Combination of YAP protacs and sorafenib for use in the treatment of cancer

Abstract

The present disclosure provides methods of treating or preventing diseases and disorders associated with YAP (e.g., cancer) using a combination therapy of a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, of a pharmaceutical composition thereof, that inhibits YAP, degrades YAP, or suppresses YAP / TEAD-led transcription, and sorafenib, or a pharmaceutical composition thereof. Also provided herein are associated kits.

Description

YAP DEGRADER COMBINATION THERAPY RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C.119(e) to U.S. Provisional Applications 63 / 665,513 filed June 28, 2024 and 63 / 694,791 filed September 13, 2024, the entirety of which are incorporated herein by reference. GOVERNMENT SUPPORT

[0002] This invention was made with government support under Grant No. HT9425-23-1- 0737 awarded by U.S. Army Medical Research Acquisition Activity and Grant No. R01 AA028035 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND

[0003] 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.1-3The Hippo signaling pathway regulates the co-activator function of YAP / TAZ by controlling their cellular localization through phosphorylation.4Activation of the upstream Hippo signaling pathway leads to the phosphorylation of large tumor suppressor 1 / 2 (Lats1 / 2) by mammalian STE20- like protein kinase 1 / 2 (Mst1 / 2) or activation by neurofibromin 2 (NF2), which acts as a scaffolding protein in the pathway.5Subsequently, 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.3, 6Conversely, 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).7-9

[0004] YAP and TAZ are considered oncogenes, as their amplification or over-expression has been observed in various human cancers, and reports of gene amplification and epigenetic modulation of the YAP and TAZ loci in cancer are similarly prevalent.9-11Studies have demonstrated that elevated YAP expression can trigger multiple oncogenic characteristics in mammalian cells.4Additionally, the nuclear localization of YAP in tumor biopsies has been correlated with a poor prognosis for cancer patients.6, 12, 131SUMMARY OF THE INVENTION

[0005] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising co-administering to the subject: a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co- crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof; wherein the compound inhibits YAP, degrades YAP degrader, or suppresses YAP / TEAD-led transcription; and sorafenib, or a pharmaceutical composition thereof.

[0006] In another aspect, provided herein is a kit comprising: a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co- crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof; wherein the compound inhibits YAP, degrades YAP, or suppresses YAP / TEAD-led transcription; sorafenib, or a pharmaceutical composition thereof; and instructions for using sorafenib, or a pharmaceutical composition thereof, and the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition thereof.

[0007] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims. It should be understood that the aspects described herein are not limited to specific embodiments, methods, or configurations, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting. BRIEFDESCRIPTION OF THEDRAWINGS

[0008] FIG.1 shows representative compounds targeting YAP.

[0009] 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. HEK 293T cells were treated with DMSO, and designed compounds or NSC68269 for 24 hours. Not Significant (N.S.); * p < 0.05; ** p < 0.01; *** p < 0.005; **** p < 0.001.2

[0010] FIG.3 shows chemical structures of designed NSC682769-based YAP degraders using tethering sites 2 and 4.

[0011] 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.

[0012] 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. Cells were treated with different compounds for 48 hours, and whole cell lysates were then analyzed by western blotting to examine the level of YAP protein. The membranes were stripped and reblotted for β-actin as the loading control. Quantified data represents mean ± SD from two independent biological replicates.

[0013] 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. *** p < 0.005; **** p < 0.001.

[0014] FIGs.7A-7D 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. IC50values were calculated using the GraphPad Prism 9 software. FIG.7C shows cell viability results for Huh7 cells or AML12 cells treated with indicated doses of YZ-6 or Sorafenib for 4 days. FIG.7D shows cell viability results for NCI-H2452 cells treated with YZ-6 for 4 days.

[0015] 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 for324 hours. Quantified data represents mean ± SD from two independent biological replicates. ** p < 0.01; **** p < 0.001.

[0016] 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.

[0017] 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 μM) for 24 hours. Quantitation is shown below. FIG.10B shows results for Huh7 cells pretreated with 200 nM or 1 μM neddylation inhibitors MLN4924, or the proteasome inhibitor MG132 (300 nM) for 2 hours, followed by treatment with DMSO or compound YZ-6 (20 μM) for 24 hours. Quantitation is shown below. FIG.10C shows results for Huh7 cells pretreated with 100 μM YAP inhibitor NSC682769 for 2 hours, followed by treatment with DMSO or compound YZ-6 (20 μM) for 24 hours. Quantitation is shown below. FIG.10D shows results for Huh7 cells treated with DMSO, or 10 μM or 20 μM YZ-6, or 10 μM or 20 μM YZ-6 NC for 24 hours. Quantitation is shown below. * p < 0.05; ** p < 0.01; *** p < 0.005; **** p < 0.001.

[0018] 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.

[0019] FIG.12 shows a schematic illustrating the design and synthesis of PROTACs based on YAP inhibitor NSC682769.

[0020] FIG.13 shows an illustration depicting targeted protein degradation.

[0021] FIGs.14A-14E show in vivo antitumor activity of compound YZ-6 and Sorafenib in an Huh7 cell-derived xenograft. FIG.14A shows tumor volume in mice after treatment of vehicle, compound YZ-6, Sorafenib, or compound YZ-6 and Sorafenib. FIG.14B shows tumor images after treatment of vehicle, compound YZ-6, Sorafenib, or compound YZ-6 and Sorafenib FIG.14C shows tumor weight in mice after treatment of vehicle, compound YZ- 6, Sorafenib, or compound YZ-6 and Sorafenib. FIG.14D shows body weight in mice after treatment of vehicle, compound YZ-6, Sorafenib, or compound YZ-6 and Sorafenib. n = 54mice per group. ∗∗∗∗p < 0.0001 (Student’s t test). FIG.14E shows western blot analysis of the excised tissue from mice bearing Huh7 tumors after treating with compound YZ-6.

[0022] FIGs.15A-E show YZ-6 administration at 35 mg / kg does not induce chronic liver injury. C57BL6 animals (10 week-old) received IP of vehicle control or YZ- 6 at 35 mg / kg body weight (n = 3 per group) every 3 days. Histological and biochemical analyses were performed 24 days later. FIG.15A shows H&E staining. FIGs.15B−15D show detected serum levels of liver injury markers ALT (FIG.15B), AST (FIG.15C), and total bilirubin (FIG.15D) in sera at 1 day after last injection. FIG.15E shows hepatic contents of triglyceride measured at 1 day after last injection. Values are means ± SD from three biological triplicates.

[0023] FIGs.16A-16C show that YZ-6 reduced YAP in the nucleus. FIG.16A shows representative images of YAP from immunofluorescence staining. Huh7 cells were treated with 0 μM (DMSO), or 5, 10, or 20 μM of YZ-6 for 12 h. FIG.16B shows quantification of integrated YAP intensity in the nucleus. Integrated YAP intensity decreases with YZ-6 concentration. P < 0.0001 for 0 vs 5 μM, P < 0.0001 for 0 vs 10 μMP < 0.0001 for 0 μMvs 20 μM(n > 85). FIG.16C shows quantification of mean YAP intensity in the nucleus. Mean YAP intensity decreases with YZ-6 concentration. P < 0.0001 for 0 vs 5 μM, P = 0.0004 for 0 vs 10 μM P < 0.0001 for 0 vs 20 μM (n > 85). Comparisons for all pairs used Tukey−Kramer HSD.

[0024] FIGs 17A-17B show Plasma concentrations of YZ-6 in Sprague−Dawley rats following IP administration (n = 3, dose = 35 mg / kg). FIG.17A shows plasma concentration curve vs time (n = 3), The curve illustrates the drug’s absorption, peak concentration, and elimination phases. FIG.17B shows pharmacokinetic parameters of YZ-6. Table displaying key pharmacokinetic parameters of YZ-6, including t1 / 2, Cmax, Tmax, AUC and MRT. DEFINITIONS

[0025] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, March’s Advanced Organic Chemistry, 7th Edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations,5John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0026] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0027] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0028] The term “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.

[0029] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “C1-6 alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0030] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.6

[0031] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1–6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1–12alkyl (such as unsubstituted C1–6alkyl, e.g., −CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1–12alkyl (such as substituted C1–6 alkyl, e.g., –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)).

[0032] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C1–20haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C1–10 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1–9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1–8haloalkyl”). In some7embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1–7haloalkyl”).In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1–6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1–5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1–4haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1–3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1–2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include –CHF2, −CH2F, −CF3, −CH2CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like.

[0033] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–20alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–12 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 (“heteroC1–11alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–10 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 (“heteroC1–9alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1–5alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC1–4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 18heteroatom within the parent chain (“heteroC1–3alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1–12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–12alkyl.

[0034] The term “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 (“C1-20alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1–12alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C1–11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1–10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1–9alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1–8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1–7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1–6alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1–5alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1–4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1–3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1–2alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C1 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 C1–4alkenyl 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 C1–6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C1-20alkenyl. In certain embodiments, the alkenyl group is a9substituted C1-20alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3 ormay be in the (E)- or (Z)- configuration.

[0035] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20 alkenyl”). In certain embodiments, 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 (“heteroC1–12alkenyl”). 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 (“heteroC1–10 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–9alkenyl”). 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 (“heteroC1–8 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 (“heteroC1–7alkenyl”). In some embodiments, a heteroalkenyl group has 1to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–6 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 (“heteroC1–5 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 (“heteroC1–4alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1–3 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 (“heteroC1–2alkenyl”). 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 (“heteroC1–6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is10independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC1–20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC1–20alkenyl.

[0036] The term “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) (“C1-20alkynyl”). 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 (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 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 (“C1-3alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“C1 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 (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C1-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl.

[0037] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20 alkynyl”). In certain embodiments, 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 (“heteroC1–10alkynyl”). In some11embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–9 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 (“heteroC1–8alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–7 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 (“heteroC1–6 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 (“heteroC1–5alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC1–4 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 (“heteroC1–3 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 (“heteroC1–2 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–6alkynyl”). 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 heteroC1–20alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC1–20alkynyl.

[0038] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some12embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-10carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0039] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl13groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0040] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0041] In some embodiments, a heterocyclyl group is a 5–10 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is14independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0042] 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]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6- dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H- thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-15b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2- c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0043] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ^ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14aryl. In certain embodiments, the aryl group is a substituted C6-14aryl.

[0044] “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.

[0045] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ^ electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl16groups 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). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0046] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5- 6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0047] 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 groups17containing 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.

[0048] “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.

[0049] The term “unsaturated bond” refers to a double or triple bond.

[0050] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0051] 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.

[0052] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0053] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means18that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not limited in any manner by the exemplary substituents described herein.

[0054] Exemplary carbon atom substituents include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)2, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3,−P(ORcc)3+X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–20alkyl, C1–20perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc;19wherein: each instance of Raais, independently, selected from C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5- 14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1–20 alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5- 14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1–10alkyl, C1–10perhaloalkyl, C1–10alkenyl, C1–1020alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, 3- 10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =O or =S; wherein X−is a counterion; each instance of Reeis, independently, selected from C1–10alkyl, C1–10perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3- 10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1–10 alkyl, C1–10perhaloalkyl, C1–10alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5- 10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1–6alkyl, −ON(C1–6alkyl)2, −N(C1–6alkyl)2, −N(C1–6alkyl)3+X−, −NH(C1–6 alkyl)2+X−, −NH2(C1–6 alkyl)+X−, −NH3+X−, −N(OC1–6 alkyl)(C1–6 alkyl), −N(OH)(C1–6 alkyl), −NH(OH), −SH, −SC1–6 alkyl, −SS(C1–6 alkyl), −C(=O)(C1–6 alkyl), −CO2H, −CO2(C1–6alkyl), −OC(=O)(C1–6alkyl), −OCO2(C1–6alkyl), −C(=O)NH2, −C(=O)N(C1–6 alkyl)2, −OC(=O)NH(C1–6 alkyl), −NHC(=O)( C1–6 alkyl), −N(C1–6 alkyl)C(=O)( C1–6 alkyl), −NHCO2(C1–6 alkyl), −NHC(=O)N(C1–6 alkyl)2, −NHC(=O)NH(C1–6alkyl), −NHC(=O)NH2, −C(=NH)O(C1–6alkyl), −OC(=NH)(C1–6 alkyl), −OC(=NH)OC1–6 alkyl, −C(=NH)N(C1–6 alkyl)2, −C(=NH)NH(C1–6 alkyl), −C(=NH)NH2, −OC(=NH)N(C1–6 alkyl)2, −OC(NH)NH(C1–6alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6alkyl), −SO2N(C1–6alkyl)2, −SO2NH(C1–6alkyl), −SO2NH2, −SO2C1–6alkyl, −SO2OC1–6 alkyl, −OSO2C1–6 alkyl, −SOC1–6 alkyl, −Si(C1–6 alkyl)3, −OSi(C1–6 alkyl)3 −C(=S)N(C1–6 alkyl)2, C(=S)NH(C1–6 alkyl), C(=S)NH2, −C(=O)S(C1–6 alkyl), −C(=S)SC1–6alkyl, −SC(=S)SC1–6alkyl, −P(=O)(OC1–6alkyl)2, −P(=O)(C1–6alkyl)2,21−OP(=O)(C1–6alkyl)2, −OP(=O)(OC1–6alkyl)2, C1–10alkyl, C1–10perhaloalkyl, C1–10alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3- 10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; and each X−is a counterion.

[0055] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −ORaa,−OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, −ORaa, −SRaa,−OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1–10 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).22

[0056] In certain embodiments, the molecular weight of a carbon atom substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0057] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0058] The term “hydroxyl” or “hydroxy” refers to the group −OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from −ORaa, −ON(Rbb)2, −OC(=O)SRaa,−OC(=NRbb)N(Rbb)2, −OS(=O)Raa, −OSO2Raa, −OSi(Raa)3, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, and −OP(=O)(N(Rbb))2, wherein X−, Raa, Rbb, and Rccare as defined herein.

[0059] The term “thiol” or “thio” refers to the group –SH. The term “substituted thiol” or “substituted thio,” by extension, refers to a thiol group wherein the sulfur atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from –SRaa, –S=SRcc, –SC(=S)SRaa, –SC(=S)ORaa, –SC(=S) N(Rbb)2, –wherein Raaand Rccare as defined herein.

[0060] The term “amino” refers to the group −NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

[0061] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from −NH(Rbb), −NHC(=O)Raa, −NHCO2Raa, −NHC(=O)N(Rbb)2, −NHC(=NRbb)N(Rbb)2, −NHSO2Raa, −NHP(=O)(ORcc)2,23and −NHP(=O)(N(Rbb)2)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group −NH(Rbb) is not hydrogen.

[0062] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from −N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −NRbbSO2Raa, −NRbbP(=O)(ORcc)2, and −NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0063] The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from −N(Rbb)3and −N(Rbb)3+X−, wherein Rbband X−are as defined herein.

[0064] The term “sulfonyl” refers to a group selected from –SO2N(Rbb)2, –SO2Raa, and – SO2ORaa, wherein Raaand Rbbare as defined herein.

[0065] The term “sulfinyl” refers to the group –S(=O)Raa, wherein Raais as defined herein.

[0066] The term “acyl” refers to a group having the general formula −C(=O)RX1, −C(=O)ORX1, −C(=O)−O−C(=O)RX1, −C(=O)SRX1, −C(=O)N(RX1)2, −C(=S)RX1, −C(=S)N(RX1)2, and −C(=S)S(RX1), −C(=NRX1)RX1, −C(=NRX1)ORX1, −C(=NRX1)SRX1, and −C(=NRX1)N(RX1)2, wherein RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro,24hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0067] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (–C(=O)Raa), carboxylic acids (–CO2H), aldehydes (– CHO), esters (–CO2Raa, –C(=O)SRaa, –C(=S)SRaa), amides (–C(=O)N(Rbb)2, – C(=O)NRbbSO2Raa, −C(=S)N(Rbb)2), and imines (–C(=NRbb)Raa, –C(=NRbb)ORaa), – C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0068] The term “phosphino” refers to the group –P(Rcc)2, wherein Rccis as defined herein.

[0069] The term “phosphono” refers to the group – (P=O)(ORcc)2, wherein Raaand Rccare as defined herein.

[0070] The term “phosphoramido” refers to the group –O(P=O)(N(Rbb)2)2, wherein each Rbbis as defined herein.

[0071] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2,−SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(ORcc)2, −P(=O)(Raa)2, −P(=O)(N(Rcc)2)2, C1–20 alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, hetero C1–20 alkyl, hetero C1–20 alkenyl, hetero C1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0072] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or25unsubstituted C1-10alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a nitrogen protecting group.

[0073] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1–10alkyl (e.g., aralkyl, heteroaralkyl), C1–20alkenyl, C1–20alkynyl, hetero C1–20alkyl, hetero C1–20alkenyl, hetero C1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0074] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3- phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o- nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4- chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0075] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting26group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9- fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2- phenylethyl carbamate (hZ), 1–(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1- dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1- dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4- nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p- nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4- dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1- dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)- 6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o- nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N- dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2- pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-27cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl- 1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4- pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-tbutylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0076] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9- anthracenesulfonamide, 4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0077] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N’-p-toluenesulfonylaminoacyl derivatives, N’-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N- acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N- dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4- tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5- triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1- substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2- (trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4- nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N’- oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-28methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N-(N’,N’-dimethylaminomethylene)amine, N-p- nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1- cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N- [phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N- nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine.

[0078] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0079] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl or an oxygen protecting group.

[0080] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa,−Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb) 2)2, wherein X−, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting29Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0081] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of 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-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p- methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 4,4'-Dimethoxy-3"'-[N-(imidazolylmethyl) ]trityl Ether (IDTr- OR), 4,4'-Dimethoxy-3"'-[N-(imidazolylethyl)carbamoyl]trityl Ether (IETr-OR), 1,1-bis(4- methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate,30triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p- nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4- ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4- nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0082] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0083] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a sulfur protecting group.

[0084] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur31protecting group is selected from the group consisting of −Raa, −N(Rbb)2, −C(=O)SRaa,−S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0085] In certain embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0086] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO − 3 , HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid– 2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5- (CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−,B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.32

[0087] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0088] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not limited in any manner by the above exemplary listing of substituents.

[0089] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this invention include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0090] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well33known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(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.

[0091] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.34

[0092] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0093] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0094] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0095] The term “crystalline” or “crystalline form” refers to a solid form substantially exhibiting three-dimensional order. In certain embodiments, a crystalline form of a solid is a solid form that is substantially not amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more sharply defined peaks.

[0096] The term “amorphous” or “amorphous form” refers to a form of a solid (“solid form”), the form substantially lacking three-dimensional order. In certain embodiments, an amorphous form of a solid is a solid form that is substantially not crystalline. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of an amorphous form includes a wide scattering band with a peak at 2θ of, e.g., between 20 and 70°, inclusive, using CuKα radiation. In certain embodiments, the XRPD pattern of an amorphous form further includes one or more peaks attributed to crystalline structures. In certain embodiments, the maximum intensity of any one of the one or more peaks attributed to crystalline structures observed at a 2θ 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 intensity35of the wide scattering band. In certain embodiments, the XRPD pattern of an amorphous form includes no peaks attributed to crystalline structures.

[0097] The term “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. In certain embodiments, 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. In the salt, 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. In the co-crystal, however, 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. In certain embodiments, in the co-crystal, there is no proton transfer from the acid to a compound disclosed herein. In certain embodiments, 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.

[0098] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0099] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, 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 aromatic36esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases, it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C1-C8 alkyl, C2-C8alkenyl, C2-C8alkynyl, aryl, C7-C12substituted aryl, and C7-C12arylalkyl esters of the compounds described herein may be preferred.

[0100] The terms “composition” and “formulation” are used interchangeably.

[0101] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0102] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.

[0103] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0104] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0105] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in37the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0106] 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.

[0107] 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. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0108] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0109] In certain embodiments, 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 about3840 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.

[0110] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0111] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for 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.

[0112] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting the activity and / or production of YAP. In certain embodiments, a prophylactically effective amount is an amount sufficient for degrading YAP. In certain embodiments, a prophylactically effective39amount 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.

[0113] As used herein the term “inhibit” or “inhibition” in the context of proteins, for example, in the context of YAP, 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. In some embodiments, 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.

[0114] 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.

[0115] The term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically40stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and / or is associated with a disease.

[0116] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0117] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast,41mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B- cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma);42liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva). DETAILEDDESCRIPTION OFCERTAINEMBODIMENTSMethods

[0118] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising co-administering to the subject: a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co- crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a43pharmaceutical composition thereof; wherein the compound inhibits YAP, degrades YAP degrader, or suppresses YAP / TEAD-led transcription; and sorafenib, or a pharmaceutical composition thereof.

[0119] In some embodiments, the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, inhibits YAP. In some embodiments, the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, degrades YAP. In some embodiments, the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, suppresses YAP / TEAD-led transcription. In some embodiments, the compound is of Formula (0), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0120] In some embodiments, the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or sorafenib is administered via oral administration, intraperitoneal injection, or subcutaneous injection. In some embodiments, the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered via oral administration, intraperitoneal injection, or subcutaneous injection. In some embodiments, the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered via oral administration. In some embodiments, the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered via intraperitoneal injection. In some embodiments, the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered via subcutaneous injection. In some embodiments, sorafenib is administered via oral administration, intraperitoneal injection, or subcutaneous injection. In some embodiments, sorafenib is administered via oral administration. In some embodiments, sorafenib is administered via intraperitoneal injection. In some embodiments, sorafenib is administered via subcutaneous injection.

[0121] In some embodiments, the cancer is liver cancer, breast cancer, pancreatic cancer, or mesothelioma. In some embodiments, the cancer is liver cancer. In some embodiments, the44cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is mesothelioma.

[0122] In some embodiments, the method further comprises suppressing YAP / TEAD-led transcription. In some embodiments, the method further comprises inhibiting YAP. In some embodiments, the method further comprises inhibiting the activity and / or production of YAP. In some embodiments, the method further comprises degrading YAP.

[0123] In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co- crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in an effective amount. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 1 mg / kg to about 200 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 1 mg / kg to about 150 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 1 mg / kg to about 100 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co- crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 1 mg / kg to about 75 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 1 mg / kg to about 70 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 1 mg / kg to about 60 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 1 mg / kg to about 55 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 10 mg / kg to about 200 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co- crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 10 mg / kg to about 150 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 1045mg / kg to about 100 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 10 mg / kg to about 75 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 10 mg / kg to about 70 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 10 mg / kg to about 60 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co- crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 10 mg / kg to about 55 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 20 mg / kg to about 200 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 20 mg / kg to about 150 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 20 mg / kg to about 100 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 20 mg / kg to about 75 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co- crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 20 mg / kg to about 70 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 20 mg / kg to about 60 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 20 mg / kg to about 55 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 30 mg / kg to about 40 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 10 mg / kg, about 1546mg / kg, about 20 mg / kg about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, or about 55 mg / kg. In some embodiments, the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 35 mg / kg.

[0124] In some embodiments, sorafenib is co-administered on the same schedule as the compound provided herein, or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In some embodiments, the co-administration increases sensitivity to sorafenib. In some embodiments, the co- administration increases sensitivity to the compound provided herein, or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0125] In some embodiments, sorafenib is administered in the amount of about 1 mg / kg to about 200 mg / kg. In some embodiments, sorafenib is administered in the amount of about 10 mg / kg to about 200 mg / kg. In some embodiments, sorafenib is administered in the amount of about 20 mg / kg to about 200 mg / kg. In some embodiments, sorafenib is administered in the amount of about 50 mg / kg to about 200 mg / kg. In some embodiments, sorafenib is administered in the amount of about 1 mg / kg to about 150 mg / kg. In some embodiments, sorafenib is administered in the amount of about 10 mg / kg to about 150 mg / kg. In some embodiments, sorafenib is administered in the amount of about 20 mg / kg to about 150 mg / kg. In some embodiments, sorafenib is administered in the amount of about 50 mg / kg to about 150 mg / kg. In some embodiments, sorafenib is administered in the amount of about 75 mg / kg to about 125 mg / kg. In some embodiments, sorafenib is administered in the amount of about 80 mg / kg. In some embodiments, sorafenib is administered in the amount of about 90 mg / kg. In some embodiments, sorafenib is administered in the amount of about 100 mg / kg. In some embodiments, sorafenib is administered in the amount of about 110 mg / kg. In some embodiments, sorafenib is administered in the amount of about 120 mg / kg.

[0126] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a human. In some embodiments, the subject is a human aged 18 or older. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In47certain 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. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile. Compounds

[0127] In some embodiments, the compound is of Formula (0):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: A1, A2, and A3are each independently –N= or –C(R9)=; C1, C2, C3, and C4are each independently –N= or D1, D2, D3, and D4are each independently –N= or R1, R3, and R4are each independently hydrogen, –, – NRAC(=O)ORA, –NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, optionally substituted C1-C4alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C3-C6 carbocyclyl, or –L1– Y1; R2is hydrogen, –N(RA)2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAS(=O)2RA, – NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4heteroalkenyl, optionally substituted C2-C4heteroalkynyl, or optionally substituted C3-C6 carbocyclyl; R5is hydrogen, a nitrogen protecting group, or –L1–Y1;48one of R1, R3, R4, or R5is –L1–Y1; each instance of R6, R7, R8, and R9is independently hydrogen, halogen, 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, –CN, –ORB, –SCN, –SRB, – SSRB, –N3, –NO, –N(RB)2, –NO2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, –C(=O)N(RB)2, – C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, –C(=NRB)N(RB)2, –S(=O)RB, –S(=O)ORB, – S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, –S(=O)2ORB, –S(=O)2SRB, –S(=O)2N(RB)2, – OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –OC(=NRB)RB, – OC(=NRB)ORB, –OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, –OS(=O)ORB, – OS(=O)SRB, –OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, – OS(=O)2N(RB)2, –ON(RB)2, –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, –SC(=O)N(RB)2, – SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, –SC(=NRB)N(RB)2, –NRBC(=O)RB, – NRBC(=O)ORB, –NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, – NRBC(=NRB)ORB, –NRBC(=NRB)SRB, –NRBC(=NRB)N(RB)2, –NRBS(=O)RB, – NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, – NRBS(=O)2SRB, or –NRBS(=O)2N(RB)2; each instance of RAand RBis 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 RAor RBattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; –L1– is optionally substituted C1-C25 alkylene, optionally substituted C2-C25 alkenylene, optionally substituted C2-C25 alkynylene, optionally substituted C1-C25 heteroalkylene, optionally substituted C2-C25heteroalkenylene, optionally substituted C2-C25heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or any combination thereof; and49–Y1is of Formula (Y-A) or (Y-B):(Y-A) (Y-B) wherein: each instance of Ra1is independently hydrogen, –ORC, –N(RC)2, –CN, –NO2, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8heteroalkynyl, optionally substituted C3-C10carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl; each instance of Ra2is independently –RaL–, hydrogen, –ORC, –N(RC)2, –CN, –NO2, optionally substituted C1-C8alkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C1-C8heteroalkyl, optionally substituted C2-C8heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C3-C10 membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl; Ra3is hydrogen,–C(=O)RC, –C(=O)ORC, –C(=O)N(RC)2, –PO(ORC)2, or –C(RC)2– OPO(ORC)2;optionally substituted C3-C10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; Ra5is hydrogen or halogen; Ra6is hydrogen, halogen, –ORC, –N(RC)2, –CN, –NO2, optionally substituted C1-C8alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8heteroalkynyl, optionally substituted C3-C10carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of Ra7and Ra8is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted50heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –ORC, –SCN, –SRC, –SSRC, –N3, –NO, –NRCC(=NRC)N(RC)2, –NRCS(=O)RC, –NRCS(=O)ORC, –NRCS(=O)SRC, –NRCS(=O)N(RC)2, –NRCS(=O)2RC, –NRCS(=O)2ORC, –NRCS(=O)2SRC, or –NRCS(=O)2N(RC)2; Ra9is hydrogen or a nitrogen protecting group; Ra10is –RaL– or hydrogen; one instance of Ra2, Ra4, or Ra10is –RaL–; –RaL– is a bond, –O–, –N(RC)–, –N(RC)C(=O)–, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8heteroalkylene, optionally substituted C2-C8heteroalkenylene, optionally substituted C2-C8heteroalkynylene, optionally substituted C3-C10carbocyclylene, optionally substituted 3- to 10-membered heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; q is 0, 1, 2, 3, 4, or 5; r is 0, 1, 2, or 3; each instance of Rb1is independently halogen, –ORD, –CN, –NO2, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C8 carbocyclyl, or optionally substituted 3- to 8-membered heterocyclyl; Rb2is hydrogen or a nitrogen protecting group; Vb is –N–, –CH–, or –C(Rb1)–; Wb is a bond, –Wb1–, or –Wb1–Wb2–; wherein51Wb1and Wb2are each independently –C(=O)–, –O–, –C(RE)2–, or –NRD–, provided that –Wb1–Wb2– is not –O–O–;designates the point of attachment to Wb; each instance of Rb3is independently halogen, optionally substituted C1-C3alkyl, or – ORD; t is 0, 1, 2, 3, 4, or 5; Zbis –(Rb4)u–, wherein Rb4, at each occurrence, is independently Rb5or Rb6; wherein Rb5, at each occurrence, is independently a bond, –C(=O)–, –C(RE)2–, –NRD–, –O–, optionally substituted C1-C10 alkylene, optionally substituted C1-C10 alkenylene, or optionally substituted C1-C10alkynylene; Rb6, at each occurrence, is independently a bond, optionally substituted C3-C10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; u is 0, l, 2, 3, 4, 5, or 6; provided that –Rb4–Rb4– is not –O–O–; s is 0, 1, 2, 3, or 4; each instance of RCand RDis 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 RCor RDattached to the52same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; and each instance of REis independently hydrogen, halogen, –ORD, =O, –CN, –NO2, – N(RD)2, 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, or optionally substituted heteroaryl.

[0128] In some embodiments, 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.

[0129] In some embodiments, 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.53

[0130] In some embodiments, 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.

[0131] In some embodiments, 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.

[0132] In some embodiments, the compound is of Formula (0-f):54or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0133] In some embodiments, 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.

[0134] In some embodiments, the compound is of Formula (0-g):55or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0135] In some embodiments, 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.

[0136] In some embodiments, 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.

[0137] In some embodiments, the compound is of Formula (0-H):56or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0138] In some embodiments, 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.

[0139] In some embodiments, 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.57

[0140] In some embodiments, 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.

[0141] In some embodiments, 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.58

[0142] In some embodiments, 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.

[0143] In some embodiments, 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.59

[0144] In some embodiments, 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.

[0145] In some embodiments, 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.60

[0146] In some embodiments, 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.

[0147] In some embodiments, 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.61

[0148] In some embodiments, 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.

[0149] In some embodiments, in Formulae (0-B)-(0-N) and (0-f)-(0-n), each variable is independently as defined in Formula (0) unless specified otherwise.

[0150] In another aspect, the compound is of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.62

[0151] In some embodiments, 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.

[0152] In some embodiments, 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.

[0153] In some embodiments, 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.63

[0154] In some embodiments, 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.

[0155] In some embodiments, 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.

[0156] In some embodiments, the compound is of Formula (I-f):64or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0157] In some embodiments, 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.

[0158] In some embodiments, 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.65

[0159] In some embodiments, 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.

[0160] In some embodiments, 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.

[0161] In some embodiments, 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.66

[0162] In some embodiments, 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.

[0163] In some embodiments, 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.67

[0164] In some embodiments, 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.

[0165] In some embodiments, 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.68

[0166] In some embodiments, 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.

[0167] In some embodiments, the compound is of Formula (I-K):stereoisomer, isotopically labeled compound, or prodrug thereof.

[0168] In some embodiments, in Formulae (I-A)-(I-K) and (I-f)-(I-k), each variable is independently as defined in Formula (I) unless specified otherwise.

[0169] As defined herein, A1, A2, and A3are each independently –N= or –C(R9)=. In some embodiments, at least one of A1, A2, and A3is –C(R9)=. In some embodiments, at least two of A1, A2, and A3are –C(R9)=. In some embodiments, A1, A2, and A3are –C(R9)=. In some embodiments, A1is –C(R9)=. In some embodiments, A2is –C(R9)=. In some embodiments, A3is –C(R9)=. In some embodiments, A1is –CH=. In some embodiments, A2is –CH=. In some embodiments, A3is –CH=. In some embodiments, A1, A2, and A3 are –C(H)=. In some69embodiments, A1is –N=. In some embodiments, A2is –N=. In some embodiments, A3is – N=.

[0170] As defined herein, C1, C2, C3, and C4are each independently –N= or –C(R8)=. In some embodiments, at least one of C1, C2, C3, and C4is –C(R9)=. In some embodiments, at least two of C1, C2, C3, and C4are –C(R9)=. In some embodiments, at least three of C1, C2, C3, and C4are –C(R9)=. In some embodiments, C1, C2, C3, and C4are –C(R9)=. In some embodiments, C1is –C(R9)=. In some embodiments, C2is –C(R9)=. In some embodiments, C3is –C(R9)=. In some embodiments, C4is –C(R9)=. In some embodiments, C1is –CH=. In some embodiments, C2is –CH=. In some embodiments, C3is –CH=. In some embodiments, C4is –CH=. In some embodiments, C1, C2, C3, and C4 are –C(H)=. In some embodiments, C1is –N=. In some embodiments, C2is –N=. In some embodiments, C3is –N=. In some embodiments, C4is –N=.

[0171] As defined herein, D1, D2, D3, and D4are each independently –N= or –C(R7)=. In some embodiments, at least one of D1, D2, D3, and D4is –C(R9)=. In some embodiments, at least two of D1, D2, D3, and D4are –C(R9)=. In some embodiments, at least three of D1, D2, D3, and D4are –C(R9)=. In some embodiments, D1, D2, D3, and D4are –C(R9)=. In some embodiments, D1is –C(R9)=. In some embodiments, D2is –C(R9)=. In some embodiments, D3is –C(R9)=. In some embodiments, D4is –C(R9)=. In some embodiments, D1is –CH=. In some embodiments, D2is –CH=. In some embodiments, D3is –CH=. In some embodiments, D4is –CH=. In some embodiments, D1, D2, D3, and D 4 are –C(H)=. In some embodiments, D1is –N=. In some embodiments, D2is –N=. In some embodiments, D3is –N=. In some embodiments, D4is –N=.

[0172] As defined herein, R1is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, – NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, optionally substituted C1-C4alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4heteroalkynyl, optionally substituted C3-C6carbocyclyl, or –L1–Y1. In some embodiments, R1is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, – NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, or –L1–Y1. In some embodiments, R1is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, –NRAS(=O)2ORA, – ORA, –SRA, or –L1–Y1. In some embodiments, R1is –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, –SRA, or –L1–Y1. In some embodiments, R1is –N(RA)2, –ORA, or –SRA, or –L1–Y1. In some embodiments, R1is –NH2, –NH(optionally substituted C1-4alkyl), –N(optionally substituted C1-4alkyl)2, –OH, –70O(optionally substituted C1-4alkyl), –SH, or –S(optionally substituted C1-4alkyl), or –L1–Y1. In some embodiments, R1is –N(RA)2, –ORA, or –L1–Y1. In some embodiments, R1is –NH2, – NH(optionally substituted C1-4 alkyl), –N(optionally substituted C1-4 alkyl)2, –OH, – O(optionally substituted C1-4alkyl), or –L1–Y1. In some embodiments, R1is –ORA, –SRA, or –L1–Y1. In some embodiments, R1is –OH, –O(optionally substituted C1-4 alkyl), –SH, or – S(optionally substituted C1-4 alkyl), or –L1–Y1. In some embodiments, R1is –N(RA)2 or –L1– Y1. In some embodiments, R1is –NH2, –NH(optionally substituted C1-4alkyl), –N(optionally substituted C1-4 alkyl)2 or –L1–Y1. In some embodiments, R1is –ORAor –L1–Y1. In some embodiments, R1is –OH, –O(optionally substituted C1-4 alkyl), or –L1–Y1. In some embodiments, R1is –OH, –OMe, –OEt, or –L1–Y1. In some embodiments, R1is –OMe or – L1–Y1. In some embodiments, R1is–SRAor –L1–Y1. In some embodiments, R1is –SH, or – S(optionally substituted C1-4 alkyl), or –L1–Y1. In some embodiments, R1is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C3-C6 carbocyclyl, or –L1–Y1. In some embodiments, R1is optionally substituted C1-C4 alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or –L1–Y1. In some embodiments, R1is optionally substituted C1-C4alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C3-C6carbocyclyl, or –L1–Y1. In some embodiments, R1is optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or –L1–Y1. In some embodiments, R1is hydrogen or –L1–Y1. In some embodiments, R1is –L1–Y1. In some embodiments, R1is hydrogen,– NH2, –NHRA, –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 –L1–Y1. In some embodiments, R1is hydrogen,–NH2, –NHRA, –OH, –CN, halogen, unsubstituted C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy(C1-C4 alkoxy), C3-C6 carbocyclyl, or –L1–Y1. In some embodiments, R1is hydrogen,–NH2, –NHRA, –OH, –OMe, –CN, or halogen, or –L1–Y1. In some embodiments, R1is hydrogen,–NH2, –NHRA, –OH, – CN, or halogen, or –L1–Y1. In some embodiments, R1is unsubstituted C1-C4alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy(C1-C4 alkoxy), C3-C6 carbocyclyl, or – L1–Y1.71

[0173] In some embodiments, R1is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, – NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or optionally substituted C3-C6 carbocyclyl. In some embodiments, R1is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, – NRAS(=O)2ORA, –ORA, –SRA, –CN, or halogen. In some embodiments, R1is hydrogen, – N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, or – SRA. In some embodiments, R1is –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, – NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, or –SRA. In some embodiments, R1is –N(RA)2, – ORA, or –SRA. In some embodiments, R1is –NH2, –NH(optionally substituted C1-4alkyl), – N(optionally substituted C1-4 alkyl)2, –OH, –O(optionally substituted C1-4 alkyl), –SH, or – S(optionally substituted C1-4 alkyl). In some embodiments, R1is –N(RA)2 or –ORA. In some embodiments, R1is –NH2, –NH(optionally substituted C1-4alkyl), –N(optionally substituted C1-4 alkyl)2, –OH, or –O(optionally substituted C1-4 alkyl). In some embodiments, R1is –ORAor –SRA. In some embodiments, R1is –OH, –O(optionally substituted C1-4 alkyl), –SH, or – S(optionally substituted C1-4alkyl). In some embodiments, R1is –N(RA)2. In some embodiments, R1is –NH2, –NH(optionally substituted C1-4 alkyl), –N(optionally substituted C1-4 alkyl)2. In some embodiments, R1is –ORA. In some embodiments, R1is –OH or – O(optionally substituted C1-4alkyl). In some embodiments, R1is –OH, –OMe, or –OEt. In some embodiments, R1is –OMe. In some embodiments, R1is–SRA. In some embodiments, R1is –SH or –S(optionally substituted C1-4 alkyl). In some embodiments, R1is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or optionally substituted C3-C6 carbocyclyl. In some embodiments, R1is optionally substituted C1-C4 alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4 heteroalkenyl, or optionally substituted C2-C4 heteroalkynyl. In some embodiments, R1is optionally substituted C1-C4 alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, or optionally substituted C3- C6carbocyclyl. In some embodiments, R1is optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4 heteroalkenyl, or optionally substituted C2-C4 heteroalkynyl. In some embodiments, R1is hydrogen. In some embodiments, R1is hydrogen,–NH2, –NHRA, – OH, –OMe, –CN, halogen, unsubstituted C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C472haloalkoxy, hydroxy(C1-C4alkoxy), or C3-C6carbocyclyl. In some embodiments, R1is hydrogen,–NH2, –NHRA, –OH, –CN, halogen, unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy(C1-C4 alkoxy), or C3-C6 carbocyclyl. In some embodiments, R1is hydrogen,–NH2, –NHRA, –OH, –OMe, –CN, or halogen. In some embodiments, R1is hydrogen,–NH2, –NHRA, –OH, –CN, or halogen. In some embodiments, R1is unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy(C1-C4alkoxy), or C3-C6carbocyclyl.

[0174] As defined herein, R2is hydrogen, –N(RA)2, –NRAC(=O)RA, –NRAC(=O)ORA, – NRAS(=O)2RA, – NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or optionally substituted C3-C6 carbocyclyl. In some embodiments, R2is hydrogen, –N(RA)2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAS(=O)2RA, – NRAS(=O)2ORA, –ORA, –SRA, –CN, or halogen. In some embodiments, R2is –N(RA)2, – NRAC(=O)RA, –NRAC(=O)ORA, –NRAS(=O)2RA, – NRAS(=O)2ORA, –ORA, –SRA, –CN, or halogen. In some embodiments, R2is –N(RA)2, –NRAC(=O)RA, –NRAC(=O)ORA, – NRAS(=O)2RA, or – NRAS(=O)2ORA. In some embodiments, R2is –N(RA)2, –ORA, or –SRA. In some embodiments, R2is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4heteroalkenyl, optionally substituted C2-C4heteroalkynyl, or optionally substituted C3-C6carbocyclyl. In some embodiments, R2is 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 C2-C4heteroalkynyl. In some embodiments, R2is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl. In some embodiments, R2is hydrogen, optionally substituted C1-C4alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, or optionally substituted C3-C6 carbocyclyl. In some embodiments, R2is hydrogen, methyl, or ethyl. In some embodiments, R2is hydrogen. In some embodiments, R2is hydrogen,–NH2, –NHRA, –OH, –CN, halogen, unsubstituted C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, hydroxy(C1-C4alkoxy), or C3-C6carbocyclyl. In some embodiments, R2is hydrogen,–NH2, –NHRA, –OH, –CN, or halogen. In some embodiments, R2is unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy(C1-C4alkoxy), or C3-C6carbocyclyl. In some embodiments, R2is hydrogen.73

[0175] As defined herein, R3is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, – NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C3-C6 carbocyclyl, or –L1–Y1. In some embodiments, R3is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, – NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, or –L1–Y1. In some embodiments, R3is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, –NRAS(=O)2ORA, – ORA, –SRA, or –L1–Y1. In some embodiments, R3is –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, –SRA, or –L1–Y1. In some embodiments, R3is –N(RA)2, –ORA, or –SRA, or –L1–Y1. In some embodiments, R3is –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 C1-4 alkyl), or –L1–Y1. In some embodiments, R3is –N(RA)2, –ORA, or –L1–Y1. In some embodiments, R3is –NH2, – NH(optionally substituted C1-4 alkyl), –N(optionally substituted C1-4 alkyl)2, –OH, – O(optionally substituted C1-4 alkyl), or –L1–Y1. In some embodiments, R3is –ORA, –SRA, or –L1–Y1. In some embodiments, R3is –OH, –O(optionally substituted C1-4alkyl), –SH, or – S(optionally substituted C1-4 alkyl), or –L1–Y1. In some embodiments, R3is –N(RA)2 or –L1– Y1. In some embodiments, R3is –NH2, –NH(optionally substituted C1-4 alkyl), –N(optionally substituted C1-4alkyl)2, or –L1–Y1. In some embodiments, R3is –ORAor –L1–Y1. In some embodiments, R3is –OH, –O(optionally substituted C1-4alkyl), or –L1–Y1. In some embodiments, R1is –OH, –OMe, –OEt, or –L1–Y1. In some embodiments, R1is –OMe or – L1–Y1. In some embodiments, R3is–SRAor –L1–Y1. In some embodiments, R3is –SH, or – S(optionally substituted C1-4alkyl), or –L1–Y1. In some embodiments, R3is 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 C2-C4heteroalkynyl, optionally substituted C3-C6carbocyclyl, or –L1–Y1. In some embodiments, R3is optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4heteroalkenyl, optionally substituted C2-C4heteroalkynyl, or –L1–Y1. In some embodiments, R3is optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or –L1–Y1. In some embodiments, R3is optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4heteroalkenyl,74optionally substituted C2-C4heteroalkynyl, or –L1–Y1. In some embodiments, R3is hydrogen or –L1–Y1. In some embodiments, R3is –L1–Y1. In some embodiments, R3is hydrogen,–NH2, –NHRA, –OH, –OMe, –CN, halogen, unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4haloalkoxy, hydroxy(C1-C4alkoxy), C3-C6carbocyclyl, or –L1–Y1. In some embodiments, R3is hydrogen,–NH2, –NHRA, –OH, –CN, halogen, unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy(C1-C4 alkoxy), C3-C6 carbocyclyl, or –L1–Y1. In some embodiments, R3is hydrogen,–NH2, –NHRA, –OH, –OMe, –CN, or halogen, or –L1–Y1. In some embodiments, R3is hydrogen,–NH2, –NHRA, –OH, – CN, or halogen, or –L1–Y1. In some embodiments, R3is unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, hydroxy(C1-C4alkoxy), C3-C6carbocyclyl, or – L1–Y1.

[0176] In some embodiments, R3is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, – NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or optionally substituted C3-C6 carbocyclyl. In some embodiments, R3is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, – NRAS(=O)2ORA, –ORA, –SRA, –CN, or halogen. In some embodiments, R3is hydrogen, – N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, or – SRA. In some embodiments, R3is –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, – NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, or –SRA. In some embodiments, R3is –N(RA)2, – ORA, or –SRA. In some embodiments, R3is –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 C1-4alkyl). In some embodiments, R3is –N(RA)2or –ORA. In some embodiments, R3is –NH2, –NH(optionally substituted C1-4 alkyl), –N(optionally substituted C1-4 alkyl)2, –OH, –O(optionally substituted C1-4 alkyl). In some embodiments, R3is –ORAor –SRA. In some embodiments, R3is –OH, –O(optionally substituted C1-4alkyl), –SH, or – S(optionally substituted C1-4 alkyl). In some embodiments, R3is –N(RA)2. In some embodiments, R3is –NH2, –NH(optionally substituted C1-4 alkyl), or –N(optionally substituted C1-4alkyl)2. In some embodiments, R3is –ORA. In some embodiments, R3is –OH or –O(optionally substituted C1-4alkyl). In some embodiments, R1is –OH, –OMe, or –OEt. In some embodiments, R1is –OMe. In some embodiments, R3is–SRA. In some embodiments, R3is –SH or –S(optionally substituted C1-4 alkyl). In some embodiments, R3is hydrogen, optionally substituted C1-C4alkyl, optionally substituted C2-C4alkenyl, optionally substituted75C2-C4alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or optionally substituted C3-C6 carbocyclyl. In some embodiments, R3is optionally substituted C1-C4 alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4 heteroalkenyl, or optionally substituted C2-C4 heteroalkynyl. In some embodiments, R3is optionally substituted C1-C4 alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, or optionally substituted C3- C6 carbocyclyl. In some embodiments, R3is optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, or optionally substituted C2-C4 heteroalkynyl. In some embodiments, R3is hydrogen. In some embodiments, R3is hydrogen,–NH2, –NHRA, – OH, –OMe, –CN, halogen, unsubstituted C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, hydroxy(C1-C4 alkoxy), or C3-C6 carbocyclyl. In some embodiments, R3is hydrogen,–NH2, –NHRA, –OH, –CN, halogen, unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, hydroxy(C1-C4alkoxy), or C3-C6carbocyclyl. In some embodiments, R3is hydrogen,–NH2, –NHRA, –OH, –OMe, –CN, or halogen. In some embodiments, R3is hydrogen,–NH2, –NHRA, –OH, –CN, or halogen. In some embodiments, R3is unsubstituted C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, hydroxy(C1-C4 alkoxy), or C3-C6 carbocyclyl.

[0177] As defined herein, R4is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, – NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, optionally substituted C1-C4alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C3-C6 carbocyclyl, or –L1–Y1. In some embodiments, R4is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, – NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, or –L1–Y1. In some embodiments, R4is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, –NRAS(=O)2ORA, – ORA, –SRA, or –L1–Y1. In some embodiments, R4is –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, –SRA, or –L1–Y1. In some embodiments, R4is –N(RA)2, –ORA, or –SRA, or –L1–Y1. In some embodiments, R4is – N(RA)2, –ORA, or –L1–Y1. In some embodiments, R4is –ORA, –SRA, or –L1–Y1. In some embodiments, R4is –N(RA)2or –L1–Y1. In some embodiments, R4is –ORAor –L1–Y1. In some embodiments, R4is–SRAor –L1–Y1. In some embodiments, R4is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4heteroalkenyl,76optionally substituted C2-C4heteroalkynyl, optionally substituted C3-C6carbocyclyl, or –L1– Y1. In some embodiments, R4is optionally substituted C1-C4 alkyl, optionally substituted C2- C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4heteroalkenyl, optionally substituted C2-C4heteroalkynyl, or – L1–Y1. In some embodiments, R4is optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or –L1–Y1. In some embodiments, R4is optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or –L1–Y1. In some embodiments, R4is hydrogen or –L1–Y1. In some embodiments, R4is –L1–Y1.

[0178] In some embodiments, R4is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, – NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, optionally substituted C1-C4alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4heteroalkynyl, or optionally substituted C3-C6carbocyclyl. In some embodiments, R4is hydrogen, –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, – NRAS(=O)2ORA, –ORA, –SRA, –CN, or halogen. In some embodiments, R4is hydrogen, – N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, –NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, or – SRA. In some embodiments, R4is –N(RA)2, –NRAC(=O)RA, – NRAC(=O)ORA, – NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, or –SRA. In some embodiments, R4is –N(RA)2, – ORA, or –SRA. In some embodiments, R4is –N(RA)2or –ORA. In some embodiments, R4is – ORAor –SRA. In some embodiments, R4is –N(RA)2. In some embodiments, R4is –ORA. In some embodiments, R4is–SRA. In some embodiments, R4is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or optionally substituted C3-C6 carbocyclyl. In some embodiments, R4is optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4 heteroalkenyl, or optionally substituted C2-C4 heteroalkynyl. In some embodiments, R4is optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4alkynyl, or optionally substituted C3-C6carbocyclyl. In some embodiments, R4is optionally substituted C1-C4heteroalkyl, optionally substituted C2- C4 heteroalkenyl, or optionally substituted C2-C4 heteroalkynyl. In some embodiments, R4is hydrogen.77

[0179] As defined herein, R5is hydrogen, a nitrogen protecting group, or –L1–Y1. In some embodiments, R5is hydrogen or a nitrogen protecting group. In some embodiments, R5is hydrogen or –L1–Y1. In some embodiments, R5is a nitrogen protecting group or –L1–Y1. In some embodiments, R5is hydrogen. In some embodiments, R5is a nitrogen protecting group. In some embodiments, R5is –L1–Y1. In some embodiments, R5is hydrogen.

[0180] As defined herein, each instance of R6is independently hydrogen, halogen, 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, –CN, –ORB, –SCN, –SRB, – SSRB, –N3, –NO, –N(RB)2, –NO2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, –C(=O)N(RB)2, – C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, –C(=NRB)N(RB)2, –S(=O)RB, –S(=O)ORB, – S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, –S(=O)2ORB, –S(=O)2SRB, –S(=O)2N(RB)2, – OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –OC(=NRB)RB, – OC(=NRB)ORB, –OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, –OS(=O)ORB, – OS(=O)SRB, –OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, – OS(=O)2N(RB)2, –ON(RB)2, –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, –SC(=O)N(RB)2, – SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, –SC(=NRB)N(RB)2, –NRBC(=O)RB, – NRBC(=O)ORB, –NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, – NRBC(=NRB)ORB, –NRBC(=NRB)SRB, –NRBC(=NRB)N(RB)2, –NRBS(=O)RB, – NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, – NRBS(=O)2SRB, or –NRBS(=O)2N(RB)2.

[0181] In some embodiments, R6is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, –ORB, –SRB, or – N(RB)2. In some embodiments, R6is optionally substituted C1-10 alkyl, optionally substituted C1-10alkenyl, optionally substituted C1-10alkynyl, optionally substituted C1-10heteroalkyl, optionally substituted C1-10 heteroalkenyl, or optionally substituted C1-10 heteroalkynyl. In some embodiments, R6is C1-10 haloalkyl. In some embodiments, R6is C1-4 haloalkyl. In some embodiments, R6is C1-4fluoroalkyl (e.g., C1-4perfluoroalkyl). In some embodiments, R6is – CF3. In some embodiments, R6is hydrogen, optionally substituted C1-C6alkyl, or halogen. In some embodiments, R6is hydrogen, fluorine, –CH3, –CH2F, –CHF2, or –CF3. In some embodiments, R6is hydrogen, fluorine, –CH3, or –CF3. In some embodiments, R6is hydrogen or halogen. In some embodiments, R6is hydrogen or fluorine. In some embodiments, R6is78hydrogen or optionally substituted C1-C6alkyl. In some embodiments, R6is hydrogen, unsubstituted C1-C6 alkyl, or C1-6 haloalkyl. In some embodiments, R6is hydrogen. In some embodiments, each instance of R6is hydrogen.

[0182] In some embodiments, R6is halogen. In some embodiments, R6is bromine, chlorine, or fluorine. In some embodiments, R6is bromine or chlorine. In some embodiments, R6is chlorine or fluorine. In some embodiments, R6is bromine. In some embodiments, R6is chlorine. In some embodiments, R6is fluorine.

[0183] In some embodiments, R6is –ORB, –SRB, or –N(RB)2 (e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R6is –OH. In some embodiments, R6is –SH. In some embodiments, R6is –NH2. In some embodiments, R6is –CN, –SCN, –SSRB, –N3, –NO, or –NO2. In some embodiments, R6is –, wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R6is – C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, or –C(=NRB)N(RB)2(e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R6is –S(=O)RB, –S(=O)ORB, –S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, – S(=O)2ORB, –S(=O)2SRB, or –S(=O)2N(RB)2(e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R6is –OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –OC(=NRB)RB, –OC(=NRB)ORB, – OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, –OS(=O)ORB, –OS(=O)SRB, – OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, –OS(=O)2N(RB)2, or –ON(RB)2(e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R6is –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, – SC(=O)N(RB)2, –SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, or –SC(=NRB)N(RB)2(e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R6is –NRBC(=O)RB, –NRBC(=O)ORB, –NRBC(=O)SRB, – NRBC(=O)N(RB)2, –NRBC(=NRB)RB, –NRBC(=NRB)ORB, –NRBC(=NRB)SRB, – NRBC(=NRB)N(RB)2, –NRBS(=O)RB, –NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, –NRBS(=O)2SRB, or –NRBS(=O)2N(RB)2 (e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0184] In some embodiments, R6is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R6is optionally substituted C3-14 carbocyclyl. In some embodiments, R6is optionally substituted monocyclic C3-7carbocyclyl. In some embodiments, R6is optionally79substituted monocyclic C3-4carbocyclyl. In some embodiments, R6is optionally substituted monocyclic C5-7 carbocyclyl. In some embodiments, R6is saturated carbocyclyl. In some embodiments, R6is carbocyclyl comprising only one unsaturated bond (e.g., C=C bond) in the carbocyclic ring system.

[0185] In some embodiments, R6is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R6is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R6is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and / or S atoms but no N atoms. In some embodiments, R6is 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, R6is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and / or S atoms but no N atoms. In some embodiments, R6is 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, R6is saturated heterocyclyl. In some embodiments, R6is heterocyclyl comprising only one unsaturated bond (e.g., C=C bond) in the heterocyclic ring system.

[0186] In some embodiments, R6is optionally substituted monocyclic aryl. In some embodiments, R6is optionally substituted bicyclic aryl. In some embodiments, R6is optionally substituted C6-14 aryl. In some embodiments, R6is optionally substituted C6-10 aryl. In some embodiments, R6is optionally substituted phenyl. In some embodiments, R6is optionally substituted naphthyl.

[0187] In some embodiments, R6is optionally substituted monocyclic heteroaryl. In some embodiments, R6is optionally substituted bicyclic heteroaryl. In some embodiments, R6is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R6is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R6is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0188] As defined herein, each instance of R7is independently hydrogen, halogen, 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, –CN, –ORB, –SCN, –SRB, – SSRB, –N3, –NO, –N(RB)2, –NO2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, –C(=O)N(RB)2, – C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, –C(=NRB)N(RB)2, –S(=O)RB, –S(=O)ORB, – S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, –S(=O)2ORB, –S(=O)2SRB, –S(=O)2N(RB)2, –80OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –OC(=NRB)RB, – OC(=NRB)ORB, –OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, –OS(=O)ORB, – OS(=O)SRB, –OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, – OS(=O)2N(RB)2, –ON(RB)2, –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, –SC(=O)N(RB)2, – SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, –SC(=NRB)N(RB)2, –NRBC(=O)RB, – NRBC(=O)ORB, –NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, – NRBC(=NRB)ORB, –NRBC(=NRB)SRB, –NRBC(=NRB)N(RB)2, –NRBS(=O)RB, – NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, – NRBS(=O)2SRB, or –NRBS(=O)2N(RB)2.

[0189] In some embodiments, R7is hydrogen, halogen, optionally substituted C1-C4alkyl, optionally substituted C1-C4alkenyl, optionally substituted C1-C4alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 heteroalkenyl, optionally substituted C1-C4 heteroalkynyl, –CN, –ORB, or –N(RB)2. In some embodiments, R7is hydrogen, halogen, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, –CN, –ORB, or –N(RB)2. In some embodiments, R7is hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, –CN, –OH, or – NH2. In some embodiments, R7is hydrogen, halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, –CN, –OH, or –NH2.

[0190] In some embodiments, R7is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, –ORB, –SRB, or – N(RB)2. In some embodiments, R7is optionally substituted C1-10 alkyl, optionally substituted C1-10 alkenyl, optionally substituted C1-10 alkynyl, optionally substituted C1-10 heteroalkyl, optionally substituted C1-10heteroalkenyl, or optionally substituted C1-10heteroalkynyl. In some embodiments, R7is C1-10 haloalkyl. In some embodiments, R7is C1-4 haloalkyl. In some embodiments, R7is C1-4 fluoroalkyl (e.g., C1-4 perfluoroalkyl). In some embodiments, R7is – CF3. In some embodiments, R7is hydrogen, optionally substituted C1-C7alkyl, or halogen. In some embodiments, R7is hydrogen, fluorine, –CH3, –CH2F, –CHF2, or –CF3. In some embodiments, R7is hydrogen, fluorine, –CH3, or –CF3. In some embodiments, R7is hydrogen or halogen. In some embodiments, R7is hydrogen or fluorine. In some embodiments, R7is hydrogen or optionally substituted C1-C6alkyl. In some embodiments, R7is hydrogen, unsubstituted C1-C6 alkyl, or C1-6 haloalkyl. In some embodiments, R7is hydrogen. In some embodiments, each instance of R7is hydrogen.81

[0191] In some embodiments, R7is halogen. In some embodiments, R7is bromine, chlorine, or fluorine. In some embodiments, R7is bromine or chlorine. In some embodiments, R7is chlorine or fluorine. In some embodiments, R7is bromine. In some embodiments, R7is chlorine. In some embodiments, R7is fluorine.

[0192] In some embodiments, R7is –ORB, –SRB, or –N(RB)2 (e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R7is –OH. In some embodiments, R7is –SH. In some embodiments, R7is –NH2. In some embodiments, R7is –CN, –SCN, –SSRB, –N3, –NO, or –NO2. In some embodiments, R7is –, wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R7is – C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, or –C(=NRB)N(RB)2(e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R7is –S(=O)RB, –S(=O)ORB, –S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, – S(=O)2ORB, –S(=O)2SRB, or –S(=O)2N(RB)2(e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R7is –OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –OC(=NRB)RB, –OC(=NRB)ORB, – OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, –OS(=O)ORB, –OS(=O)SRB, – OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, –OS(=O)2N(RB)2, or –ON(RB)2 (e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R7is –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, – SC(=O)N(RB)2, –SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, or –SC(=NRB)N(RB)2(e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R7is –NRBC(=O)RB, –NRBC(=O)ORB, –NRBC(=O)SRB, – NRBC(=O)N(RB)2, –NRBC(=NRB)RB, –NRBC(=NRB)ORB, –NRBC(=NRB)SRB, – NRBC(=NRB)N(RB)2, –NRBS(=O)RB, –NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, –NRBS(=O)2SRB, or –NRBS(=O)2N(RB)2 (e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0193] In some embodiments, R7is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R7is optionally substituted C3-14carbocyclyl. In some embodiments, R7is optionally substituted monocyclic C3-7carbocyclyl. In some embodiments, R7is optionally substituted monocyclic C3-4 carbocyclyl. In some embodiments, R7is optionally substituted monocyclic C5-7 carbocyclyl. In some embodiments, R7is saturated carbocyclyl. In some82embodiments, R7is carbocyclyl comprising only one unsaturated bond (e.g., C=C bond) in the carbocyclic ring system.

[0194] In some embodiments, R7is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R7is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R7is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and / or S atoms but no N atoms. In some embodiments, R7is 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, R7is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and / or S atoms but no N atoms. In some embodiments, R7is 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, R7is saturated heterocyclyl. In some embodiments, R7is heterocyclyl comprising only one unsaturated bond (e.g., C=C bond) in the heterocyclic ring system.

[0195] In some embodiments, R7is optionally substituted monocyclic aryl. In some embodiments, R7is optionally substituted bicyclic aryl. In some embodiments, R7is optionally substituted C6-14aryl. In some embodiments, R7is optionally substituted C6-10aryl. In some embodiments, R7is optionally substituted phenyl. In some embodiments, R7is optionally substituted naphthyl.

[0196] In some embodiments, R7is optionally substituted monocyclic heteroaryl. In some embodiments, R7is optionally substituted bicyclic heteroaryl. In some embodiments, R7is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R7is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R7is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0197] As defined herein, each instance of R8is independently hydrogen, halogen, 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, –CN, –ORB, –SCN, –SRB, – SSRB, –N3, –NO, –N(RB)2, –NO2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, –C(=O)N(RB)2, – C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, –C(=NRB)N(RB)2, –S(=O)RB, –S(=O)ORB, – S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, –S(=O)2ORB, –S(=O)2SRB, –S(=O)2N(RB)2, – OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –OC(=NRB)RB, – OC(=NRB)ORB, –OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, –OS(=O)ORB, –83OS(=O)SRB, –OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, – OS(=O)2N(RB)2, –ON(RB)2, –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, –SC(=O)N(RB)2, – SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, –SC(=NRB)N(RB)2, –NRBC(=O)RB, – NRBC(=O)ORB, –NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, – NRBC(=NRB)ORB, –NRBC(=NRB)SRB, –NRBC(=NRB)N(RB)2, –NRBS(=O)RB, – NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, – NRBS(=O)2SRB, or –NRBS(=O)2N(RB)2.

[0198] In some embodiments, R8is hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkenyl, optionally substituted C1-C4 alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4heteroalkenyl, optionally substituted C1-C4heteroalkynyl, –CN, –ORB, or –N(RB)2. In some embodiments, R8is hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, –CN, –ORB, or –N(RB)2. In some embodiments, R8is hydrogen, halogen, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, –CN, –OH, or – NH2. In some embodiments, R8is hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4haloalkoxy, –CN, –OH, or –NH2.

[0199] In some embodiments, R8is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, –ORB, –SRB, or – N(RB)2. In some embodiments, R8is optionally substituted C1-10alkyl, optionally substituted C1-10alkenyl, optionally substituted C1-10alkynyl, optionally substituted C1-10heteroalkyl, optionally substituted C1-10 heteroalkenyl, or optionally substituted C1-10 heteroalkynyl. In some embodiments, R8is C1-10 haloalkyl. In some embodiments, R8is C1-4 haloalkyl. In some embodiments, R8is C1-4fluoroalkyl (e.g., C1-4perfluoroalkyl). In some embodiments, R8is – CF3. In some embodiments, R8is hydrogen, optionally substituted C1-C8alkyl, or halogen. In some embodiments, R8is hydrogen, fluorine, –CH3, –CH2F, –CHF2, or –CF3. In some embodiments, R8is hydrogen, fluorine, –CH3, or –CF3. In some embodiments, R8is hydrogen or halogen. In some embodiments, R8is hydrogen or fluorine. In some embodiments, R8is hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, R8is hydrogen, unsubstituted C1-C6alkyl, or C1-6haloalkyl. In some embodiments, R8is hydrogen. In some embodiments, each instance of R8is hydrogen.

[0200] In some embodiments, R8is halogen. In some embodiments, R8is bromine, chlorine, or fluorine. In some embodiments, R8is bromine or chlorine. In some embodiments, R8is84chlorine or fluorine. In some embodiments, R8is bromine. In some embodiments, R8is chlorine. In some embodiments, R8is fluorine.

[0201] In some embodiments, R8is –ORB, –SRB, or –N(RB)2 (e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R8is –OH. In some embodiments, R8is –SH. In some embodiments, R8is –NH2. In some embodiments, R8is –CN, –SCN, –SSRB, –N3, –NO, or –NO2. In some embodiments, R8is –, wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R8is – C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, or –C(=NRB)N(RB)2 (e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R8is –S(=O)RB, –S(=O)ORB, –S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, – S(=O)2ORB, –S(=O)2SRB, or –S(=O)2N(RB)2 (e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R8is –OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –OC(=NRB)RB, –OC(=NRB)ORB, – OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, –OS(=O)ORB, –OS(=O)SRB, – OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, –OS(=O)2N(RB)2, or –ON(RB)2 (e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R8is –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, – SC(=O)N(RB)2, –SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, or –SC(=NRB)N(RB)2 (e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R8is –NRBC(=O)RB, –NRBC(=O)ORB, –NRBC(=O)SRB, – NRBC(=O)N(RB)2, –NRBC(=NRB)RB, –NRBC(=NRB)ORB, –NRBC(=NRB)SRB, – NRBC(=NRB)N(RB)2, –NRBS(=O)RB, –NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, –NRBS(=O)2SRB, or –NRBS(=O)2N(RB)2(e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0202] In some embodiments, R8is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R8is optionally substituted C3-14 carbocyclyl. In some embodiments, R8is optionally substituted monocyclic C3-7 carbocyclyl. In some embodiments, R8is optionally substituted monocyclic C3-4carbocyclyl. In some embodiments, R8is optionally substituted monocyclic C5-7carbocyclyl. In some embodiments, R8is saturated carbocyclyl. In some embodiments, R8is carbocyclyl comprising only one unsaturated bond (e.g., C=C bond) in the carbocyclic ring system.85

[0203] In some embodiments, R8is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R8is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R8is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and / or S atoms but no N atoms. In some embodiments, R8is 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, R8is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and / or S atoms but no N atoms. In some embodiments, R8is 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, R8is saturated heterocyclyl. In some embodiments, R8is heterocyclyl comprising only one unsaturated bond (e.g., C=C bond) in the heterocyclic ring system.

[0204] In some embodiments, R8is optionally substituted monocyclic aryl. In some embodiments, R8is optionally substituted bicyclic aryl. In some embodiments, R8is optionally substituted C6-14 aryl. In some embodiments, R8is optionally substituted C6-10 aryl. In some embodiments, R8is optionally substituted phenyl. In some embodiments, R8is optionally substituted naphthyl.

[0205] In some embodiments, R8is optionally substituted monocyclic heteroaryl. In some embodiments, R8is optionally substituted bicyclic heteroaryl. In some embodiments, R8is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R8is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R8is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0206] As defined herein, each instance of R9is independently hydrogen, halogen, 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, –CN, –ORB, –SCN, –SRB, – SSRB, –N3, –NO, –N(RB)2, –NO2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, –C(=O)N(RB)2, – C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, –C(=NRB)N(RB)2, –S(=O)RB, –S(=O)ORB, – S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, –S(=O)2ORB, –S(=O)2SRB, –S(=O)2N(RB)2, – OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –OC(=NRB)RB, – OC(=NRB)ORB, –OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, –OS(=O)ORB, – OS(=O)SRB, –OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, – OS(=O)2N(RB)2, –ON(RB)2, –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, –SC(=O)N(RB)2, –86SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, –SC(=NRB)N(RB)2, –NRBC(=O)RB, – NRBC(=O)ORB, –NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, – NRBC(=NRB)ORB, –NRBC(=NRB)SRB, –NRBC(=NRB)N(RB)2, –NRBS(=O)RB, – NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, – NRBS(=O)2SRB, or –NRBS(=O)2N(RB)2.

[0207] In some embodiments, R9is hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4alkenyl, optionally substituted C1-C4alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 heteroalkenyl, optionally substituted C1-C4 heteroalkynyl, –CN, –ORB, or –N(RB)2. In some embodiments, R9is hydrogen, halogen, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, –CN, –ORB, or –N(RB)2. In some embodiments, R9is hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, –CN, –OH, or – NH2. In some embodiments, R9is hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4haloalkoxy, –CN, –OH, or –NH2.

[0208] In some embodiments, R9is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, –ORB, –SRB, or – N(RB)2. In some embodiments, R9is optionally substituted C1-10 alkyl, optionally substituted C1-10 alkenyl, optionally substituted C1-10 alkynyl, optionally substituted C1-10 heteroalkyl, optionally substituted C1-10heteroalkenyl, or optionally substituted C1-10heteroalkynyl. In some embodiments, R9is C1-10haloalkyl. In some embodiments, R9is C1-4haloalkyl. In some embodiments, R9is C1-4 fluoroalkyl (e.g., C1-4 perfluoroalkyl). In some embodiments, R9is – CF3. In some embodiments, R9is hydrogen, optionally substituted C1-C9alkyl, or halogen. In some embodiments, R9is hydrogen, fluorine, –CH3, –CH2F, –CHF2, or –CF3. In some embodiments, R9is hydrogen, fluorine, –CH3, or –CF3. In some embodiments, R9is hydrogen or halogen. In some embodiments, R9is hydrogen or fluorine. In some embodiments, R9is hydrogen or optionally substituted C1-C6alkyl. In some embodiments, R9is hydrogen, unsubstituted C1-C6 alkyl, or C1-6 haloalkyl. In some embodiments, R9is hydrogen. In some embodiments, each instance of R9is hydrogen.

[0209] In some embodiments, R9is halogen. In some embodiments, R9is bromine, chlorine, or fluorine. In some embodiments, R9is bromine or chlorine. In some embodiments, R9is chlorine or fluorine. In some embodiments, R9is bromine. In some embodiments, R9is chlorine. In some embodiments, R9is fluorine.87

[0210] In some embodiments, R9is –ORB, –SRB, or –N(RB)2(e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R9is –OH. In some embodiments, R9is –SH. In some embodiments, R9is –NH2. In some embodiments, R9is –CN, –SCN, –SSRB, –N3, –NO, or –NO2. In some embodiments, R9is –, wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R9is – C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, or –C(=NRB)N(RB)2(e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R9is –S(=O)RB, –S(=O)ORB, –S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, – S(=O)2ORB, –S(=O)2SRB, or –S(=O)2N(RB)2(e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R9is –OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –OC(=NRB)RB, –OC(=NRB)ORB, – OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, –OS(=O)ORB, –OS(=O)SRB, – OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, –OS(=O)2N(RB)2, or –ON(RB)2(e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R9is –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, – SC(=O)N(RB)2, –SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, or –SC(=NRB)N(RB)2(e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, R9is –NRBC(=O)RB, –NRBC(=O)ORB, –NRBC(=O)SRB, – NRBC(=O)N(RB)2, –NRBC(=NRB)RB, –NRBC(=NRB)ORB, –NRBC(=NRB)SRB, – NRBC(=NRB)N(RB)2, –NRBS(=O)RB, –NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, –NRBS(=O)2SRB, or –NRBS(=O)2N(RB)2 (e.g., wherein RBis hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0211] In some embodiments, R9is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R9is optionally substituted C3-14 carbocyclyl. In some embodiments, R9is optionally substituted monocyclic C3-7carbocyclyl. In some embodiments, R9is optionally substituted monocyclic C3-4 carbocyclyl. In some embodiments, R9is optionally substituted monocyclic C5-7 carbocyclyl. In some embodiments, R9is saturated carbocyclyl. In some embodiments, R9is carbocyclyl comprising only one unsaturated bond (e.g., C=C bond) in the carbocyclic ring system.

[0212] In some embodiments, R9is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R9is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, R9is optionally substituted 3- to 14-membered88heterocyclyl comprising one or more O and / or S atoms but no N atoms. In some embodiments, R9is 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, R9is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and / or S atoms but no N atoms. In some embodiments, R9is 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, R9is saturated heterocyclyl. In some embodiments, R9is heterocyclyl comprising only one unsaturated bond (e.g., C=C bond) in the heterocyclic ring system.

[0213] In some embodiments, R9is optionally substituted monocyclic aryl. In some embodiments, R9is optionally substituted bicyclic aryl. In some embodiments, R9is optionally substituted C6-14 aryl. In some embodiments, R9is optionally substituted C6-10 aryl. In some embodiments, R9is optionally substituted phenyl. In some embodiments, R9is optionally substituted naphthyl.

[0214] In some embodiments, R9is optionally substituted monocyclic heteroaryl. In some embodiments, R9is optionally substituted bicyclic heteroaryl. In some embodiments, R9is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R9is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R9is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0215] As defined herein, each instance of RAis 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 RAattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring. In some embodiments, at least one instance of RAis 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 RAis independently optionally substituted C1-C4 alkyl. In some embodiments, at least one instance of RAis independently unsubstituted C1-C4 alkyl. In some embodiments, at least one instance of RAis independently methyl. In some89embodiments, RAis optionally substituted C1-C4alkyl. In some embodiments, RAis unsubstituted C1-C4 alkyl. In some embodiments, RAis methyl. In some embodiments, RAis –CO(C1-C3 alkyl), –CO(C1-C3 alkoxy), –SO2(C1-C3 alkyl), or –SO2(C1-C3 alkoxy). In some embodiments, RAis –CO(C1-C3alkyl) or –CO(C1-C3alkoxy). In some embodiments, RAis – SO2(C1-C3 alkyl) or –SO2(C1-C3 alkoxy). In some embodiments, at least one instance of RAis optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of RAis 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 C6-14aryl. In some embodiments, at least one instance of RAis independently hydrogen, optionally substituted C1-10alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of RAis 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. In some embodiments, two instances of RAattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0216] As defined herein, each instance of RBis 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 RBattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring. In some embodiments, at least one instance of RBis 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 RBis optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of RBis independently hydrogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkenyl, optionally substituted C1-10 alkynyl, optionally substituted C3-14carbocyclyl, or optionally substituted C6-14aryl. In some90embodiments, at least one instance of RBis independently hydrogen, optionally substituted C1-10 alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of RBis 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. In some embodiments, two instances of RBattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0217] As defined herein, –L1– is optionally substituted C1-C25 alkylene, optionally substituted C2-C25 alkenylene, optionally substituted C2-C25 alkynylene, optionally substituted C1-C25heteroalkylene, optionally substituted C2-C25heteroalkenylene, optionally substituted C2-C25heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or any combination thereof. In some embodiments, –L1– is optionally substituted C1-C25alkylene, optionally substituted C2-C25alkenylene, optionally substituted C2-C25 alkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or any combination thereof. In some embodiments, –L1– is optionally substituted C1-C25alkylene, optionally substituted C2-C25 alkenylene, optionally substituted C2-C25 alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, or any combination thereof. In some embodiments, –L1– is optionally substituted C1-C25heteroalkylene, optionally substituted C2-C25heteroalkenylene, optionally substituted C2-C25heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or any combination thereof. In some embodiments, –L1– is optionally substituted C1-C25heteroalkylene, optionally substituted C2- C25 heteroalkenylene, optionally substituted C2-C25 heteroalkynylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, or any combination thereof.

[0218] In some embodiments, –L1– comprises optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, –L1– comprises optionally substituted C3-C7 carbocyclylene, optionally substituted 3- to 7-membered heterocyclylene, optionally substituted C6-C10arylene, or optionally substituted 5- to 10-membered heteroarylene. In some embodiments, –L1– comprises optionally substituted carbocyclylene or optionally substituted heterocyclylene. In some embodiments, –L1– comprises optionally substituted C3- C7carbocyclylene or optionally substituted 3- to 7-membered heterocyclylene. In some91embodiments, –L1– comprises optionally substituted arylene or optionally substituted heteroarylene. In some embodiments, –L1– comprises optionally substituted C6-C10 arylene or optionally substituted 5- to 10-membered heteroarylene. In some embodiments, –L1– comprises optionally substituted carbocyclylene or optionally substituted arylene. In some embodiments, –L1– comprises optionally substituted C3-C7 carbocyclylene or optionally substituted C6-C10 arylene. In some embodiments, –L1– comprises optionally substituted heterocyclylene or optionally substituted heteroarylene. In some embodiments, –L1– comprises optionally substituted 3- to 7-membered heterocyclylene or optionally substituted 5- to 10-membered heteroarylene. In some embodiments, –L1– comprises optionally substituted phenylene or optionally substituted naphthylene. In some embodiments, –L1– comprises optionally substituted cyclobutylene, optionally substituted cyclopentylene, or optionally substituted cyclohexylene. In some embodiments, –L1– 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. In some embodiments, –L1– comprises optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydrothiophenyl, optionally substituted piperidinyl, optionally substituted tetrahydropyranyl, or optionally substituted piperazinyl.

[0219] In some embodiments, –L1– comprises optionally substituted C1-C25alkylene, optionally substituted C2-C25alkenylene, optionally substituted C2-C25alkynylene, optionally substituted C1-C25 heteroalkylene, optionally substituted C2-C25 heteroalkenylene, optionally substituted C2-C25 heteroalkynylene. In some embodiments, –L1– comprises optionally substituted C1-C25alkylene, optionally substituted C2-C25alkenylene, or optionally substituted C2-C25 alkynylene. In some embodiments, –L1– comprises optionally substituted C3-C12 alkylene, optionally substituted C3-C12 alkenylene, or optionally substituted C3-C12 alkynylene. In some embodiments, –L1– comprises optionally substituted C3-C12alkylene. In some embodiments, –L1– comprises optionally substituted C3-C12 alkenylene. In some embodiments, –L1– comprises optionally substituted C3-C12 alkynylene. In some embodiments, –L1– comprises optionally substituted C1-C25heteroalkylene, optionally substituted C2-C25heteroalkenylene, optionally substituted C2-C25heteroalkynylene. In some embodiments, –L1– comprises optionally substituted C3-C12 heteroalkylene, optionally substituted C3-C25 heteroalkenylene, optionally substituted C3-C25 heteroalkynylene. In some embodiments, –L1– comprises optionally substituted C3-C12heteroalkylene. In some92embodiments, –L1– comprises optionally substituted C3-C25heteroalkenylene. In some embodiments, –L1– comprises optionally substituted C3-C25 heteroalkynylene.

[0220] In some embodiments, –L1– is optionally substituted C1-C25 alkylene, optionally substituted C2-C25alkenylene, optionally substituted C2-C25alkynylene, optionally substituted C1-C25 heteroalkylene, optionally substituted C2-C25 heteroalkenylene, optionally substituted C2-C25 heteroalkynylene. In some embodiments, –L1– is optionally substituted C1- C25alkylene, optionally substituted C2-C25alkenylene, or optionally substituted C2-C25alkynylene. In some embodiments, –L1– is optionally substituted C3-C12 alkylene, optionally substituted C3-C12 alkenylene, or optionally substituted C3-C12 alkynylene. In some embodiments, –L1– is optionally substituted C3-C12alkylene. In some embodiments, –L1– is optionally substituted C3-C12alkenylene. In some embodiments, –L1– is optionally substituted C3-C12 alkynylene. In some embodiments, –L1– is optionally substituted C1-C25 heteroalkylene, optionally substituted C2-C25 heteroalkenylene, optionally substituted C2-C25 heteroalkynylene. In some embodiments, –L1– is optionally substituted C3-C12heteroalkylene, optionally substituted C3-C25 heteroalkenylene, optionally substituted C3-C25 heteroalkynylene. In some embodiments, –L1– is optionally substituted C3-C12 heteroalkylene. In some embodiments, –L1– is optionally substituted C3-C25heteroalkenylene. In some embodiments, –L1– is optionally substituted C3-C25 heteroalkynylene.

[0221] In some embodiments, –L1– 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 Y1. In some embodiments, –L1– is, wherein n is 4, 5, 6, 7, 8, 9, or 10, and y1 designates the point of attachment to Y1. In some embodiments, –L1– comprises, wherein m is 1, 2, 3, 4, or 5, and y1 designates the point of attachment to Y1. In some embodiments, –L1– comprises, wherein m is 1, 2, 3, or 4, and y1 designates the point of attachment to Y1.

[0222] In some embodiments, –L1– comprises,93, wherein y1 designates the point of attachment to Y1. In some embodiments, –L1– has the formula,, wherein y1 designates the point of attachment to Y1. In some embodiments, –L1– comprises,9495

[0223] As defined herein, –Y1is of Formula (Y-A) or (Y-B):

[0224] In some embodiments, –Y1is of Formula (Y-A).

[0225] In some embodiments, –Y1is of Formula (Y-A-1):

[0226] In some embodiments, –Y1is of Formula (Y-A-2):(Y-A-2).

[0227] In some embodiments, –Y1is of Formula (Y-A-3):(Y-A-3).96

[0228] In some embodiments, –Y1is of Formula (Y-A-4):(Y-A-4).

[0229] In some embodiments, –Y1is of Formula (Y-A-5):

[0230] As defined herein, each instance of Ra1is independently hydrogen, –ORC, –N(RC)2, – CN, –NO2, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8heteroalkenyl, optionally substituted C2-C8heteroalkynyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, each instance of Ra1is independently hydrogen, –OH, –NH2, –CN, – NO2, optionally substituted C1-C8alkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C1-C8alkoxy, optionally substituted C1-C8aminoalkyl, or optionally substituted 3-10 membered heterocyclyl. In some embodiments, each instance of Ra1is independently hydrogen, –OH, –NH2, –CN, –NO2, unsubstituted C1- C8alkyl, unsubstituted C2-C8alkenyl, optionally substituted C1-C8haloalkyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, or optionally substituted 3-10 membered heterocyclyl.

[0231] In some embodiments, at least one instance of Ra1is hydrogen, –ORC, –N(RC)2, – CN, or –NO2. In some embodiments, at least one instance of Ra1is hydrogen, optionally substituted C1-C8alkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C1-C8heteroalkyl, optionally substituted C2-C8heteroalkenyl, or optionally substituted C2-C8 heteroalkynyl. In some embodiments, at least one instance of97Ra1is optionally substituted C3-C10carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, at least one instance of Ra1is optionally substituted C1- C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, or optionally substituted C3-C10carbocyclyl. In some embodiments, at least one instance of Ra1is optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, or optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, each instance of Ra1is independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, or optionally substituted C2-C8heteroalkynyl. In some embodiments, each instance of Ra1is independently hydrogen or unsubstituted C1-C4alkyl. In some embodiments, at least one instance of Ra1is hydrogen. In some embodiments, at least one instance of Ra1is unsubstituted C1-C4 alkyl. In some embodiments, at least one instance of Ra1is tert-butyl.

[0232] In some embodiments, one instance of Ra1is hydrogen, and the other instance of Ra1is independently hydrogen, –ORC, –N(RC)2, –CN, –NO2, optionally substituted C1-C8 alkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, one instance of Ra1is hydrogen, and the other instance of Ra1is independently hydrogen, –OH, –NH2, –CN, –NO2, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 aminoalkyl, or optionally substituted 3-10 membered heterocyclyl. In some embodiments, one instance of Ra1is hydrogen, and the other instance of Ra1is independently hydrogen, –OH, –NH2, –CN, – NO2, unsubstituted C1-C8 alkyl, unsubstituted C2-C8 alkenyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8alkoxy-C1-C8alkyl, optionally substituted C1-C8hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, or optionally substituted 3-10 membered heterocyclyl. In some embodiments, one instance of Ra1is hydrogen, and the other instance of Ra1is optionally substituted C1-C4alkyl. In some embodiments, one instance of Ra1is hydrogen, and the other instance of Ra1is unsubstituted C1-C4 alkyl. In some embodiments, one instance of Ra1is hydrogen, and the other instance of Ra1is tert-butyl.98

[0233] As defined herein, each instance of Ra2is independently –RaL–, hydrogen, –ORC, – N(RC)2, –CN, –NO2, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8heteroalkenyl, optionally substituted C2-C8heteroalkynyl, optionally substituted C3-C10 membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, each instance of Ra2is independently –RaL–, hydrogen, – OH, –NH2, –CN, –NO2, optionally substituted C1-C8alkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 aminoalkyl, or optionally substituted 3-10 membered heterocyclyl. In some embodiments, each instance of Ra2is independently –RaL–, hydrogen, –OH, –NH2, –CN, – NO2, unsubstituted C1-C8alkyl, unsubstituted C2-C8alkenyl, optionally substituted C1-C8haloalkyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8alkyl, or optionally substituted 3-10 membered heterocyclyl.

[0234] In some embodiments, each instance of Ra2is independently –RaL–, hydrogen, –ORC, –N(RC)2, –CN, or –NO2. In some embodiments, each instance of Ra2is independently –RaL–, hydrogen, optionally substituted C1-C8alkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2- C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C3-C10 membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, each instance of Ra2is independently –RaL–, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8heteroalkynyl. In some embodiments, each instance of Ra2is independently –RaL–, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2- C8 alkenyl, or optionally substituted C2-C8 alkynyl. In some embodiments, each instance of Ra2is independently –RaL–, hydrogen, or unsubstituted C1-C4alkyl. In some embodiments, each instance of Ra2is independently –RaL–, hydrogen, or methyl. In some embodiments, at least one instance Ra2is –RaL–.

[0235] In some embodiments, each instance of Ra2is independently hydrogen, –OH, –NH2, –CN, –NO2, optionally substituted C1-C8alkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 aminoalkyl, or optionally substituted 3-10 membered heterocyclyl. In some embodiments, each instance of Ra2is independently hydrogen, –OH, –NH2, –CN, –NO2,99unsubstituted C1-C8alkyl, unsubstituted C2-C8alkenyl, optionally substituted C1-C8haloalkyl, optionally substituted C1-C8 alkoxy-C1-C8 alkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8alkyl, or optionally substituted 3-10 membered heterocyclyl.

[0236] In some embodiments, each instance of Ra2is independently hydrogen, –ORC, – N(RC)2, –CN, or –NO2. In some embodiments, each instance of Ra2is independently hydrogen, optionally substituted C1-C8alkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2- C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C3-C10 membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, each instance of Ra2is independently hydrogen, optionally substituted C1-C8alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8heteroalkynyl. In some embodiments, each instance of Ra2is independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, or optionally substituted C2-C8 alkynyl. In some embodiments, each instance of Ra2is independently hydrogen or unsubstituted C1-C4alkyl. In some embodiments, each instance of Ra2is independently hydrogen or methyl. In some embodiments, at least one instance of Ra1is hydrogen. In some embodiments, at least one instance of Ra1is unsubstituted C1-C4 alkyl. In some embodiments, at least one instance of Ra1is methyl.

[0237] As defined herein, Ra3is hydrogen, –C(=O)RC, –C(=O)ORC, –C(=O)N(RC)2, – PO(ORC)2, or –C(RC)2–OPO(ORC)2. In some embodiments, Ra3is hydrogen, –C(=O)RC, – C(=O)ORC, or –C(=O)N(RC)2. In some embodiments, Ra3is hydrogen, –PO(ORC)2, or – C(RC)2–OPO(ORC)2. In some embodiments,PO(ORC)2, or –C(RC)2–OPO(ORC)2. In some embodiments, Ra3is hydrogen.

[0238] As defined herein, Ra4is –RaL–, –ORC, –N(RC)2, –N(RC)C(=O)RC, optionally substituted C3-C10carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, Ra4is –RaL–, –ORC, –N(RC)2, or –N(RC)C(=O)RC. In some embodiments, Ra4is –RaL–, optionally substituted C3-C10carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, Ra4is –RaL–, optionally substituted C3-C7 carbocyclyl, or optionally substituted 3- to 7-membered heterocyclyl. In some embodiments, Ra4is –RaL–, optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, Ra4is –RaL–. In100some embodiments, Ra4is –ORC, –N(RC)2, or –N(RC)C(=O)RC. In some embodiments, Ra4is -NHC(=O)Me. In some embodiments, Ra4is -NHC(=O)(1-fluorocyclopropanyl) In some embodiments, Ra4is optionally substituted C3-C10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, Ra4is optionally substituted C3-C7 carbocyclyl, or optionally substituted 3- to 7-membered heterocyclyl. In some embodiments, Ra4is optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0239] As defined herein, Ra5is hydrogen or halogen. In some embodiments, Ra5is hydrogen. In some embodiments, Ra5is halogen. In some embodiments, Ra5is –Br, –Cl, or – F. In some embodiments, Ra5is –F or hydrogen. In some embodiments, Ra5is –F.

[0240] As defined herein, Ra6is hydrogen, halogen, –ORC, –N(RC)2, –CN, –NO2, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8heteroalkynyl, optionally substituted C3-C10carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, Ra6is hydrogen, halogen, –ORC, – N(RC)2, –CN, –NO2, optionally substituted C1-C8alkyl, optionally substituted C1-C8alkoxy, optionally substituted C3-C8 carbocyclyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, Ra6is hydrogen, halogen, –ORC, –N(RC)2, –CN, or –NO2. In some embodiments, Ra6is hydrogen, optionally substituted C1-C8alkyl, optionally substituted C2- C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, or optionally substituted C2-C8 heteroalkynyl. In some embodiments, Ra6is optionally substituted C1-C4alkyl, optionally substituted C2-C4alkenyl, or optionally substituted C2-C4 alkynyl. In some embodiments, Ra6is optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4heteroalkynyl. In some embodiments, Ra6is optionally substituted C3-C10carbocyclyl or optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, Ra6is optionally substituted C3-C7 carbocyclyl or optionally substituted 3- to 7-membered heterocyclyl. In some embodiments, Ra6is optionally substituted C3-C7carbocyclyl or optionally substituted aryl. In some embodiments, Ra6is optionally substituted 3- to 7- membered heterocyclyl or optionally substituted heteroaryl. In some embodiments, Ra6is optionally substituted C6-C10 aryl or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, Ra6is optionally substituted heteroaryl. In some embodiments, Ra6is101optionally substituted heteroaryl comprising one or more nitrogen atoms. In some embodiments, Ra6is optionally substituted heteroaryl comprising one or more sulfur atoms. In some embodiments, Ra6is optionally substituted 5- or 6-membered heteroaryl. In some embodiments, Ra6is optionally substituted thiazolyl. In some embodiments, Ra6is optionally substituted. In some embodiments, Ra6is.

[0241] As defined herein, each instance of Ra7is independently halogen, 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, –CN, –ORC, –SCN, –SRC, –SC(=NRC)RC, –SC(=NRC)ORC, –SC(=NRC)SRC, –SC(=NRC)N(RC)2, –NRCC(=O)RC, – NRCC(=O)ORC, –NRCC(=O)SRC, –NRCC(=O)N(RC)2, –NRCC(=NRC)RC, – NRCC(=NRC)ORC, –NRCC(=NRC)SRC, –NRCC(=NRC)N(RC)2, –NRCS(=O)RC, – NRCS(=O)ORC, –NRCS(=O)SRC, –NRCS(=O)N(RC)2, –NRCS(=O)2RC, –NRCS(=O)2ORC, – NRCS(=O)2SRC, or –NRCS(=O)2N(RC)2.

[0242] In some embodiments, Ra7is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, –ORC, –SRC, or – N(RC)2. In some embodiments, Ra7is optionally substituted C1-10alkyl, optionally substituted C1-10alkenyl, optionally substituted C1-10alkynyl, optionally substituted C1-10heteroalkyl, optionally substituted C1-10 heteroalkenyl, or optionally substituted C1-10 heteroalkynyl. In some embodiments, Ra7is C1-10haloalkyl. In some embodiments, Ra7is C1-4haloalkyl. In some embodiments, Ra7is C1-4fluoroalkyl (e.g., C1-4perfluoroalkyl). In some embodiments, Ra7is –CF3. In some embodiments, Ra7is hydrogen, optionally substituted C1-C7 alkyl, or halogen. In some embodiments, Ra7is hydrogen, fluorine, –CH3, –CH2F, –CHF2, or –CF3. In102some embodiments, Ra7is hydrogen, fluorine, –CH3, or –CF3. In some embodiments, Ra7is hydrogen or halogen. In some embodiments, Ra7is hydrogen or fluorine. In some embodiments, Ra7is hydrogen or optionally substituted C1-C7 alkyl. In some embodiments, Ra7is hydrogen, unsubstituted C1-C7alkyl, or C1-7haloalkyl.

[0243] In some embodiments, Ra7is halogen. In some embodiments, Ra7is bromine, chlorine, or fluorine. In some embodiments, Ra7is bromine or chlorine. In some embodiments, Ra7is chlorine or fluorine. In some embodiments, Ra7is bromine. In some embodiments, Ra7is chlorine. In some embodiments, Ra7is fluorine.

[0244] In some embodiments, Ra7is –ORC, –SRC, or –N(RC)2 (e.g., wherein RCis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, Ra7is –OH. In some embodiments, Ra7is –SH. In some embodiments, Ra7is –NH2. In some embodiments, Ra7is –CN, –SCN, –SSRC, –N3, –NO, or –NO2. In some embodiments, Ra7is –, wherein RCis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, Ra7is – C(=NRC)RC, –C(=NRC)ORC, –C(=NRC)SRC, or –C(=NRC)N(RC)2 (e.g., wherein RCis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments,S(=O)2ORC, –S(=O)2SRC, or –S(=O)2N(RC)2 (e.g., wherein RCis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, Ra7is –OC(=O)RC,(e.g., wherein RCis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, Ra7is –NRCC(=O)RC, –NRCC(=O)ORC, –NRCC(=O)SRC, –NRCC(=NRC)N(RC)2, –NRCS(=O)RC, –NRCS(=O)ORC, –NRCS(=O)SRC, –NRCS(=O)N(RC)2, –NRCS(=O)2RC, –NRCS(=O)2ORC, –NRCS(=O)2SRC, or –NRCS(=O)2N(RC)2(e.g., wherein RCis hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0245] In some embodiments, Ra7is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, Ra7is optionally substituted C3-14carbocyclyl. In some embodiments, Ra7103is optionally substituted monocyclic C3-7carbocyclyl. In some embodiments, Ra7is optionally substituted monocyclic C3-4 carbocyclyl. In some embodiments, Ra7is optionally substituted monocyclic C5-7 carbocyclyl. In some embodiments, Ra7is saturated carbocyclyl. In some embodiments, Ra7is carbocyclyl comprising only one unsaturated bond (e.g., C=C bond) in the carbocyclic ring system.

[0246] In some embodiments, Ra7is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, Ra7is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, Ra7is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and / or S atoms but no N atoms. In some embodiments, Ra7is 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, Ra7is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and / or S atoms but no N atoms. In some embodiments, Ra7is 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, Ra7is saturated heterocyclyl. In some embodiments, Ra7is heterocyclyl comprising only one unsaturated bond (e.g., C=C bond) in the heterocyclic ring system.

[0247] In some embodiments, Ra7is optionally substituted monocyclic aryl. In some embodiments, Ra7is optionally substituted bicyclic aryl. In some embodiments, Ra7is optionally substituted C6-14aryl. In some embodiments, Ra7is optionally substituted C6-10aryl. In some embodiments, Ra7is optionally substituted phenyl. In some embodiments, Ra7is optionally substituted naphthyl.

[0248] In some embodiments, Ra7is optionally substituted monocyclic heteroaryl. In some embodiments, Ra7is optionally substituted bicyclic heteroaryl. In some embodiments, Ra7is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, Ra7is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, Ra7is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0249] As defined herein, each instance of Ra8is independently halogen, 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, –CN, –ORC, –SCN, –SRC, –C(=NRC)RC, –C(=NRC)ORC, –C(=NRC)SRC, –C(=NRC)N(RC)2, –S(=O)RC, –S(=O)ORC, –104SC(=NRC)RC, –SC(=NRC)ORC, –SC(=NRC)SRC, –SC(=NRC)N(RC)2, –NRCC(=O)RC, – NRCC(=O)ORC, –NRCC(=O)SRC, –NRCC(=O)N(RC)2, –NRCC(=NRC)RC, – NRCC(=NRC)ORC, –NRCC(=NRC)SRC, –NRCC(=NRC)N(RC)2, –NRCS(=O)RC, – NRCS(=O)ORC, –NRCS(=O)SRC, –NRCS(=O)N(RC)2, –NRCS(=O)2RC, –NRCS(=O)2ORC, – NRCS(=O)2SRC, or –NRCS(=O)2N(RC)2.

[0250] In some embodiments, Ra8is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, –ORC, –SRC, or – N(RC)2. In some embodiments, Ra8is optionally substituted C1-10alkyl, 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. In some embodiments, Ra8is C1-10haloalkyl. In some embodiments, Ra8is C1-4haloalkyl. In some embodiments, Ra8is C1-4 fluoroalkyl (e.g., C1-4 perfluoroalkyl). In some embodiments, Ra8is –CF3. In some embodiments, Ra8is hydrogen, optionally substituted C1-Ca8alkyl, or halogen. In some embodiments, Ra8is hydrogen, fluorine, –CH3, –CH2F, –CHF2, or –CF3. In some embodiments, Ra8is hydrogen, fluorine, –CH3, or –CF3. In some embodiments, Ra8is hydrogen or halogen. In some embodiments, Ra8is hydrogen or fluorine. In some embodiments, Ra8is hydrogen or optionally substituted C1-C7 alkyl. In some embodiments, Ra8is hydrogen, unsubstituted C1-C7alkyl, or C1-7haloalkyl.

[0251] In some embodiments, Ra8is halogen. In some embodiments, Ra8is bromine, chlorine, or fluorine. In some embodiments, Ra8is bromine or chlorine. In some embodiments, Ra8is chlorine or fluorine. In some embodiments, Ra8is bromine. In some embodiments, Ra8is chlorine. In some embodiments, Ra8is fluorine.

[0252] In some embodiments, Ra8is –ORC, –SRC, or –N(RC)2 (e.g., wherein RCis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, Ra8is –OH. In some embodiments, Ra8is –SH. In some embodiments, Ra8is –NH2. In some embodiments, Ra8is –CN, –SCN, –SSRC, –N3, –NO, or –NO2. In some embodiments, Ra8is –, wherein RCis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, Ra8is –105C(=NRC)RC, –C(=NRC)ORC, –C(=NRC)SRC, or –C(=NRC)N(RC)2(e.g., wherein RCis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments,S(=O)2ORC, –S(=O)2SRC, or –S(=O)2N(RC)2(e.g., wherein RCis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, Ra8is –OC(=O)RC,(e.g., wherein RCis hydrogen or optionally substituted alkyl, or optionally substituted phenyl). In some embodiments, Ra8is –NRCC(=O)RC, –NRCC(=O)ORC, –NRCC(=O)SRC, –NRCC(=NRC)N(RC)2, –NRCS(=O)RC, –NRCS(=O)ORC, –NRCS(=O)SRC, –NRCS(=O)N(RC)2, –NRCS(=O)2RC, –NRCS(=O)2ORC, –NRCS(=O)2SRC, or –NRCS(=O)2N(RC)2 (e.g., wherein RCis hydrogen or optionally substituted alkyl, or optionally substituted phenyl).

[0253] In some embodiments, Ra8is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, Ra8is optionally substituted C3-14carbocyclyl. In some embodiments, Ra8 is optionally substituted monocyclic C3-7carbocyclyl. In some embodiments, Ra8is optionally substituted monocyclic C3-4 carbocyclyl. In some embodiments, Ra8is optionally substituted monocyclic C5-7 carbocyclyl. In some embodiments, Ra8is saturated carbocyclyl. In some embodiments, Ra8is carbocyclyl comprising only one unsaturated bond (e.g., C=C bond) in the carbocyclic ring system.

[0254] In some embodiments, Ra8is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, Ra8is optionally substituted monocyclic 3- to 7-membered heterocyclyl. In some embodiments, Ra8is optionally substituted 3- to 14-membered heterocyclyl comprising one or more O and / or S atoms but no N atoms. In some embodiments, Ra8is 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, Ra8is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more O and / or S atoms but no N atoms. In some embodiments, Ra8is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising one or more N atoms and optionally106one or more O and / or S atoms. In some embodiments, Ra8is saturated heterocyclyl. In some embodiments, Ra8is heterocyclyl comprising only one unsaturated bond (e.g., C=C bond) in the heterocyclic ring system.

[0255] In some embodiments, Ra8is optionally substituted monocyclic aryl. In some embodiments, Ra8is optionally substituted bicyclic aryl. In some embodiments, Ra8is optionally substituted C6-14 aryl. In some embodiments, Ra8is optionally substituted C6-10 aryl. In some embodiments, Ra8is optionally substituted phenyl. In some embodiments, Ra8is optionally substituted naphthyl.

[0256] In some embodiments, Ra8is optionally substituted monocyclic heteroaryl. In some embodiments, Ra8is optionally substituted bicyclic heteroaryl. In some embodiments, Ra8is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, Ra8is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, Ra8is optionally substituted 5- to 6-membered monocyclic heteroaryl.

[0257] As defined herein, Ra9is hydrogen or a nitrogen protecting group. In some embodiments, Ra9is hydrogen. In some embodiments, Ra9is a nitrogen protecting group.

[0258] As defined herein, Ra10is –RaL– or hydrogen. In some embodiments, Ra10is hydrogen. In some embodiments, Ra10is –RaL–.

[0259] As defined herein, –RaL– is a bond, –O–, –N(RC)–, –N(RC)C(=O)–, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2- C8alkynylene, optionally substituted C1-C8heteroalkylene, optionally substituted C2-C8heteroalkenylene, optionally substituted C2-C8heteroalkynylene, optionally substituted C3- C10 carbocyclylene, optionally substituted 3- to 10-membered heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, –RaL– is a bond, –O–, –N(RC)–, –N(RC)C(=O)–, optionally substituted C1-C4alkylene, optionally substituted C2-C4 alkenylene, optionally substituted C2-C4 alkynylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 heteroalkenylene, optionally substituted C2-C4heteroalkynylene, optionally substituted C3-C7carbocyclylene, optionally substituted 3- to 7-membered heterocyclylene, optionally substituted C6 arylene, or optionally substituted 5- to 6- membered heteroarylene. In some embodiments, –RaL– is a bond, –O–, –N(RC)–, – N(RC)C(=O)–, optionally substituted C1-C4alkylene, optionally substituted C2-C4alkenylene, optionally substituted C2-C4alkynylene, optionally substituted C1-C4heteroalkylene, optionally substituted C2-C4 heteroalkenylene, or optionally substituted C2-C4 heteroalkynylene. In some embodiments, –RaL– is a bond, –O–, –N(RC)–, or –N(RC)C(=O)–. In some embodiments, –RaL– is optionally substituted C1-C4alkylene or optionally107substituted C1-C4heteroalkylene. In some embodiments, –RaL– is optionally substituted C2- C8 heteroalkynylene, optionally substituted C3-C10 carbocyclylene, optionally substituted 3- to 10-membered heterocyclylene, optionally substituted C6-C10 arylene, or optionally substituted 5- to 10-membered heteroarylene. In some embodiments, –RaL– is –N(C1-C4alkyl)C(=O)–.In some embodiments, –RaL– is –NHC(=O)–. In some embodiments, –RaL– is – N(Me)C(=O)–. In some embodiments, –RaL– is a bond. In some embodiments, –RaL– is –O–. In some embodiments, –RaL– is –NH–. In some embodiments, –RaL– is –N(Me) –. In some embodiments,

[0260] As defined herein, each instance of RCis 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 RCattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring. In some embodiments, at least one instance of RCis independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, optionally substituted C1-C8 alkynyl, optionally substituted C1-C8heteroalkyl, optionally substituted C1-C8heteroalkenyl, optionally substituted C1-C8heteroalkynyl, optionally substituted C3-C10carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of RCis independently hydrogen, optionally substituted C1-C8alkyl, optionally substituted C1-C8alkoxy C1-C8alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C10carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of RCis 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 RCis independently optionally substituted C1-C4 alkyl. In some embodiments, at least one instance of RCis independently methyl. In some embodiments, at least one instance of RCis optionally substituted carbocyclyl, optionally108substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of RCis independently hydrogen, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkenyl, optionally substituted C1-10 alkynyl, optionally substituted C3-14carbocyclyl, or optionally substituted C6-14aryl. In some embodiments, at least one instance of RCis hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C3-C8 carbocyclyl, or optionally substituted 3- to 8-membered heterocyclyl. In some embodiments, at least one instance of RCis hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, or optionally substituted 3- to 8-membered heterocyclyl. In some embodiments, at least one instance of RCis independently hydrogen, optionally substituted C1-10alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of RCis hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 carbocyclyl, –C(O)(optionally substituted C1-C8 alkyl, –C(O)(optionally substituted C1-C8 carbocyclyl), –C(O)(optionally substituted C1-C8alkyl-C3-C8carbocyclyl), –C(O)(optionally substituted 3- to 10-membered heterocyclyl), –C(O)(C1-C8 alkyl-optionally substituted 3- to 10-membered heterocyclyl), – C(O)(optionally substituted aryl), –C(O)(C1-C8 alkyl-optionally substituted aryl), – C(O)(optionally substituted heteroaryl), –C(O)(C1-C8alkyl-optionally substituted heteroaryl), optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of RCis 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. In some embodiments, two instances of RCattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0261] As defined herein, q is 0, 1, 2, 3, 4, or 5. In some embodiments, q is 0, 1, 2, 3, or 4. In some embodiments, q is 1, 2, 3, 4, or 5. In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 2, 3, 4, or 5. In some embodiments, 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.

[0262] As defined herein, r is 0, 1, 2, or 3. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 1, 2, or 3. In some embodiments, r is 0 or 1. In some embodiments, r is 1 or1092. 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 3.110

[0264] In some embodiments, –Y1is of Formula (Y-B).

[0265] In some embodiments, –Y1is of Formula (Y-B-1):111(Y-B-1).

[0266] In some embodiments, –Y1is of Formula (Y-B-2):(Y-B-2).

[0267] In some embodiments, –Y1is of Formula (Y-B-3):(Y-B-3).

[0268] In some embodiments, –Y1is of Formula (Y-B-4):112(Y-B-4).

[0269] As defined herein, each instance of Rb1is independently halogen, –ORD, –CN, – NO2, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C1-C6heteroalkyl, optionally substituted C2- C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C8 carbocyclyl, or optionally substituted 3- to 8-membered heterocyclyl. In some embodiments, Rb1is halogen, –ORD, –CN, –NO2, optionally substituted C1-C6alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 carbocyclyl, or optionally substituted 3- to 8- membered heterocyclyl. In some embodiments, Rb1is halogen, –CN, –NO2, optionally substituted C1-C6alkyl, optionally substituted C1-C3haloalkyl, C1-C3hydroxyalkyl, optionally substituted C3-C8carbocyclyl, or optionally substituted 3- to 8-membered heterocyclyl. In some embodiments, at least one instance of Rb1is halogen, –ORD, –CN, or – NO2. In some embodiments, at least one instance of Rb1is optionally substituted C1-C6 alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, or optionally substituted C2-C6 heteroalkynyl. In some embodiments, at least one instance of Rb1is optionally substituted C1-C4alkyl, optionally substituted C2-C4alkenyl, or optionally substituted C2-C4 alkynyl. In some embodiments, at least one instance of Rb1is optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, or optionally substituted C2-C4heteroalkynyl. In some embodiments, at least one instance of Rb1is optionally substituted C3-C8carbocyclyl or optionally substituted 3- to 8-membered heterocyclyl. In some embodiments, at least one instance of Rb1is optionally substituted C4- C6 carbocyclyl. In some embodiments, at least one instance of Rb1is optionally substituted 4- to 6-membered heterocyclyl.

[0270] As defined herein, Rb2is hydrogen or a nitrogen protecting group. In some embodiments, Rb2is hydrogen. In some embodiments, Rb2is a nitrogen protecting group.

[0271] As defined herein, Vbis –N–, –CH–, or –C(Rb1)–. In some embodiments, Vbis –N– or –CH–. In some embodiments, Vb is –N– or –C(Rb1)–. In some embodiments, Vb is –CH– or –C(Rb1)–. In some embodiments, Vb is –N–. In some embodiments, Vb is –CH–. In some embodiments, Vbis –C(Rb1)–.

[0272] As defined herein, Wbis a bond, –Wb1–, or –Wb1–Wb2–, wherein Wb1and Wb2are each independently –C(=O)–, –O–, –C(RE)2–, or –NRD–, provided that –Wb1–Wb2– is not – O–O–. In some embodiments, Wb is a bond or –Wb1–. In some embodiments, Wb is a bond or –Wb1–Wb2–. In some embodiments, Wbis –Wb1– or –Wb1–Wb2–. In some embodiments, Wb113is a bond. In some embodiments, Wbis –Wb1–. In some embodiments, Wbis –C(=O)–, –O–, –C(RE)2–, or –NRD–. In some embodiments, Wb is –C(=O)–, –O–, –CH2–, or –NH–. In some embodiments, Wb is –Wb1–Wb2–. In some embodiments, Wb is –C(=O)O–, –C(=O)C(RE)2–, – C(=O)NRD–, –OC(RE)2–,–C(RE)2NRD–, or – C(RE)2C(RE)2–., wherein w1 designates the point of attachment to Wb. In some embodiments, Ring B is ,embodiments, Ringwherein w1 designates the point of114attachment to Wb. In some embodiments, Ringwherein w1 designates the point of attachment to Wb.

[0274] As defined herein, each instance of Rb3is independently halogen, optionally substituted C1-C3alkyl, or –ORD. In some embodiments, each instance of Rb3is independently halogen, optionally substituted C1-C3 alkyl, or –O(optionally substituted C1-C3 alkyl). In some embodiments, at least one instance of Rb3is halogen or optionally substituted C1-C3alkyl. In some embodiments, at least one instance of Rb3is halogen or –ORD. In some embodiments, at least one instance of Rb3is optionally substituted C1-C3 alkyl or –ORD. In some embodiments, at least one instance of Rb3is halogen. In some embodiments, at least one instance of Rb3is –Br, –Cl, or –F. In some embodiments, at least one instance of Rb3is optionally substituted C1-C3alkyl. In some embodiments, at least one instance of Rb3is methyl, ethyl, n-propyl, or i-propyl. In some embodiments, at least one instance of Rb3is – OH, –OMe, –OEt, or –OPr.

[0275] As defined herein, t is 0, 1, 2, 3, 4, or 5. In some embodiments, t is 0, 1, 2, 3, or 4. In some embodiments, 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. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 5.

[0276] As defined herein, Zb is –(Rb4)u–, wherein Rb4, at each occurrence, is independently Rb5or Rb6; provided that –Rb4–Rb4– is not –O–O–. In some embodiments, Zbis a bond.

[0277] As defined herein, Rb5, at each occurrence, is independently a bond, –C(=O)–, – C(RE)2–, –NRD–, –O–, optionally substituted C1-C10 alkylene, optionally substituted C1-C10 alkenylene, or optionally substituted C1-C10alkynylene. In some embodiments, Rb5, at each occurrence, is independently a bond, –C(=O)–, –C(RE)2–, –NRD–, –O–, optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, or optionally substituted C1-C4 alkynylene. In some embodiments, Rb5, at each occurrence, is independently a bond, –115C(=O)–, –C(RE)2–, optionally substituted C1-C4alkylene, optionally substituted C1-C4alkenylene, or optionally substituted C1-C4 alkynylene. In some embodiments, Rb5, at each occurrence, is a bond, –C(=O)–, –C(RE)2–, –NRD–, or –O–. In some embodiments, Rb5, at each occurrence, is optionally substituted C1-C4alkylene, optionally substituted C1-C4alkenylene, or optionally substituted C1-C4 alkynylene. In some embodiments, Rb5is a bond.

[0278] As defined herein, Rb6, at each occurrence, is independently a bond, optionally substituted C3-C10carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, Rb6is a bond. In some embodiments, Rb6, at each occurrence, is a bond, optionally substituted C3- C7carbocyclyl, or optionally substituted 3- to 7-membered heterocyclyl. In some embodiments, Rb6, at each occurrence, is a bond, optionally substituted C6-C10aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, Rb6, at each occurrence, is a bond, optionally substituted C3-C7 carbocyclyl, or optionally substituted C6- C10aryl. In some embodiments, Rb6, at each occurrence, is a bond, optionally substituted 3- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl.

[0279] 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. In some embodiments, 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. In some embodiments, 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.

[0280] 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. In some embodiments, s is 3 or 4. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4.116

[0281] As defined herein, each instance of RDis 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 RDattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring. In some embodiments, at least one instance of RDis 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 RDis independently optionally substituted C1-C4 alkyl. In some embodiments, at least one instance of RDis independently methyl. In some embodiments, at least one instance of RDis optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of RDis 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 RDis independently hydrogen, optionally substituted C1-10alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of RDis 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. In some embodiments, two instances of RDattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring.

[0282] As defined herein, each instance of REis independently hydrogen, halogen, –ORD, =O, –CN, –NO2, –N(RD)2, 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, or optionally substituted heteroaryl. In some embodiments, each instance of REis independently hydrogen, halogen, – OH, =O, –CN, –NO2, –NH2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted117heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of REis 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 REis independently optionally substituted C1-C4alkyl. In some embodiments, at least one instance of REis independently methyl. In some embodiments, at least one instance of REis optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, at least one instance of REis independently hydrogen, optionally substituted C1-10alkyl, optionally substituted C1-10alkenyl, optionally substituted C1-10 alkynyl, optionally substituted C3-14 carbocyclyl, or optionally substituted C6-14 aryl. In some embodiments, at least one instance of REis independently hydrogen, optionally substituted C1-10alkyl, or optionally substituted phenyl. In some embodiments, at least one instance of REis independently hydrogen, halogen, –ORD, =O, –CN, –NO2, or –N(RD)2. In some embodiments, at least one instance of REis independently hydrogen, halogen, –OH, =O, –CN, –NO2, or –NH2. In some embodiments, at least one instance of REis independently hydrogen, halogen, –ORD, =O, –CN, –NO2,– N(RD)2, or optionally substituted C1-C6 alkyl. In some embodiments, at least one instance of REis independently hydrogen, halogen, –ORD, –CN, –NO2, or –N(RD)2. In some embodiments, at least one instance of REis independently hydrogen, halogen, –CN, or –NO2. In some embodiments, at least one instance of REis independently hydrogen, halogen, –OH, –CN, –NO2, or –NH2. In some embodiments, at least one instance of REis independently hydrogen, –OH, or –NH2. In some embodiments, at least one instance of REis independently hydrogen, halogen, –ORD, –CN, –NO2,–N(RD)2, or optionally substituted C1-C6 alkyl.118[.

[0284] In some embodiments, the compounds is:119120121122, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0285] In some embodiments, the compounds is: ,,123, , ,,124, , ,,125,,126, , ,,127,,128,,129, ,,130,131,, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0286] In some embodiments, 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.

[0287] In another aspect, provided herein is a compound is of Formula (0), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0288] As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art, including the embodiments in the schemes and examples herein, which are representative of the transformations, synthesis methods, intermediates, reagents and conditions for methods of making the compounds, and salts thereof, delineated herein. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired132compounds. In addition, the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired compounds of the present disclosure. Pharmaceutical Compositions, Kits, and Administration

[0289] In some embodiments, a method provided herein comprises administering to the subject a pharmaceutical composition comprising a compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In some embodiments, a method provided herein comprises administering to the subject a pharmaceutical composition comprising sorafenib.

[0290] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0291] 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.

[0292] 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.

[0293] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.133

[0294] 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.

[0295] 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.

[0296] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween®20), polyoxyethylene sorbitan (Tween®60), polyoxyethylene sorbitan monooleate (Tween®80), sorbitan monopalmitate (Span®40), sorbitan monostearate (Span®60), sorbitan tristearate (Span®65), glyceryl monooleate, sorbitan monooleate (Span®80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj®45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij®30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic®F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.134

[0297] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0298] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0299] Exemplary 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.

[0300] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0301] 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.

[0302] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.135

[0303] 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.

[0304] 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®.

[0305] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0306] 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.

[0307] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride,136cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0308] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0309] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0310] 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.

[0311] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a137parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0312] 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.

[0313] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0314] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0315] 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 controlling138coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0316] Dosage forms for topical and / or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0317] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0318] 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 as139high 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.

[0319] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0320] 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).

[0321] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.140

[0322] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0323] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0324] 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.

[0325] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled141veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0326] 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.

[0327] 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. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0328] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described142herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 µg and 1 µg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0329] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a143child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0330] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and / or in inhibiting the activity of a protein kinase in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.

[0331] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease (e.g., proliferative disease, 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 other144and / or with the compound or composition described herein in a single dose or composition or administered separately in dif...

Claims

CLAIMS What is claimed is:

1. A method of treating cancer in a subject in need thereof, the method comprising co- administering to the subject: a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co- crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof; wherein the compound inhibits YAP, degrades YAP, or suppresses YAP / TEAD-led transcription; and sorafenib, or a pharmaceutical composition thereof.

2. The method of claim 1, wherein the compound is of Formula (0):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: A1, A2, and A3are each independently –N= or –C(R9)=; C1, C2, C3, and C4are each independently –N= or –C(R8)=; D1, D2, D3, and D4are each independently –N= or –C(R7)=; R1, R3, and R4are each independently hydrogen, –N(RA)2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, optionally substituted C1-C4alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4heteroalkynyl, optionally substituted C3-C6carbocyclyl, or –L1– Y1; R2is hydrogen, –N(RA)2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAS(=O)2RA, –NRAS(=O)2ORA, –ORA, –SRA, –CN, halogen, optionally substituted C1-C4alkyl, optionally236substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, optionally substituted C1-C4heteroalkyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 heteroalkynyl, or optionally substituted C3-C6 carbocyclyl; R5is hydrogen, a nitrogen protecting group, or –L1–Y1; one of R1, R3, R4, or R5is –L1–Y1; each instance of R6, R7, R8, and R9is independently hydrogen, halogen, 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, –CN, –ORB, –SCN, –SRB, – SSRB, –N3, –NO, –N(RB)2, –NO2, –C(=O)RB, –C(=O)ORB, –C(=O)SRB, –C(=O)N(RB)2, – C(=NRB)RB, –C(=NRB)ORB, –C(=NRB)SRB, –C(=NRB)N(RB)2, –S(=O)RB, –S(=O)ORB, – S(=O)SRB, –S(=O)N(RB)2, –S(=O)2RB, –S(=O)2ORB, –S(=O)2SRB, –S(=O)2N(RB)2, – OC(=O)RB, –OC(=O)ORB, –OC(=O)SRB, –OC(=O)N(RB)2, –OC(=NRB)RB, – OC(=NRB)ORB, –OC(=NRB)SRB, –OC(=NRB)N(RB)2, –OS(=O)RB, –OS(=O)ORB, – OS(=O)SRB, –OS(=O)N(RB)2, –OS(=O)2RB, –OS(=O)2ORB, –OS(=O)2SRB, – OS(=O)2N(RB)2, –ON(RB)2, –SC(=O)RB, –SC(=O)ORB, –SC(=O)SRB, –SC(=O)N(RB)2, – SC(=NRB)RB, –SC(=NRB)ORB, –SC(=NRB)SRB, –SC(=NRB)N(RB)2, –NRBC(=O)RB, – NRBC(=O)ORB, –NRBC(=O)SRB, –NRBC(=O)N(RB)2, –NRBC(=NRB)RB, – NRBC(=NRB)ORB, –NRBC(=NRB)SRB, –NRBC(=NRB)N(RB)2, –NRBS(=O)RB, – NRBS(=O)ORB, –NRBS(=O)SRB, –NRBS(=O)N(RB)2, –NRBS(=O)2RB, –NRBS(=O)2ORB, – NRBS(=O)2SRB, or –NRBS(=O)2N(RB)2; each instance of RAand RBis 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 RAor RBattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; –L1– is optionally substituted C1-C25 alkylene, optionally substituted C2-C25 alkenylene, optionally substituted C2-C25 alkynylene, optionally substituted C1-C25 heteroalkylene, optionally substituted C2-C25heteroalkenylene, optionally substituted C2-C25237heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or any combination thereof; and –Y1is of Formula (Y-A) or (Y-B):(Y-A) (Y-B) wherein: each instance of Ra1is independently hydrogen, –ORC, –N(RC)2, –CN, –NO2, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8heteroalkynyl, optionally substituted C3-C10carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl; each instance of Ra2is independently –RaL–, hydrogen, –ORC, –N(RC)2, –CN, –NO2, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C1-C8heteroalkyl, optionally substituted C2-C8heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C3-C10 membered carbocyclyl, or optionally substituted 3- to 10-membered heterocyclyl; Ra3is hydrogen,–C(=O)RC, –C(=O)ORC, –C(=O)N(RC)2, –PO(ORC)2, or –C(RC)2– OPO(ORC)2;optionally substituted C3-C10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; Ra5is hydrogen or halogen; Ra6is hydrogen, halogen, –ORC, –N(RC)2, –CN, –NO2, optionally substituted C1-C8alkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C3-C10 carbocyclyl, optionally238substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of Ra7and Ra8is independently halogen, 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, –CN, –ORC, –SCN, –SRC, –SSRC, –N3, –NO, –NRCC(=NRC)N(RC)2, –NRCS(=O)RC, –NRCS(=O)ORC, –NRCS(=O)SRC, –NRCS(=O)N(RC)2, –NRCS(=O)2RC, –NRCS(=O)2ORC, –NRCS(=O)2SRC, or –NRCS(=O)2N(RC)2; Ra9is hydrogen or a nitrogen protecting group; Ra10is –RaL– or hydrogen; one instance of Ra2, Ra4, or Ra10is –RaL–; –RaL– is a bond, –O–, –N(RC)–, –N(RC)C(=O)–, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8heteroalkylene, optionally substituted C2-C8heteroalkenylene, optionally substituted C2-C8 heteroalkynylene, optionally substituted C3-C10 carbocyclylene, optionally substituted 3- to 10-membered heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; q is 0, 1, 2, 3, 4, or 5; r is 0, 1, 2, or 3; each instance of Rb1is independently halogen, –ORD, –CN, –NO2, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C8 carbocyclyl, or optionally substituted 3- to 8-membered heterocyclyl;239Rb2is hydrogen or a nitrogen protecting group; Vb is –N–, –CH–, or –C(Rb1)–; Wb is a bond, –Wb1–, or –Wb1–Wb2–; wherein Wb1and Wb2are each independently –C(=O)–, –O–, –C(RE)2–, or –NRD–, provided that –Wb1–Wb2– is not –O–O–;designates the point of attachment to Wb; each instance of Rb3is independently halogen, optionally substituted C1-C3alkyl, or –ORD; t is 0, 1, 2, 3, 4, or 5; Zbis –(Rb4)u–, wherein Rb4, at each occurrence, is independently Rb5or Rb6; wherein Rb5, at each occurrence, is independently a bond, –C(=O)–, –C(RE)2–, –NRD–, –O–, optionally substituted C1-C10 alkylene, optionally substituted C1-C10 alkenylene, or optionally substituted C1-C10alkynylene; Rb6, at each occurrence, is independently a bond, optionally substituted C3-C10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; u is 0, l, 2, 3, 4, 5, or 6; provided that –Rb4–Rb4– is not –O–O–; s is 0, 1, 2, 3, or 4; each instance of RCand RDis 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 substituted240aryl, 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 RCor RDattached to the same intervening atom are joined together with the intervening atom to form an optionally substituted, monocyclic, heterocyclic or heteroaryl ring; and each instance of REis independently hydrogen, halogen, –ORD, =O, –CN, –NO2, – N(RD)2, 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, or optionally substituted heteroaryl.

3. The method of claim 1 or 2, wherein the compound is of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

4. The method of any one of claims 1-3, wherein 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.2415. The method of any one of claims 1-4, wherein 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.

6. The method of any one of claims 1-4, wherein 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.

7. The method of any one of claims 1-4, wherein 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.2428. The method of any one of claims 1-4, wherein 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.

9. The method of any one of claims 1-3, wherein 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.

10. The method of any one of claims 1-3, wherein the compound is of Formula (I-G):243or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

11. The method of any one of claims 1-3, wherein 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.

12. The method of any one of claims 1-3, wherein 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.24413. The method of any one of claims 1-3, wherein 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.

14. The method of any one of claims 1-3, wherein 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.

15. The method of claim 2, wherein A1is –C(R9)=.24516. The method of claim 2 or 15, wherein A2is –C(R9)=.

17. The method of any one of claims 2, 15, or 16, wherein A3is –C(R9)=.

18. The method of any one of claims 2, 3, or 9-17, wherein R9is hydrogen.

19. The method of any one of claims 2 or 15-18, wherein C1is –C(R8)=.

20. The method of any one of claims 2 or 15-19, wherein C2is –C(R8)=.

21. The method of any one of claims 2 or 15-20, wherein C3is –C(R8)=.

22. The method of any one of claims 2 or 15-21, wherein C4is –C(R8)=.

23. The method of any one of claims 2, 3, or 9-22, wherein R8is hydrogen.

24. The method of any one of claims 2 or 15-23, wherein D1is –C(R7)=.

25. The method of any one of claims 2 or 15-24, wherein D2is –C(R7)=.

26. The method of any one of claims 2 or 15-25, wherein D3is –C(R7)=.

27. The method of any one of claims 2 or 15-26, wherein D4is –C(R7)=.

28. The method of any one of claims 2, 3, or 9-27, wherein R7is hydrogen.

29. The method of any one of claims 2-28, wherein R2is hydrogen.

30. The method of any one of claims 2-4 or 15-29, wherein R1is –L1–Y1.

31. The method of any one of claims 2-4 or 15-30, wherein R3is –L1–Y1.

32. The method of any one of claims 2-4 or 15-31, wherein R4is –L1–Y1.

33. The method of any one of claims 2-4 or 15-32, wherein R5is –L1–Y1.

34. The method of any one of claims 2-4, 6-10, or 13-33, wherein R1is –ORA.

35. The method of any one of claims 2-5, 7, 8, or 11-34, wherein R3is –ORA.24636. The method of any one of claims 2-35, wherein RAis optionally substituted C1-C4 alkyl.

37. The method of any one of claims 2-36, wherein RAis methyl.

38. The method of any one of claims 2-6, 8-12, or 15-37, wherein R4is hydrogen.

39. The method of any one of claims 2-7 or 9-38 wherein R5is hydrogen.

40. The method of any one of claims 1-39, wherein –Y1is of Formula (Y-A).

41. The method of any one of claims 1-40, wherein –Y1is of Formula (Y-A-1):

42. The method of any one of claims 1-40, wherein –Y1is of Formula (Y-A-2):(Y-A-2).

43. The method of any one of claims 1-40, wherein –Y1is of Formula (Y-A-3):(Y-A-3).24744. The method of any one of claims 1-40, wherein –Y1is of Formula (Y-A-4):

45. The method of any one of claims 2-43, wherein q is 0.

46. The method of any one of claims 2-43, wherein r is 0.

47. The method of any one of claims 2-8 or 15-46, wherein each instance of Ra1is independently hydrogen or unsubstituted C1-C4 alkyl.

48. The method of any one of claims 2-8 or 15-47, wherein each instance of Ra2is independently hydrogen or unsubstituted C1-C4alkyl.

49. The method of any one of claims 2-8 or 15-47, wherein one instance of Ra2is –RaL–.

50. The method of any one of claims 2-8 or 15-49, wherein Ra3is hydrogen.

51. The method of any one of claims 2-8, 15-40, 42, 43, or 45-50, wherein Ra4is – N(RC)C(=O)RC.

52. The method of any one of claims 2-8, 15-40, 42, 43, or 45-50, wherein Ra4is –RaL–.

53. The method of any one of claims 2-8 or 15-52, wherein –RaL– is –NHC(=O)–.

54. The method of any one of claims 2-8 or 15-52, wherein –RaL– is a bond.

55. The method of any one of claims 2-8, 15-43, or 45-54, wherein Ra5is hydrogen.

56. The method of any one of claims 2-8, 15-43, or 45-54, wherein Ra5is –F.24857. The method of any one of claims 2-8 or 15-56, wherein Ra6is optionally substituted heteroaryl.

58. The method of any one of claims 2-8 or 15-57, wherein Ra6is optionally substituted thiazolyl. . The method of any one of claims 2-8 or 15-58, wherein Ra9is hydrogen.

60. The method of any one of claims 2-8 or 15-40, wherein Ra10is –RaL–.

61. The method of any one of claims 2-40, wherein –Y1is.

62. The method of any one of claims 2-39, wherein –Y1is of Formula (Y-B).

63. The method of any one of claims 2-39 or 62, wherein –Y1is of Formula (Y-B-1):249(Y-B-1).

64. The method of any one of claims 2-39 or 62, wherein –Y1is of Formula (Y-B-2):

65. The method of any one of claims 2-39 or 62, wherein –Y1is of Formula (Y-B-3):

66. The method of any one of claims 2-39 or 62, wherein –Y1is of Formula (Y-B-4):250(Y-B-4).

67. The method of any one of claims 2-39 or 62-66, wherein s is 0.

68. The method of any one of claims 2-39 or 62-67, wherein Rb2is hydrogen.

69. The method of any one of claims 2-39, 62, or 65-68, wherein Vbis –CH–.

70. The method of any one of claims 2-39, 62, or 65-68, wherein Wb is a bond.

71. The method of any one of claims 2-39, 62, or 67-70, wherein Ringwherein w1 designates the point of attachment to Wb.25172. The method of any one of claims 2-39, 62, or 67-71, wherein Ring,wherein w1 designates the point of attachment to Wb.

73. The method of any one of claims 2-39, 62, or 65-72, wherein Zbis a bond.

74. The method of any one of claims 2-39, 62, or 66-72, wherein.

75. The method of any one of claims 1-74, wherein –L1– is optionally substituted C1-C25 heteroalkylene.

76. The method of any one of claims 1-75, wherein –L1– is optionally substituted C3-C12 heteroalkylene.

77. The method of any one of claims 1-76, wherein –L1– 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 Y1.25278. The method of any one of claims 1-76, wherein –L1– comprises, wherein m is 1, 2, 3, or 4, and y1 designates the point of attachment to Y1.

79. The method of any one of claims 1-76, wherein –L1– has the formula.

80. The method of any one of claims 1-76, wherein –L1– has the formula, ,25381. The method of any one of claims 1-80, wherein the compound is:254255,256257or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

82. The method of any one of claims 1-80, wherein the compound is: ,,258, , ,,259, , ,,260,,261, , ,,262,,263,,264, ,,265,266,, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

83. The method of any one of claims 1-82, wherein the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or sorafenib is administered via oral administration, intraperitoneal injection, or subcutaneous injection.

84. The method of any one of claims 1-83, wherein the cancer is liver cancer, breast cancer, pancreatic cancer, or mesothelioma.

85. The method of any one of claims 1-84, wherein the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, inhibits the activity and / or production of YAP.26786. The method of any one of claims 1-85, wherein the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, degrades YAP.

87. The method of any one of claims 1-86, wherein the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, suppresses YAP / TEAD-led transcription.

88. The method of any one of claims 1-87, wherein sorafenib is co-administered on the same schedule as the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

89. The method of any one of claims 1-88, wherein the co-administration increases sensitivity to sorafenib.

90. The method of any one of claims 1-89, wherein the co-administration increases sensitivity to the compound, or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

91. The method of any one of claims 1-90, wherein sorafenib is administered in the amount of about 1 mg / kg to about 200 mg / kg.

92. The method of any one of claims 1-91, wherein sorafenib is administered in the amount of about 50 mg / kg to about 150 mg / kg.

93. The method of any one of claims 1-92, wherein sorafenib is administered in the amount of about 100 mg / kg.

94. The method of any one of claims 1-93, wherein the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 10 mg / kg to about 100 mg / kg.26895. The method of any one of claims 1-94, wherein the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 20 mg / kg to about 55 mg / kg.

96. The method of any one of claims 1-95, wherein the compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is administered in the amount of about 35 mg / kg.

97. The method of any one of claims 1-96, wherein the subject is a human.

98. The method of claim 97, wherein the subject is a human aged 18 or older.

99. A kit comprising: a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co- crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof; wherein the compound inhibits YAP, degrades YAP, or suppresses YAP / TEAD-led transcription; sorafenib, or a pharmaceutical composition thereof; and instructions for using sorafenib, or a pharmaceutical composition thereof, and / or the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, prodrug, or pharmaceutical composition thereof.269

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