates Tcl7 cell differentiation. In certain embodiments, the increased IL17 secretion modulates Thl7 and Tcl7 cell differentiation.

[0262] In certain embodiments, the cell, tissue, or biological sample is in vivo. In certain embodiments, the cell, tissue, or biological sample is in vitro.EXAMPLES

[0263] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope.

[0264] R1, R3, R4, R5, and R6are defined as previously throughout the Examples unless otherwise specified:R3is hydrogen, -CH3, -Cl, or -Br;

[0265] General procedure for synthesis of 3-amino-2-substituted-quinazolin-4(3 / / )-one analogues: To a stirred solution of the corresponding benzol d I [1,3] oxazin-4-one (1 mmol) in EtOH (2.0 mL) was added N2H4.H2O (4.0 mL) at room temperature. After the addition was completed, the reaction mixture was heated at 100 °C for 3-4 h (monitored by TLC). After completion of the reaction, the mixture was cooled to room temperature and the solid product was formed upon addition of crushed ice. The product was filtered, dried, and collected in a pure form. The yield was quantitative in most cases.

[0266] General procedure for Suzuki-coupling with aryl boronic acids: 3-Amino-2-cyclopropyl- 6-iodoquinazolin-4(3H)-one (1.0 equiv.), aryl boronic acid (1.2 equiv.), potassium carbonate (2.5 equiv.), Pd(PPh3)4(l-6 mg, 5 mol%), 3:1 ratio of 4 mL of dioxane and water were charged into a 10 mL vial and purged with argon for 30 minutes. The reaction mixture was heated under microwave irradiation at 120 °C for 12 h. The solvent was then evaporated under reduced pressure and the crude reaction mixture was loaded on silica gel and purified by automated flash column chromatography using hexane and ethyl acetate (3:2). The products were obtained in moderate to high yields. R4can

[0267] Procedure for acetylation of Compound 19: To a stirred solution of 3-amino-2-(4-(tert- butyl)phenyl)quinazolin-4(3H)-one (100.0 mg, 0.34 mmol) in pyridine (4.0 mL) was added AC2O (69.68 mg, 0.68 mmol, 64.0pL) at room temperature. After the addition was completed, the reaction mixture was stirred at the same temperature for 12 h (monitored by TLC). After completion of the reaction, the pyridine was removed in vacuo, and the mixture was directly used for purification by flash column chromatography. Yield: 126.2 mg (Hexane / EtOAc = 8:2, 98%), Colorless solid.

[0268] Procedure for benzoylation of Compound 19: To a stirred solution of 3-amino-2-(4-(tert- butyl)phenyl)quinazolin-4(3H)-one (100.0 mg, 0.34 mmol) in pyridine (4.0 mL) was added benzoyl chloride (57.6 mg, 0.40 mmol, 47.0pL) at room temperature. After the addition was completed, the reaction mixture was stirred at the same temperature for 8 h (monitored by TLC). After completion of the reaction, the pyridine was removed in vacuo, and the mixture was directly used for purification by flash column chromatography. Yield: 121.0 mg (Hexane / EtOAc = 8:2, 90%), Colorless solid.

[0269] Procedure for Tosylation of Compound 19: To a stirred solution of 3-amino-2-(4-(tert- butyl) phenyl)quinazolin-4(3H)-one (51.0 mg, 0.17 mmol) in pyridine (2.0 mL) was added tosyl chloride (39.8 mg, 0.20 mmol) at room temperature. After the addition was completed, the reaction mixture was stirred at the same temperature for 12 h (monitored by TLC). After completion of the reaction, the pyridine was removed in vacuo, and the mixture was directly used for purification by flash column chromatography. Yield: 27.0 mg (Hexane / EtOAc = 8:2, 34%), Colorless solid.Example 2: REV-ERB Antagonist Screening.

[0270] REV-ERB antagonists were identified using methodology described in Kojetin et al., ACS Chem. Biol. 2011, 6, 2, 131-134. HEK293 cells were transfected with an expression vector directing the expression of full-length human REV-ERB[3 and a reporter vector with luciferase expression driven by a fragment of the Bmall reporter that is directly responsive to REV-ERB transcriptional activity (Solt LA, et al., Nature. 2012 Mar 29;485(7396):62-8. doi: 10.1038 / nature 11030) due to several REV-ERB DNA response elements located in the promoter. Basal luciferase activity driven by this reporter vector is under the control of REV-ERB and its natural agonist, heme, that isomnipresent (Raghuram S, et al., Nat Struct Mol Biol. 2007 Dec;14(12):1207-13. doi: 10.1038 / nsmbl344. Epub 2007 Nov 25). REV-ERB is a ligand dependent transcriptional repressor, thus heme leads to basal suppression of the luciferase reporter. REV-ERB antagonists would compete with heme leading to increased reporter activity due to their ability to suppress the action of the agonist.

[0271] HEK293 cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum at 37C under 5% CO2. Cells were seeded in 96-well plates at 25,000 cells and transfected with the expression and reporter vectors using Lipof ectamine 2000. After 24h, cells were treated with various concentrations of compounds for 24 hours followed by assessment of luciferase activity.Table 1. LC-MS and REV-ERB Luciferase Assay Data for Compounds of the PresentDisclosure.Example 3: Induction of Myogenesis by Compound 19.

[0272] Novel REV-ERB agonist compound 19 induces myogenesis in mouse primary skeletal muscle myoblasts in culture. Mouse primary skeletal muscle myoblasts were cultured as previously described (Kim KH, et al., EMBO Rep. 2023 Aug 3;24(8):e57306. doi: 10.15252 / embr.202357306. Epub 2023 Jun 19.). Cells were treated with either a control REV-ERB antagonist (SR8278; 10 p M; Welch RD, et al., Sci Rep. 2017 Dec 7;7(1): 17142. doi: 10.1038 / s41598-017-17496-7; Welch RD, et al., Mol Metab. 2017 May 19;6(7):703-714. doi: 10.1016 / j.molmet.2017.05.001) or a novel REVERB antagonist (compound 19; 10 pM), and their ability to induce myogenesis was assessed using three criteria: percentage of MyoG expressing cells, differentiation index (Yue F, et al., Cell Rep.2022 Jan 18;38(3): 110267. doi: 10.1016 / j.celrep.2021.110267), and the fusion index (Oprescu SN, et al., Skelet Muscle. 2023 Sep 13;13(1):15. doi: 10.1186 / sl3395-023-00324-0) (FIGs. 1A-1F). The magnitude of response in terms of markers of induction of differentiation was greater in the cells treated with compound 19 than in the positive control treated cells.

[0273] REV-ERB antagonist compound 19 is therapeutic in the CTX model of muscle injury, using muscle cross-sectional area as a marker of myogenesis and accelerated muscle recovery after injury. Compound 19 treatment (and SR8278 treatment (positive control)) increases the cross-sectional area of skeletal muscle fibers following injury with cardiotoxin (CTX) (FIGs. 2A-2B). Mice were dosed either twice per day with SR8278 (s.c.) or compound 19 (i.p.) for 3 days post CTX administration. *p<0.05. Individual vehicle controls were run for the two drugs as one vehicle was administered s.c. and the other i.p.INCORPORATION BY REFERENCE

[0274] The present application refers to various issued patent, published patent applications, scientific journal articles, and other publications, all of which are incorporated herein by reference. The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Figures, the Examples, and the Claims.EQUIVALENTS AND SCOPE

[0275] In the 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. Embodiments 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.

[0276] Furthermore, the disclosure 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 claims 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 disclosure or aspects of the disclosure 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. It is also noted that the terms “comprising” and “containing” 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.

[0277] 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 embodiments. Because such embodiments aredeemed 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 embodiment, for any reason, whether or not related to the existence of prior art.

[0278] 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 embodiments. 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

CLAIMSWhat is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:each of R2aand R2bis independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to formR3is hydrogen, -CH3, -Cl, or -Br;provided that:if R3is -Cl or -CH3, and R4, R5, and R6are each hydrogen, then R1is notif R4is -CH3, and R3, R5, and R6are each hydrogen, then R1is notif R4is -OCH3 or -F, and R3, R5, and R6are each hydrogen, then R1is notif R4is -Cl or -I, and R3, R5, and R6are each hydrogen, then R1is notif R4is -Br, and R3, R5, and R6are each hydrogen, then R1is notif R5is -CH3, and R3, R4, and R6are each hydrogen, then R1is notif R5is -CF3, and R3, R4, and R6are each hydrogen, then R1is notif R5is -F, and R3, R4, and R6are each hydrogen, then R1is notif R5is -Br, and R3, R4, and R6are each hydrogen, then R1is notif R6is -OCH3, and R3, R4, and R5are each hydrogen, then R1is notif R6is -Cl or -Br, and R3, R4, and R5are each hydrogen, then R1is notif R4and R5are each -F, and R3and R6are each hydrogen, then R1is notif R4and R5are each -OCH3, and R3and R6are each hydrogen, then R1is notif R4and R6are each -Br, and R3and R5are each hydrogen, then R1is notif R4, R5, and R6are each -OCH3, and R3is hydrogen, then R1is not2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R2aand R2bis hydrogen.

3. The compound of any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each of R2aand R2bis hydrogen.

4. The compound of any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein at least one of R2aand R2bis p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to form5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof,6. The compound of any one of claims 1-3 or 5, wherein the compound is of Formula (X):or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein9. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof,10. The compound of any one of claims 1-6, 8, or 9, or a pharmaceutically acceptable salt thereof,11. The compound of any one of claims 1-6 or 8-10, or a pharmaceutically acceptable salt thereof, wherein12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen or -CH3.

13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R3is -Cl or -Br.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen, -CH3, or -Cl.

15. The compound of any one of claims 1-11 or 14, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen, -CH3, -CF3, -OCH3, or -OCF3,17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R4is -F, -Cl, -Br, or -I.

18. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof,19. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof,21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof,22. The compound of any one of claims 1-17 or 19-21, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen, -CH3, -CF3, -OCH3, -F, -Cl, -Br, -I, or23. The compound of any one of claims 1-17 or 19-22, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen, -CH3, -OCH3, -Cl, -I, or24. The compound of any one of claims 1-16 or 20-23, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen, -CH3 or -CF3.

26. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R5is -OCH3, -NH2, or -NHNH2.

27. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R5is -F or -Br.

28. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen,30. The compound of any one of claims 1-26 or 29, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen or -OCH3.

31. The compound of any one of claims 1-25, 29, or 30, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen, -CH3, or -CF3.

33. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R6is -OCH3.

34. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R6is -Cl or -Br.

35. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof,36. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen, -CH3, -OCH3, -Cl, or -Br.

37. The compound of any one of claims 1-34 or 36, or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen, -OCH3, or -Cl.

38. The compound of any one of claims 1-32, 36, or 37, or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen.

39. The compound of any one of claims 1-38, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

40. A composition comprising the compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, and an excipient.

41. A compound of Formula (!') :or a pharmaceutically acceptable salt thereof, wherein:each of R2aand R2bis independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R2aand R2bare joined together with their intervening nitrogen atom to formR3is hydrogen, -CH3, -Cl, or -Br;42. The compound of claim 41, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

43. A composition comprising the compound of any one of claims 41 or 42, or a pharmaceutically acceptable salt thereof, and an excipient.

44. A method of binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of: a compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof; or the composition of claim 40.

45. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, or the composition of claim 40, for use in binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample.

46. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, or the composition of claim 40, for use in the manufacture of a medicament for binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample.

47. A method of binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of:a compound of any one of claims 41 or 42, or a pharmaceutically acceptable salt thereof; or the composition of claim 43.

48. The compound of any one of claims 41 or 42, or a pharmaceutically acceptable salt thereof, or the composition of claim 43, for use in binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample.

49. The compound of any one of claims 41 or 42, or a pharmaceutically acceptable salt thereof, or the composition of claim 43, for use in the manufacture of a medicament for binding REV-ERB in a subject in need thereof or in a cell, tissue, or biological sample.

50. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 44-49, wherein binding REV-ERB comprises binding REVERB a.

51. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 44-50, wherein binding REV-ERB comprises binding REV- ERBp.

52. A method of inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of: a compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof; or the composition of claim 40.

53. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, or the composition of claim 40, for use in inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample.

54. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, or the composition of claim 40, for use in the manufacture of a medicament for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample.

55. A method of inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of: a compound of any one of claims 41 or 42, or a pharmaceutically acceptable salt thereof; orthe composition of claim 43.

56. The compound of any one of claims 41 or 42, or a pharmaceutically acceptable salt thereof, or the composition of claim 43, for use in inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample.

57. The compound of any one of claims 41 or 42, or a pharmaceutically acceptable salt thereof, or the composition of claim 43, for use in the manufacture of a medicament for inhibiting cell proliferation or promoting apoptosis in a subject in need thereof or in a cell, tissue, or biological sample.

58. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 44-57, wherein the cell, tissue, or biological sample is in vivo.

59. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 44-57, wherein the cell, tissue, or biological sample is in vitro.

60. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 44-59, wherein binding REV-ERB comprises inhibiting REV-ERB.

61. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 44-60, wherein inhibiting REV-ERB comprises inhibiting at least one of REV-ERBa and REV-ERBp.

62. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 44-61, comprising inducing myogenesis in the subject or in the cell, tissue, or biological sample.

63. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 44-62, comprising increasing an amount of one or more myogenesis gene markers.

64. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of claim 63, wherein the one or more myogenesis gene markers are Myod, Myodl, Myf5, Myog, Myog5, p21, Mhcl , Mhc2, Mhc2b, Mhc2x, Mhc3, or a combination thereof.

65. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 1-64, comprising increasing an amount of one or more mitochondrial biogenesis gene markers.

66. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of claim 65, wherein the one or more mitochondrial biogenesis gene markers are Tfam, Pgcla, Nampt, Sirt3, Nrfl, or a combination thereof.

67. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 1-66, comprising increasing an amount of one or more myogenic regulatory factors.

68. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of claim 67, wherein the one or more myogenic regulatory factors are MYOD, MYOG, MYF5, or a combination thereof.

69. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 1-68, comprising increasing IL 17 secretion.

70. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of claim 69, wherein the increased IL17 secretion modulates at least one of Thl7 or Tcl7 cell differentiation.

71. A method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of: the compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof; or the composition of claim 40.

72. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, or the composition of claim 40, for use in treating a disease in a subject in need thereof.

73. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, or the composition of claim 40, for use in the manufacture of a medicament for treatment of a disease in a subject in need thereof.

74. A method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of: the compound of any one of claims 41 or 42, or a pharmaceutically acceptable salt thereof; or the composition of claim 43.

75. The compound of any one of claims 41 or 42, or a pharmaceutically acceptable salt thereof, or the composition of claim 43, for use in treating a disease in a subject in need thereof.

76. The compound of any one of claims 41 or 42, or a pharmaceutically acceptable salt thereof, or the composition of claim 43, for use in the manufacture of a medicament for treatment of a disease in a subject in need thereof.

77. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 71-76, wherein the disease is associated with REV-ERB.

78. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 71-77, wherein the disease is a muscular disease.

79. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 71-78, wherein the disease is sarcopenia or Duchenne muscular dystrophy (DMD).

80. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 71-79, comprising increasing a number of satellite cells in dystrophic muscle in the subject.

81. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 71-80, comprising reducing fibrosis in dystrophic muscle in the subject.

82. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 71-81, comprising increasing a muscle fiber cross-sectional area in the subject.

83. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 71-82, wherein the subject has suffered an injury to one or more muscles.

84. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 71-83, comprising improving muscle regeneration in the subject.

85. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 71-84, comprising increasing a rate of muscle regeneration in the subject.

86. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 71-85, comprising inducing muscle hypertrophy in the subject.

87. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 71-86, comprising increasing grip strength in the subject.

88. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 71-87, comprising increasing lean mass in the subject.

89. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of any one of claims 71-76, wherein the disease is a proliferative disease.

90. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of claim 89, wherein the proliferative disease is cancer.

91. The method, compound for use, pharmaceutically acceptable salt thereof for use, or composition for use of claim 90, wherein the cancer is adenocarcinoma, lung cancer, non-small cell lung cancer (NSCLC), esophageal cancer, cervical cancer, gastric cancer, colorectal cancer, brain cancer, glioblastoma, or adrenocortical carcinoma.

92. A kit comprising: the compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, or the composition of claim 40;and instructions for its use.

93. A kit comprising: the compound of any one of claims 41 or 42, or a pharmaceutically acceptable salt thereof, or the composition of claim 43; and instructions for its use.

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