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WO2025024550A1 - Antagonistes rev-erb - Google Patents

Antagonistes rev-erb Download PDF

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Publication number
WO2025024550A1
WO2025024550A1 PCT/US2024/039337 US2024039337W WO2025024550A1 WO 2025024550 A1 WO2025024550 A1 WO 2025024550A1 US 2024039337 W US2024039337 W US 2024039337W WO 2025024550 A1 WO2025024550 A1 WO 2025024550A1
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compound
pharmaceutically acceptable
acceptable salt
hydrogen
certain embodiments
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Bahaa ELGENDY
Lamees HEGAZY
Thomas Burris
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University of Florida
University of Florida Research Foundation Inc
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University of Florida
University of Florida Research Foundation Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/92—Oxygen atoms with hetero atoms directly attached to nitrogen atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • REV-ERB ANTAGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS 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.
  • 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-ERB ⁇ and REV-ERB ⁇ has been shown to increase expression of markers of myogenesis. Reduced expression of REV-ERB ⁇ results in increased muscle mass and grip strength in mouse models, and allows for more rapid recovery from a muscle injury.
  • REV-ERB e.g., REV-ERB ⁇ and REV-ERB ⁇
  • Pharmacological inhibition of REV-ERB 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).
  • diseases such as sarcopenia and Duchenne muscular dystrophy (DMD).
  • DMD Duchenne muscular dystrophy
  • 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.
  • IL-17 interleukin 17
  • each of R 2a and R 2b is independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R 2a and R 2b are joined together with their intervening nitrogen atom to form
  • R 3 is hydrogen, -CH 3 , -Cl, or -Br;
  • R 3 is -Cl or -CH3, and R 4 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -CH3, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -OCH3 or -F, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -Cl or -I, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -Br, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 5 is -CH3, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is not if R 5 is -CF3, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is not if R 5 is -F, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is
  • the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein.
  • the pharmaceutical composition comprises an excipient.
  • 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.
  • 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))).
  • a muscular disease e.g., sarcopenia, Duchenne muscular dystrophy (DMD)
  • a proliferative disease e.g., cancer (e.g., adenocarcinoma, lung cancer (e.g., non
  • 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.
  • the cell, tissue, or biological sample is in vivo.
  • the cell, tissue, or biological sample is in vitro.
  • the method comprises binding REV-ERB (e.g., REV- ERBa, REV-ERBP).
  • kits comprising a provided compound or pharmaceutical composition disclosed herein and instructions for its use.
  • 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.
  • FIGs. ID MyoG expressing cells
  • FIG. IE differentiation index
  • FIG. IF fusion index
  • FIG. 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.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • 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.
  • 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.
  • 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.
  • aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • 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 (“C 1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1–7 alkyl”).
  • an alkyl group has 1 to 6 carbon atoms (“C 1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • C 1–6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2- butanyl, tert-amyl), and hexyl (C 6 ) (e.g., n-hexyl).
  • alkyl groups include n- heptyl (C 7 ), n-octyl (C 8 ), n-dodecyl (C 12 ), 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).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C 1–12 alkyl (such as unsubstituted C 1–6 alkyl, e.g., ⁇ CH 3 (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)).
  • unsubstituted C 1–12 alkyl such as unsubstituted C 1–6 alkyl, e.g.
  • 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)).
  • 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.
  • the haloalkyl moiety has 1 to 20 carbon atoms (“C1–20 haloalkyl”).
  • the haloalkyl moiety has 1 to 10 carbon atoms (“C1–10 haloalkyl”).
  • the haloalkyl moiety has 1 to 9 carbon atoms (“C1–9 haloalkyl”).
  • 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”).
  • 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.
  • haloalkyl groups include –CHF2, ⁇ CH2F, ⁇ CF3, ⁇ CH2CF3, ⁇ CF 2 CF 3 , ⁇ CF 2 CF 2 CF 3 , ⁇ CCl 3 , ⁇ CFCl 2 , ⁇ CF 2 Cl, and the like.
  • 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.
  • a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–20 alkyl”). 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 (“heteroC 1–12 alkyl”). 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 (“heteroC 1–11 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“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 (“heteroC 1–7 alkyl”).
  • 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”).
  • 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.
  • the heteroalkyl group is an unsubstituted heteroC1–12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–12 alkyl.
  • 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”).
  • 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 (“C 2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2–6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms (“C 2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2–4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2–6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • the alkenyl group is an unsubstituted C 2-20 alkenyl.
  • the alkenyl group is a substituted C2-20 alkenyl.
  • 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.
  • 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”).
  • 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”).
  • 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 (“heteroC 2–8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–7 alkenyl”).
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2–5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2–4 alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2–3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2–6 alkenyl”).
  • each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents.
  • the heteroalkenyl group is an unsubstituted heteroC 2–20 alkenyl.
  • the heteroalkenyl group is a substituted heteroC 2–20 alkenyl.
  • 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 (“C 2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”).
  • 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).
  • C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.
  • C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like.
  • alkynyl examples 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.
  • 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.
  • 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”).
  • 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– 10 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–8 alkynyl”).
  • a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2–5 alkynyl”).
  • a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2–4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2–3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2 alkynyl”).
  • 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.
  • carbocyclyl 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.
  • a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”).
  • a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”).
  • a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”).
  • 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”).
  • 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 (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3-10 carbocyclyl groups include the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include the aforementioned C 3-10 carbocyclyl groups as well as cycloundecyl (C 11 ), spiro[5.5]undecanyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl.
  • the carbocyclyl group is a substituted C3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”).
  • a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”).
  • 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).
  • C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is an unsubstituted C3-14 cycloalkyl.
  • the cycloalkyl group is a substituted C3-14 cycloalkyl.
  • 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”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3–14 membered heterocyclyl.
  • 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.
  • 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”).
  • 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”).
  • 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”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • 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]diaze
  • 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 (“C 6-14 aryl”).
  • aromatic ring system e.g., having 6, 10, or 14 pi electrons shared in a cyclic array
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is an unsubstituted C6-14 aryl.
  • the aryl group is a substituted C6-14 aryl.
  • “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.
  • 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”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, 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).
  • 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.
  • 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.
  • 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”).
  • 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”).
  • 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”).
  • the 5-6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include 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.
  • 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.
  • the term “unsaturated bond” refers to a double or triple bond.
  • the term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
  • 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.
  • 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
  • heteroarylene is the divalent moiety of heteroaryl.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • 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).
  • 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.
  • 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.
  • 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.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the invention is not limited in any manner by the exemplary substituents described herein.
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, ⁇ OR aa , ⁇ SR aa , ⁇ N(R bb )2, –CN, –SCN, or –NO2.
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1–10 alkyl, ⁇ OR aa , ⁇ SR aa , ⁇ N(R bb )2, – CN, –SCN, or –NO 2 , wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C 1–10 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-pyr
  • 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.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms.
  • halo or “halogen” refers to fluorine (fluoro, ⁇ F), chlorine (chloro, ⁇ Cl), bromine (bromo, ⁇ Br), or iodine (iodo, ⁇ I).
  • hydroxyl or “hydroxy” refers to the group ⁇ OH.
  • thiol refers to the group –SH.
  • amino refers to the group ⁇ NH2.
  • 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.
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from ⁇ N(R bb ) 3 and ⁇ N(R bb ) 3 + X ⁇ , wherein R bb and X ⁇ are as defined herein.
  • sulfonyl refers to a group selected from –SO 2 N(R bb ) 2 , –SO 2 R aa , and –SO 2 OR aa , wherein R aa and R bb are as defined herein.
  • 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, alkyl
  • sil refers to the group –Si(R aa ) 3 , wherein R aa is as defined herein.
  • phosphino refers to the group –P(R cc ) 2 , wherein R cc is as defined herein.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • 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.
  • the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • each nitrogen protecting group 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
  • each nitrogen protecting group 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
  • each nitrogen protecting group 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),
  • Ts p-toluenesulfonamide
  • each nitrogen protecting group 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-dibenzy
  • two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine.
  • at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
  • 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.
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • each oxygen protecting group 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-methoxycycl
  • At least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.
  • 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.
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”).
  • 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.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms.
  • 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 – ), NO 3 – , ClO 4 – , OH – , H 2 PO 4 – , HCO 3 ⁇ , HSO 4 – , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5– sulfonate, ethan–1–sulfonic
  • Exemplary counterions which may be multivalent include CO3 2 ⁇ , HPO 4 2 ⁇ , PO 4 3 ⁇ , B 4 O 7 2 ⁇ , SO 4 2 ⁇ , S 2 O 3 2 ⁇ , 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.
  • 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
  • carboranes e.g., tartrate, citrate, fumarate, maleate, mal
  • a “leaving group” 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.
  • 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).
  • 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.
  • the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy.
  • 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.
  • phosphineoxide e.g., formed during a Mitsunobu reaction
  • Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper
  • non-hydrogen group refers to any group that is defined for a particular variable that is not hydrogen.
  • salt refers to any and all salts and encompasses pharmaceutically acceptable salts.
  • 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.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • 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.
  • 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, per
  • 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.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • 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.
  • 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, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1–4 alkyl)4- salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • 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.
  • 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.
  • 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.
  • 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 H 2 O, 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 H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H2O) and hexahydrates (R ⁇ 6 H2O)).
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition.
  • 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 an atom, 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.
  • 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.
  • 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.
  • Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound.
  • 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.
  • 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.
  • 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.
  • the isotope enriched above its natural abundance is 2 H.
  • the isotope enriched above its natural abundance is 13 C, 15 N, or 18 O.
  • prodrugs refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include 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.
  • the terms “pharmaceutical composition,” “composition,” and “formulation” are used interchangeably.
  • 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.
  • 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)).
  • 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.
  • patient refers to a human subject in need of treatment of a disease.
  • tissue 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).
  • 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) or samples of cells obtained by microdissection
  • samples of whole organisms such as samples of yeasts or bacteria
  • cell fractions, fragments or organelles such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise.
  • 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.
  • administered refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a pharmaceutical composition thereof, in or on a subject.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease.
  • 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.
  • 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.
  • 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.
  • the subject is at risk of developing a disease or condition due to environmental factors (e.g., exposure to the sun).
  • 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.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactic treatment.
  • an effective amount is the amount of a compound described herein in a single dose.
  • an effective amount is the combined amounts of a compound described herein in multiple doses.
  • 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.
  • 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).
  • 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.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • a “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • 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.
  • 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.,
  • 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%).
  • 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%).
  • inhibiting REV-ERB comprises inhibiting at least one of REV-ERB ⁇ and REV-ERB ⁇ .
  • 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.
  • the prophylactically effective amount is an amount that improves overall prophylaxis and/or enhances the prophylactic efficacy of another prophylactic agent.
  • 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.
  • a disease or disorder e.g., a disease associated with REV-ERB (e.g., a muscular disease (e.
  • 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.
  • 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.,
  • 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 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%).
  • 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%).
  • inhibiting REV-ERB comprises inhibiting at least one of REV-ERB ⁇ and REV- ERB ⁇ .
  • 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.
  • 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), med
  • 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.
  • HCC hepatocellular cancer
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma 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
  • pancreatic cancer e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors
  • a proliferative disease refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases)
  • the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
  • 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.
  • 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).
  • VEGF growth factors
  • “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and/or is associated with a disease.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the term “inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation.
  • the term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death.
  • An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes.
  • Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, per
  • An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.
  • 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 cardio
  • each of R 2a and R 2b is independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R 2a and R 2b are joined together with their intervening nitrogen atom to form
  • R 3 is hydrogen, -CH 3 , -Cl, or -Br;
  • R 3 is -Cl or -CH3, and R 4 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -CH3, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -OCH3 or -F, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -Cl or -I, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -Br, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 5 is -CH3, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is not if R 5 is -CF3, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is not if R 5 is -F, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is
  • each of R 2a and R 2b is independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R 2a and R 2b are joined together with their intervening nitrogen atom to form R 3 is hydrogen, -CH 3 , -Cl, or -Br;
  • R 1 is certain embodiments, certain embodiments, R 1 is embodiments, embodiments, embodiments, embodiments, certain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, embodiments, R 1 is . In certain embodiments, R 1 embodiments, certain embodiments, R 1 i certain embodiments, [0114] In certain embodiments, R 1 is not . In certain embodiments, R 1 is not certain embodiments, R 1 is not . In certain embodiments, R 1 is not embodiments, embodiments, embodiments,
  • R 1 is not certain embodiments, R 1 is not
  • each of R 2a and R 2b is independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R 2a and R 2b are joined together with their intervening nitrogen atom to form
  • At least one of R 2a and R 2b is hydrogen. In certain embodiments, each of R 2a and R 2b is hydrogen. In certain embodiments, at least one of R 2a and R 2b is p-toluenesulfonyl, acetyl, or benzoyl, or R 2a and R 2b are joined together with their intervening nitrogen atom to form . In certain embodiments, at least one of R 2a and R 2b is p-toluenesulfonyl. In certain embodiments, at least one of R 2a and R 2b is acetyl. In certain embodiments, at least one of R 2a and R 2b is benzoyl.
  • R 2a and R 2b are joined together with their intervening nitrogen atom to form .
  • at least one of R 2a and R 2b is hydrogen, and at least one of R 2a and R 2b is p-toluenesulfonyl.
  • each of R 2a and R 2b is acetyl.
  • at least one of R 2a and R 2b is hydrogen, and at least one of R 2a and R 2b is benzoyl.
  • R 3 is hydrogen, -CH3, -Cl, or -Br. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is -CH3. In certain embodiments, R 3 is -Cl or -Br. In certain embodiments, R 3 is -Cl. In certain embodiments, R 3 is -Br. In certain embodiments, R 3 is hydrogen, - CH3, or -Cl. In certain embodiments, R 3 is hydrogen or -CH3. In certain embodiments, R 3 is -CH3 - Cl. In certain embodiments, R 3 is hydrogen or -Cl.
  • R 3 is not hydrogen. In certain embodiments, R 3 is not -CH3. In certain embodiments, R 3 is not -Cl. In certain embodiments, R 3 is not -Br.
  • R 4 is hydrogen, -CH3, -CF3, -OCH3, -OCF3, -F, -Cl, -Br, -I,
  • R 4 is hydrogen. In certain embodiments, R 4 is -CH3, -CF3, -OCH3, or -OCF3. In certain embodiments, R 4 is -CH3. In certain embodiments, R 4 is -CF3. In certain embodiments, R 4 is -OCH3. In certain embodiments, R 4 is -OCF3. In certain embodiments, R 4 is -F, - Cl, -Br, or -I. In certain embodiments, R 4 is -F. In certain embodiments, R 4 is -Cl. In certain , certain embodiments, R 4 is certain embodiments, R 4 is . In certain embodiments, . In certain embodiments, R 4 is hydrogen.
  • R 4 is not hydrogen. In certain embodiments, R 4 is not -CH 3 . In certain embodiments, R 4 is not -CF 3 . In certain embodiments, R 4 is not -OCH 3 . In certain embodiments, R 4 is not -OCF 3 . In certain embodiments, R 4 is not -F. In certain embodiments, R 4 is not -Cl. In certain embodiments, R 4 is not -Br. In certain embodiments, R 4 is not -I. In certain embodiments, R 4 is not .
  • R 4 is not certain embodiments, R 4 is not certain embodiments, R 4 is not certain embodiments, R 4 is not certain embodiments, R 4 is not certain embodiments, R 4 is not certain embodiments, R 4 is not in embodiments, R 4 is not certain embodiments, R 4 is not in embodiments, R 4 is not . In certain embodiments, R 4 is . In certain embodiments, R 4 is not embodiments, R 4
  • R 4 is not . In certain embodiments, R 4 is not
  • R 5 is hydrogen, -CH3, -CF3, -OCH3, -NH2, -NHNH2, -F, -Br,
  • R 5 is hydrogen. In certain embodiments, R 5 is -CH3 or -CF3. In certain embodiments, R 5 is -CH3. In certain embodiments, R 5 is -CF3. In certain embodiments, R 5 is - OCH3, -NH2, or -NHNH2. In certain embodiments, R 5 is -OCH3. In certain embodiments, R 5 is - NH2. In certain embodiments, R 5 is -NHNH2. In certain embodiments, R 5 is -F or -Br. In certain embodiments, R 5 is -F. In certain embodiments, R 5 is -Br. In certain embodiments, R 5 is a
  • R 5 is hydrogen
  • R 5 is hydrogen or -OCH3. In certain embodiments, R 5 is hydrogen. [0128] In certain embodiments, R 5 is not hydrogen. In certain embodiments, R 5 is not -CH3. In certain embodiments, R 5 is not -CF3. In certain embodiments, R 5 is not -OCH3. In certain embodiments, R 5 is not -NH2. In certain embodiments, R 5 is not -NHNH2. In certain embodiments,
  • R 5 is not -F. In certain embodiments, R 5 is not -Br. In certain embodiments, R 5 is not certain embodiments, R 5 is not F
  • R 6 is hydrogen
  • R 6 is hydrogen. In certain embodiments, R 6 is -CH3 or -CF3. In certain embodiments, R 6 is -CH3. In certain embodiments, R 6 is -CF3. In certain embodiments, R 6 is - OCH3. In certain embodiments, R 6 is -Cl or -Br. In certain embodiments, R 6 is -Cl. In certain embodiments, R 6 is -Br. In certain embodiments, . In certain embodiments, R 6 is , certain embodiments, R 6 is ,
  • R 6 is -CH3, -OCH3, -Cl, or -Br. In certain embodiments, R 6 is hydrogen, -OCH3, or -Cl. In certain embodiments, R 6 is hydrogen.
  • R 6 is not hydrogen. In certain embodiments, R 6 is not -CH3. In certain embodiments, R 6 is not -CF3. In certain embodiments, R 6 is not -OCH3. In certain embodiments, R 6 is not -Cl. In certain embodiments, R 6 is not -Br. In certain embodiments, R 6 is not . In certain embodiments, R 6 is not certain embodiments, R 6 is not certain embodiments, R 6 is not certain embodiments, R 6 is not hydrogen. In certain embodiments, R 6 is not -CH3. In certain embodiments, R 6 is not -CF3. In certain embodiments, R 6 is not -OCH3. In certain embodiments, R 6 is not -Cl. In certain embodiments, R 6 is not -Br. In certain embodiments, R 6 is not . In certain embodiments, R 6 is not certain embodiments, R 6 is not certain embodiments, R 6 is not certain embodiments, R 6 is not hydrogen. In certain embodiments, R 6 is not -CH3. In certain embodiments, R 6
  • each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH3, or -Cl; R 4 is hydrogen,
  • R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br.
  • each of R 3 , R 4 , R 5 , and R 6 is hydrogen. In certain embodiments, each
  • R 4 , R 5 , and R 6 is hydrogen. In certain embodiments, R 1 is
  • R 3 , R 4 , R 5 , and R 6 is hydrogen.
  • the compound is of Formula (I-b): or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (I- each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH3, or -Cl; R 4 is hydrogen, -CH3, -CF3, -OCH3, -
  • each of R 2a and R 2b is hydrogen; R 3 is hydrogen; R 4 is hydrogen, -
  • R 3 is hydrogen, -CH3, or -Cl; and each of R 4 , R 5 , and R 6 is hydrogen. In certain embodiments, R 3 is hydrogen, -CH3, or -Cl; and each of R 2a and R 2b is hydrogen. In certain embodiments, R 3 is hydrogen, -CH3, or -Cl; and each of R 2a , R 2b , R 4 , R 5 , and R 6 is is hydrogen, -CH3, or -Cl; and each of R 4 , R 5 , and R 6 is hydrogen. In certain embodiments, R 1 is is hydrogen, -CH3, or -Cl; and each of R 4 , R 5 , and R 6 is hydrogen. In certain embodiments, R 1 is
  • the compound is of Formula (I-c): or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (I- c), wherein R 3 is hydrogen, -CH3, or -Cl.
  • the compound is of Formula (I-c), certain embodiments, the compound is of hydrogen, -CH3, or -Cl.
  • each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH3, or -Cl; R 4 is each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH3, or -Cl; R 4 is hydrogen, -CH3, -OCH3, -Cl, -I, s hydrogen, -CH3, -OCH3, -Cl, or -Br.
  • each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH3, or -Cl; R 4 is hydrogen; R 3 is hydrogen, -CH3, or -Cl; R 4 is hydrogen, -CH3, -CF3, -OCH3, -F, -Cl, -Br, -I, or hydrogen, -CH3, -OCH3, -Cl, or -Br.
  • each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH3, or -Cl; R 4 is [0144] In certain embodiments, each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH3, or -Cl; R 4 is hydrogen; R 5 is hydrogen, s hydrogen, - ; each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH3, or -Cl; R 4 is hydrogen; R 5 is hydrogen, s hydrogen, -CH3, -OCH3,
  • R 2a , R 2b , R 3 , R 5 , and R 6 is hydrogen.
  • R 1 is
  • each of R 2a , R 2b , R 3 , R 5 , and R 6 is hydrogen.
  • each of R 2a and R 2b is hydrogen.
  • R 4 is hydrogen, -CH3, -OCH3, -Cl, -I,
  • R 4 is hydrogen, -CH3, -CF3, -OCH3, -F, -Cl, -Br, -I, or embodiments, R 4 is hydrogen, -CH3, -CF3, -OCH3, -F, -Cl, -Br, -I, or ; and each of each of R 3 , R 5 , and R 6 is hydrogen.
  • R 1 is of R 2a and R 2b is hydrogen.
  • R 1 is of R 2a , R 2b , R 3 , R 5 , and R 6 is hydrogen.
  • R 4 is hydrogen, -CH3, -OCH3, -Cl, -I, or ; and each of
  • R 3 , R 5 , and R 6 is hydrogen.
  • R 4 is hydrogen, -CH3, -OCH3, -Cl, -I, or embodiments,
  • R 2a , R 2b , R 3 , R 5 , and R 6 is hydrogen.
  • R 6 is hydrogen.
  • R 1 is each of R 2a and R 2b is hydrogen.
  • R 1 is each of R 2a , R 2b , R 3 , R 5 , and R 6 is hydrogen.
  • each of R 3 , R 5 , and R 6 is hydrogen.
  • R 1 is each of R 2a and R 2b is hydrogen.
  • each of R 2a , R 2b , R 3 , R 5 , and R 6 is hydrogen.
  • each of R 3 , R 5 , and R 6 is hydrogen. In certain embodiments,
  • R 4 is hydrogen, each of R 2a and R 2b is hydrogen. In certain embodiments,
  • R 4 is hydrogen
  • each of R 2a , R 2b , R 3 , R 5 , and R 6 is hydrogen. hydrogen, -CH3, -OCH3, -Cl, -I, or ; and each of R 2a and R 2b is hydrogen. In certain embodiments, each of R 2a , R 2b , R 3 , R 5 , and R 6 is hydrogen.
  • the compound is of Formula (I-d): or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (I- certain embodiments, the compound is of Formula (I-d), wherein R 4 is hydrogen, -CH3, -OCH3, -Cl, certain embodiments, the compound is of Formula (I-d), wherein R 4 is hydrogen, -CH3, -CF3, -OCH3, -F, -Cl, -Br, -I, or .
  • the compound is of Formula (I-d), wherein R 4 is hydrogen, -
  • the compound is of Formula (I-d), compound is of Formula (I-d), wherein R 1 is
  • the compound is of Formula (I-d), wherein R 1 is
  • the compound is of Formula (I-d), wherein R 1 is certain embodiments, the compound is of Formula (I-d), OCH 3 , -F, -Cl, -Br, -I, or . In certain embodiments, the compound is of Formula (I-d),
  • each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH 3 , or -Cl; R 4 is hydrogen or -OCH 3 ; and R 6 is hydrogen, -CH 3 , -OCH 3 , -Cl, or -Br.
  • R 1 is
  • each of R 2a and R 2b is hydrogen;
  • R 3 is hydrogen, -CH3, or -Cl;
  • R 4 is
  • R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br.
  • R 5 is hydrogen, and each of R 3 , R 4 , and R 6 is hydrogen.
  • R 5 is hydrogen, -CH3, -CF3, -OCH3, each of R 2a and R 2b is hydrogen.
  • R 5 is jQ hydrogen, -CH3, -CF3, -OCH3, -NH2, -F, or F ; and each of R 2a , R 2b , R 3 , R 4 , and R 6 is hydrogen.
  • R 1 is is hydrogen, each of R 3 , R 4 , and R 6 is is hydrogen, each of R 2a and R 2b is hydrogen.
  • R 5 is hydrogen or -OCH3; and each of R 3 , R 4 , and R 6 is hydrogen. In certain embodiments, R 5 is hydrogen or -OCH3; and each of R 2a and R 2b is hydrogen. In certain embodiments, R 5 is hydrogen or -OCH3; and each of R 2a , R 2b , R 3 , R 4 , and R 6 is hydrogen. In certain is hydrogen or -OCH3; and each of R 2a , R 2b , R 3 , R 4 , and R 6 is hydrogen.
  • R 5 is hydrogen, each of R 3 , R 4 , and R 6 is hydrogen. In certain embodiments,
  • R 5 is hydrogen, each of R 2a and R 2b is hydrogen.
  • R 5 is hydrogen, each of R 2a , R 2b , R 3 , R 4 , and
  • R 6 is hydrogen
  • R 5 is hydrogen or -OCH3; and each of R 3 , R 4 , and R 6 is hydrogen.
  • R 1 is s hydrogen or -OCH3; and each of R 2a , R 2b , R 3 , R 4 , and R 6 is hydrogen.
  • the compound is of Formula (I-e): or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (I e), wherein R 5 is hydrogen, -CH3, -CF3, -OCH3, -NH2, -F, or F .
  • the compound is of Formula (I-e), wherein R 5 is hydrogen or -OCH3.
  • p p
  • the compound is of Formula (I-e), wherein R 1 is certain embodiments, the compound is of Formula (I-e),
  • the compound is of
  • each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH 3 , or -Cl; R 4 is hydrogen; R 3 is hydrogen, -CH3, or -Cl; R 4 is hydrogen, -CH3, -CF3, -OCH3, -F, -Cl, -Br, -I,
  • R 6 is hydrogen, -OCH3, or -Cl.
  • each of R 2a and R 2b is hydrogen;
  • R 3 is hydrogen, -CH3, or -Cl;
  • R 4 is
  • R 6 is hydrogen
  • R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br; and each of R 3 , R 4 , and R 5 is hydrogen.
  • R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br; and each of R 2a and R 2b is hydrogen.
  • R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br; and each of is hydrogen, -CH3, -OCH3, -Cl, or -Br; and each of R 2a and R 2b is hydrogen.
  • each of R 2a , R 2b , R 3 , R 4 , and R 5 is hydrogen.
  • R 6 is hydrogen, -OCH3, or -Cl; and each of R 3 , R 4 , and R 5 is hydrogen. In certain embodiments, R 6 is hydrogen, -OCH3, or -Cl; and each of R 1 ' and R 2b is hydrogen. In certain embodiments, R 6 is hydrogen, -OCH3, or -Cl; and each of R 2 ' 1 . R 2b , R 3 , R 4 , and is hydrogen, -OCH3, or -Cl; and each of R 3 , R 4 , and R 5 is hydrogen. In certain embodiments, R 1 is ; R 6 is hydrogen, -OCH3, or -Cl; and each of R 2a , R 2b , R 3 , R 4 , and R 5 is hydrogen. [0167] In certain embodiments,
  • R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br; and each of R 3 , R 4 , and R 5 is hydrogen. In certain embodiments,
  • R 1 is s hydrogen, -CH3, -OCH3, -Cl, or -Br; and each of R 2a , R 2b , R 3 , R 4 , and R 5 is hydrogen.
  • R 6 is hydrogen, -OCH3, or -Cl; and each of R 3 , R 4 , and R 5 is hydrogen.
  • R 1 is s hydrogen, -OCH3, or -Cl; and each of R 2a , R 2b , R 3 , R 4 , and R 5 is hydrogen.
  • the compound is of Formula (I-f) : or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (I- f), wherein R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br.
  • the compound is of Formula (I-f), wherein R 6 is hydrogen, -OCH3, or -Cl.
  • the compound is of
  • R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br. In certain embodiments, the
  • R 6 is hydrogen, -OCH3, or -Cl.
  • the compound is of Formula (I-f), wherein R 1 is certain embodiments, the compound is of Formula (I-f), wherein
  • the compound is of Formula (I-f), wherein R 1 is
  • each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH3, or -Cl; each of R 4 and R 5 is -OCH3; and R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br.
  • each of R 2a , R 2b , R 3 , and R 6 is hydrogen; and each of R 4 and R 5 is -OCH3.
  • R 1 is hydrogen, -CH3, or -Cl; each of R 4 and R 5 is -OCH3; and R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br. and R 6 is hydrogen; and each of R 4 and R 5 is -OCH3.
  • each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH3, or -Cl; each of R 4 and R 5 is -OCH3; and R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br.
  • R 1 is each of R 2a , R 2b , R 3 , and R 6 is hydrogen; and each of R 4 and
  • R 5 is -OCH3.
  • each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH3, or -Cl; each of R 4 and R 5 is -F; and R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br. In certain embodiments, each of
  • R 2a , R 2b , R 3 , and R 6 is hydrogen; and each of R 4 and R 5 is -F.
  • R 1 is ; each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH3, or
  • each of R 4 and R 5 is -F; and R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br. In certain embodiments, and each of R 4 and R 5 is -F.
  • each of R 2a and R 2b is hydrogen; R 3 is hydrogen, -CH3, or -Cl; each of R 4 and R 5 is -F; and R 6 is hydrogen, -CH3, -OCH3, -Cl, or -Br.
  • R 1 is each of R 2a , R 2b , R 3 , and R 6 is hydrogen; and each of R 4 and
  • R 5 is -F.
  • the compound is of Formula (I-g): or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (I- g), wherein each of R 4 and R 5 is -OCH3.
  • the compound is of Formula (I-g), wherein each of R 4 and R 5 is -F.
  • the compound is of Formula (I-g), wherein is -OCH3.
  • the compound is of Formula (I-g), wherein R 1 is compound is of Formula (I-g), wherein R 1 is embodiments, the compound is of Formula (I-g), wherein R 1 is
  • the compound of Formula (I) is of formula:
  • the compound of Formula (I) is not of formula:
  • the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutical
  • the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is not of formula pharmaceutical
  • the compound of Formula (I') is of formula:
  • 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.
  • a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a provided compound is a compound of Formula (I'), or a pharmaceutically acceptable salt thereof.
  • a provided compound is a compound of any of the formulae herein (e.g., Formula (I), Formula (I')), or a salt thereof.
  • the present disclosure provides pharmaceutical compositions comprising a provided compound.
  • the pharmaceutical composition comprises one or more excipients.
  • the pharmaceutical compositions described herein comprise a provided compound and an excipient.
  • the pharmaceutical composition comprises an effective amount of the provided compound.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophy tactically effective amount.
  • 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.
  • 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.
  • 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., adeno
  • 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.
  • 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., a
  • 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.
  • 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.
  • 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.
  • the subject is a companion animal, such as a dog or cat.
  • the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.
  • the animal is a genetically engineered animal.
  • the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs).
  • the subject is a fish or reptile.
  • 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.
  • 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.
  • 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%).
  • 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.
  • the amount effective for inhibiting REV-ERB is effective for inhibiting at least one of REV-ERBa and REV-ERBp.
  • 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.
  • 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., adenocar
  • 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.
  • 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., adeno
  • 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.
  • a provided compound or pharmaceutical composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents).
  • the 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 need thereof
  • the additional pharmaceutical agents employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • 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.
  • the additional pharmaceutical agent achieves a desired effect for the same disorder.
  • the additional pharmaceutical agent achieves different effects.
  • 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.
  • CFR Code of Federal Regulations
  • proteins 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.
  • CFR Code of Federal Regulations
  • the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or 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)))).
  • 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., adeno
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions 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.
  • 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.
  • 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.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • 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, cell
  • 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
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • 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.
  • 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.
  • EDTA ethylenediaminetetraacetic acid
  • 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 mono
  • 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.
  • 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.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • 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.
  • 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®.
  • 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
  • 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.
  • 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
  • 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.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • 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.
  • inert diluents commonly used in the art such as, for example, water or other solvents, so
  • the oral pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • 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.
  • the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • 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 g
  • 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.
  • encapsulating compositions which can be used include polymeric substances and waxes.
  • 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.
  • 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.
  • 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.
  • encapsulating agents which can be used include polymeric substances and waxes.
  • 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.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
  • 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.
  • 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.
  • 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.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • 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.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • 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 the pharmaceutical 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions suitable for administration to humans 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.
  • compositions described herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the 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.
  • 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.
  • 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/
  • 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.
  • intraarticular administration e.g., oral administration
  • intravenous administration e.g., systemic intravenous injection
  • regional administration via blood and/or lymph supply e.g., direct administration to an affected site.
  • direct administration e.g., systemic intravenous injection
  • 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).
  • any two doses of the multiple doses include different or substantially the same amounts of an agent described herein.
  • 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).
  • 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.
  • 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.
  • 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).
  • the pharmaceutical composition described herein is administered at a dose that is below the dose at which the agent causes nonspecific effects.
  • 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.
  • 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.
  • a dose described herein is a dose to an adult human whose body weight is 70 kg.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses 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.
  • 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.
  • the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
  • kits e.g., pharmaceutical packs.
  • the kit comprises a provided compound or pharmaceutical composition described herein, and instructions for using the compound or pharmaceutical composition.
  • the kit comprises a first container, wherein the first container includes the compound or pharmaceutical composition.
  • the kit further comprises a second container.
  • the second container includes an excipient (e.g., an excipient for dilution or suspension of the compound or pharmaceutical composition).
  • the second container includes an additional pharmaceutical agent.
  • the kit further comprises a third container.
  • the third container includes an additional pharmaceutical agent.
  • 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.
  • 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.
  • each of the first, second, and third containers is independently a vial, ampule, bottle, syringe, dispenser package, tube, or inhaler.
  • 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.
  • FDA U.S. Food and Drug Administration
  • EMA European Agency for the Evaluation of Medicinal Products
  • 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, 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.
  • 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., adenocarcinom
  • 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.
  • 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., adenocar
  • 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.
  • 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., a
  • 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.
  • 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.
  • 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 R 2a and R 2b is independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R 2a and R 2b are joined together with their intervening nitrogen atom to form
  • R 3 is hydrogen, -CH 3 , -Cl, or -Br;
  • R 3 is -Cl or -CH3, and R 4 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -CH3, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -OCH3 or -F, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -Cl or -I, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -Br, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 5 is -CH3, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is not if R 5 is -CF3, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is not if R 5 is -F, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is
  • 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.
  • 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.
  • 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))).
  • 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
  • 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.
  • 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.
  • 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.
  • 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))).
  • 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.,
  • 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.
  • 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.
  • 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.
  • 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))).
  • 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.,
  • 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 each of R 2a and R 2b is independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R 2a and R 2b are joined together with their intervening nitrogen atom to form
  • R 3 is hydrogen, -CH3, -Cl, or -Br;
  • 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.
  • 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))).
  • 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.,
  • 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.
  • 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.
  • 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.
  • 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))).
  • a muscular disease e.g., sarcopenia, Duchenne muscular dystrophy (DMD)
  • a proliferative disease e.g., cancer (e.g
  • 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.
  • 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.
  • 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.
  • 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))).
  • 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.,
  • 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))).
  • 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.,
  • the disease is a muscular disease (e.g., sarcopenia, Duchenne muscular dystrophy (DMD)).
  • the muscular disease is sarcopenia.
  • the muscular disease is Duchenne muscular dystrophy (DMD).
  • 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)).
  • cancer e.g., adenocarcinoma
  • lung cancer e.g., non-small cell lung cancer (NSCLC)
  • NSCLC non-small cell lung cancer
  • esophageal cancer e.g., adenocarcinoma
  • cervical cancer e.g., non-small cell lung cancer (NSCLC)
  • gastric cancer e.g., gastric cancer
  • colorectal cancer e.g., glioblastoma
  • brain cancer e.g., glioblastoma
  • 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).
  • the cancer is adenocarcinoma.
  • the cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC)).
  • the cancer is non-small cell lung cancer (NSCLC).
  • the cancer is esophageal cancer.
  • the cancer is cervical cancer.
  • 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.
  • 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%).
  • 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%).
  • 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%).
  • the subject has suffered an injury to one or more muscles.
  • the method comprises improving muscle regeneration in the subject.
  • the method comprises inducing muscle hypertrophy in the subject.
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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 Formula
  • each of R 2a and R 2b is independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R 2a and R 2b are joined together with their intervening nitrogen atom to form
  • R 3 is hydrogen, -CH3, -Cl, or -Br;
  • R 3 is -Cl or -CH3, and R 4 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -CH3, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -OCH3 or -F, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -Cl or -I, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -Br, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 5 is -CH3, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is not if R 5 is -CF3, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is not if R 5 is -F, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 Formula each of R 2a and R 2b is independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R 2a and R 2b are joined together with their intervening nitrogen atom to form
  • R 3 is 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 R 2a and R 2b is independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R 2a and R 2b are joined together with their intervening nitrogen atom to form
  • R 3 is hydrogen, -CH3, -Cl, or -Br;
  • R 3 is -Cl or -CH3, and R 4 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -CH3, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -OCH3 or -F, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -Cl or -I, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 4 is -Br, and R 3 , R 5 , and R 6 are each hydrogen, then R 1 is not if R 5 is -CH3, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is not if R 5 is -CF3, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is not if R 5 is -F, and R 3 , R 4 , and R 6 are each hydrogen, then R 1 is
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • each of R 2a and R 2b is independently hydrogen, p-toluenesulfonyl, acetyl, or benzoyl, or R 2a and R 2b are joined together with their intervening nitrogen atom to form
  • R 3 is hydrogen, -CH3, -Cl, or -Br;
  • 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.
  • 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.
  • 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.
  • 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.
  • the method comprises inducing myogenesis in the subject or in the cell, tissue, or biological sample.
  • 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%).
  • 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
  • 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.
  • the one or more myogenesis gene markers are Myod, Myodl, Myf5, Myog, Myog5, p21, Mhcl, Mhc2, Mhc2b, Mhc2x, Mhc3, or a combination thereof.
  • the myogenesis gene marker is Myod.
  • the myogenesis gene marker is Myodl.
  • the myogenesis gene marker is Myf5.
  • the myogenesis gene marker is Myog.
  • the myogenesis gene marker is Myog5.
  • 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.
  • 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 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%).
  • 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.
  • the one or more mitochondrial biogenesis gene markers are Tfam, Pgcla, Nampt, Sirt3, Nrfl, or a combination thereof.
  • the mitochondrial biogenesis gene marker is Tfam.
  • the mitochondrial biogenesis gene marker is Pgcla.
  • the mitochondrial biogenesis gene marker is Nampt.
  • the mitochondrial biogenesis gene marker is Sirt3.
  • the mitochondrial biogenesis gene marker is Nrfl.
  • 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%).
  • 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.
  • the one or more myogenic regulatory factors are MYOD, MYOG, MYF5, or a combination thereof.
  • the myogenic regulatory factor is MYOD.
  • the myogenic regulatory factor is MYOG.
  • the myogenic regulatory factor is MYF5.
  • the method comprises increasing IL17 secretion.
  • the increased IL17 secretion modulates at least one of Thl7 or Tcl7 cell differentiation.
  • the increased IL17 secretion modulates Thl7 cell differentiation.
  • the increased IL17 secretion modulates Tcl7 cell differentiation.
  • the increased IL17 secretion modulates Thl7 and Tcl7 cell differentiation.
  • the cell, tissue, or biological sample is in vivo. In certain embodiments, the cell, tissue, or biological sample is in vitro.
  • R 1 , R 3 , R 4 , R 5 , and R 6 are defined as previously throughout the Examples unless otherwise specified:
  • R 3 is hydrogen, -CH3, -Cl, or -Br;
  • 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 is omnipresent (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.
  • 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.
  • DMEM Dulbecco’s modified Eagle’s medium
  • 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.
  • 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).
  • CTX cardiotoxin
  • 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
  • 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.
  • 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.
  • 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.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne des composés de formules (par exemple, formule (I), formule (I')), ainsi que des sels pharmaceutiquement acceptables de ceux-ci, qui se lient à REV-ERB. La présente divulgation concerne également des compositions pharmaceutiques et des kits comprenant les composés, ou des sels ou promédicaments pharmaceutiquement acceptables de ceux-ci, ainsi que des méthodes de traitement ou de prévention de maladies par administration à un sujet en ayant besoin des composés, de sels ou de promédicaments pharmaceutiquement acceptables de ceux-ci ou de compositions pharmaceutiques associées.
PCT/US2024/039337 2023-07-25 2024-07-24 Antagonistes rev-erb Pending WO2025024550A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021263278A1 (fr) * 2020-06-23 2021-12-30 The Scripps Research Institute Agonistes rev-erb pour le traitement de troubles inflammatoires à médiation par th17
CN110041306B (zh) * 2018-01-15 2022-01-11 中国医学科学院药物研究所 4-羟基-2-喹诺酮-氮-(4-喹唑啉酮)-3-甲酰胺类衍生物
WO2022093552A9 (fr) * 2020-10-16 2022-06-23 Saint Louis Univeristy Agonistes rev-erb
WO2023122093A1 (fr) * 2021-12-20 2023-06-29 University Of Florida Research Foundation, Incorporated Agonistes rev-erb pour des troubles inflammatoires à médiation par th17

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CN110041306B (zh) * 2018-01-15 2022-01-11 中国医学科学院药物研究所 4-羟基-2-喹诺酮-氮-(4-喹唑啉酮)-3-甲酰胺类衍生物
WO2021263278A1 (fr) * 2020-06-23 2021-12-30 The Scripps Research Institute Agonistes rev-erb pour le traitement de troubles inflammatoires à médiation par th17
WO2022093552A9 (fr) * 2020-10-16 2022-06-23 Saint Louis Univeristy Agonistes rev-erb
WO2023122093A1 (fr) * 2021-12-20 2023-06-29 University Of Florida Research Foundation, Incorporated Agonistes rev-erb pour des troubles inflammatoires à médiation par th17

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