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WO2025059538A1 - Agents de dégradation de yap utilisés en tant que médicaments anticancéreux potentiels - Google Patents

Agents de dégradation de yap utilisés en tant que médicaments anticancéreux potentiels Download PDF

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WO2025059538A1
WO2025059538A1 PCT/US2024/046717 US2024046717W WO2025059538A1 WO 2025059538 A1 WO2025059538 A1 WO 2025059538A1 US 2024046717 W US2024046717 W US 2024046717W WO 2025059538 A1 WO2025059538 A1 WO 2025059538A1
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optionally substituted
compound
solvate
pharmaceutically acceptable
polymorph
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Chenglong Li
Chen Zhou
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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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • YAP DEGRADERS AS POTENTIAL ANTICANCER DRUGS BACKGROUND [0001]
  • Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are downstream regulators of the Hippo pathway and play a role in regulating tissue homeostasis, organ size, regeneration and tumorigenesis.
  • the Hippo signaling pathway regulates the co-activator function of YAP/TAZ by controlling their cellular localization through phosphorylation.
  • Lats1/2 large tumor suppressor 1/2
  • Mst1/2 mammalian STE20- like protein kinase 1/2
  • NF2 neurofibromin 2
  • phosphorylated Lats1/2 phosphorylates YAP/TAZ in the cytoplasm.
  • Phosphorylated YAP/TAZ are recognized by protein 14-3-3, which sequesters these co-activators in the cytoplasm, resulting in the suppression of Hippo- induced gene transcription.
  • YAP/TAZ when YAP/TAZ are not phosphorylated, the co- activators are able to translocate into the nucleus by an unknown mechanism, bind the TEAD transcription factors and drive transcriptional targets, including genes involved in cell growth and proliferation, such as connective tissue growth factor (CTGF) and Cysteine-rich angiogenic inducer 61 (Cyr61).
  • CTGF connective tissue growth factor
  • Cyr61 Cysteine-rich angiogenic inducer 61
  • a compound of Formula (0) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein A 1 , A 2 , A 3 , C 1 , C 2 , C 3 , C 4 , D 1 , D 2 , D 3 , D 4 , R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined herein.
  • a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are as defined herein.
  • a pharmaceutical composition comprising a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, and a pharmaceutically acceptable excipient.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of modulating the activity and/or production of YAP in a subject in need thereof comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of modulating the activity and/or production of YAP in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of inhibiting the activity and/or production of YAP in a subject in need thereof comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of inhibiting the activity and/or production of YAP in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of binding YAP in a subject in need thereof comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of binding YAP in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of degrading YAP in a subject in need thereof comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of degrading YAP in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of modulating YAP/TEAD-led transcription in a subject in need thereof comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of modulating YAP/TEAD-led transcription in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a compound provided herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • FIG.1 shows representative compounds targeting YAP.
  • FIGs.2A-2B show a strategy to assess tethering sites for the design of YAP PROTACs.
  • FIG.2A shows structures of designed compounds built from four tethering sites with small substituents attached.
  • FIG.2B shows a TEAD dependent luciferase reporter assay.
  • FIG.3 shows chemical structures of designed NSC682769-based YAP degraders using tethering sites 2 and 4.
  • FIG.4 shows a cell viability assay. NCI-H226 cells were treated with indicated doses of compounds for 3 days. Cell viability was determined by CCK8 assay.
  • FIGs.5A-5C show degradation of YAP protein by synthesized compounds.
  • FIG.5A shows western blotting analysis of YAP protein in NCI-H226 cells treated with compounds YZ-1, YZ-2, YZ-11, and YZ-12. Quantitation is shown below.
  • FIG.5B shows western blotting analysis of YAP protein in NCI-H226 cells treated with compounds YZ-4, YZ-5, YZ-6, and YZ-7. Quantitation is shown below.
  • FIG.5C shows western blotting analysis of YAP protein in NCI-H226 cells treated with compounds YZ-8, YZ-9, YZ-10, YZ-14, YZ- 15, and YZ-16. Quantitation is shown below.
  • FIGs.6A-6B show compounds YZ-4 (FIG.6A) and YZ-6 (FIG.6B) concentration- dependently reduced YAP protein level and inhibit YAP-TEAD target gene CTGF expression. Quantitation is shown below. NCI-H226 cells were treated with DMSO, NSC682769 or serial dilutions of compounds for 48 hours. Quantified data represents mean ⁇ SD from two independent biological replicates.
  • FIGs.7A-7B show cell viability assays of YZ-6 and NSC682769 in NCI-H226 and Huh7 cell lines.
  • FIG.7A shows cell viability results for NCI-H226 cells treated with the indicated doses of compounds for 4 days.
  • FIG.7B shows cell viability results for Huh7 cells treated with indicated doses of two compounds for 4 days. Cell viability was determined by CCK8 assay. IC50 values were calculated using the GraphPad Prism 9 software.
  • FIGs.8A-8B show YAP degradation activity in Huh7 cells.
  • FIG.8A shows that compound YZ-6 concentration-dependently reduced YAP protein level and inhibited YAP- TEAD target gene CTGF expression. Quantitation is shown on the right. Huh7 cells were treated with DMSO or serial dilutions of compounds for 48 hours. FIG.8B shows that compound YZ-6 concentration-dependently reduced TAZ protein level. Quantitation is shown on the right. Huh7 cells were treated with DMSO or serial dilutions of compounds for 24 hours. Quantified data represents mean ⁇ SD from two independent biological replicates. ** p ⁇ 0.01; **** p ⁇ 0.001.
  • FIGs.9A-9B show that compound YZ-6 reduced YAP protein levels in a time- dependent manner and inhibited YAP-TEAD target gene CTGF expression.
  • NCI-H226 (FIG. 9A) and Huh7 (FIG.9B) cells were treated with DMSO or YZ-6 for the indicated time. Quantitation is shown below. * p ⁇ 0.05; **** p ⁇ 0.001.
  • FIGs.10A-10D show that degradation was dependent on VHL, YAP, and proteasome.
  • FIG.10A shows results for Huh7 cells pretreated with VHL ligand 56 (1 mM) or 2 mM for 2 hours, followed by treatment with DMSO or compound YZ-6 (20 ⁇ M) for 24 hours. Quantitation is shown below.
  • FIG.10B shows results for Huh7 cells pretreated with 200 nM or 1 ⁇ M neddylation inhibitors MLN4924, or the proteasome inhibitor MG132 (300 nM) for 2 hours, followed by treatment with DMSO or compound YZ-6 (20 ⁇ M) for 24 hours. Quantitation is shown below.
  • FIG.10C shows results for Huh7 cells pretreated with 100 ⁇ M YAP inhibitor NSC682769 for 2 hours, followed by treatment with DMSO or compound YZ-6 (20 ⁇ M) for 24 hours. Quantitation is shown below.
  • FIG.10D shows results for Huh7 cells treated with DMSO, or 10 ⁇ M or 20 ⁇ M YZ-6, or 10 ⁇ M or 20 ⁇ M YZ-6 NC for 24 hours. Quantitation is shown below. * p ⁇ 0.05; ** p ⁇ 0.01; *** p ⁇ 0.005; **** p ⁇ 0.001. [0028]
  • FIGs.11A-11C show chemical structures, western blotting analysis, and cell viability relating to tethering site 3.
  • FIG.11A shows chemical structure of designed NSC682769- based YAP degraders using tethering site 3.
  • FIG.11B shows western blotting analysis of YAP protein in NCI-H226 cells treated with compounds YZ-17 to YZ-23. Quantitation is shown below.
  • FIG.11C shows a cell viability assay. NCI-H226 cells were treated with indicated doses of compounds for 4 days.
  • FIG.12 shows a schematic illustrating the design and synthesis of PROTACs based on YAP inhibitor NSC682769.
  • FIG.13 shows an illustration depicting targeted protein degradation.
  • FIGs.14A-14C show that YZ-6 reduced YAP in the nucleus.
  • FIG.14A shows representative images of YAP from immunofluorescence staining. Huh7 cells were treated with 0 ⁇ M (DMSO), or 5, 10, or 20 ⁇ M of YZ-6 for 12 h.
  • FIG.14B shows quantification of integrated YAP intensity in the nucleus. Integrated YAP intensity decreases with YZ-6 concentration. P ⁇ 0.0001 for 0 vs 5 ⁇ M, P ⁇ 0.0001 for 0 vs 10 ⁇ MP ⁇ 0.0001 for 0 ⁇ Mvs 20 ⁇ M(n > 85).
  • FIG.14C shows quantification of mean YAP intensity in the nucleus. Mean YAP intensity decreases with YZ-6 concentration.
  • FIG.15B shows pharmacokinetic parameters of YZ-6.
  • 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.
  • formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • isotopes refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.
  • range 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.
  • C 1-6 alkyl encompasses, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and 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 (“C 1–20 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”).
  • an alkyl group has 1 to 8 carbon atoms (“C 1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1–2 alkyl”).
  • 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”). Examples of C 1–6 alkyl groups include methyl (C1), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (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., ⁇ CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)).
  • unsubstituted C 1–12 alkyl such as unsubstituted C 1–6 alkyl, e.g.
  • the alkyl group is a substituted C 1–12 alkyl (such as substituted C 1–6 alkyl, e.g., –CH 2 F, –CHF 2 , –CF 3 , –CH 2 CH 2 F, –CH 2 CHF 2 , –CH 2 CF 3 , 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 (“C 1–20 haloalkyl”).
  • the haloalkyl moiety has 1 to 10 carbon atoms (“C 1–10 haloalkyl”).
  • the haloalkyl moiety has 1 to 9 carbon atoms (“C 1–9 haloalkyl”).
  • the haloalkyl moiety has 1 to 8 carbon atoms (“C 1–8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C 1–7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C 1–6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C 1–5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C 1–4 haloalkyl”).
  • the haloalkyl moiety has 1 to 3 carbon atoms (“C 1–3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C 1–2 haloalkyl”). 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 –CHF 2 , ⁇ CH 2 F, ⁇ CF 3 , ⁇ CH 2 CF 3 , ⁇ 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 (“heteroC1–11 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 (“heteroC1–9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC 1–4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1–3 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
  • the heteroalkyl group is an unsubstituted heteroC 1–12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1–12 alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 1 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 1 to 20 carbon atoms (“C1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C 1–12 alkenyl”).
  • an alkenyl group has 1 to 11 carbon atoms (“C 1–11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C 1–10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1–9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C 1–8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C 1–7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C 1–6 alkenyl”).
  • an alkenyl group has 1 to 5 carbon atoms (“C 1–5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C 1–4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C 1–3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C 1–2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C 1 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 C1–4 alkenyl groups include methylidenyl (C1), ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
  • Examples of C 1–6 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 (C7), octenyl (C8), octatrienyl (C8), 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 C1-20 alkenyl.
  • the alkenyl group is a substituted C1-20 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 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–20 alkenyl”).
  • a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–11 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–10 alkenyl”).
  • a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–8 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkenyl”).
  • a heteroalkenyl group has 1to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1–5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–4 alkenyl”).
  • a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 1–3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 1–2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1–6 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 1–20 alkenyl.
  • the heteroalkenyl group is a substituted heteroC 1–20 alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 1 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 1 to 10 carbon atoms (“C1-10 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C 1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C 1- 8 alkynyl”).
  • an alkynyl group has 1 to 7 carbon atoms (“C1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C 1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C 1-2 alkynyl”).
  • an alkynyl group has 1 carbon atom (“C 1 alkynyl”).
  • the one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C1-4 alkynyl groups include, without limitation, methylidynyl (C1), ethynyl (C2), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • C1-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 1-20 alkynyl.
  • the alkynyl group is a substituted C 1-20 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 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–20 alkynyl”).
  • a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–10 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–8 alkynyl”).
  • a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–6 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1–5 alkynyl”).
  • a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC 1–4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 1–3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 1–2 alkynyl”).
  • a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1–6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC 1–20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 1–20 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 (“C 3-14 carbocyclyl”).
  • a carbocyclyl group has 3 to 13 ring carbon atoms (“C 3-13 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 (“C 3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“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 (“C 4-6 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 C 3-6 carbocyclyl groups include cyclopropyl (C 3 ), cyclopropenyl (C 3 ), 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 C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like.
  • Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.
  • Exemplary C3-8 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (C 11 ), spiro[5.5]undecanyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C13), cyclotetradecane (C14), 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 C3-14 carbocyclyl.
  • the carbocyclyl group is a substituted C 3-14 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 (“C 3-8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 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 (“C 5-10 cycloalkyl”). Examples of C 5-6 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 (C 4 ).
  • C 3-8 cycloalkyl groups include the aforementioned C 3-6 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 C 3-14 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, tetra- hydrobenzothienyl, 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]di
  • 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 (“C10 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 C 6- 14 aryl.
  • the aryl group is a substituted C 6-14 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”).
  • 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 –NO 2 .
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C 1–10 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-
  • 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 ⁇ NH 2 .
  • 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 –SO2N(R bb ) 2 , –SO2R aa , and – SO 2 OR aa , wherein R aa and R bb are as defined herein.
  • acyl groups include aldehydes ( ⁇ CHO), carboxylic acids ( ⁇ CO 2 H), 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
  • 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 carba
  • 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-d
  • 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 methoxy, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxy
  • 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. [0094] 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 – , H2PO4 – , HCO3 ⁇ , HSO4 – , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid
  • Exemplary counterions which may be multivalent include CO 3 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 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 invention 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.
  • 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,
  • 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 invention include those derived from suitable inorganic and organic acids and bases.
  • 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
  • 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 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.
  • 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 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.
  • isomers compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the term “crystalline” or “crystalline form” refers to a solid form substantially exhibiting three-dimensional order.
  • a crystalline form of a solid is a solid form that is substantially not amorphous.
  • the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more sharply defined peaks.
  • amorphous or “amorphous form” refers to a form of a solid (“solid form”), the form substantially lacking three-dimensional order.
  • an amorphous form of a solid is a solid form that is substantially not crystalline.
  • the X-ray powder diffraction (XRPD) pattern of an amorphous form includes a wide scattering band with a peak at 2 ⁇ of, e.g., between 20 and 70°, inclusive, using CuK ⁇ radiation.
  • the XRPD pattern of an amorphous form further includes one or more peaks attributed to crystalline structures.
  • the maximum intensity of any one of the one or more peaks attributed to crystalline structures observed at a 2 ⁇ of between 20 and 70°, inclusive is not more than 300-fold, not more than 100-fold, not more than 30-fold, not more than 10-fold, or not more than 3-fold of the maximum intensity of the wide scattering band.
  • the XRPD pattern of an amorphous form includes no peaks attributed to crystalline structures.
  • co-crystal refers to a crystalline structure comprising at least two different components (e.g., a compound disclosed herein 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.
  • At least one of the components is a solvent.
  • a co-crystal of a compound disclosed herein and an acid is different from a salt formed from a compound disclosed herein and the acid.
  • a compound disclosed herein is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound disclosed herein easily occurs at room temperature.
  • a compound disclosed herein is complexed with the acid in a way that proton transfer from the acid to a compound disclosed herein does not easily occur at room temperature.
  • co-crystals in the co-crystal, there is partial proton transfer from the acid to a compound disclosed herein.
  • Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate.
  • prodrugs refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases, it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • 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.
  • 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 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. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.
  • 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, severeity 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.
  • the compounds of the invention may be administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 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 effect.
  • 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 inhibiting the activity and/or production of YAP. In certain embodiments, a therapeutically effective amount is an amount sufficient for degrading YAP. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating cancer. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting the activity and/or production of YAP and treating cancer. In certain embodiments, a therapeutically effective amount is an amount sufficient for degrading YAP the activity and/or production of YAP and treating cancer. [00120]
  • a “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • a prophylactically effective amount is an amount sufficient for inhibiting the activity and/or production of YAP.
  • a prophylactically effective amount is an amount sufficient for degrading YAP.
  • a prophylactically effective amount is an amount sufficient for preventing cancer.
  • a prophylactically effective amount is an amount sufficient for inhibiting the activity and/or production of YAP and preventing cancer. In certain embodiments, a prophylactically effective amount is an amount sufficient for degrading YAP the activity and/or production of YAP and preventing cancer.
  • the term “inhibit” or “inhibition” in the context of proteins refers to a reduction in the activity of the protein. In some embodiments, the term refers to a reduction of the level of protein activity, e.g., YAP activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of activity.
  • the term refers to a reduction of the level of activity, e.g., YAP activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of activity.
  • YAP activity e.g., YAP activity
  • the terms “degrade” or “degradation” refer to partial or complete breakdown of a target, e.g., YAP, such as by the cellular proteasome system. In some embodiments, the terms “degrade” or “degradation” to refer to breakdown of a target, e.g., YAP, to an extent that the biological activity of the target is reduced or eliminated. In some embodiments, degradation is achieved through mediation of an E3 ubiquitin ligase.
  • the term refers to degradation in the amount of between 10% and 20%, between 20% and 30%, between 30% and 40%, between 40% and 50%, between 50% and 60%, between 60% and 70%, between 70% and 80%, between 80% and 90%, between 90% and 99%, or at least about 99% of the target as compared to the initial amount or level of the target.
  • the biological activity of the target is reduced to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level.
  • a “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
  • 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).
  • angiogenic proteins such as growth factors (e.g., VEGF).
  • VEGF growth factors
  • 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.
  • a malignant neoplasm generally has the capacity to metastasize to distant sites.
  • metastasis 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.
  • 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), medul
  • angiosarcoma e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosar
  • 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
  • the compound is of Formula (0-B): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-C): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-D): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-E): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-f): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-F): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-g): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-G): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-h): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-H): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-i): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-I): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-j): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-J): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-k): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-K): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-L): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-m): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-M): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-n): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (0-N): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • each variable is independently as defined in Formula (0) unless specified otherwise.
  • the compound is of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-A): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-B): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-C): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-D): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-E): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-f): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-F): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-g): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-G): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-h): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-H): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-i): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-I): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-j): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-J): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-k): , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound is of Formula (I-K): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • each variable is independently as defined in Formula (I) unless specified otherwise.
  • R 1 is –N(R A ) 2 , –OR A , or –SR A , or –L 1 –Y 1 .
  • R 1 is –NH2, –NH(optionally substituted C 1-4 alkyl), –N(optionally substituted C 1-4 alkyl) 2 , –OH, – O(optionally substituted C 1-4 alkyl), –SH, or –S(optionally substituted C 1-4 alkyl), or –L 1 –Y 1 .
  • R 1 is –N(R A ) 2 , –OR A , or –L 1 –Y 1 .
  • R 1 is –NH2, – NH(optionally substituted C1-4 alkyl), –N(optionally substituted C1-4 alkyl) 2 , –OH, – O(optionally substituted C 1-4 alkyl), or –L 1 –Y 1 .
  • R 1 is –OR A , –SR A , or –L 1 –Y 1 .
  • R 1 is –OH, –O(optionally substituted C1-4 alkyl), –SH, or – S(optionally substituted C1-4 alkyl), or –L 1 –Y 1 .
  • R 1 is –N(R A ) 2 or –L 1 – Y 1 .
  • R 1 is –NH 2 , –NH(optionally substituted C 1-4 alkyl), –N(optionally substituted C1-4 alkyl) 2 or –L 1 –Y 1 .
  • R 1 is –OR A or –L 1 –Y 1 .
  • R 1 is –OH, –O(optionally substituted C1-4 alkyl), or –L 1 –Y 1 .
  • R 1 is –OH, –OMe, –OEt, or –L 1 –Y 1 .
  • R 1 is –OMe or – L 1 –Y 1 .
  • R 1 is–SR A or –L 1 –Y 1 .
  • R 1 is –SH, or – S(optionally substituted C1-4 alkyl), or –L 1 –Y 1 .
  • R 1 is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 2 -C 4 heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C3-C6 carbocyclyl, or –L 1 –Y 1 .
  • R 1 is optionally substituted C1-C4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or –L 1 –Y 1 .
  • R 1 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 3 -C 6 carbocyclyl, or –L 1 –Y 1 .
  • R 1 is optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or –L 1 –Y 1 .
  • R 1 is hydrogen or –L 1 –Y 1 .
  • R 1 is –L 1 –Y 1 .
  • R 1 is hydrogen,– NH2, –NHR A , –OH, –OMe, –CN, halogen, unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy(C1-C4 alkoxy), C3-C6 carbocyclyl, or –L 1 –Y 1 .
  • R 1 is hydrogen,–NH 2 , –NHR A , –OH, –CN, halogen, unsubstituted C 1 -C 4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy(C1-C4 alkoxy), C3-C6 carbocyclyl, or –L 1 –Y 1 .
  • R 1 is hydrogen,–NH2, –NHR A , –OH, –OMe, –CN, or halogen, or –L 1 –Y 1 .
  • R 1 is hydrogen,–NH 2 , –NHR A , –OH, – CN, or halogen, or –L 1 –Y 1 .
  • R 1 is unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy(C1-C4 alkoxy), C3-C6 carbocyclyl, or – L 1 –Y 1 .
  • R 1 is –N(R A ) 2 , – OR A , or –SR A .
  • R 1 is –NH 2 , –NH(optionally substituted C 1-4 alkyl), – N(optionally substituted C1-4 alkyl) 2 , –OH, –O(optionally substituted C1-4 alkyl), –SH, or – S(optionally substituted C1-4 alkyl).
  • R 1 is –N(R A ) 2 or –OR A .
  • R 1 is –NH 2 , –NH(optionally substituted C 1-4 alkyl), –N(optionally substituted C1-4 alkyl) 2 , –OH, or –O(optionally substituted C1-4 alkyl).
  • R 1 is –OR A or –SR A .
  • R 1 is –OH, –O(optionally substituted C1-4 alkyl), –SH, or – S(optionally substituted C 1-4 alkyl). In some embodiments, R 1 is –N(R A ) 2 . In some embodiments, R 1 is –NH2, –NH(optionally substituted C1-4 alkyl), –N(optionally substituted C1-4 alkyl) 2 . In some embodiments, R 1 is –OR A . In some embodiments, R 1 is –OH or – O(optionally substituted C 1-4 alkyl). In some embodiments, R 1 is –OH, –OMe, or –OEt. In some embodiments, R 1 is –OMe.
  • R 1 is–SR A . In some embodiments, R 1 is –SH or –S(optionally substituted C1-4 alkyl). In some embodiments, R 1 is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 2 -C 4 heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or optionally substituted C3-C6 carbocyclyl.
  • R 1 is optionally substituted C1-C4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, or optionally substituted C2-C4 heteroalkynyl.
  • R 1 is optionally substituted C1-C4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted C 3 - C 6 carbocyclyl.
  • R 1 is optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, or optionally substituted C2-C4 heteroalkynyl.
  • R 1 is hydrogen.
  • R 1 is hydrogen,–NH2, –NHR A , – OH, –OMe, –CN, halogen, unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, hydroxy(C 1 -C 4 alkoxy), or C 3 -C 6 carbocyclyl.
  • R 1 is hydrogen,–NH2, –NHR A , –OH, –CN, halogen, unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy(C1-C4 alkoxy), or C3-C6 carbocyclyl.
  • R 1 is hydrogen,–NH 2 , –NHR A , –OH, –OMe, –CN, or halogen.
  • R 1 is hydrogen,–NH2, –NHR A , –OH, –CN, or halogen.
  • R 1 is unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy(C 1 -C 4 alkoxy), or C 3 -C 6 carbocyclyl.
  • R 2 is –N(R A ) 2 , –OR A , or –SR A .
  • R 2 is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C 2 -C 4 heteroalkenyl, optionally substituted C 2 -C 4 heteroalkynyl, or optionally substituted C 3 -C 6 carbocyclyl.
  • R 2 is optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, or optionally substituted C 2 -C 4 heteroalkynyl.
  • R 2 is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl.
  • R 2 is hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted C3-C6 carbocyclyl. In some embodiments, R 2 is hydrogen, methyl, or ethyl. In some embodiments, R 2 is hydrogen.
  • R 2 is hydrogen,–NH 2 , –NHR A , –OH, –CN, halogen, unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, hydroxy(C 1 -C 4 alkoxy), or C 3 -C 6 carbocyclyl.
  • R 2 is hydrogen,–NH2, –NHR A , –OH, –CN, or halogen.
  • R 2 is unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy(C 1 -C 4 alkoxy), or C 3 -C 6 carbocyclyl. In some embodiments, R 2 is hydrogen.
  • R 3 is –N(R A ) 2 , –OR A , or –SR A , or –L 1 –Y 1 .
  • R 3 is –NH 2 , –NH(optionally substituted C1-4 alkyl), –N(optionally substituted C1-4 alkyl) 2 , –OH, – O(optionally substituted C1-4 alkyl), –SH, or –S(optionally substituted C1-4 alkyl), or –L 1 –Y 1 .
  • R 3 is –N(R A ) 2 , –OR A , or –L 1 –Y 1 .
  • R 3 is –NH 2 , – NH(optionally substituted C1-4 alkyl), –N(optionally substituted C1-4 alkyl) 2 , –OH, – O(optionally substituted C1-4 alkyl), or –L 1 –Y 1 .
  • R 3 is –OR A , –SR A , or –L 1 –Y 1 .
  • R 3 is –OH, –O(optionally substituted C 1-4 alkyl), –SH, or – S(optionally substituted C1-4 alkyl), or –L 1 –Y 1 .
  • R 3 is –N(R A ) 2 or –L 1 – Y 1 .
  • R 3 is –NH2, –NH(optionally substituted C1-4 alkyl), –N(optionally substituted C 1-4 alkyl) 2 , or –L 1 –Y 1 .
  • R 3 is –OR A or –L 1 –Y 1 .
  • R 3 is –OH, –O(optionally substituted C 1-4 alkyl), or –L 1 –Y 1 .
  • R 1 is –OH, –OMe, –OEt, or –L 1 –Y 1 .
  • R 1 is –OMe or – L 1 –Y 1 .
  • R 3 is–SR A or –L 1 –Y 1 .
  • R 3 is –SH, or – S(optionally substituted C 1-4 alkyl), or –L 1 –Y 1 .
  • R 3 is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C 2 -C 4 heteroalkynyl, optionally substituted C 3 -C 6 carbocyclyl, or –L 1 –Y 1 .
  • R 3 is optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 2 -C 4 heteroalkenyl, optionally substituted C 2 -C 4 heteroalkynyl, or –L 1 –Y 1 .
  • R 3 is optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or –L 1 –Y 1 .
  • R 3 is optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 2 -C 4 heteroalkenyl, optionally substituted C 2 -C 4 heteroalkynyl, or –L 1 –Y 1 .
  • R 3 is hydrogen or –L 1 –Y 1 .
  • R 3 is –L 1 –Y 1 .
  • R 3 is hydrogen,–NH2, –NHR A , –OH, –OMe, –CN, halogen, unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C 1 -C 4 haloalkoxy, hydroxy(C 1 -C 4 alkoxy), C 3 -C 6 carbocyclyl, or –L 1 –Y 1 .
  • R 3 is hydrogen,–NH2, –NHR A , –OH, –CN, halogen, unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy(C1-C4 alkoxy), C3-C6 carbocyclyl, or –L 1 –Y 1 .
  • R 3 is hydrogen,–NH 2 , –NHR A , –OH, –OMe, –CN, or halogen, or –L 1 –Y 1 .
  • R 3 is hydrogen,–NH2, –NHR A , –OH, – CN, or halogen, or –L 1 –Y 1 .
  • R 3 is unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, hydroxy(C 1 -C 4 alkoxy), C 3 -C 6 carbocyclyl, or – L 1 –Y 1 .
  • R 3 is –N(R A ) 2 , – OR A , or –SR A .
  • R 3 is –NH2, –NH(optionally substituted C1-4 alkyl), – N(optionally substituted C1-4 alkyl) 2 , –OH, –O(optionally substituted C1-4 alkyl), –SH, or – S(optionally substituted C 1-4 alkyl).
  • R 3 is –N(R A ) 2 or –OR A .
  • R 3 is –NH2, –NH(optionally substituted C1-4 alkyl), –N(optionally substituted C1-4 alkyl) 2 , –OH, –O(optionally substituted C1-4 alkyl).
  • R 3 is –OR A or –SR A .
  • R 3 is –OH, –O(optionally substituted C 1-4 alkyl), –SH, or – S(optionally substituted C1-4 alkyl). In some embodiments, R 3 is –N(R A ) 2 . In some embodiments, R 3 is –NH2, –NH(optionally substituted C1-4 alkyl), or –N(optionally substituted C 1-4 alkyl) 2 . In some embodiments, R 3 is –OR A . In some embodiments, R 3 is –OH or –O(optionally substituted C 1-4 alkyl). In some embodiments, R 1 is –OH, –OMe, or –OEt. In some embodiments, R 1 is –OMe.
  • R 3 is–SR A . In some embodiments, R 3 is –SH or –S(optionally substituted C1-4 alkyl). In some embodiments, R 3 is hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 2 -C 4 heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or optionally substituted C3-C6 carbocyclyl.
  • R 3 is optionally substituted C1-C4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, or optionally substituted C2-C4 heteroalkynyl.
  • R 3 is optionally substituted C1-C4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted C 3 - C6 carbocyclyl.
  • R 3 is optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, or optionally substituted C2-C4 heteroalkynyl.
  • R 3 is hydrogen.
  • R 3 is hydrogen,–NH 2 , –NHR A , – OH, –OMe, –CN, halogen, unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, hydroxy(C1-C4 alkoxy), or C3-C6 carbocyclyl.
  • R 3 is hydrogen,–NH2, –NHR A , –OH, –CN, halogen, unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, hydroxy(C 1 -C 4 alkoxy), or C 3 -C 6 carbocyclyl.
  • R 3 is hydrogen,–NH2, –NHR A , –OH, –OMe, –CN, or halogen.
  • R 3 is hydrogen,–NH2, –NHR A , –OH, –CN, or halogen.
  • R 3 is unsubstituted C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, hydroxy(C1-C4 alkoxy), or C3-C6 carbocyclyl.
  • R 4 is –N(R A ) 2 , –OR A , or –SR A , or –L 1 –Y 1 .
  • R 4 is – N(R A ) 2 , –OR A , or –L 1 –Y 1 .
  • R 4 is –OR A , –SR A , or –L 1 –Y 1 . In some embodiments, R 4 is –N(R A ) 2 or –L 1 –Y 1 . In some embodiments, R 4 is –OR A or –L 1 –Y 1 . In some embodiments, R 4 is–SR A or –L 1 –Y 1 .
  • R 4 is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 2 -C 4 heteroalkenyl, optionally substituted C 2 -C 4 heteroalkynyl, optionally substituted C 3 -C 6 carbocyclyl, or –L 1 – Y 1 .
  • R 4 is optionally substituted C1-C4 alkyl, optionally substituted C2- C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C 2 -C 4 heteroalkenyl, optionally substituted C 2 -C 4 heteroalkynyl, or – L 1 –Y 1 .
  • R 4 is optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or –L 1 –Y 1 .
  • R 4 is optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or –L 1 –Y 1 .
  • R 4 is hydrogen or –L 1 –Y 1 .
  • R 4 is –L 1 –Y 1 .
  • R 4 is –N(R A ) 2 , – OR A , or –SR A .
  • R 4 is –N(R A ) 2 or –OR A .
  • R 4 is – OR A or –SR A .
  • R 4 is –N(R A ) 2 .
  • R 4 is –OR A . In some embodiments, R 4 is–SR A . In some embodiments, R 4 is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 2 -C 4 heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or optionally substituted C3-C6 carbocyclyl.
  • R 4 is optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, or optionally substituted C2-C4 heteroalkynyl.
  • R 4 is optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted C 3 -C 6 carbocyclyl.
  • R 4 is optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 2 - C4 heteroalkenyl, or optionally substituted C2-C4 heteroalkynyl. In some embodiments, R 4 is hydrogen.
  • R 5 is hydrogen, a nitrogen protecting group, or –L 1 –Y 1 . In some embodiments, R 5 is hydrogen or a nitrogen protecting group. In some embodiments, R 5 is hydrogen or –L 1 –Y 1 . In some embodiments, R 5 is a nitrogen protecting group or –L 1 –Y 1 . In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is a nitrogen protecting group.
  • R 5 is –L 1 –Y 1 . In some embodiments, R 5 is hydrogen.
  • R 6 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, –OR B , –SR B , or – N(R B ) 2 .
  • R 6 is optionally substituted C1-10 alkyl, optionally substituted C 1-10 alkenyl, optionally substituted C 1-10 alkynyl, optionally substituted C 1-10 heteroalkyl, optionally substituted C1-10 heteroalkenyl, or optionally substituted C1-10 heteroalkynyl.
  • R 6 is C1-10 haloalkyl. In some embodiments, R 6 is C1-4 haloalkyl. In some embodiments, R 6 is C 1-4 fluoroalkyl (e.g., C 1-4 perfluoroalkyl). In some embodiments, R 6 is – CF 3 . In some embodiments, R 6 is hydrogen, optionally substituted C 1 -C 6 alkyl, or halogen. In some embodiments, R 6 is hydrogen, fluorine, –CH3, –CH 2 F, –CHF 2 , or –CF 3 . In some embodiments, R 6 is hydrogen, fluorine, –CH3, or –CF 3 . In some embodiments, R 6 is hydrogen or halogen.
  • R 6 is hydrogen or fluorine. In some embodiments, R 6 is hydrogen or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 6 is hydrogen, unsubstituted C 1 -C 6 alkyl, or C1-6 haloalkyl. In some embodiments, R 6 is hydrogen. In some embodiments, each instance of R 6 is hydrogen. [00182] In some embodiments, R 6 is halogen. In some embodiments, R 6 is bromine, chlorine, or fluorine. In some embodiments, R 6 is bromine or chlorine. In some embodiments, R 6 is chlorine or fluorine. In some embodiments, R 6 is bromine. In some embodiments, R 6 is chlorine. In some embodiments, R 6 is fluorine.
  • R 6 is –OR B , –SR B , or –N(R B ) 2 (e.g., wherein R B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).
  • R 6 is –OH.
  • R 6 is –SH.
  • R 6 is –NH 2 .
  • R 6 is –CN, –SCN, –SSR B , –N 3 , –NO, or –NO 2 .
  • R 6 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R 6 is optionally substituted C3-14 carbocyclyl. In some embodiments, R 6 is optionally substituted monocyclic C 3-7 carbocyclyl. In some embodiments, R 6 is optionally substituted monocyclic C 3-4 carbocyclyl. In some embodiments, R 6 is optionally substituted monocyclic C5-7 carbocyclyl. In some embodiments, R 6 is saturated carbocyclyl.
  • R 6 is optionally substituted 3- to 14-membered heterocyclyl.
  • R 6 is optionally substituted monocyclic 3- to 7-membered heterocyclyl.
  • R 6 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms.
  • R 6 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms.
  • R 6 is optionally substituted C6-14 aryl. In some embodiments, R 6 is optionally substituted C6-10 aryl. In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is optionally substituted naphthyl. [00187] In some embodiments, R 6 is optionally substituted monocyclic heteroaryl. In some embodiments, R 6 is optionally substituted bicyclic heteroaryl. In some embodiments, R 6 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R 6 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R 6 is optionally substituted 5- to 6-membered monocyclic heteroaryl.
  • R 7 is hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 alkenyl, optionally substituted C 1 -C 4 alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 heteroalkenyl, optionally substituted C1-C4 heteroalkynyl, –CN, –OR B , or –N(R B ) 2 .
  • R 7 is hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, –CN, –OR B , or –N(R B ) 2 .
  • R 7 is hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, –CN, –OH, or – NH 2 .
  • R 7 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C1-C4haloalkoxy, –CN, –OH, or –NH2. [00190] In some embodiments, R 7 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, –OR B , –SR B , or – N(R B ) 2 .
  • R 7 is optionally substituted C1-10 alkyl, optionally substituted C1-10 alkenyl, optionally substituted C1-10 alkynyl, optionally substituted C1-10 heteroalkyl, optionally substituted C 1-10 heteroalkenyl, or optionally substituted C 1-10 heteroalkynyl.
  • R 7 is C1-10 haloalkyl.
  • R 7 is C1-4 haloalkyl.
  • R 7 is C1-4 fluoroalkyl (e.g., C1-4 perfluoroalkyl).
  • R 7 is – CF 3 .
  • R 7 is hydrogen, optionally substituted C 1 -C 7 alkyl, or halogen. In some embodiments, R 7 is hydrogen, fluorine, –CH3, –CH 2 F, –CHF 2 , or –CF 3 . In some embodiments, R 7 is hydrogen, fluorine, –CH3, or –CF 3 . In some embodiments, R 7 is hydrogen or halogen. In some embodiments, R 7 is hydrogen or fluorine. In some embodiments, R 7 is hydrogen or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 7 is hydrogen, unsubstituted C 1 -C 6 alkyl, or C1-6 haloalkyl. In some embodiments, R 7 is hydrogen.
  • each instance of R 7 is hydrogen.
  • R 7 is halogen. In some embodiments, R 7 is bromine, chlorine, or fluorine. In some embodiments, R 7 is bromine or chlorine. In some embodiments, R 7 is chlorine or fluorine. In some embodiments, R 7 is bromine. In some embodiments, R 7 is chlorine. In some embodiments, R 7 is fluorine.
  • R 7 is –OR B , –SR B , or –N(R B ) 2 (e.g., wherein R B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R 7 is –OH.
  • R 7 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R 7 is optionally substituted C 3-14 carbocyclyl. In some embodiments, R 7 is optionally substituted monocyclic C 3-7 carbocyclyl. In some embodiments, R 7 is optionally substituted monocyclic C3-4 carbocyclyl. In some embodiments, R 7 is optionally substituted monocyclic C5-7 carbocyclyl. In some embodiments, R 7 is saturated carbocyclyl.
  • R 7 is optionally substituted 3- to 14-membered heterocyclyl.
  • R 7 is optionally substituted monocyclic 3- to 7-membered heterocyclyl.
  • R 7 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms.
  • R 7 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms.
  • R 7 is optionally substituted C 6-14 aryl. In some embodiments, R 7 is optionally substituted C 6-10 aryl. In some embodiments, R 7 is optionally substituted phenyl. In some embodiments, R 7 is optionally substituted naphthyl. [00196] In some embodiments, R 7 is optionally substituted monocyclic heteroaryl. In some embodiments, R 7 is optionally substituted bicyclic heteroaryl. In some embodiments, R 7 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R 7 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R 7 is optionally substituted 5- to 6-membered monocyclic heteroaryl.
  • R 8 is hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 1 -C 4 heteroalkenyl, optionally substituted C 1 -C 4 heteroalkynyl, –CN, –OR B , or –N(R B ) 2 .
  • R 8 is hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, –CN, –OR B , or –N(R B ) 2 .
  • R 8 is hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, –CN, –OH, or – NH2.
  • R 8 is hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4haloalkoxy, –CN, –OH, or –NH2.
  • R 8 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, –OR B , –SR B , or – N(R B ) 2 .
  • R 8 is optionally substituted C 1-10 alkyl, optionally substituted C 1-10 alkenyl, optionally substituted C 1-10 alkynyl, optionally substituted C 1-10 heteroalkyl, optionally substituted C1-10 heteroalkenyl, or optionally substituted C1-10 heteroalkynyl.
  • R 8 is C1-10 haloalkyl. In some embodiments, R 8 is C1-4 haloalkyl. In some embodiments, R 8 is C 1-4 fluoroalkyl (e.g., C 1-4 perfluoroalkyl). In some embodiments, R 8 is – CF 3 . In some embodiments, R 8 is hydrogen, optionally substituted C1-C 8 alkyl, or halogen. In some embodiments, R 8 is hydrogen, fluorine, –CH3, –CH 2 F, –CHF 2 , or –CF 3 . In some embodiments, R 8 is hydrogen, fluorine, –CH 3 , or –CF 3 . In some embodiments, R 8 is hydrogen or halogen.
  • R 8 is hydrogen or fluorine. In some embodiments, R 8 is hydrogen or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 8 is hydrogen, unsubstituted C 1 -C 6 alkyl, or C 1-6 haloalkyl. In some embodiments, R 8 is hydrogen. In some embodiments, each instance of R 8 is hydrogen. [00200] In some embodiments, R 8 is halogen. In some embodiments, R 8 is bromine, chlorine, or fluorine. In some embodiments, R 8 is bromine or chlorine. In some embodiments, R 8 is chlorine or fluorine. In some embodiments, R 8 is bromine. In some embodiments, R 8 is chlorine. In some embodiments, R 8 is fluorine.
  • R 8 is –OR B , –SR B , or –N(R B ) 2 (e.g., wherein R B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).
  • R B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl.
  • R 8 is –OH.
  • R 8 is –SH.
  • R 8 is –NH2.
  • R 8 is –CN, –SCN, –SSR B , –N3, –NO, or –NO 2 .
  • R 8 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R 8 is optionally substituted C3-14 carbocyclyl. In some embodiments, R 8 is optionally substituted monocyclic C3-7 carbocyclyl. In some embodiments, R 8 is optionally substituted monocyclic C 3-4 carbocyclyl. In some embodiments, R 8 is optionally substituted monocyclic C 5-7 carbocyclyl. In some embodiments, R 8 is saturated carbocyclyl.
  • R 8 is optionally substituted 3- to 14-membered heterocyclyl.
  • R 8 is optionally substituted monocyclic 3- to 7-membered heterocyclyl.
  • R 8 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms.
  • R 8 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms.
  • R 9 is hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted C 1 -C 4 alkenyl, optionally substituted C 1 -C 4 alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 heteroalkenyl, optionally substituted C1-C4 heteroalkynyl, –CN, –OR B , or –N(R B ) 2 .
  • R 9 is hydrogen, halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, –CN, –OR B , or –N(R B ) 2 .
  • R 9 is hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, –CN, –OH, or – NH2.
  • R 9 is hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C 1 -C 4 haloalkoxy, –CN, –OH, or –NH 2 .
  • R 9 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, –OR B , –SR B , or – N(R B ) 2 .
  • R 9 is optionally substituted C1-10 alkyl, optionally substituted C1-10 alkenyl, optionally substituted C1-10 alkynyl, optionally substituted C1-10 heteroalkyl, optionally substituted C 1-10 heteroalkenyl, or optionally substituted C 1-10 heteroalkynyl.
  • R 9 is C 1-10 haloalkyl. In some embodiments, R 9 is C 1-4 haloalkyl. In some embodiments, R 9 is C1-4 fluoroalkyl (e.g., C1-4 perfluoroalkyl). In some embodiments, R 9 is – CF 3 . In some embodiments, R 9 is hydrogen, optionally substituted C1-C 9 alkyl, or halogen. In some embodiments, R 9 is hydrogen, fluorine, –CH 3 , –CH 2 F, –CHF 2 , or –CF 3 . In some embodiments, R 9 is hydrogen, fluorine, –CH3, or –CF 3 . In some embodiments, R 9 is hydrogen or halogen.
  • R 9 is hydrogen or fluorine. In some embodiments, R 9 is hydrogen or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 9 is hydrogen, unsubstituted C 1 -C 6 alkyl, or C1-6 haloalkyl. In some embodiments, R 9 is hydrogen. In some embodiments, each instance of R 9 is hydrogen. [00209] In some embodiments, R 9 is halogen. In some embodiments, R 9 is bromine, chlorine, or fluorine. In some embodiments, R 9 is bromine or chlorine. In some embodiments, R 9 is chlorine or fluorine. In some embodiments, R 9 is bromine. In some embodiments, R 9 is chlorine. In some embodiments, R 9 is fluorine. In some embodiments, R 9 is fluorine.
  • R 9 is –OR B , –SR B , or –N(R B ) 2 (e.g., wherein R B is hydrogen or optionally substituted alkyl, or optionally substituted phenyl).
  • R 9 is –OH.
  • R 9 is –SH.
  • R 9 is –NH2.
  • R 9 is –CN, –SCN, –SSR B , –N 3 , –NO, or –NO 2 .
  • R 9 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R 9 is optionally substituted C3-14 carbocyclyl. In some embodiments, R 9 is optionally substituted monocyclic C 3-7 carbocyclyl. In some embodiments, R 9 is optionally substituted monocyclic C3-4 carbocyclyl. In some embodiments, R 9 is optionally substituted monocyclic C5-7 carbocyclyl. In some embodiments, R 9 is saturated carbocyclyl.
  • R 9 is optionally substituted 3- to 14-membered heterocyclyl.
  • R 9 is optionally substituted monocyclic 3- to 7-membered heterocyclyl.
  • R 9 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms.
  • R 9 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms.
  • R 9 is optionally substituted bicyclic aryl. In some embodiments, R 9 is optionally substituted C6-14 aryl. In some embodiments, R 9 is optionally substituted C6-10 aryl. In some embodiments, R 9 is optionally substituted phenyl. In some embodiments, R 9 is optionally substituted naphthyl. [00214] In some embodiments, R 9 is optionally substituted monocyclic heteroaryl. In some embodiments, R 9 is optionally substituted bicyclic heteroaryl. In some embodiments, R 9 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R 9 is optionally substituted 5- to 10-membered heteroaryl.
  • R 9 is optionally substituted 5- to 6-membered monocyclic heteroaryl.
  • each instance of R A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R A attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.
  • At least one instance of R A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R A is independently optionally substituted C1-C4 alkyl. In some embodiments, at least one instance of R A is independently unsubstituted C1-C4 alkyl. In some embodiments, at least one instance of R A is independently methyl. In some embodiments, R A is optionally substituted C 1 -C 4 alkyl. In some embodiments, R A is unsubstituted C1-C4 alkyl.
  • R A is methyl. In some embodiments, R A is —CO(C1-C3 alkyl), –CO(C1-C3 alkoxy), –SO2(C1-C3 alkyl), or –SO2(C1-C3 alkoxy). In some embodiments, R A is –CO(C 1 -C 3 alkyl) or –CO(C 1 -C 3 alkoxy). In some embodiments, R A is – SO2(C1-C3 alkyl) or –SO2(C1-C3 alkoxy).
  • At least one instance of R A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of R A is independently hydrogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkenyl, optionally substituted C1-10 alkynyl, optionally substituted C3-14 carbocyclyl, or optionally substituted C 6-14 aryl. In some embodiments, at least one instance of R A is independently hydrogen, optionally substituted C 1-10 alkyl, or optionally substituted phenyl.
  • At least one instance of R A is a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.
  • two instances of R A attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.
  • each instance of R B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R B attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.
  • At least one instance of R B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R B is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • At least one instance of R B is independently hydrogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkenyl, optionally substituted C1-10 alkynyl, optionally substituted C 3-14 carbocyclyl, or optionally substituted C 6-14 aryl. In some embodiments, at least one instance of R B is independently hydrogen, optionally substituted C1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R B is a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.
  • –L 1 – is optionally substituted C1-C25 alkylene, optionally substituted C2-C25 alkenylene, optionally substituted C2-C25 alkynylene, optionally substituted C 1 -C 25 heteroalkylene, optionally substituted C 2 -C 25 heteroalkenylene, optionally substituted C 2 -C 25 heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or any combination thereof.
  • –L 1 – is optionally substituted C 1 -C 25 alkylene, optionally substituted C 2 -C 25 alkenylene, optionally substituted C2-C25 alkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or any combination thereof.
  • –L 1 – is optionally substituted C 1 -C 25 alkylene, optionally substituted C2-C25 alkenylene, optionally substituted C2-C25 alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, or any combination thereof.
  • –L 1 – is optionally substituted C 1 -C 25 heteroalkylene, optionally substituted C 2 -C 25 heteroalkenylene, optionally substituted C 2 -C 25 heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or any combination thereof.
  • –L 1 – is optionally substituted C 1 -C 25 heteroalkylene, optionally substituted C 2 - C25 heteroalkenylene, optionally substituted C2-C25 heteroalkynylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, or any combination thereof.
  • –L 1 – comprises optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.
  • –L 1 – comprises optionally substituted C3-C7 carbocyclylene, optionally substituted 3- to 7-membered heterocyclylene, optionally substituted C 6 -C 10 arylene, or optionally substituted 5- to 10-membered heteroarylene.
  • –L 1 – comprises optionally substituted carbocyclylene or optionally substituted heterocyclylene.
  • –L 1 – comprises optionally substituted C3- C 7 carbocyclylene or optionally substituted 3- to 7-membered heterocyclylene. In some embodiments, –L 1 – comprises optionally substituted arylene or optionally substituted heteroarylene. In some embodiments, –L 1 – comprises optionally substituted C6-C10 arylene or optionally substituted 5- to 10-membered heteroarylene. In some embodiments, –L 1 – comprises optionally substituted carbocyclylene or optionally substituted arylene. In some embodiments, –L 1 – comprises optionally substituted C3-C7 carbocyclylene or optionally substituted C6-C10 arylene.
  • –L 1 – comprises optionally substituted heterocyclylene or optionally substituted heteroarylene. In some embodiments, –L 1 – comprises optionally substituted 3- to 7-membered heterocyclylene or optionally substituted 5- to 10-membered heteroarylene. In some embodiments, –L 1 – comprises optionally substituted phenylene or optionally substituted naphthylene. In some embodiments, –L 1 – comprises optionally substituted cyclobutylene, optionally substituted cyclopentylene, or optionally substituted cyclohexylene.
  • –L 1 – comprises optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted furan, optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted indole, optionally substituted quinoline, or optionally substituted isoquinoline.
  • –L 1 – comprises optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydrothiophenyl, optionally substituted piperidinyl, optionally substituted tetrahydropyranyl, or optionally substituted piperazinyl.
  • –L 1 – comprises optionally substituted C 1 -C 25 alkylene, optionally substituted C 2 -C 25 alkenylene, optionally substituted C 2 -C 25 alkynylene, optionally substituted C1-C25 heteroalkylene, optionally substituted C2-C25 heteroalkenylene, optionally substituted C2-C25 heteroalkynylene.
  • –L 1 – comprises optionally substituted C 1 -C 25 alkylene, optionally substituted C 2 -C 25 alkenylene, or optionally substituted C2-C25 alkynylene.
  • –L 1 – comprises optionally substituted C3-C12 alkylene, optionally substituted C3-C12 alkenylene, or optionally substituted C3-C12 alkynylene. In some embodiments, –L 1 – comprises optionally substituted C 3 -C 12 alkylene. In some embodiments, –L 1 – comprises optionally substituted C3-C12 alkenylene. In some embodiments, –L 1 – comprises optionally substituted C3-C12 alkynylene.
  • –L 1 – comprises optionally substituted C 1 -C 25 heteroalkylene, optionally substituted C 2 -C 25 heteroalkenylene, optionally substituted C 2 -C 25 heteroalkynylene. In some embodiments, –L 1 – comprises optionally substituted C3-C12 heteroalkylene, optionally substituted C3-C25 heteroalkenylene, optionally substituted C3-C25 heteroalkynylene. In some embodiments, –L 1 – comprises optionally substituted C 3 -C 12 heteroalkylene. In some embodiments, –L 1 – comprises optionally substituted C 3 -C 25 heteroalkenylene.
  • –L 1 – comprises optionally substituted C3-C25 heteroalkynylene.
  • –L 1 – is optionally substituted C1-C25 alkylene, optionally substituted C 2 -C 25 alkenylene, optionally substituted C 2 -C 25 alkynylene, optionally substituted C1-C25 heteroalkylene, optionally substituted C2-C25 heteroalkenylene, optionally substituted C2-C25 heteroalkynylene.
  • –L 1 – is optionally substituted C1- C 25 alkylene, optionally substituted C 2 -C 25 alkenylene, or optionally substituted C 2 -C 25 alkynylene.
  • –L 1 – is optionally substituted C3-C12 alkylene, optionally substituted C3-C12 alkenylene, or optionally substituted C3-C12 alkynylene. In some embodiments, –L 1 – is optionally substituted C 3 -C 12 alkylene. In some embodiments, –L 1 – is optionally substituted C 3 -C 12 alkenylene. In some embodiments, –L 1 – is optionally substituted C3-C12 alkynylene. In some embodiments, –L 1 – is optionally substituted C1-C25 heteroalkylene, optionally substituted C2-C25 heteroalkenylene, optionally substituted C2-C25 heteroalkynylene.
  • –L 1 – is optionally substituted C 3 -C 12 heteroalkylene, optionally substituted C3-C25 heteroalkenylene, optionally substituted C3-C25 heteroalkynylene. In some embodiments, –L 1 – is optionally substituted C3-C12 heteroalkylene. In some embodiments, –L 1 – is optionally substituted C 3 -C 25 heteroalkenylene. In some embodiments, –L 1 – is optionally substituted C3-C25 heteroalkynylene.
  • –L 1 – is , wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 and y1 designates the point of attachment to Y 1 .
  • –L 1 – is , wherein n is 4, 5, 6, 7, 8, 9, or 10, and y1 designates the point of attachment to Y 1 .
  • –L 1 – comprises , wherein m is 1, 2, 3, 4, or 5, and y1 designates the point of attachment to Y 1 .
  • –L 1 – comprises , wherein m is 1, 2, 3, or 4, and y1 designates the point of attachment to Y 1 .
  • –L 1 – comprises , wherein m is 1, 2, 3, or 4, and y1 designates the point of attachment to Y 1 .
  • –L 1 – comprises , , ,
  • ⁇ 1 designates the point of attachment to Y 1 .
  • –L 1 – has the formula , wherein y1 designates the point of attachment to Y 1 .
  • –L 1 – comprises , [00223] As defined herein, –Y 1 is of Formula (Y-A) or (Y-B): [00224] In some embodiments, –Y 1 is of Formula (Y-A). [00225] In some embodiments, –Y 1 is of Formula (Y-A-1): [00226] In some embodiments, –Y 1 is of Formula (Y-A-2): (Y-A-2).
  • –Y 1 is of Formula (Y-A-3): (Y-A-3). [00228] In some embodiments, –Y 1 is of Formula (Y-A-4): (Y-A-4). [00229] In some embodiments, –Y 1 is of Formula (Y-A-5): (Y-A-5).
  • each instance of R a1 is independently hydrogen, –OR C , –N(R C ) 2 , – CN, –NO 2 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl.
  • each instance of R a1 is independently hydrogen, –OH, –NH2, –CN, – NO 2 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 aminoalkyl, or optionally substituted 3-10 membered heterocyclyl.
  • each instance of R a1 is independently hydrogen, –OH, –NH 2 , –CN, –NO 2 , unsubstituted C 1 - C8 alkyl, unsubstituted C 2 -C 8 alkenyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 alkoxy-C 1 -C 8 alkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 aminoalkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, or optionally substituted 3-10 membered heterocyclyl.
  • At least one instance of R a1 is hydrogen, –OR C , –N(R C ) 2 , – CN, or –NO 2 .
  • at least one instance of R a1 is hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, or optionally substituted C 2 -C 8 heteroalkynyl.
  • At least one instance of R a1 is optionally substituted C 3 -C 10 carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, at least one instance of R a1 is optionally substituted C1- C8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, or optionally substituted C 3 -C 10 carbocyclyl.
  • At least one instance of R a1 is optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, or optionally substituted 3- to 10-membered heterocyclyl.
  • each instance of R a1 is independently hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, or optionally substituted C 2 -C 8 heteroalkynyl.
  • each instance of R a1 is independently hydrogen or unsubstituted C 1 -C 4 alkyl. In some embodiments, at least one instance of R a1 is hydrogen. In some embodiments, at least one instance of R a1 is unsubstituted C1-C4 alkyl. In some embodiments, at least one instance of R a1 is tert-butyl.
  • one instance of R a1 is hydrogen, and the other instance of R a1 is independently hydrogen, –OR C , –N(R C ) 2 , –CN, –NO 2 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl.
  • one instance of R a1 is hydrogen, and the other instance of R a1 is independently hydrogen, –OH, –NH 2 , –CN, –NO 2 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 aminoalkyl, or optionally substituted 3-10 membered heterocyclyl.
  • one instance of R a1 is hydrogen, and the other instance of R a1 is independently hydrogen, –OH, –NH2, –CN, – NO 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted C 2 -C 8 alkenyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 alkoxy-C 1 -C 8 alkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 aminoalkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, or optionally substituted 3-10 membered heterocyclyl.
  • one instance of R a1 is hydrogen, and the other instance of R a1 is optionally substituted C 1 -C 4 alkyl. In some embodiments, one instance of R a1 is hydrogen, and the other instance of R a1 is unsubstituted C1-C4 alkyl. In some embodiments, one instance of R a1 is hydrogen, and the other instance of R a1 is tert-butyl.
  • each instance of R a2 is independently –R aL –, hydrogen, –OR C , – N(R C ) 2 , –CN, –NO 2 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C3-C10 membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl.
  • each instance of R a2 is independently –R aL –, hydrogen, – OH, –NH 2 , –CN, –NO 2 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 aminoalkyl, or optionally substituted 3-10 membered heterocyclyl.
  • each instance of R a2 is independently –R aL –, hydrogen, –OH, –NH 2 , –CN, – NO 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted C 2 -C 8 alkenyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 alkoxy-C 1 -C 8 alkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 aminoalkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, or optionally substituted 3-10 membered heterocyclyl.
  • each instance of R a2 is independently –R aL –, hydrogen, –OR C , –N(R C ) 2 , –CN, or –NO 2 .
  • each instance of R a2 is independently –R aL –, hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C2- C8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C3-C10 membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl.
  • each instance of R a2 is independently –R aL –, hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl.
  • each instance of R a2 is independently –R aL –, hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C2- C8 alkenyl, or optionally substituted C 2 -C 8 alkynyl.
  • each instance of R a2 is independently –R aL –, hydrogen, or unsubstituted C 1 -C 4 alkyl. In some embodiments, each instance of R a2 is independently –R aL –, hydrogen, or methyl. In some embodiments, at least one instance R a2 is –R aL –.
  • each instance of R a2 is independently hydrogen, –OH, –NH 2 , –CN, –NO 2 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 aminoalkyl, or optionally substituted 3-10 membered heterocyclyl.
  • each instance of R a2 is independently hydrogen, –OH, –NH 2 , –CN, –NO 2 , unsubstituted C 1 -C 8 alkyl, unsubstituted C 2 -C 8 alkenyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 alkoxy-C 1 -C 8 alkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 aminoalkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, or optionally substituted 3-10 membered heterocyclyl.
  • each instance of R a2 is independently hydrogen, –OR C , – N(R C ) 2 , –CN, or –NO 2 .
  • each instance of R a2 is independently hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C2- C8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C3-C10 membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl.
  • each instance of R a2 is independently hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl.
  • each instance of R a2 is independently hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, or optionally substituted C 2 -C 8 alkynyl.
  • each instance of R a2 is independently hydrogen or unsubstituted C 1 -C 4 alkyl. In some embodiments, each instance of R a2 is independently hydrogen or methyl. In some embodiments, at least one instance of R a1 is hydrogen. In some embodiments, at least one instance of R a1 is unsubstituted C1-C4 alkyl. In some embodiments, at least one instance of R a1 is methyl.
  • R a3 is hydrogen, –PO(OR C ) 2 , or – C(R C ) 2 –OPO(OR C ) 2 .
  • R a3 is hydrogen.
  • R a4 is –R aL –, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R a4 is –R aL –, optionally substituted C3-C7 carbocyclyl, or optionally substituted 3- to 7-membered heterocyclyl. In some embodiments, R a4 is –R aL –, optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R a4 is –R aL –.
  • R a4 is optionally substituted C3-C10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R a4 is optionally substituted C3-C7 carbocyclyl, or optionally substituted 3- to 7-membered heterocyclyl. In some embodiments, R a4 is optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl.
  • R a5 is hydrogen or halogen. In some embodiments, R a5 is hydrogen. In some embodiments, R a5 is halogen. In some embodiments, R a5 is –Br, –Cl, or – F. In some embodiments, R a5 is –F or hydrogen. In some embodiments, R a5 is –F.
  • R a6 is hydrogen, halogen, –OR C , –N(R C ) 2 , –CN, –NO 2 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted C 2 -C 8 heteroalkynyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R a6 is hydrogen, halogen, –OR C , – N(R C ) 2 , –CN, –NO 2 , optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 3 -C 8 carbocyclyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R a6 is hydrogen, halogen, –OR C , –N(R C ) 2 , –CN, or –NO 2 .
  • R a6 is hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 - C8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 2 -C 8 heteroalkenyl, or optionally substituted C 2 -C 8 heteroalkynyl.
  • R a6 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C2-C4 alkynyl.
  • R a6 is optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C 2 -C 4 heteroalkynyl. In some embodiments, R a6 is optionally substituted C 3 -C 10 carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, R a6 is optionally substituted C3-C7 carbocyclyl or optionally substituted 3- to 7-membered heterocyclyl. In some embodiments, R a6 is optionally substituted C 3 -C 7 carbocyclyl or optionally substituted aryl.
  • R a6 is optionally substituted 3- to 7- membered heterocyclyl or optionally substituted heteroaryl. In some embodiments, R a6 is optionally substituted C6-C10 aryl or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R a6 is optionally substituted heteroaryl. In some embodiments, R a6 is optionally substituted heteroaryl comprising one or more nitrogen atoms. In some embodiments, R a6 is optionally substituted heteroaryl comprising one or more sulfur atoms. In some embodiments, R a6 is optionally substituted 5- or 6-membered heteroaryl. In some embodiments, R a6 is optionally substituted thiazolyl.
  • R a7 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, –OR C , –SR C , or – N(R C ) 2 .
  • R a7 is optionally substituted C 1-10 alkyl, optionally substituted C 1-10 alkenyl, optionally substituted C 1-10 alkynyl, optionally substituted C 1-10 heteroalkyl, optionally substituted C1-10 heteroalkenyl, or optionally substituted C1-10 heteroalkynyl.
  • R a7 is C1-10 haloalkyl. In some embodiments, R a7 is C1-4 haloalkyl. In some embodiments, R a7 is C 1-4 fluoroalkyl (e.g., C 1-4 perfluoroalkyl). In some embodiments, R a7 is –CF 3 . In some embodiments, R a7 is hydrogen, optionally substituted C1-C7 alkyl, or halogen. In some embodiments, R a7 is hydrogen, fluorine, –CH3, –CH 2 F, –CHF 2 , or –CF 3 . In some embodiments, R a7 is hydrogen, fluorine, –CH 3 , or –CF 3 .
  • R a7 is hydrogen or halogen. In some embodiments, R a7 is hydrogen or fluorine. In some embodiments, R a7 is hydrogen or optionally substituted C1-C7 alkyl. In some embodiments, R a7 is hydrogen, unsubstituted C 1 -C 7 alkyl, or C 1-7 haloalkyl. [00243] In some embodiments, R a7 is halogen. In some embodiments, R a7 is bromine, chlorine, or fluorine. In some embodiments, R a7 is bromine or chlorine. In some embodiments, R a7 is chlorine or fluorine. In some embodiments, R a7 is bromine. In some embodiments, R a7 is chlorine.
  • R a7 is fluorine. [00244] In some embodiments, R a7 is –OR C , –SR C , or –N(R C ) 2 (e.g., wherein R C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R a7 is –OH. In some embodiments, R a7 is –SH. In some embodiments, R a7 is –NH 2 . In some embodiments, R a7 is –CN, –SCN, –SSR C , –N3, –NO, or –NO 2 .
  • R a7 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R a7 is optionally substituted C 3-14 carbocyclyl. In some embodiments, R a7 is optionally substituted monocyclic C 3-7 carbocyclyl. In some embodiments, R a7 is optionally substituted monocyclic C3-4 carbocyclyl. In some embodiments, R a7 is optionally substituted monocyclic C5-7 carbocyclyl. In some embodiments, R a7 is saturated carbocyclyl.
  • R a7 is optionally substituted 3- to 14-membered heterocyclyl.
  • R a7 is optionally substituted monocyclic 3- to 7-membered heterocyclyl.
  • R a7 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms.
  • R a7 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R a7 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R a7 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R a7 is saturated heterocyclyl.
  • R a7 is optionally substituted monocyclic aryl.
  • R a7 is optionally substituted bicyclic aryl.
  • R a7 is optionally substituted C 6-14 aryl.
  • R a7 is optionally substituted C 6-10 aryl.
  • R a7 is optionally substituted phenyl.
  • R a7 is optionally substituted naphthyl.
  • R a7 is optionally substituted monocyclic heteroaryl. In some embodiments, R a7 is optionally substituted bicyclic heteroaryl. In some embodiments, R a7 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R a7 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R a7 is optionally substituted 5- to 6-membered monocyclic heteroaryl.
  • R a8 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, –OR C , –SR C , or – N(R C ) 2 .
  • R a8 is optionally substituted C 1-10 alkyl, optionally substituted C1-10 alkenyl, optionally substituted C1-10 alkynyl, optionally substituted C1-10 heteroalkyl, optionally substituted C1-10 heteroalkenyl, or optionally substituted C1-10 heteroalkynyl.
  • R a8 is C 1-10 haloalkyl. In some embodiments, R a8 is C 1-4 haloalkyl. In some embodiments, R a8 is C1-4 fluoroalkyl (e.g., C1-4 perfluoroalkyl). In some embodiments, R a8 is –CF 3 . In some embodiments, R a8 is hydrogen, optionally substituted C1-C a8 alkyl, or halogen. In some embodiments, R a8 is hydrogen, fluorine, –CH 3 , –CH 2 F, –CHF 2 , or –CF 3 .
  • R a8 is hydrogen, fluorine, –CH 3 , or –CF 3 . In some embodiments, R a8 is hydrogen or halogen. In some embodiments, R a8 is hydrogen or fluorine. In some embodiments, R a8 is hydrogen or optionally substituted C1-C7 alkyl. In some embodiments, R a8 is hydrogen, unsubstituted C 1 -C 7 alkyl, or C 1-7 haloalkyl. [00251] In some embodiments, R a8 is halogen. In some embodiments, R a8 is bromine, chlorine, or fluorine. In some embodiments, R a8 is bromine or chlorine.
  • R a8 is chlorine or fluorine. In some embodiments, R a8 is bromine. In some embodiments, R a8 is chlorine. In some embodiments, R a8 is fluorine. [00252] In some embodiments, R a8 is –OR C , –SR C , or –N(R C ) 2 (e.g., wherein R C is hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R a8 is –OH. In some embodiments, R a8 is –SH. In some embodiments, R a8 is –NH 2 .
  • R a8 is –CN, –SCN, –SSR C , –N3, –NO, or –NO 2 .
  • R a8 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R a8 is optionally substituted C 3-14 carbocyclyl. In some embodiments, R a8 is optionally substituted monocyclic C 3-7 carbocyclyl. In some embodiments, R a8 is optionally substituted monocyclic C3-4 carbocyclyl. In some embodiments, R a8 is optionally substituted monocyclic C5-7 carbocyclyl. In some embodiments, R a8 is saturated carbocyclyl.
  • R a8 is optionally substituted 3- to 14-membered heterocyclyl.
  • R a8 is optionally substituted monocyclic 3- to 7-membered heterocyclyl.
  • R a8 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms.
  • R a8 is optionally substituted 3- to 14-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/S atoms. In some embodiments, R a8 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and/or S atoms but no N atoms. In some embodiments, R a8 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally one or more O and/or S atoms. In some embodiments, R a8 is saturated heterocyclyl.
  • R a8 is optionally substituted monocyclic aryl.
  • R a8 is optionally substituted bicyclic aryl.
  • R a8 is optionally substituted C6-14 aryl.
  • R a8 is optionally substituted C6-10 aryl.
  • R a8 is optionally substituted phenyl.
  • R a8 is optionally substituted naphthyl.
  • R a8 is optionally substituted monocyclic heteroaryl. In some embodiments, R a8 is optionally substituted bicyclic heteroaryl. In some embodiments, R a8 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R a8 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R a8 is optionally substituted 5- to 6-membered monocyclic heteroaryl. [00257] As defined herein, R a9 is hydrogen or a nitrogen protecting group. In some embodiments, R a9 is hydrogen. In some embodiments, R a9 is a nitrogen protecting group.
  • each instance of R C is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R C attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.
  • At least one instance of R C is independently hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkenyl, optionally substituted C 1 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 1 -C 8 heteroalkenyl, optionally substituted C 1 -C 8 heteroalkynyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • At least one instance of R C is independently hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 aminoalkyl, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • At least one instance of R C is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R C is independently optionally substituted C1-C4 alkyl. In some embodiments, at least one instance of R C is independently methyl. In some embodiments, at least one instance of R C is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • At least one instance of R C is independently hydrogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkenyl, optionally substituted C1-10 alkynyl, optionally substituted C 3-14 carbocyclyl, or optionally substituted C 6-14 aryl. In some embodiments, at least one instance of R C is hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 3 -C 8 carbocyclyl, or optionally substituted 3- to 8-membered heterocyclyl.
  • At least one instance of R C is hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 carbocyclyl, or optionally substituted 3- to 8-membered heterocyclyl. In some embodiments, at least one instance of R C is independently hydrogen, optionally substituted C 1-10 alkyl, or optionally substituted phenyl.
  • R C is hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 carbocyclyl, –C(O)(optionally substituted C 1 -C 8 alkyl, –C(O)(optionally substituted C 1 -C 8 carbocyclyl), –C(O)(optionally substituted C 1 -C 8 alkyl-C 3 -C 8 carbocyclyl), –C(O)(optionally substituted 3- to 10-membered heterocyclyl), –C(O)(C 1 -C 8 alkyl-optionally substituted 3- to 10-membered heterocyclyl), – C(O)(optionally substituted aryl), –C(O)(C 1 -C 8 alkyl-optionally substituted aryl), – C(O)(optionally substituted heteroaryl), –C(O)(C 1 -C 8 alkyl-optionally substituted heteroaryl), –C(O)(C
  • At least one instance of R C is a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.
  • two instances of R C attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.
  • q is 0, 1, 2, 3, 4, or 5.
  • q is 0, 1, 2, 3, or 4.
  • q is 1, 2, 3, 4, or 5.
  • q is 0, 1, 2, or 3.
  • q is 1, 2, 3, or 4.
  • q is 2, 3, 4, or 5.
  • q is 0, 1, or 2. In some embodiments, q is 1, 2, or 3. In some embodiments, q is 2, 3, or 4. In some embodiments, q is 3, 4, or 5. In some embodiments, q is 0 or 1. In some embodiments, q is 1 or 2. In some embodiments, q is 2 or 3. In some embodiments, q is 3 or 4. In some embodiments, q is 4 or 5. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. [00262] As defined herein, r is 0, 1, 2, or 3. In some embodiments, r is 0, 1, or 2.
  • r is 1, 2, or 3. In some embodiments, r is 0 or 1. In some embodiments, r is 1 or 2. In some embodiments, r is 2 or 3. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. [00263] In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments
  • –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . In some embodiments, –Y 1 is . [00264] In some embodiments, –Y 1 is of Formula (Y-B). [00265] In some embodiments, –Y 1 is of Formula (Y-B-1): (Y-B-1). [00266] In some embodiments, –Y 1 is of Formula (Y-B-2): (Y-B-2). [00267] In some embodiments, –Y 1 is of Formula (Y-B-3): (Y-B-3).
  • –Y 1 is of Formula (Y-B-4): (Y-B-4).
  • each instance of R b1 is independently halogen, –OR D , –CN, – NO 2 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 - C6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted C 3 -C 8 carbocyclyl, or optionally substituted 3- to 8-membered heterocyclyl.
  • R b1 is halogen, –OR D , –CN, –NO 2 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 8 carbocyclyl, or optionally substituted 3- to 8- membered heterocyclyl.
  • R b1 is halogen, –CN, –NO 2 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, optionally substituted C 3 -C 8 carbocyclyl, or optionally substituted 3- to 8-membered heterocyclyl.
  • At least one instance of R b1 is halogen, –OR D , –CN, or – NO 2 .
  • at least one instance of R b1 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, or optionally substituted C 2 -C 6 heteroalkynyl.
  • At least one instance of R b1 is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C2-C4 alkynyl. In some embodiments, at least one instance of R b1 is optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, or optionally substituted C 2 -C 4 heteroalkynyl. In some embodiments, at least one instance of R b1 is optionally substituted C 3 -C 8 carbocyclyl or optionally substituted 3- to 8-membered heterocyclyl.
  • R b1 is optionally substituted C4- C6 carbocyclyl. In some embodiments, at least one instance of R b1 is optionally substituted 4- to 6-membered heterocyclyl.
  • R b2 is hydrogen or a nitrogen protecting group. In some embodiments, R b2 is hydrogen. In some embodiments, R b2 is a nitrogen protecting group.
  • V b is –N–, –CH–, or –C(R b1 )–. In some embodiments, V b is –N– or –CH–. In some embodiments, Vb is –N– or –C(R b1 )–.
  • each instance of R b3 is independently halogen, optionally substituted C 1 -C 3 alkyl, or –OR D .
  • each instance of R b3 is independently halogen, optionally substituted C1-C3 alkyl, or –O(optionally substituted C1-C3 alkyl).
  • at least one instance of R b3 is halogen or optionally substituted C 1 -C 3 alkyl.
  • at least one instance of R b3 is halogen or –OR D .
  • at least one instance of R b3 is optionally substituted C 1 -C 3 alkyl or –OR D .
  • At least one instance of R b3 is halogen. In some embodiments, at least one instance of R b3 is –Br, –Cl, or –F. In some embodiments, at least one instance of R b3 is optionally substituted C 1 -C 3 alkyl. In some embodiments, at least one instance of R b3 is methyl, ethyl, n-propyl, or i-propyl. In some embodiments, at least one instance of R b3 is – OH, –OMe, –OEt, or –OPr. [00275] As defined herein, t is 0, 1, 2, 3, 4, or 5. In some embodiments, t is 0, 1, 2, 3, or 4.
  • t is 1, 2, 3, 4, or 5. In some embodiments, t is 0, 1, 2, or 3. In some embodiments, t is 1, 2, 3, or 4. In some embodiments, t is 2, 3, 4, or 5. In some embodiments, t is 0, 1, or 2. In some embodiments, t is 1, 2, or 3. In some embodiments, t is 2, 3, or 4. In some embodiments, t is 3, 4, or 5. In some embodiments, t is 0 or 1. In some embodiments, t is 1 or 2. In some embodiments, t is 2 or 3. In some embodiments, t is 3 or 4. In some embodiments, t is 4 or 5. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2.
  • t is 3. In some embodiments, t is 4. In some embodiments, t is 5. [00276] As defined herein, Zb is –(R b4 )u–, wherein R b4 , at each occurrence, is independently R b5 or R b6 ; provided that –R b4 –R b4 – is not –O–O–. In some embodiments, Z b is a bond.
  • R b5 at each occurrence, is optionally substituted C 1 -C 4 alkylene, optionally substituted C 1 -C 4 alkenylene, or optionally substituted C1-C4 alkynylene.
  • R b5 is a bond.
  • R b6 is independently a bond, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R b6 is a bond.
  • R b6 at each occurrence, is a bond, optionally substituted C3- C 7 carbocyclyl, or optionally substituted 3- to 7-membered heterocyclyl.
  • R b6 at each occurrence, is a bond, optionally substituted C 6 -C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl.
  • R b6 at each occurrence, is a bond, optionally substituted C3-C7 carbocyclyl, or optionally substituted C6- C 10 aryl. In some embodiments, R b6 , at each occurrence, is a bond, optionally substituted 3- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl. [00279] As defined herein, u is 0, l, 2, 3, 4, 5, or 6. In some embodiments, u is 0, l, 2, 3, 4, or 5. In some embodiments, u is l, 2, 3, 4, 5, or 6. In some embodiments, u is 0, 1, 2, 3, or 4. In some embodiments, u is 1, 2, 3, 4, or 5.
  • u is 2, 3, 4, 5, or 6. In some embodiments, u is 0, 1, 2, or 3. In some embodiments, u is 1, 2, 3, or 4. In some embodiments, u is 2, 3, 4, or 5. In some embodiments, u is 3, 4, 5, or 6. In some embodiments, u is 0, 1, or 2. In some embodiments, u is 1, 2, or 3. In some embodiments, u is 2, 3, or 4. In some embodiments, u is 3, 4, or 5. In some embodiments, u is 4, 5, or 6. In some embodiments, u is 0 or 1. In some embodiments, u is 1 or 2. In some embodiments, u is 2 or 3. In some embodiments, u is 3 or 4. In some embodiments, u is 4 or 5.
  • u is 5 or 6. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, u is 6. [00280] As defined herein, s is 0, 1, 2, 3, or 4. In some embodiments, s is 0, 1, 2, or 3. In some embodiments, s is 1, 2, 3, or 4. In some embodiments, s is 0, 1, or 2. In some embodiments, s is 1, 2, or 3. In some embodiments, s is 2, 3, or 4. In some embodiments, s is 0 or 1. In some embodiments, s is 1 or 2. In some embodiments, s is 2 or 3.
  • each instance of R D is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R D attached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.
  • At least one instance of R D is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R D is independently optionally substituted C1-C4 alkyl. In some embodiments, at least one instance of R D is independently methyl. In some embodiments, at least one instance of R D is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • At least one instance of R D is independently hydrogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkenyl, optionally substituted C1-10 alkynyl, optionally substituted C3-14 carbocyclyl, or optionally substituted C6-14 aryl. In some embodiments, at least one instance of R D is independently hydrogen, optionally substituted C 1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of R D is a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.
  • At least one instance of R E is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, or optionally substituted heteroalkynyl. In some embodiments, at least one instance of R E is independently optionally substituted C 1 -C 4 alkyl. In some embodiments, at least one instance of R E is independently methyl. In some embodiments, at least one instance of R E is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • At least one instance of R E is independently hydrogen, halogen, –OH, –CN, –NO 2 , or –NH2. In some embodiments, at least one instance of R E is independently hydrogen, –OH, or –NH 2 . In some embodiments, at least one instance of R E is independently hydrogen, halogen, –OR D , –CN, –NO 2 ,–N(R D ) 2 , or optionally substituted C 1 -C 6 alkyl.
  • the compounds is: 23, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compounds is: , , , , , , , , , ,
  • a compound of the present disclosure is a compound provided herein (e.g., a compound of any of the formulae herein), or a pharmaceutically acceptable salt thereof.
  • compositions, Kits, and Administration [00288]
  • a pharmaceutical composition comprising a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises an additional agent.
  • the compound described herein is provided in an effective amount in the pharmaceutical composition.
  • the effective amount is a therapeutically effective amount.
  • a therapeutically effective amount is an amount sufficient for inhibiting the activity and/or production of YAP.
  • a therapeutically effective amount is an amount sufficient for degrading YAP. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating cancer. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting the activity and/or production of YAP and treating cancer. In certain embodiments, a therapeutically effective amount is an amount sufficient for degrading YAP the activity and/or production of YAP and treating cancer. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting the activity and/or production of YAP. In certain embodiments, a prophylactically effective amount is an amount sufficient for degrading YAP.
  • a prophylactically effective amount is an amount sufficient for preventing cancer. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting the activity and/or production of YAP and preventing cancer. In certain embodiments, a prophylactically effective amount is an amount sufficient for degrading YAP the activity and/or production of YAP and preventing cancer. [00290] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology.
  • Such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
  • 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 active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • 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,
  • Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum ® ), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol
  • 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 hydroxyanisole, 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.
  • Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant ® Plus, Phenonip ® , methylparaben, Germall ® 115, Germaben ® II, Neolone ® , Kathon ® , and Euxyl ® .
  • 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,
  • 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, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • the oral 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.
  • 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.
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • 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 compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • 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 glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (a) fillers or
  • the dosage form may include a buffering agent.
  • 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.
  • 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 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.
  • 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. Examples of 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.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable.
  • 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.
  • 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 compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • 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).
  • Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • a flavoring agent such as saccharin sodium
  • a volatile oil such as a liquid oil
  • a buffering agent such as a liquid oil
  • a surface active agent such as methylhydroxybenzoate
  • 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.
  • 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 in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
  • Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, 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, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams, and/or drops
  • mucosal nasal,
  • Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
  • intravenous administration e.g., systemic intravenous injection
  • regional administration via blood and/or lymph supply e.g., via blood and/or lymph supply
  • direct administration e.g., direct administration to an affected site.
  • 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).
  • the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day.
  • 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.
  • a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 ⁇ g and 1 ⁇ g, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein.
  • a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein. [00329] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
  • the additional pharmaceutical agent achieves a desired effect for the same disorder.
  • the additional pharmaceutical agent achieves different effects.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies.
  • Pharmaceutical agents include therapeutically active agents.
  • Pharmaceutical agents also include prophylactically active agents.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S.
  • CFR Code of Federal Regulations
  • proteins proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • CFR Code of Federal Regulations
  • the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder).
  • a disease e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder.
  • Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • the additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions.
  • 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.
  • 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 additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is an binder or inhibitor of a protein kinase.
  • the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation.
  • epigenetic or transcriptional modulators e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors
  • antimitotic drugs e.g., taxanes and vinca
  • the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.
  • an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.
  • Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.
  • kits e.g., pharmaceutical packs.
  • kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein.
  • the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.
  • kits including a first container comprising a compound or pharmaceutical composition described herein.
  • the kits are useful for treating a disease (e.g., cancer) in a subject in need thereof.
  • kits are useful for preventing a disease (e.g., cancer) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease (e.g., cancer) in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting the activity and/or production of YAP. In certain embodiments, the kits are useful for degrading YAP. [00335] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information.
  • FDA U.S. Food and Drug Administration
  • kits and instructions provide for treating a disease (e.g., cancer) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., cancer) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., cancer) in a subject in need thereof. In certain embodiments, the kits and instructions provide for inhibiting the activity and/or production of YAP. In certain embodiments, the kits and instructions provide for degrading YAP.
  • a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • the cancer is liver cancer, breast cancer, pancreatic cancer, or mesothelioma.
  • the cancer is liver cancer.
  • the cancer is breast cancer.
  • the cancer is pancreatic cancer.
  • the cancer is mesothelioma.
  • a method of modulating the activity and/or production of YAP in a subject in need thereof comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of modulating the activity and/or production of YAP in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • the modulating is altering. In some embodiments, the modulating is decreasing. In some embodiments, the modulating is inhibiting.
  • a method of inhibiting the activity and/or production of YAP in a subject in need thereof comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of inhibiting the activity and/or production of YAP in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • the method reduces of the level of YAP activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level of activity.
  • the method reduces of the level of YAP production, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level of production.
  • a method of binding YAP in a subject in need thereof comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of binding YAP in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of degrading YAP in a subject in need thereof comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of degrading YAP in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • the method degrades YAP as compared to an initial amount or level prior to treatment with the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition.
  • the method degrades YAP by between 10% and 20%, between 20% and 30%, between 30% and 40%, between 40% and 50%, between 50% and 60%, between 60% and 70%, between 70% and 80%, between 80% and 90%, between 90% and 99%, or at least about 99% of the target as compared to the initial amount or level prior to treatment with the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition.
  • a method of modulating YAP/TEAD-led transcription in a subject in need thereof comprising administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • a method of modulating YAP/TEAD-led transcription in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition provided herein.
  • the method further comprises suppressing YAP/TEAD-led transcription.
  • the effective amount is effective for modulating the activity and/or production of YAP.
  • the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal.
  • the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs).
  • the subject is a fish or reptile.
  • the cell, tissue, or biological sample is in vitro.
  • the cell, tissue, or biological sample is in vivo.
  • YZ-6 In addition to its degradation capabilities, YZ-6 also exhibited potent antiproliferative activity in both cell lines. These findings highlight PROTAC-mediated degradation as a strategy for reducing oncogenic YAP levels, attenuating downstream signaling in cancer cells, and treating YAP-driven malignancies.
  • YAP and its paralogue TAZ are characterized as intrinsically disordered proteins. 14, 15 Due to their inherent flexibility, they have the ability to adopt diverse conformations, making them challenging targets for intervention. 16,17 [00357]
  • High-throughput screening (HTS) is one method used for targeting disordered proteins. 18 HTS involves experimental screening of large libraries of small molecules to identify compounds that can interact with the target protein.
  • Verteporfin (VP) (FIG.1), a drug commonly used in the treatment of macular degeneration, is the first and most renowned YAP inhibitor obtained through a luciferase reporter assay screening. 20 It has been demonstrated to bind to YAP, leading to a conformational change in the protein and disrupting its interaction with TEAD. However, further investigations have revealed the presence of off-target effects that are independent of YAP.
  • pazopanib specifically triggered the proteasomal degradation of YAP/TAZ, contributing to their transcriptional suppression.
  • Taccioli et al. using the Mutations and Drugs Portal (MDP) at http://mdp.unimore.it, also found that individually, dasatinib and fluvastatin were able to partially reduce the nuclear localization of YAP/TAZ.
  • MDP Mutations and Drugs Portal
  • NSC682769 Utilizing a high-throughput yeast two-hybrid based screen, NSC682769 (FIG.1) was identified to inhibit the association of the co-transcriptional activator YAP1 and the TEA domain family member 1 (TEAD1) transcription factor protein–protein interaction. 26 NSC682769 potently blocked association of YAP and TEAD in vitro in GBM cells treated with submicromolar concentrations of drug. To investigate the mechanism of action, the researchers performed surface plasmon resonance (SPR) analysis to study the binding of NSC682769 to immobilized YAP. They observed that NSC682769 bound to YAP in a concentration-dependent manner and quickly reached binding equilibrium.
  • SPR surface plasmon resonance
  • the dissociation constant (KD) was determined to be 738 nM, indicating a direct interaction between NSC682769 and YAP. Further confirmation was obtained through inhibitor-coupled bead pull-down assays, which further demonstrated that NSC682769 binds directly to YAP. Collectively, these findings provide evidence that NSC682769 directly binds to YAP, preventing its association with TEAD and inhibiting their protein-protein interaction. This study highlights NSC682769 as a potential therapeutic compound for disrupting YAP/TEAD- induced oncogenic signaling. [00359] In the meanwhile, computational methods can also be utilized to identify binders for disordered proteins.
  • the process of identifying molecules that interact with disordered regions requires additional steps similar to traditional drug design approaches that focus on well-ordered pockets.
  • the first step involves characterizing the conformational ensembles of the target protein. This can be achieved through a combination of computational techniques and experimental methods. Once the conformational ensembles are established, the next step is to select druggable conformers. Ligands that bind to druggable conformers can then be identified using virtual screenings based on ensemble docking or receptor-based pharmacophore models.
  • the shift from the traditional drug design pipeline that primarily targets well-ordered pockets to the identification of binders for disordered proteins has been relatively slow and has not gained significant momentum.
  • PROTACs PROteolysis TArgeting Chimeras
  • HK24 Based on the YAP-binding capability of HK13, the researchers synthesized a series of YAP degraders using PROTAC technology. These degraders linked platanic acid with LCL-161, a compound known for its high affinity for cIAP (cellular inhibitor of apoptosis protein), an E3 ubiquitin ligase. Among these compounds, HK24 (FIG.1) showed the ability to inhibit the growth of NCI-H290 cells that overexpress YAP and to induce YAP degradation in a dose-dependent manner. However, it should be noted that HK24 exhibited weak YAP degradation, less than 50% degradation at 5 ⁇ M.
  • NSC682769 is one of the few small molecules whose reported binding to YAP validated by SPR with a KD value less than 1 ⁇ M. NSC682769 has a lower molecular weight compared to VP.
  • NSC682769 has demonstrated significant anti-tumor responses, increased overall survival, and notable penetration across the blood-brain barrier (BBB). 26 Based on these promising characteristics, a series of novel YAP PROTACs based on NSC682769 were designed and synthesized. These PROTACs were created by linking NSC682769 with either pomalidomide or a VHL ligand, using various linker lengths and types. The resulting compounds displayed rapid degradation of YAP in cells overexpressing YAP, functioning through a bona fide PROTAC mechanism. These PROTACs demonstrated acute and sustained degradation of YAP in multiple cancer cell lines .
  • this example represents a significant advancement in the development of PROTAC-based therapeutics targeting the degradation of oncogenic YAP.
  • YAP which is an intrinsically disordered protein often considered undruggable
  • this example provides a compelling proof of concept for the application of PROTACs in degrading such challenging protein targets.
  • NSC682769 due to the lack of an experimental structure of NSC682769 in complex with YAP, the binding mode and solvent-exposed regions of NSC682769 are not known, making the design of YAP PROTACs more challenging.
  • suitable tethering sites for linker attachment were identified based on the structure of NSC682769.
  • Four potential tethering sites were explored: site 1, the NH of the amide; site 2, the para substitution of the methoxy group; site 3, the para substitution of the 2-phenyl ring; and site 4, the meta substitution of the methoxy group (as shown in FIGs.2A-2B).
  • Compounds 7, 12, 13, 14, 19, 20, 21, 25, 26, and 27 were synthesized using short linker moieties at these tethering sites.
  • a TEAD-dependent luciferase reporter was then employed to determine if these compounds retained YAP/TEAD transcriptional inhibition activity. The retention of activity would indicate that the respective tethering sites are available for linker attachment without affecting the binding to YAP.
  • a PROTAC design and synthesis campaign was initiated (FIG.3).
  • VHL-1/cullin 2 E3 ligase system has been employed for the design of PROTAC degraders of a number of proteins. 39-42 Thus, it was investigated whether the VHL-1/cullin 2 E3 ligase system can be employed for the successful design of PROTAC YAP degraders.
  • VHL ligand 2 was used, which has been successfully used for the design of BCL-XL PROTAC degrader DT2216, which is the only VHL-recruiting PROTAC in clinical trial. 43, 44
  • CRBN/cullin 4A E3 ligase has been employed extensively for the design of PROTAC degraders of various proteins. 45-47 Pomalidomide is a potent, small- molecule ligand which binds to cereblon (CRBN), an adaptor protein in the cullin 4A E3 ligase degradation system.
  • the NCI-H226 cell line is recognized as a well-characterized YAP-dependent mesothelioma cell line, 51, 52 and among the three YAP-TEAD inhibitors currently undergoing clinical trials, all of them are intended for the treatment of mesothelioma (Clinical trial information: NCT05228015, NCT04857372, NCT04665206).
  • YZ-3 and YZ-13 demonstrated no cell killing activities on NCI-H226 cells, even at a concentration of 12.5 ⁇ M.
  • YZ-3 was synthesized by connecting NSC682769to VHL ligand 2, while YZ-13 utilized pomalidomide to recruit CRBN. Consequently, the effect of these two compounds on YAP expression level was not assessed.
  • YZ-6 can firmly inhibit the CTGF expression at a low concentration of 5 ⁇ M in NCI-H226 cells, which is more potent than NSC682769.
  • a cell proliferation assay was conducted specifically for YZ-6 (FIGs.7A-7B).
  • YZ-6 exhibited an IC50 value of 15.3 ⁇ M.
  • the maximum cell inhibition achieved by YZ-6 was 60%, whereas NSC682769 was able to reach 95% cell growth inhibition. Due to solubility limitations, the concentration could not be increased further for either compound.
  • YZ-6 demonstrated significantly superior performance compared to the YAP ligand NSC682769 alone.
  • YZ-6 exhibited an IC 50 value of 2.9 ⁇ M, making it twenty times more potent than the warhead NSC682769.
  • YZ-6 was able to induce the degradation of YAP with a DC50 value of 4.3 ⁇ M and effectively inhibit CTGF expression dose dependently in the Huh7 cell line (FIG. 8A). 53
  • TAZ is a homolog of YAP
  • YZ-6 can also degrade TAZ protein like YAP protein in the Huh7 cell line.
  • YZ-6 might be able to target cancer cells expressing not only YAP but also TAZ at a high level.
  • FIG. 9A-9B time-course studies were conducted in both NCI-H226 and Huh7 cells (FIGs. 9A-9B). YAP was significantly downregulated 24 hours after the treatment with compound YZ-6 at a dose of 20 ⁇ M in both cells.
  • YAP could be almost completely degraded by compound YZ-6 (20 ⁇ M) after 48 hours in both NCI-H226 and Huh7 cells, demonstrating degradation levels of 97% and 98%, respectively.
  • YZ-6-Induced YAP Degradation Occurs via a Bona Fide PROTAC Mechanism
  • competition experiments were performed in Huh7 cells that were pretreated for 2 hours with molar excess of VHL ligand 2 before being treated with 20 ⁇ M YZ-6. Competition of YZ-6 with VHL ligand rescued YAP levels (FIG.10A) by preventing PROTAC engagement with VHL.
  • YZ-6-Inhibits YAP Nuclear Localization Because YAP only functions in the nucleus when binding to TEAD, whether YZ-6 induces YAP degradation in the nucleus was evaluated. To verify the location of YAP degradation, immunofluorescence staining of YAP was performed to quantify the YAP expression level in the nucleus. After 12 h treatment of YZ-6, the (1) integrated YAP intensity in the nucleus to represent the total amount of YAP in the nucleus, and the (2) mean intensity of YAP in the nucleus to represent the concentration of YAP in the nucleus were measured.
  • the drug reached its maximum concentration (Cmax) of 193 ng/mL approximately 3.33 h (Tmax) postadministration, indicating relatively rapid absorption.
  • Cmax maximum concentration
  • Tmax time zero to infinity
  • AUClast AUC from time zero to the last measurable concentration
  • MRTinf mean residence time
  • YZ-6 pharmacokinetic attributes of YZ-6, particularly the prolonged MRTinf and sustained systemic presence, likely contribute to the observed efficacy of the dosing regimen used in our studies.
  • Administering YZ-6 every 3 days in the efficacy model has proven effective, likely because the extended duration of action allows for sustained therapeutic levels of the drug, ensuring continuous degradation of the target protein YAP.
  • This dosing schedule aligns well with the drug’s pharmacokinetic profile, minimizing the need for daily administration while maintaining potent antitumor activity.
  • Such a regimen not only enhances patient compliance in a clinical setting but also maximizes the therapeutic window of YZ-6, illustrating a key advantage of PROTAC technology in achieving prolonged biological effects even with intermittent dosing.
  • YZ-6 is potent in inhibition of liver cancer cell Huh7 growth and is more than 20 times more potent than the YAP inhibitor NSC682769. This example demonstrates that YZ-6 exhibits rapid engagement with YAP and sustains YAP degradation over time. Additionally, it leads to attenuated Hippo signaling in both NCI-H226 and Huh7 cell lines.
  • the use of PROTACs allows for more precise temporal control over YAP degradation compared to traditional knockdown methods, enabling researchers to explore the dynamic effects of YAP modulation on cellular processes. [00436] The ability to target YAP with small molecules was itself a milestone in drug discovery.
  • HEK 293T (CRL-3216) cell line was bought from the American Type Culture Collection (ATCC).
  • NCI-H226 cell line was provided by Dr. Maria Zajac-Kaye’s lab at the University of Florida.
  • the Huh7 cell line used in the study was provided by Dr. Liya Pi's lab at Tulane University. All cells were grown at 37 °C with 5% CO2 in media as recommended by the supplier.
  • Luciferase reporter assay was used in the study.
  • HEK 293T cells were plated at 2 ⁇ 10 4 cells/well in a 96 well microplate and were transfected with 50 ng of 8xGTIIC-luciferase plasmid (Addgene #34615) and 0.5 ng of pRL-CMV (Promega #E226A) by using lipofectamine 3000 (Life Technologies #L3000). After 6 hours, cells were treated with various concentrations of compounds or DMSO control for 24 hours. Luciferase signals were measured using the Dual Luciferase Reporter Assay System (Promega, E1960) according to the manufacturer’s instructions. Experiments were performed in triplicate and repeated at least three times.
  • Huh7 cells were treated for 24 hours, after which cells were lysed by scraping in RIPA buffer supplemented as described previously. For an individual experiment conducted on a given day, two separate wells of cells were treated identically for every condition and harvested side-by-side [00550] Western blot analysis. Treated cells were harvested and lysed in cold RIPA lysis buffer containing proteasome and phosphatase inhibitors. The protein concentrations were determined using the BCA Protein Assay kit. The prepared protein samples were loaded on and separated by 10% SDS-PAGE gel and then were transferred to PVDF membrane.
  • Verteporfin exhibits YAP-independent anti-proliferative and cytotoxic effects in endometrial cancer cells.
  • a pharmaceutical composition comprising a compound of any any preceding embodiment, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of embodiment 83 further comprising an additional agent.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of embodiments 1-82, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of embodiment 83 or 84.
  • a pharmaceutical composition of embodiment 83 or 84 comprising administering to the subject an effective amount of a compound of any one of embodiments 1-82, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of embodiment 83 or 84.
  • 86. The method of embodiment 85, wherein the cancer is liver cancer, breast cancer, pancreatic cancer, or mesothelioma.
  • the method of embodiment 85 or 86, wherein the effective amount is effective in inhibiting the
  • a method of modulating the activity and/or production of YAP in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of embodiments 1-82, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of embodiment 83 or 84.
  • a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof or a pharmaceutical composition of embodiment 83 or 84.
  • a method of modulating the activity and/or production of YAP in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of any one of embodiments 1-82, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of embodiment 83 or 84.
  • 92. The method of embodiment 90 or 91, wherein the modulating is inhibiting. 93.
  • a method of binding YAP in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of embodiments 1-82, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of embodiment 83 or 84. 94.
  • a method of binding YAP in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of any one of embodiments 1-82, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of embodiment 83 or 84. 95.
  • a method of degrading YAP in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of embodiments 1-82, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of embodiment 83 or 84.
  • a compound of any one of embodiments 1-82 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of embodiment 83 or 84.
  • a method of degrading YAP in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of any one of embodiments 1-82, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of embodiment 83 or 84. 97.
  • a method of modulating YAP/TEAD-led transcription in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of embodiments 1-82, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of embodiment 83 or 84. 98.
  • a method of modulating YAP/TEAD-led transcription in a cell, tissue, or biological sample comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of any one of embodiments 1-82, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of embodiment 83 or 84.
  • 99. The method of any of embodiments 85-98, wherein the method further comprises suppressing YAP/TEAD-led transcription.
  • a kit comprising: a compound of any one of embodimentembodiments 1-82, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; or a pharmaceutical composition of any one embodimentembodiments 83 and 84; and instructions for using the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition.
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

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Abstract

La présente divulgation concerne des composés selon les formules décrits dans la description, par exemple, formule (0), et sels, solvates, hydrates, polymorphes, co-cristaux, tautomères, stéréoisomères, composés marqués de manière isotopique, et promédicaments pharmaceutiquement acceptables de ceux-ci. La présente divulgation concerne également des compositions pharmaceutiques, des polythérapies et des kits comprenant les composés, et des sels, solvates, hydrates, polymorphes, co-cristaux, tautomères, stéréoisomères, composés marqués de manière isotopique ou promédicaments pharmaceutiquement acceptables de ceux-ci, et des méthodes de traitement ou de prévention de maladies et de troubles associés à YAP (par exemple, le cancer).
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WO2022164835A1 (fr) * 2021-01-26 2022-08-04 The United States Government As Represented By The Department Of Veterans Affairs Compositions et procédés d'inhibition de yap

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DATABASE PubChem 19 December 2011 (2011-12-19), PUBCHEM: "NSC-673435", XP093295136, Database accession no. SID 515254 *

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