Bifunctional p53-binding compounds and uses thereof

Abstract

Provided herein are bifunctional compounds that bind p53 and / or promote targeted phosphorylation of p53. The induced phosphorylation of p53 can alter the substrate's structure and function, thus providing compounds which enable phosphorylation of p53, and providing new modes for inducing strategic phosphorylation of p53. Also provided are compounds that are intermediates of the bifunctional compounds. Also provided are pharmaceutical compositions comprising the disclosed compounds, methods of promoting the phosphorylation of p53, and methods of treating a disease or conditions associated with p53 (e.g., cancer) by administering a compound or composition described herein.

Description

BIFUNCTIONAL P53-BINDING COMPOUNDS AND USES THEREOFRELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application,U.S.S.N. 63 / 618,649, filed January 8, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0001] Protein kinases regulate critical substrates (e.g., protein) and cellular functions like substrate half-life, substrate engagement with various biomolecules, metabolism, differentiation, proliferation, and apoptosis. Kinase dysfunction is also associated with a variety of human diseases, including, but not limited to, cancer, inflammatory conditions, autoimmune disorders, and cardiovascular diseases. Agents that block protein phosphorylation via kinase inhibition have had a transformative impact in basic science and medicine. However, agents that can both engage a kinase and one or more other target substrates of interest (e.g., proteins) to be phosphorylated may also be useful as a means of evoking desired attributes or responses from those target substrates.

[0002] Recently, a new strategy for promoting the phosphorylation of target proteins of interest, PHICS (phosphorylation-inducing chimeric small molecules), was introduced. PHICS are bifunctional molecules containing two small molecule binding moieties, joined together by a linker. One of the small molecule moieties is designed to bind to a target protein while the other small molecule moiety binds to a protein kinase. The PHICS selectively binds to the target substrate of interest and simultaneously binds to and recruits a specific kinase to phosphorylate the target substrate.The PHICS then dissociate from the target substrate and initiate another catalytic cycle.SUMMARY

[0003] Phosphorylation of any given target substrate (e.g., a protein) can alter its structure, activity, localization, and / or function. Such modifications may be accomplished by compounds that bring a kinase in proximity to a target substrate. Provided herein are PHICS compounds which enable a kinase to phosphorylate p53. The compounds provide new modes for inducing alterations of p53 via strategic phosphorylation leading to therapeutic uses of the compounds such as the treatment of cancers associated with p53. Also provided are bifunctional compounds that comprise a first functional moiety that engages / binds p53 and a second functional moiety that comprises a detectable moiety (e.g., a chromophore, dye, fluorophore, luminophore or luminescent material, or radioactive material) joined together by a linker. Also provided are compounds that are useful as synthetic intermediates in methods of preparing the aforementioned bifunctional compounds. Accordingly, the present disclosure provides new compounds, compositions, kits, uses, and methods for modulating (e.g., phosphorylating) p53 via proximity-induced engagement between a kinase and p53.

[0004] In one aspect, provided herein are compounds of Formula (I):KB-A-L-B(I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:KB is a kinase binding moiety or a detectable moiety;A is a bond or an orienting moiety;L is a bond or linker; andB is a p53 binding moiety.

[0005] In another aspect, provided herein are compounds of Formula (II):T-A-L-B(II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle;A is a bond or an orienting moiety;L is a linker; andB is a p53 binding moiety.

[0006] In another aspect, provided are pharmaceutical compositions comprising a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0007] In another aspect, provided are methods of phosphorylating p53, the method comprising administering a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a compound of the disclosure, to a mixture that comprises a kinase and p53.

[0008] In another aspect, provided are methods of promoting the phosphorylation of p53, the method comprising contacting p53 with a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a compound of the disclosure.

[0009] In another aspect, provided are methods of modulating a protein kinase, the method comprising contacting the protein kinase with a compound of the disclosure, or a pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a compound of the disclosure.

[0010] In another aspect, provided are methods of treating a disease or condition in a subject in need thereof, the method comprising administering a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the disclosure, to the subject. In certain embodiments, the disease or condition is cancer.

[0011] In another aspect, provided are kits comprising a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a compound of the disclosure. In certain embodiments, the kit further comprises instructions for administration and / or use.

[0012] 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.DEFINITIONSChemical definitions

[0013] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modem Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0014] 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 andOptical 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.

[0015] Where compound structures are depicted, stereocenters labeled with “abs” indicate known absolute stereochemistry, stereocenters labeled with “&i” indicate a mixture of the two trans or cis stereoisomers, and stereocenters labeled with “ori” indicate a single stereoisomer with unknown absolute stereochemistry.

[0016] In a formula, - / vvvis a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, - is absent or a single bond, and = or =-^= is a single or double bond.

[0017] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of12C with13C or14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0018] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-6 alkyl” is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, CM, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C34, C4-6, C4-5, and C5-6 alkyl.

[0019] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0020] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10 alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci- 8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“ C1 alkyl”). In certain 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, zso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n- hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted Ci-10 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl(n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i- Bu)). In certain embodiments, the alkyl group is a substituted C1-10 alkyl (such as substituted C1-6 alkyl, e.g., -CF3, Bn).

[0021] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In certain embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“Ci-8 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CC13, -CFCI2, -CF2C1, and the like.

[0022] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-20alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-8 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-16 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-14 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-12 alkyl”). In certain 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 certain 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 certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3 alkyl”). In certain 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 certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In certain embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chainand at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. 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 heteroC1-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCrio alkyl.

[0023] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3 oror(Z)-double bond.

[0024] 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 (z.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2 10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC29 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC28 alkenyl”). In certain embodiments, a heteroalkenylgroup has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC27 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC25 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC23 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2 10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted he teroC2 10 alkenyl.

[0025] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.

[0026] 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 (z.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2 10alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2- 9alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“hetero2-8 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC27 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2 10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2 10 alkynyl.

[0027] 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 certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3 -7 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, 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 C3-10 carbocyclyl groups include, without limitation, 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. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocycliccarbocyclyl”) 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 C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0028] In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3 -10 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.

[0029] 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 thepoint 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.

[0030] In certain embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In certain 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 certain 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 certain embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0031] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl- 2, 5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8-naphthyridinyl, octahydropyrrolo[3,2- / ?]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1 H-benzo[e][ 1 ,4]diazepinyl, 1,4,5 ,7-tetrahydropyrano[3,4-Z?]pyrrolyl, 5,6-dihydro-4H- furo[3,2- / ?]pyrrolyl, 6,7-dihydro-5H-furo[ 3,2-b ] pyranyl, 5,7-dihydro-4H-thieno[2,3-c] pyranyl, 2,3- dihydro-1 H-pyrrolo[2,3- / ?]pyridinyl, 2,3-dihydrofuro[2,3-Z?]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo- [2,3- / ?]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2- / ?]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0032] 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 (“Ctu aryl”). In certain embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In certain embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In certain embodiments, an aryl group has 14 ring carbon atoms (“Cu aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted Ce-i4 aryl. In certain embodiments, the aryl group is a substituted Ce u aryl.

[0033] “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.

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

[0035] In certain 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 certain 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 certain 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 certain embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain 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.

[0036] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0037] “Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0038] The term “unsaturated bond” refers to a double or triple bond.

[0039] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0040] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0041] 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.

[0042] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” acyl, “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents described herein.

[0043] Exemplary carbon atom substituents include, but are not limited to, 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)3, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)(Raa)2, -P(=O)(ORCC)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3+X-, -P(ORCC)3+X-, -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3+X-, -OP(ORCC)2, -OP(ORCC)3+X-, -OP(RCC)4, -OP(ORCC)4, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), Ci-10 alkyl, Ci-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCrio alkyl, heteroCrio alkenyl, heteroCrio alkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, Ce-i4aryl, 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 =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; each instance of Raais, independently, selected from Ci-10 alkyl, Ci-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCrio alkyl, heteroCrio alkenyl, heteroCrio alkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, Ce i4aryl, 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 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, -OR311, -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, Ci-10 alkyl, Ci-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCr 10 alkyl, heteroCrio alkenyl, heteroCri oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce i4aryl, 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; wherein X“ is a counterion; each instance of Rccis, independently, selected from hydrogen, Ci-10 alkyl, Ci-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCrio alkyl, heteroCrio alkenyl, heteroCrio alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce i4aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, whereineach 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, C1-6 alkyl, C1-6 perhaloalkyl, C2<> alkenyl, C2<> alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =0 or =S; wherein X“ is a counterion; each instance of Reeis, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6> alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, Ce-io 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, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6> alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3- 10 membered heterocyclyl, Ce-io 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; and each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(C1-6 alkyl)2, -N(C1-6 alkyl)2, -N(C1-6 alkyl)3+X-, -NH(C1-6 alkyl)2+X-, -NH2(C1-6 alkyl)+X“, -NH3+X“, -N(0C1-6 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(C1-6 alkyl), -OC(=O)(C1-6 alkyl), -OCO2(C1-6 alkyl), -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(C1-6 alkyl), -NHC(=0)NH2, -C(=NH)O(C1-6 alkyl), -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(C1-6 alkyl), -0C(=NH)NH2, -NHC(=NH)N(C1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6 alkyl), -SO2N(C1-6 alkyl)2, -SO2NH(C1-6 alkyl), -SO2NH2, -SO2(C1-6 alkyl), -SO2O(C1-6 alkyl), -OSO2(C1-6 alkyl), -SO(C1-6 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)SC1-6 alkyl,-SC(=S)SC1-6 alkyl, -P(=O)(OC1-6 alkyl)2, -P(=O)(C1-6 alkyl)2, -OP(=O)(C1-6 alkyl)2, -OP(=O)(OCi- 6 alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2<, alkenyl, C2<, alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; wherein X“ is a counterion.

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

[0045] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -ORaa, -ON(Rbb)2, -OC(=O)SRaa, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OSi(Raa)3, -OP(RCC)2, -OP(RCC)3+X-, -OP(ORCC)2, -OP(ORCC)3+X-, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, and -OP(=O)(N(Rbb)2)2, wherein X“, Raa, Rbb, and Rccare as defined herein.

[0046] 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.

[0047] 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, -NHCChR^, -NHC(=O)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, -NHSO2Raa, -NHP(=O)(ORCC)2, and -NHP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, and wherein Rbbof the group -NH(Rbb) is not hydrogen.

[0048] 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.

[0049] 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.

[0050] 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, -C(=S)O(RX1), -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 orunsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0051] The term “carbonyl” refers a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen (z.e., -C(=O)-).

[0052] The term “silyl” refers to the group -Si(Raa)3, wherein Raais as defined herein.

[0053] The term “oxo” refers to the group =0, and the term “thiooxo” refers to the group =S.

[0054] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(ORCC)2, -P(=O)(Raa)2, -P(=O)(N(RCC)2)2, Ci-10 alkyl, Ci-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCrioalkyl, heteroC2 uoalkenyl, heteroC2 walkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce -14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rcc, and Rddare as defined herein.

[0055] 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, but are not limited to, -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, CI-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, heteroCrio alkyl, heteroC210 alkenyl, heteroC210 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce -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.

[0056] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N- benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o- nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3- methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0057] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1- dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(20- and 4c-pyridyl)cthyl 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-(l,3-dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cy anoethyl 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, l,l-dimethyl-3-(N,N- dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1 -methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1 -methyl- 1- (3,5-dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1- phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0058] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (40,80-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0059] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, Ne-p-tolucncsulfonylaminoacyl derivative, Ne -phenylaminothioacyl derivative, N- benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N- phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4- tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5- triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,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-(l-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 (Fem), N-2-picolylamino N’-oxide, N- 1,1 -dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N- (N’ ,N’ -dimethylaminomethylene) amine, N,N’ -isopropylidenediamine, N-p-nitrobenzylideneamine,N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l- cyclohexenyl) amine, N-borane derivative, N-diphenylborinic acid derivative, N- [phenyl(pentaacylchromium- or tungsten)acyl] amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphor amidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3 -nitropyridinesulf enamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9- flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p- methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2- trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0060] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X-, -P(ORCC)2, -P(ORCC)3+X“, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb)2)2, wherein X", Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0061] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4- methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2- chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, l-[(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- ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1- methyl- 1 -benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p- methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4- (4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-l- yl)bis(4',4"-dimethoxyphenyl)methyl, 1 , 1 -bis(4-methoxyphenyl)- 1 '-pyrenylmethyl, 9-anthryl, 9-(9- phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,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, methoxy acetate, triphenylmethoxy acetate, 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-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4- azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(l,l,3,3-tetramethylbutyl)phenoxyacetate, 2,4- bis(l,l-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2- methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2- trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p- methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p- methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0062] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X“, -P(ORCC)2, -P(ORCC)3+X“, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0063] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F", CP, Br , I"), NO3, CIO4 , OH , H2PO4 , HCOf, 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~, PEp, PFe", AsFe", SbFe", B[3,5-(CF3)2C6H3]4]-, B(C6Fs)4“, BPtu , A1(OC(CF3)3)4-, and carborane anions (e.g., CB| | H|2or (HCBi iMesBre) ). 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.

[0064] The term “leaving group” is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March’s Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, A,O-dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3(nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. The leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Further exemplaryleaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SRaa, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OP(RCC)2, -OP(RCC)3, -OP(=O)2Raa, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -OP(=O)2N(Rbb)2, and -OP(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein).

[0065] As used herein, use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0066] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0067] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, Figures, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.Other definitions

[0068] The following definitions are more general terms used throughout the present application.

[0069] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.

[0070] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Saltsderived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI~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.

[0071] 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.

[0072] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula Rxx H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (Rx0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (Rx2 H2O) and hexahydrates (Rx6 H2O)).

[0073] 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.

[0074] 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”.

[0075] 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 itsasymmetric 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”.

[0076] 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.

[0077] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Ci-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, C7-12 substituted aryl, and C7-12 arylalkyl esters of the compounds described herein may be preferred.

[0078] The terms “composition” and “formulation” are used interchangeably.

[0079] 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 subject may also be a plant. In certain embodiments, the plant is a land plant. In certain embodiments, the plant is a non-vascular land plant. In certain embodiments, the plant is avascular land plant. In certain embodiments, the plant is a seed plant. In certain embodiments, the plant is a cultivated plant. In certain embodiments, the plant is a dicot. In certain embodiments, the plant is a monocot. In certain embodiments, the plant is a flowering plant. In certain embodiments, the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet. In certain embodiments, the plant is a legume, e.g., a bean plant, e.g., soybean plant. In certain embodiments, the plant is a tree or shrub.

[0080] 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.

[0081] The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is the object to which a compound and / or composition of the disclosure is delivered. A tissue may be an abnormal or unhealthy tissue. A tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy.

[0082] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into a biological system.

[0083] An “effective amount” of a compound described herein refers to an amount sufficient to elicit a desired outcome (e.g., induce phosphorylation of a target substrate). An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint (e.g., extent of phosphorylation) and the nature of the biological sample.

[0084] The term “small molecule” refers to molecules, whether naturally occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than about 1 ,000 g / mol, not more than about 900 g / mol, not more than about 800 g / mol, not more than about 700 g / mol, not more than about 600 g / mol, not more than about 500 g / mol, not more than about 400 g / mol, not more than about 300 g / mol, not more than about 200 g / mol, or not more than about 100 g / mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at leastabout 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol and not more than about 500 g / mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present invention.

[0085] The term “targeting moiety” refers to any chemical entity that serves to bind or otherwise direct the compound to a particular location or association.

[0086] The term “detectable moiety” refers to a chemical entity that can be used to produce a detectable signal that indicates the presence or concentration of the compound having the detectable moiety in a sample.

[0087] The term “bioactive moiety” refers to an agent or moiety that can influence (z.e., effect a change in) a biological system, such as in an organism, tissue, or cell. In certain embodiments, the bioactive moiety is a small molecule. In certain embodiments, the bioactive moiety is a peptide or protein. In certain embodiments, the bioactive moiety is an FDA-approved drug.

[0088] The term “nucleophilic group” refers to a chemical entity having a nucleophile, a moiety that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Nucleophiles may take part in nucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge, and nucleophilic addition.

[0089] The term “electrophilic group” refers to a chemical entity having an electrophile, a moiety that forms bonds with nucleophiles by accepting an electron pair. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons. Electrophiles mainly interact with nucleophiles through addition and substitution reactions.BRIEF DESCRIPTION OF THE DRAWINGS

[0090] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the invention and together with the description, provide non-limiting examples of the invention.

[0091] FIGs 1A-1H show antiproliferative activity of compound 88 measured across a panel of p53 Y220C mutant, p53 wildtype and p53 null cell lines using a 5d Cell Titer Gio assay. FIG. 1A Cell line: NUGC3; P53 status: P53 Y220C homozygous; Rezatapopt IC50 (pM): 0.46; compound 88 IC50 (pM): 1.24. FIG. IB Cell line: KON; P53 status: P53 Y220C homozygous; Rezatapopt IC50 (pM): 0.97; compound 88 IC50 (pM): 0.26. FIG. 1C Cell line: T3M4; P53 status: P53 Y220C homozygous; Rezatapopt IC50 (pM): 2.99; compound 88 IC50 (pM): 0.69. FIG. ID Cell line: HUH7; P53 status: P53 Y220C homozygous; Rezatapopt IC50 (pM): 0.27; compound 88 IC50 (pM): 3.07. FIG. IE Cell line: BXPC3; P53 status: P53 Y220C homozygous; Rezatapopt IC50 (pM): 0.33; compound 88 IC50 (pM): 0.43. FIG. IF Cell line: HCC1419; P53 status: P53 Y220C heterozygous; Rezatapopt IC50 (pM): 7.93; compound 88 IC50 (pM): 2.95. FIG. 1G Cell line: H1299; P53 status: P53 null; Rezatapopt IC50 (mM): >10; compound 88 IC50 (pM): 4.19. FIG. 1H Cell line: HCT116; P53 status: P53 wildtype; Rezatapopt IC50 (pM): 3.94; compound 88 IC50 (pM): 2.66.

[0092] FIG. 2 shows compound 88 inhibits growth of T3M4 xenografts. Graphs represent tumor volumes of T3M4 xenografts in mm3over the course of 22d treatment.

[0093] FIG. 3 shows percent body weight change of T3M4-tumor bearing Balb / c-nude mice over the course of 22d treatment.

[0094] FIG. 4 shows compound 88 inhibits growth of NUGC3 xenografts. Graphs represent tumor volumes of NUGC3 xenografts in mm3 over the course of 21d treatment.

[0095] FIG. 5 shows percent body weight change of NUGC3-tumor bearing Balb / c-nude mice over the course of 21d treatment.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0096] Provided herein are bifunctional compounds that bind p53 and recruit a kinase to promote the phosphorylation of p53. Also provided are compounds that act as chemical probes having a detectable moiety (e.g., luminescent materials, such as dyes) that bind p53. Also provided are compounds useful in the production and manufacture of the bifunctional compounds and probes described herein.

[0097] In one aspect, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. In certain embodiments, provided herein are compounds of Formula (I):KB-A-L-B(I), or a pharmaceutically acceptable salt thereof, wherein:KB is a kinase binding moiety or a detectable moiety;A is a bond or an orienting moiety;L is a bond or linker; andB is a p53 binding moiety.

[0098] In certain embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, tautomers thereof, and stereoisomers, and pharmaceutical compositions thereof. In certain embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, and tautomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

[0099] In one aspect, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. In certain embodiments, provided herein are compounds of Formula (II):T-A-L-B(II), or a pharmaceutically acceptable salt thereof, wherein:T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle;A is a bond or an orienting moiety;L is a linker; andB is a p53 binding moiety.

[0100] In certain embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In certainembodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, and tautomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

[0101] In certain embodiments, the disclosure may provide additional compounds (z.e., not of Formula (I), (II)), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure may provide additional compounds (z.e., not of Formula (I), (II)), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure may provide additional compounds (z.e., not of Formula (I), (II)), and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure may provide additional compounds (z.e., not of Formula (I), (II)), and pharmaceutically acceptable salts and tautomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure may provide additional compounds (z.e., not of Formula (I), (II)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

[0102] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I), (II), or otherwise as provided herein) bind p53 with a Kd of less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.I. B - p53 binding moiety

[0103] p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53), is a transcription factor that acts as a tumor suppressor protein, regulating cell growth in response to cellular stresses including, for example, UV radiation, hypoxia, oncogene activation, and DNA damage. p53 has various mechanisms for inhibiting the progression of cancer including, for example, initiation of apoptosis, maintenance of genomic stability, cell cycle arrest, induction of senescence, and inhibition of angiogenesis. Due to the critical role of p53 in tumor suppression, p53 is inactivated in almost all cancers either by direct mutation or through perturbation of associated signaling pathways involved in tumor suppression. Homozygous loss of the p53 gene occurs in almost all types of cancer, including carcinomas of the breast, colon, and lung. The presence of certain p53 mutations in several types of human cancers can correlate with less favorable patient prognosis.

[0104] In the absence of stress signals, p53 levels are maintained at low levels via the interaction of p53 with Mdm2, an E3 ubiquitin ligase. In an unstressed cell, Mdm2 can target p53 for degradation by the proteasome. Under stress conditions, the interaction between Mdm2 and p53 is disrupted, and p53 accumulates. The critical event leading to the activation of p53 is phosphorylation of the N- terminal domain of p53 by protein kinases, thereby transducing upstream stress signals. The phosphorylation of p53 leads to a conformational change, which can promote DNA binding by p53 and allow transcription of downstream effectors. The activation of p53 can induce, for example, the intrinsic apoptotic pathway, the extrinsic apoptotic pathway, cell cycle arrest, senescence, and DNA repair. p53 can activate proteins involved in the above pathways including, for example, Fas / Apol, KILLER / DR5, Bax, Puma, Noxa, Bid, caspase-3, caspase-6, caspase-7, caspase-8, caspase-9, and p21 (WAF1). Additionally, p53 can repress the transcription of a variety of genes including, for example, c-MYC, Cyclin B, VEGF, RAD51, and hTERT.

[0105] Each chain of the p53 tetramer is composed of several functional domains including the transactivation domain (amino acids 1-100), the DNA-binding domain (amino acids 101-306), and the tetramerization domain (amino acids 307-355), which are highly mobile and largely unstructured. Most p53 cancer mutations are in the DNA-binding core domain of the protein, which contains a central P-sandwich of anti-parallel P-sheets that serves as a basic scaffold for the DNA-binding surface. The DNA-binding surface is composed of two P-turn loops, L2 and L3, which are stabilized by a zinc ion, for example, at Argl75 and Arg248, and a loop-sheet-helix motif. Altogether, these structural elements form an extended DNA-binding surface that is rich in positively-charged amino acids, and makes specific contact with various p53 response elements.

[0106] In certain embodiments, the p53 protein comprises an amino acid sequence: MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEA PRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTY SPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDG LAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNSSCMGGMNR RPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALPNNT SSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPGGSRAHSSHLKSKKG QSTSRHKKLMFKTEGPDSD (SEQ ID NO: 1).

[0107] As used herein, “p53”, unless otherwise indicated, is intended to refer to any p53 protein, including p53 according to SEQ ID NO: 1 as well as p53 mutants.

[0108] Mutations in p53 located in the DNA-binding domain of the protein or periphery of the DNA-binding surface result in aberrant protein folding required for DNA recognition and binding. Mutations in p53 can occur, for example, at amino acids Vall43, Hisl68, Argl75, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, and Arg282. p53 mutations that can abrogate the activity of p53 include, for example, R175H, Y220C, G245S, R248Q, R248W, R249S, R273H, R273C, R282W, andR282H. These p53 mutations can either distort the structure of the DNA-binding site or thermodynamically destabilize the folded protein at body temperature.

[0109] Due to the prevalence of p53 mutations in virtually every type of cancer, the reactivation of wild type p53 function in a cancerous cell can be an effective therapy. Phosphorylation of mutated p53 is one exemplary way to restore wild type function. Native phosphorylation of p53 can occur at any number of key residues, including S15, T18, S20, S46, and S392, and aid in stabilization and activation of p53, suppression of nuclear export, and enhancement of DNA binding and tetramer formation. Without being bound to any particular theory, it is hypothesized that neo-phosphorylation on any serine, threonine, or tyrosine residue will also lend these improvements to mutant p53 proteins, restoring wild type function and tumor suppression.

[0110] In certain embodiments, the bifunctional compounds of the present disclosure provide a method of altering the phosphorylation state of p53. In certain embodiments, the bifunctional compounds of the present disclosure provide a method of altering the phosphorylation state of a p53 mutant.

[0111] In certain embodiments, the p53 mutant comprises a substitution at residue 135 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises C135Y.

[0112] In certain embodiments, the p53 mutant comprises a substitution at residue 141 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises C141Y.

[0113] In certain embodiments, the p53 mutant comprises a substitution at residue 143 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises V143A.

[0114] In certain embodiments, the p53 mutant comprises a substitution at residue 151 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises P151S.

[0115] In certain embodiments, the p53 mutant comprises a substitution at residue 152 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises P152L.

[0116] In certain embodiments, the p53 mutant comprises a substitution at residue 157 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises V157F.

[0117] In certain embodiments, the p53 mutant comprises a substitution at residue 158 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises R158H. In certain embodiments, the substitution comprises R158L.

[0118] In certain embodiments, the p53 mutant comprises a substitution at residue 161 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises A161T.

[0119] In certain embodiments, the p53 mutant comprises a substitution at residue 163 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises Y163C.

[0120] In certain embodiments, the p53 mutant comprises a substitution at residue 168 as compared to the wild type (SEQ ID NO: 1).

[0121] In certain embodiments, the p53 mutant comprises a substitution at residue 173 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises V173L. In certain embodiments, the substitution comprises V173M.

[0122] In certain embodiments, the p53 mutant comprises a substitution at residue 175 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises R175H.

[0123] In certain embodiments, the p53 mutant comprises a substitution at residue 176 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises C176F. In certain embodiments, the substitution comprises C176Y.

[0124] In certain embodiments, the p53 mutant comprises a substitution at residue 178 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises V178M.

[0125] In certain embodiments, the p53 mutant comprises a substitution at residue 179 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises H179R. In certain embodiments, the substitution comprises H179Y.

[0126] In certain embodiments, the p53 mutant comprises a substitution at residue 180 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises E180R.

[0127] In certain embodiments, the p53 mutant comprises a substitution at residue 193 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises H193R.

[0128] In certain embodiments, the p53 mutant comprises a substitution at residue 195 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises I195S. In certain embodiments, the substitution comprises I195T.

[0129] In certain embodiments, the p53 mutant comprises a substitution at residue 205 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises Y205C.

[0130] In certain embodiments, the p53 mutant comprises a substitution at residue 213 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises R213Q. In certain embodiments, the substitution comprises R213K.

[0131] In certain embodiments, the p53 mutant comprises a substitution at residue 214 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises H214R.

[0132] In certain embodiments, the p53 mutant comprises a substitution at residue 216 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises V216M.

[0133] In certain embodiments, the p53 mutant comprises a substitution at residue 220 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises Y220C, Y220N, or Y220S. In certain embodiments, the substitution comprises Y220C. In certain embodiments, the substitution comprises Y220N. In certain embodiments, the substitution comprises Y220S.

[0134] In certain embodiments, the p53 mutant comprises a substitution at residue 234 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises Y234C.

[0135] In certain embodiments, the p53 mutant comprises a substitution at residue 236 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises Y236C.

[0136] In certain embodiments, the p53 mutant comprises a substitution at residue 237 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises M237I.

[0137] In certain embodiments, the p53 mutant comprises a substitution at residue 238 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises C238Y.

[0138] In certain embodiments, the p53 mutant comprises a substitution at residue 241 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises S241F.

[0139] In certain embodiments, the p53 mutant comprises a substitution at residue 242 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises C242F.

[0140] In certain embodiments, the p53 mutant comprises a substitution at residue 245 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises G245C. In certain embodiments, the substitution comprises G245D. In certain embodiments, the substitution comprises G245S. In certain embodiments, the substitution comprises G245V.

[0141] In certain embodiments, the p53 mutant comprises a substitution at residue 248 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises R248L. In certain embodiments, the substitution comprises R248Q. In certain embodiments, the substitution comprises R248W.

[0142] In certain embodiments, the p53 mutant comprises a substitution at residue 249 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises R249S.

[0143] In certain embodiments, the p53 mutant comprises a substitution at residue 266 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises G266E. In certain embodiments, the substitution comprises G266R.

[0144] In certain embodiments, the p53 mutant comprises a substitution at residue 270 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises F270L.

[0145] In certain embodiments, the p53 mutant comprises a substitution at residue 272 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises V272M.

[0146] In certain embodiments, the p53 mutant comprises a substitution at residue 273 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises R273C. In certain embodiments, the substitution comprises R273H. In certain embodiments, the substitution comprises R273L.

[0147] In certain embodiments, the p53 mutant comprises a substitution at residue 275 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises C275Y.

[0148] In certain embodiments, the p53 mutant comprises a substitution at residue 278 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises P278L. In certain embodiments, the substitution comprises P278S.

[0149] In certain embodiments, the p53 mutant comprises a substitution at residue 280 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises R280K. In certain embodiments, the substitution comprises R280T.

[0150] In certain embodiments, the p53 mutant comprises a substitution at residue 282 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises R282W. In certain embodiments, the substitution comprises R282H.

[0151] In certain embodiments, the p53 mutant comprises a substitution at residue 285 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises E285K.

[0152] In certain embodiments, the p53 mutant comprises a substitution at residue 286 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises E286K.

[0153] In certain embodiments, the p53 mutant comprises a substitution at residue 309 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises P309S.

[0154] In certain embodiments, the p53 mutant comprises a substitution at residue 337 as compared to the wild type (SEQ ID NO: 1). In certain embodiments, the substitution comprises R337H.

[0155] As described herein, B is a p53-binding moiety. In certain embodiments, B binds wild type p53. In certain embodiments, B binds a p53 mutant. In certain embodiments, B binds any of the p53 mutants described herein.

[0156] In certain embodiments, B comprises a compound or compound fragment that binds to p53. In certain embodiments, B comprises a compound or compound fragment that binds to a p53 mutant.

[0157] In certain embodiments, B is any compound described in U.S. Patent Application U.S.S.N. 17 / 317,423, U.S. Patent Application U.S.S.N. 17 / 348,488, U.S. Patent Application U.S.S.N. 17 / 351,880, U.S. Patent Application U.S.S.N. 17 / 351,970, International Patent Application No. PCT / US2023 / 065549, International Patent Application No. PCT / US2023 / 067005, U.S. Patent Application U.S.S.N. 17 / 028,720, U.S. Patent Application U.S.S.N. 17 / 679,568, U.S. Patent Application U.S.S.N. 16 / 819,934, U.S. Patent Application U.S.S.N. 16 / 163,829, and U.S. Patent Application U.S.S.N. 15 / 436,333, all of which are incorporated herein by reference.

[0158] In certain embodiments of B, the p-53 binding moiety is represented by a chemical structure in brackets with a bond drawn to the p-53 binding moiety indicating attachment to L. In such embodiments, L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B. In such embodiments, any group on B or substituent of a group on B may be replaced with a bond to L. In an example of an embodiment, R1in Formula (B-l), depicted below, may become a bivalent moiety where an atom of R1is replaced with a bond to L (e.g., Formula (B-lg-2) below). In another embodiment, R3in Formula (B-l), depicted below, may become a bivalent moiety where an atom of R3is replaced with a bond to L. In another embodiment, R4in Formula (B-l), depicted below, may become a bivalent moiety where an atom of R4is replaced with a bond to L (e.g., Formula (B-lg- 1) below).

[0159] In certain embodiments, B is of the formula:wherein: each = is independently a single bond or a double bond;X1is C, CR5, CR5R6, N, NR5, O, S, C=O, or C=S;X2is C, CR7, CR7R8, N, NR7, O, S, C=O, or C=S;X3is C, CR9, CR9R10, N, NR9, O, S, C=O, or C=S;X4is C, CR", CR"R12, N, NR", O, S, C=O, or C=S;X5is C or N;X6is C or N;X7is CR13, N, S, O, or NR13;X8is C, CR5, or N; wherein at least one of X1, X2, X3, and X4is a carbon atom connected to Q1;A1is a linking group;Q1is C=O, C=S, C=CR14R15, C=NR14, alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted, or a bond; m is 1, 2, 3, or 4;Y is N, O, or absent;R1is -C(O)R16, -C(O)OR16, -C(O)NR16R17, -OR16, -SR16, -NR16R17, -NR16C(O)R16, - OC(O)R16, -SiR16R17R18, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, or halo, or a combination thereof, each of which is independently substituted or unsubstituted, or hydrogen; each R3and R4is independently -C(O)R19, -C(O)OR19, -C(O)NR19R20, -SOR19, -SO2R19, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted, or R3is absent; each R2, R5, R6, R7, R8, R9, R10, R", R12, R13, R14, R15, R16, R17, and R18is independently - C(O)R21, -C(O)OR21, -C(O)NR21R22, -OR21, -SR21, -NR21R22, -NR21C(O)R22, -OC(O)R21, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen, or R2is absent;each R19and R20is independently -C(O)R23, -C(O)OR23, -C(O)NR23R24, -OR23, -SR23, - NR23R24, -NR23C(O)R24, -OC(O)R23, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; each R21and R22is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen; and each R23and R24is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0160] In certain embodiments, R1is -C(O)R16, -C(O)OR16, -C(O)NR16R17, -OR16, -SR16, - NR16R17, -NR16C(O)R16, -OC(O)R16, -SiR16R17R18, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, or halo, each of which is independently substituted or unsubstituted, or hydrogen.

[0161] In certain embodiments of Formula (B-l), L is attached directly to or on a substituent of X1, X2, X7, R3, R4, Y, or R1. In certain embodiments, L is attached directly to or on a substituent of X1. In certain embodiments, L is attached directly to or on a substituent of X2. In certain embodiments, L is attached directly to or on a substituent of X7. In certain embodiments, L is attached directly to or on a substituent of R3. In certain embodiments, L is attached directly to or on a substituent of R4. In certain embodiments, L is attached directly to or on a substituent of Y. In certain embodiments, L is attached directly to or on a substituent of R1.

[0162] In certain embodiments, B is of the formula:wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0163] In certain embodiments of Formula (B-l’), L is attached directly to or on a substituent of X1, X2, X7, R3, R4, Y, or R1. In certain embodiments, L is attached directly to or on a substituent of X1. In certain embodiments, L is attached directly to or on a substituent of X2. In certain embodiments, L is attached directly to or on a substituent of X7. In certain embodiments, L is attached directly to or on a substituent of R3. In certain embodiments, L is attached directly to or on a substituent of R4. In certain embodiments, L is attached directly to or on a substituent of Y. In certain embodiments, L is attached directly to or on a substituent of R1.

[0164] In certain embodiments, B is of the formula:wherein: each = is independently a single bond or a double bond;X1is C, CR5, CR5R6, N, NR5, O, S, C=O, or C=S;X2is C, CR7, CR7R8, N, NR7, O, S, C=O, or C=S;X3is C, CR9, CR9R10, N, NR9, O, S, C=O, or C=S;X4is C, CR", CR"R12, N, NR", O, S, C=O, or C=S;X7is CR13, N, or NR13; wherein at least one of X1, X2, X3, and X4is a carbon atom connected to Q1;A1is a linking group;Q1is C=O, C=S, C=CR14R15, C=NR14, alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted, or a bond; m is 1, 2, 3, or 4;Y is N, O, or absent;R1is -C(O)R16, -C(O)OR16, -C(O)NR16R17, -OR16, -SR16, -NR16R17, -NR16C(O)R16, - OC(O)R16, -SiR16R17R18, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, or halo, or a combination thereof, each of which is independently substituted or unsubstituted, or hydrogen; each R3and R4is independently -C(O)R19, -C(O)OR19, -C(O)NR19R20, -SOR19, -SO2R19, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted, or R3is absent; each R2, R5, R6, R7, R8, R9, R10, R", R12, R13, R14, R15, R16, R17, and R18is independently - C(O)R21, -C(O)OR21, -C(O)NR21R22, -OR21, -SR21, -NR21R22, -NR21C(O)R22, -OC(O)R21, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; each R19and R20is independently -C(O)R23, -C(O)OR23, -C(O)NR23R24, -OR23, -SR23, - NR23R24, -NR23C(O)R24, -OC(O)R23, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen;each R21and R22is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen; and each R23and R24is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0165] In certain embodiments, R1is -C(O)R16, -C(O)OR16, -C(O)NR16R17, -OR16, -SR16, - NR16R17, -NR16C(O)R16, -OC(O)R16, -SiR16R17R18, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, or halo, each of which is independently substituted or unsubstituted, or hydrogen.

[0166] In certain embodiments of Formula (B-la), L is attached directly to or on a substituent of X1, X2, X7, R3, R4, Y, or R1. In certain embodiments, L is attached directly to or on a substituent of X1. In certain embodiments, L is attached directly to or on a substituent of X2. In certain embodiments, L is attached directly to or on a substituent of X7. In certain embodiments, L is attached directly to or on a substituent of R3. In certain embodiments, L is attached directly to or on a substituent of R4. In certain embodiments, L is attached directly to or on a substituent of Y. In certain embodiments, L is attached directly to or on a substituent of R1.

[0167] In certain embodiments, A1is substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heteroalkenylene, or substituted or unsubstituted heteroalkynylene. In certain embodiments, A1is substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted alkynylene. In certain embodiments, A1is substituted or unsubstituted heteroarylene, or substituted or unsubstituted alkynylene. In certain embodiments, A1is unsubstituted heteroarylene, or -C=C-. In certain embodiments, A1is unsubstituted 5 -membered heteroarylene or - C=C-. In certain embodiments, A1is unsubstituted oxadiazole or -C=C-.In certain embodiments,

[0168] In certain embodiments, B is any compound described in International Patent Application No. PCT / CN2022 / 085296, which is incorporated herein by reference. In certain embodiments, B is of the formula:-lb), wherein: each = is independently a single bond or a double bond;X, is C, CR5, N, NR6, O, S, C=O, or C=S;X2is C, CR7, N, NR8, O, S, C=O, or C=S;X3is C, CR9, N, NRIO, O, S, C=O, or C=S;X4is C, CRn, N, NR12, O, S, C=O, or C=S;X5 and Xe are each independently selected from C, CR13 and N;X7is CRu or NRu; wherein at least one of Xi, X2, X3and X4is a carbon atom connected to R2; at least one of X5 and Xe is N;Ri is H, alkyl, cycloalkyl, haloalkyl, halogen, hydroxyl, alkoxyl, -SR15, -S(O)Ris, -S(O)2RIS, nitro, nitroso, cyano, amino, carboxyl, -C(O)ORis, -NRieRn, aryl, heteroaryl or heterocyclyl; wherein said alkyl, cycloalkyl, alkoxyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one or more RJ8;R2is alkyl, cycloalkyl, -NRi9R2o, -CrealkylNRi9R2o, haloalkyl, halogen, hydroxyl, alkoxyl, - C(0)NRi9R2o, aryl, heteroaryl or heterocyclyl; wherein said alkyl, alkoxyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one or more R2I ;R3is independently H, hydroxyl, halogen, nitro, cyano, carboxyl, amino, alkyl, alkoxyl, haloalkyl or cycloalkyl;R4is aryl, heteroaryl,each of which is optionally substituted by one or more R22; each R5, Re, R7, R8, R9, Rio, Ri 1 , RI2, and RJ3is independently H, alkyl, halogen, haloalkyl, cycloalkyl, hydroxyl, nitro, amino or alkoxyl; each R14, Rie, Rn, R19, R2o is independently H, alkyl, cycloalkyl, haloalkyl, halogen, hydroxyl, alkoxyl, -SR15, -S(O)Ris, -S(O)2RIS, nitro, nitroso, cyano, amino, carboxyl, -C(O)ORis, - NRieRn, aryl, heteroaryl or heterocyclyl; said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one or more R23;Y is (C(R15)2)m;m is 0, 1, 2, 3; each Ri5 is independently H, hydroxyl, alkyl, cycloalkyl or halogen; or Ri6, Rn, together with the N atom from which they are bound, form a 3-to-6- membered heterocyclyl, said heterocyclyl is optionally substituted by one or more R24; or R19, R20, together with N atom they are bound form a 3-to-6- membered heterocyclyl, said heterocyclyl is optionally substituted by one or more R25;Ri8 is halogen, cycloalkyl, alkyl, nitro, cyano, alkoxyl or hydroxyl;R23 is -NR26R27, alkyl, cycloalkyl, haloalkyl, halogen, hydroxyl, nitro, carboxyl, -C(O)Ci 3alkylNR2eR27, -C(O)NR2eR27, heterocyclyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxyl, hydroxyl, amino and halogen; each R21 , R22, R24, R25 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxyl, hydroxyl, amino, alkylamino-, nitro, carboxyl, cyano, halogen, -C(O)OR28, -C(0)NR29R3o, - Ci-3alkylC(0)NR29R3o, -C(0)Ci-3alkylNR29R3o, -S(O)2R28, -S(O)R28, -S(0)2NR29R3o, -P(0)R29R3o, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, amino, alkyl and alkoxyl; each R26, R27, R28, R29, R30 is independently selected from H, hydroxyl, alkyl, hydroxylalkyl, alkoxyl, amino, aminoalkyl, cycloalkyl or halogen; or R29 and R30, along with the N or P atom form a 3-to-6- membered ring which is optionally substituted by one or more substituents independently selected from -C1-6 alkyl; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0169] In certain embodiments of Formula (B-lb), L is attached directly to or on a substituent of Xi, X2, X7, R3, R4, Y, or N. In certain embodiments, L is attached directly to or on a substituent of Xi. In certain embodiments, L is attached directly to or on a substituent of X2. In certain embodiments, L is attached directly to or on a substituent of X7. In certain embodiments, L is attached directly to or on a substituent of R3. In certain embodiments, L is attached directly to or on a substituent of R4. In certain embodiments, L is attached directly to or on a substituent of Y. In certain embodiments, L is attached directly to or on a substituent of N.

[0170] In certain embodiments, B is of formula:wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0171] In certain embodiments of Formula (B-lc), L is attached directly to or on a substituent of X1, X2, X7, R3, R4, Y, or R1. In certain embodiments, L is attached directly to or on a substituent of X1. In certain embodiments, L is attached directly to or on a substituent of X2. In certain embodiments, L is attached directly to or on a substituent of X7. In certain embodiments, L is attached directly to or on a substituent of R3. In certain embodiments, L is attached directly to or on a substituent of R4. In certain embodiments, L is attached directly to or on a substituent of Y. In certain embodiments, L is attached directly to or on a substituent of R1.

[0172] In certain embodiments, B is of formula:wherein: L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0173] In certain embodiments of Formula (B-ld), L is attached directly to or on a substituent of X1, X2, X7, R3, R4, Y, or R1. In certain embodiments, L is attached directly to or on a substituent of X1. In certain embodiments, L is attached directly to or on a substituent of X2. In certain embodiments, L is attached directly to or on a substituent of X7. In certain embodiments, L is attached directly to or on a substituent of R3. In certain embodiments, L is attached directly to or on a substituent of R4. In certain embodiments, L is attached directly to or on a substituent of Y. In certain embodiments, L is attached directly to or on a substituent of R1.

[0174] In certain embodiments, B is of formula:wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0175] In certain embodiments of Formula (B-le), L is attached directly to or on a substituent of X1, X2, X7, R3, R4, Y, or R1. In certain embodiments, L is attached directly to or on a substituent of X1. In certain embodiments, L is attached directly to or on a substituent of X2. In certain embodiments, L is attached directly to or on a substituent of X7. In certain embodiments, L is attached directly to or on a substituent of R3. In certain embodiments, L is attached directly to or on a substituent of R4. In certain embodiments, L is attached directly to or on a substituent of Y. In certain embodiments, L is attached directly to or on a substituent of R1.

[0176] In certain embodiments, B is of formula:-lf), wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0177] In certain embodiments of Formula (B-lf), L is attached directly to or on a substituent of R3, R4, Y, or R1. In certain embodiments, L is attached directly to or on a substituent of R3. In certain embodiments, L is attached directly to or on a substituent of R4. In certain embodiments, L is attached directly to or on a substituent of Y. In certain embodiments, L is attached directly to or on a substituent of R1.

[0178] In certain embodiments, B is of formula:-lg),wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0179] In certain embodiments, B is of formula:-lg-1).

[0180] In certain embodiments, B is of formula:-lg-2).

[0181] In certain embodiments, B is of formula:-lh), wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0182] In certain embodiments, B is of formula:lh-1).

[0183] In certain embodiments, B is of formula:-lh-2).

[0184] In certain embodiments, B is of formula:wherein: each RQis independently, hydrogen, substituted or unsubstituted alkyl, or halogen; and L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0185] In certain embodiments, B is of formula:

[0186] In certain embodiments, B is of formula:

[0187] In certain embodiments, B is of formula:wherein: each RQis independently, hydrogen, halogen, or substituted or unsubstituted alkyl; each RNis independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; and L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0188] In certain embodiments, B is of formula:lj-1), wherein: RQis hydrogen, halogen, or substituted or unsubstituted alkyl; and each RNis independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl.

[0189] In certain embodiments, B is of formula:-lj-2), wherein: each RQis independently hydrogen, halogen, or substituted or unsubstituted alkyl; RNis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; RN1is substituted or unsubstituted alkylene, substituted or unsubstituted acyl, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene.

[0190] In certain embodiments, B is of formula:wherein: each RQis independently, hydrogen, halogen, or substituted or unsubstituted alkyl; each Rpis independently, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl; and L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0191] In certain embodiments, B is of formula:lk-1), wherein: RQis hydrogen, halogen, or substituted or unsubstituted alkyl; and each Rpis independently, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl.

[0192] In certain embodiments, B is of formula:-lk-2), wherein: each RQis independently, hydrogen, halogen, or substituted or unsubstituted alkyl; each Rpis independently, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl; and RP1is substituted or unsubstituted -O-alkylene, substituted or unsubstituted alkylene, -C(=O)O-, -C(=O)S-, or -C(=O)N(RX1)-; and RX1is hydrogen or substituted or unsubstituted alkyl.

[0193] In certain embodiments, B is of formula:-lk-2a), wherein: each RQis independently, hydrogen, halogen, or substituted or unsubstituted alkyl; each Rpis independently, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl; and RP1is substituted or unsubstituted -O-alkylene, substituted or unsubstituted alkylene, -C(=O)O-, -C(=O)S-, or -C(=O)N(RX1)-; and RX1is hydrogen or substituted or unsubstituted alkyl.

[0194] In certain embodiments, B is of formula:wherein: each RQis independently, hydrogen, halogen, or substituted or unsubstituted alkyl; each Rpis independently, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl; and RP1is substituted or unsubstituted -O-alkylene, substituted or unsubstituted alkylene, -C(=O)O-, -C(=O)S-, or -C(=O)N(RX1)-; and RX1is hydrogen or substituted or unsubstituted alkyl.

[0195] In certain embodiments, B is of formula:wherein: each RQis independently, hydrogen, halogen, or substituted or unsubstituted alkyl; each Rpis independently, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl; and RP1is substituted or unsubstituted -O-alkylene, substituted or unsubstituted alkylene, -C(=O)O-, -C(=O)S-, or -C(=O)N(RX1)-; and RX1is hydrogen or substituted or unsubstituted alkyl.

[0196] In certain embodiments, B is of formula:wherein: each RQis independently, hydrogen, halogen, or substituted or unsubstituted alkyl; each Rpis independently, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or -C(=O)N(RX1)2; and RP1is -O-, substituted or unsubstituted -O- alkylene, substituted or unsubstituted alkylene, -C(=O)O-, -C(=O)S-, or -C(=O)N(RX1)-; and RX1is hydrogen or substituted or unsubstituted alkyl.

[0197] In certain embodiments, B is of formula:

[0198] In certain embodiments, B is of formula:

[0199] In certain embodiments, B is of formula:-ll), wherein: Hy is a substituted or unsubstituted heteroaryl; and L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0200] In certain embodiments, B is of formula:-ll-1), wherein Hy is a substituted or unsubstituted heteroarylene.

[0201] In certain embodiments, B is of formula:-ll-2), wherein Hy is a substituted or unsubstituted heteroarylene.

[0202] In certain embodiments, B is of formula:

[0203] In certain embodiments, B is of formula:-lm), wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0204] In certain embodiments, B is of formula:-lm-1).

[0205] In certain embodiments, B is of formula:

[0206] In certain embodiments, B is of formula:

[0207] In certain embodiments, B is of formula:

[0208] In certain embodiments, B is of formula:-ln), wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0209] In certain embodiments, B is of formula:

[0210] In certain embodiments, B is of formula:

[0211] In certain embodiments, B is of formula:-lo), wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0212] In certain embodiments, B is of formula:

[0213] In certain embodiments, B is of formula:

[0214] In certain embodiments, B is of formula:

[0216] In certain embodiments, B is any compound described in U.S. Patent Application U.S.S.N.17 / 772,948, which is incorporated herein by reference. In certain embodiments, B is of the formula:wherein:R2is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, - SOn2R2D, -SOv2NR2AR2B, -NR2CNR2AR2B, -ONR2AR2B, -NHC(O)NR2CNR2AR2B, -NHC(O)NR2AR2B, - N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, - NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, -NS(O)F2, -NS(O)FNR2AR2B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2A, R2B, R2C, and R2Dare independently hydrogen, -CCh, -CBn, -CF3, -CI3, -CHQ2, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, - OCBr3, -OCI3, -OCHCh, -OCHBr2, -OCHI, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;X2is independently -F, -Cl, -Br, or -I; n2 is independently an integer from 0 to 4; m2 and v2 are independently 1 or 2; z2 is an integer from 0 to 7 ; andR3is an electrophilic group or a substituted or unsubstituted alkyl; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0217] In certain embodiments, B is of the formula:wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0218] In certain embodiments, B is of the formula:wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0219] In certain embodiments, B is of the formula:

[0220]

[0221] In certain embodiments, B is of the formula:

[0222] In certain embodiments, B is of the formula:

[0223] In certain embodiments, B is of the formula:wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0224] In certain embodiments, B is of the formula:wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0225] In certain embodiments, B is of the formula:wherein:wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0226] In certain embodiments, B is of the formula:

[0227] In certain embodiments of Formula (B-4b), R2is -C(=O)-.

[0228] In certain embodiments, B is of the formula:

[0229] In certain embodiments, B is any compound described in ACS Chem. Biol., 2020, 15, 657, which is incorporated herein by reference. In certain embodiments, B is any compound described inJACS, 2012, 134, 6810, which is incorporated herein by reference. In certain embodiments, B is any compound described in Future Med. Chem., 2019, 11, 2491, which is incorporated herein by reference. In certain embodiments, B is of the formula:wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0230] In certain embodiments, B is any compound described in JACS 2012, 134, 6810, which is incorporated herein by reference. In certain embodiments, B is of the formula: whewherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0231] In certain embodiments, B is any compound described in Eur. J. Med. Chem, 2018, 152, 101, which is incorporated herein by reference. In certain embodiments, B is of the formula:wherein:R1is -OH or -NHCH2CH3;R2is H, Cl, or F; andR3is H or F; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0232] In certain embodiments, B is any compound described in International Patent Application No. PCT / GB2012 / 051428, which is incorporated herein by reference. In certain embodiments, B is of the formula:wherein:A, is CR; or N;Ri is selected from -OH, -OMe. -NH2, -SH, -F and -CF3:R2is selected from -I. -Cl, -Br, and ethynyl (-C=CH);R3is selected from -R3s, -1, -Br, -Cl, ethynyl (-C=CH), -H, -OMe, and -NO?; -R3s isand each -Rg is independently selected from: RSA, -RSB, -Rec, -RSD, -RSE- -RSF, -RSG,L-RSB; -L.-Rrn, -L-Rffls and -L-R6G;R6Ais independently saturated aliphatic Cuioalkyl and is optionally substituted with one or more substituents -RT,RSB is independently saturated Cj-socycloalkyl and is optionally substituted with one or more substituents -RT,Rec is independently -Qi or -Q2,Q: is independently Cciocarboaryl, and is optionally substituted with one or more substituents -Rr,Q2 is independently Cs-nheteroaryl, and is optionally substituted with one or more substituents -RT,RED is independently aliphatic C2-?alkenyl and is optionally substituted with one or more substituents -RT,RSE is independently aliphatic Cr-salkynyl and is optionally substituted with one or more substituents -RT,RISE is independently Cj-scycloalkenyl and is optionally substituted with one or more substituents -RT.REG is independently Cs ioheterocyclyl. where the carbon ring atoms are optionally substituted with one or more substituents -RT, and any nitrogen ring atoms, where present, are optionally substituted with -RTN, and the heterocyclyl optionally comprises one or more double bonds,-L- is saturated aliphatic Crsalkylene and is optionally substituted with one or more substituents -RT;-RT is independently selected from: -F, -Cl, - Br, -I, -REI, -RE2, -RES, -RE4, -RES, -REC. -RES, - OH. -ORE. -Cl . -OCFj, -CN. -NO2, -SH, -SRE. AH . SHR: . -N(RB)2, -NREN:REN2. -C(=O)H. ■ C(=O)RE, -C(=O)OH, -C(=O)ORf!, -OC(=O) RE, -OC(=O)NH2, -OC(=O)NHRE, -OC(=O)N(RE)2, - (X1(^0)NREN:RFN2, -OC(-O)N(RE)2. -OC(-O)NRENJREN2, -NHCAOIRE. -NRECAOIRE. - C(~O)NH2, -C(-O)NHRE, -C(~O)N(RE)2, -C(^0)NREN.REN2, -NHC(-O)ORE, -NREC(>O)ORE, - NHC(=O)NH2, ■■NHC(=O)NHRE. -NHC(=O)N(RE)2, -NHC(=0)NRENIREU2, ■NREC(=O)NH2, - NREC(=O)NHRE, -NREC(=OJN(RE)2, -NREC(=O)NREN, REM2. -S(=O)NH2, -S( =O)NHRE, - S(=O)N(RE)2. -S(=O)NRENIREN2, -S(-O)2NH2, -S(-O)2NHRE. -S(-O)2N(RE12, -S(-O)2NREmREm, - NHS(>O)2RE, -NRES(-O)2RE, -NHS(-O)RE, -NRES(~O)RE, -S(~O)2RE, and -S(-O)2CF3: each -RIN is independently selected from: -RE:, -RE2, -RES, -RES, -RES, -RES, -RES, -CF2, ■■ C(=O)H, -C(=O)Rf!, -C(=O)OH, -C(=O)ORE, -C(=O)NH2, -C(=O)NHRE, -C(=O)N(RE)2, - C(-O)NREN! RENT. -S(-O)NHJ, -S(-O)NHRE, -S(-O1N(RE)2, -SAOINRENIRENT. -S(-O)2NH2, - S(~G)2NHRE. -S("O)2N(RE)2. -S(-O)2NREN;REN2. -S(-O)2RE, or -S(“O)2CF3; each -REis independently -REI, -RE2. -RES, -RES. -RES, -RES or -RES; each -REI is independently saturated aliphatic Cnioalkyl and is optionally substituted with one or more substituents -Rs; each -RE2is independently saturated Cs-iocycloalkyl and is optionally substituted with one or more substituents -Rs; each -REJ is independently -Qi or -Q2;Q< is independently Ce-iocarboaryl. and is optionally substituted with one or more substituents - R";Qj is independently Ccmlieteroaryl, and is optionally substituted with one or more substituents -R : each -RE4 is independently aliphatic Cj-ealkenyl and is optionally substituted with one or more substituents -R ; each -RES is independently aliphatic Cmsalkynyl and is optionally substituted with one or more substituents -R~: each -RES is independently Ca-ecyeloalkenyl and is optionally substituted with one or more substituents - R"; each -RE? is independently Cs-ioheterocyclyl where the carbon ring atoms are optionally substituted with one or more substituents -Rs, and any nitrogen ring atoms, where present, are optionally substituted with -RSN, and the heterocyclyl optionally comprises one or more double bonds; each -NREMRENI, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, diazepano, thiomorpholino, oxidised thiomorpholino, or octahydro-pyrrolo[ 1 ,2-a]pyrazino, where the carbon ring atoms are optionally substituted with one or more substituents ■ Rs, and any nitrogen ring atoms, where present, are optionally substituted with -RSN, and the heterocyclyl optionally comprises one or more double bonds;R4 is independently selected from -H and -R4S;-R4S is independently selected from: -F, -Cl. -Br, -I. -Rwi, -Rw2, -Rwa, -RW4, -RW5, -RW6, -RW7, -OH, -ORw. -CF3, -OCFI, -CN. -NO2, -SH. -SRw, ■ XH -. -NHRW, -N(Rw)?, -NRwmRwm, -C(=O)H, - C(-O)Rw, -C(-O)OH, -C(-O)ORw. -OC(-O1RW, -OC(-O)NH2, -OC(-O)NHRW, -OC(-O)N(RW)2, - 0Ct.~0)NRwniRwN2, -0C(~0..IN(RW)2 -OC(.:=O)NRWNJRWN2, -NHC(~O)Rw, -NRwM,:=O)Rw. - C(=O)NH2, -C(=O)NHRW, -C(=O)N(Rwh -C(=0)NRWNIRWN2, - NHC(=O)ORw, -NRwC(=O)ORw, - NHC(=O)ORW, -NRwC(=O)ORw, -NHC(=O)NH2, -NHC(=O)NHRw, -NHC(=O)N(Rw)?, - NHC(-0)NRWN!RWN2. -NRwCl-OlNHj, -NRWC(-O)NHRW. -NRC(-O)N(RE)2, - NRWC(~0)NRWNIRWN2, -S(~O..iNfi2, -S(~O)NHRw» -S(=0)N(Rw)2, -S(~0)NRWNIRWN2, -S(”G)2NH2, -S(=0)2NHRW, -S(=O)3N(RW)2, -S(=O)3NRWNIRWN2, -NHS(=O)2RW, -NRWS(=O)2RW. -NHS(==O)RW, -NRwS(=O)Rw, -S(=O)?Rw, or -S(=O)2CF3; each -Rwis independently -Rwi, -Rw2, -Rwa, -Rw-s, - Rws, -Rw6, or -Rw?; each -Rw- is independently saturated aliphatic Cmoalkyl and is optionally substituted with one or more substituents -Rs; each -Rw2 is independently saturated Cj iocycloalkyl and is optionally substituted with one or more substituents -Rs; each -Rws is independently -Qi or -Q2;Qi is independently Cfriocarboaryl, and is optionally substituted with one or more substituents -Rs:Q2 is independently Csmheteroaryl, and is optionally substituted with one or more substituents - R"; each -RW4 is independently aliphatic C^-salkenyl and is optionally substituted with one or more substituents -R3; each -Rws is independently aliphatic Cj-salkynyl and is optionally substituted with one or more substituents -Rs; each -RW6 is independently Cj.6cycloalkenyl and is optionally substituted with one or more substituents -Rs; each -Rw? is independently Cs-iobeterocyclyl where the carbon ring atoms are optionally substituted with one or more substituents -Rs, and any nitrogen ring atoms, where present, are optionally substituted with - Rsn, and the heterocyclyl optionally comprises one or more double bonds, each -NRwmRwm. if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, diazepano, thiomorpbolino, oxidised thiomorpholino, or oetahydro-pyrrolofl ,2-a]pyrazino, where the carbon ring atoms are optionally substituted with one or more substituents - Rs, and any nitrogen ring atoms, where present, sire optionally substituted with -RSN, and the heterocyclyl optionally comprises one or more double bonds;Rs is independently selected from -COOH,R?A is independently -H or -Rs;R?B is independently -H or -Rs;Rs is independently selected from: -N(RO)-LN-RNI, -NIRNSROJ). -N(RB)-RN4, and -N(RB)- RNS;R j 3 is independently selected from -H and -RsN;-LN- is independently selected from; LNJ-, LNI-C(~O)-, LNI-QRCJRCZ)-; wherein -LNI- is saturated Cmalkylene. and is optionally substituted by one or more substituents -Rs;RCJ and -Re? together with the carbon atom to which they are attached form a Cs-iocyclohexyl ting where the carbon ring atoms are optionally substituted with one or more substituents -RN, and any nitrogen ring atoms, where present, are optionally substituted with -RNN, and the heterocyclyl optionally comprises one or more double bonds;RNI is independently selected from -NH?, -NHRE, -N(RE)2, and -RENI ;-RENI is a Cj-iocyclohexyl ring where the carbon ring atoms are optionally substituted with one or more substituents -RN, and any nitrogen ring atoms, where present, are optionally substituted with - RNN, and the heterocyclyl optionally comprises one or more double bonds;RN?. and -RNJ together with the nitrogen atom to which they are attached form a CMO cyclohexyl ring where the carbon ring atoms are optionally substituted with one or more substituents - RN, and any nitrogen ring atoms, where present, are optionally substituted with -RNN. and the heterocyclyl optionally comprises one or more double bonds;Rm is independently saturated aliphatic Ci-salkyl and is optionally substituted with one or more substituents -Rs;RNS is independently a nitrogen-containing Cs ioheterocyclyl group, and the carbon ring atoms are optionally substituted with one or more substituents -RN. and any nitrogen ring atoms, where present, are optionally substituted with -RNN; each -RN is independently selected from:-F, -Cl, -Br, -I, -REJ, -RE2, -RES, -RE4, -RES. -REE, -RE?, -OH, -ORE, -CF3, -OCF3, -CN, -NO2. -SH, -SRE, -NH2, -NHRE, -N(RE£, -NRENIRENS, -C(=O)H, ■ C(=O)Rf;, -C(=O)OH, -C(=O)ORf!, -OC(=O)Rf!, -OC(=O)NH2, -OC(=O)NHRE, -OC(=O)N(RE)2, - OCt — 0)NREN:REN2, -OC(— O)N(RE)?., and -OC(— O / NRFNIREN2; each -RNN is independently selected from: -REJ, -RE2, -RES, -RE4, -RES. -RE6, -RE?, -CF3, - C(~O)H, “C(-O)RE, -C(-O)OH, -C(~O)ORE, -C(-O)NH2, -C( -C ))N HR- -C(=O)N(RE)2. - C(=0)NRENIREN2, “S( =O)NH2, -S(=O)NHRE. -S(=O)N(RE)2, -S(=O)NRENIREN2, -S(=O)2NH2, - S(=0)2NHRf!, -S(=O)2N(RE)2, -S(=O)2NREN IRENS, -S(=O)2RE, and -S(=O)2.CF5;R?,A is independently =N-Rs, where -R§ is independently selected from: -NRENIREN2, -NH2, - NHRE, -N(RE)2-NRENIRENZ, -C(-O)H, -C(-O)RE, -C(-O)OH, -C(^O)ORE, -NHC(-O)RE, - NREC(=O)RE. -C(=O)NH2, -C(=O)NHRE. -C(=O)N(RE)2-C(=O)NR£NIREN2, -NHC(=O)ORE, - NRf;C(=O)ORE. -NHC(=0)NH2, -NHC(=O)NHRE, -NHC(=O)N(Rt!)?, -NHC(=O)NRKNIR:-N?, - NREC(— O)NH2, -NREC(.-O)NHRE, -NREC(~O)N(RE)2, and -NRF.C(— O)NRENIREN?.S each -Rs is independently selected from: -Rs-., -Rss, -Rss, -Rs4, -Rss, -Rss, -Rs?, -OH, -ORB, - CF3. -OCF3. -CN, “NO3, -SH, -SRB. “NH2, -NHRB, -N(RB)2, -NRSNIRSN?. -C(=O)H, -C(=O)RB, - C(=O)OH, -C(=O)ORs, -OC(=O)RB, -OC(=O)NH2, -OC(=O)NHRB, -OC(=O)N(RB)2, - 0C(-0)NRsmRsN2, -OC(^O)N(RB)2, -OC(^O)NRSN:RSN2, -NHC(-O)RB, -NRBC(-O)RB, -Ci-OINH?, -C(-O)NHRE, -C("0)N(RB)2, -C(-O)NRSNIRSN2, -NHC(-O)ORB, -NRSC(-O)ORB, -NHC(-O)NH2, - NHC(=O)NHRB, “NHC(=0)N(RB)2, “NHC(=O)NRSNIRSN2, “NRBC(=O)NH2, -NRBC( =O)NHRB, - NRSC(=O)N(R8)2, -NRBC(=O)NRSN!RSN2-, -S(=O)NH2, -S(=O)NHRB, -S(=O)N(R8.)2, - S(-O1NRSN!RSN2, -S(^O)?.NH2, -S(^O)2NHRS, -S(=O)2N(RS)2, -S(-O)2NRSN:RSN2, -NHS(-O)JRS, - NRBS( “O)2RS, “NHS(-O)RB, -NRBS( -O)RS. -S( -O)2RB. and S{ H ri Cl c each d<sN is independently selected from: -Rsi, -RS2, -RSS, -RS4. -RSS, -RS6, -RS?, -CF3, ■■ C(=O)H, ■C(=O)RB, “C(=O)OH, “C(=O)ORB, “C(=O)NH2, -C(=O)NHRB, -C(=0)N(RB)2 ■ C(=O)NRSNIRSN2, -S(=O)NH 2, -S(=O)NHRB, -S(=O)N( RB)2, -S(=O)NRSNIRSN2, -S(=O)2NH 2. - S(— 0)2NHRB, -S(~O)2N(RB)2, -S(~O)2NRSNIRSN2, -S(— O)?.RB, and -S(— O)2Cf'3; each -RB is independently -Rsi, -RSJ, -RS3- Rsr, -Rss. -Rse or -Rs?;each -Rsi is independently saturated aliphatic Cinoalkyl and is optionally substituted with one or more substituents selected from: -F. -Cl, -Br, -I, -CFs. -OH, -OR*”, and -OCF3, wherein each - Rw uis independently saturated aliphatic. Cmalkyl; each -Rs?, is independently saturated Ci-scycloalkyl and is optionally substituted with one or more substituents selected from: -Rwu, -F, -Cl, -Br, -1, -CF3. -OH, -CN, -NO2, -ORWH, and -OCF3, wherein each -Rwn is independently saturated aliphatic Cmalkyl; each -RS3 is independently -Q? or -Q4;Qa is independently Ce iocarboaryl, and is optionally substituted with one or more substituents selected from: -Rwu. -F, -Cl. -Br, -1, -CF3, -OH, -CN, -NO;, -ORWH, and -OCF3, wherein each -Rwn is independently saturated aliphatic Cmalkyl;Q4 is independently Cwmheteroaryl, and is optionally substituted with one or more substituents selected from: -Rw u. -F, -Cl, -Br, -I, -CF3, -OH, -CN, -NO?, -ORWH, and -OCF3, wherein each -Rwu is independently saturated aliphatic CH alkyl; each -RS4 is independently aliphatic C2-6alkenyl and is optionally substituted with one or more substituents selected from: -Rwu, -F, -Cl, -Br, -I, -CF3, -OH, -CN, -NO?, -ORWH, and -OCF3, wherein each -Rwn is independently saturated aliphatic Ciualkyl; each -Rs? is independently aliphatic C2.6alk.ynyl and is optionally substituted with one or more substituents selected from: -Rwn, -F, -Cl, -Br. -I, -CFj, -OH, -CN. -NO2. -ORwu, and -OCFj, wherein each -Rwu is independently saturated aliphatic Cj aalkyl; each -Rs6 is independently Cj-scycloalkenyl and is optionally substituted with one or more substituents selected from: -Rw u. -F, -Cl, -Br, -I, -CF3, -OH, -CN, -NO?, -ORWH, and -OCF3, wherein each -Rwn is independently saturated aliphatic Cmalkyl; each -Rs? is independently Cs-ioheterocyclyl where the carbon ring atoms are optionally substituted with one or more substituents selected from: -Rwu , -F, -CL -Br, -I, -CF?. -OH, -CN, -NO?, -ORwu. and -OCFj, wherein each -Rwu is independently saturated aliphatic Cmalkyl; and any nitrogen ring atoms, where present, are optionally substituted with -Rwo or -CF3, and the heterocyclyl optionally comprises one or more double bonds: each -NRSNIRSN?, if present, is independently azetidino, pyrrolidino, piperidino, piperazino. morpholino, azepano. diazepano, thiomorpbolmo, oxidised thiomorpholino, or oetahydro-pyrrolo[l ,2-ajpyrazino, where the carbon ring atoms are optionally substituted with one or more substituents selected from: -Rwn , -F, -Cl, -Br, -I, -CF3, -OH, -CN, -NO?, -ORwu, and -OCF3, wherein each -Rwn is independently saturated aliphatic Cmalkyl: and any nitrogen ring atoms, where present, are optionally substituted with -Rwu or -CF3, and the heterocyclyl optionally comprises one or more double bonds; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0233] In certain embodiments, B is any compound described in Chinese Patent Application No. 202210840426 (published February 3, 2023), which is incorporated herein by reference. In certain embodiments, B is of the formula:ll), wherein:Xi, X2, and X3 is each independently selected from O, S, NR', C=O, S=O, O=S=O, or C(R'), and X4, X5, and Xe is each independently selected from N or CR';Ri is independently selected from hydrogen, deuterium, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -Crehaloalkyl, -C(O)R', -C(O)N(R')2, -C(O)OR’, -S(O)R', -S(O)N(R')2, -S(O)2R', -S(O)2N(R’)2, 3-12- membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocycloalkyl, 3-12- membered heterocycloalkenyl, 6-12-membered aryl and 5-12-membered heteroaryl; wherein the -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C1-6haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl are each independently optionally replaced by one or more (such as 1, 2 , 3, 4, 5, or 6) substituents selected from: deuterium, halogen, -C1-6alkyl, -C2 ealkenyl, -C2 ealkynyl, -C1-6haloalkyl, -CN, oxo, -OR', -SR', -C(O)R', -C(0)N(R')2, -C(O)OR', - OC(O)R’, -0C(0)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, -S(O)N(R’)2, -NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R', -S(O)2N(R’)2, -NR'S(O)2R', -NR’S(O)2N(R’)2, -PO(R')2, -PO2, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-12 membered cycloalkenyl, optionally substituted 3-12 membered heterocycloalkyl, optionally substituted 3-12 membered heterocycloalkenyl, optionally substituted 6-12 membered aryl, and 5-12 membered heteroaryl;R2 is independently selected from hydrogen, deuterium, -CN, oxo, -OR', -SR', -N(R')2, -Ci- ealkyl, -C2-6alkenyl, -C2 -ealkyne base, -C1-6haloalkyl, -C1-6alkylN(R')2, -C(O)R', -C(0)N(R')2, - C(O)OR’, -S(O)R’, -S(0)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -PO(R')2, -PO2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl; wherein the -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C1-6haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl are each independently optionally replaced by one or more (such as 1, 2, 3, 4 , 5, or 6) substituents selected from: deuterium, halogen, -C1-6alkyl, -C26alkenyl, -C2-6alkynyl, -Crehaloalkyl, -CN, Oxo, -OR’, -SR', -C(O)R', -C(O)N(R')2, -C(O)OR', - OC(O)R', -OC( O)N(R')2, -N(R')2, -NR'C(O)R', -NR’C(O)OR’, -NR'C(O)N(R')2, -S(O)R', - S(O)N(R')2, -NR'S(O)R', -NR'S(O)N(R')2, -S(O)2R', - S(O)2N(R')2, -NR'S(O)2R', -NR'S(O)2N(R')2, - PO(R')2, -PO2, optionally substituted 3- 12-membered cycloalkyl, optionally substituted 3-12- membered cycloalkenyl, optionally substituted 3-12-membered heterocycloalkyl, optionally substituted 3-12-membered heterocycloalkenyl, optionally substituted 6-12 membered aryl, and 5-12 membered heteroaryl;R3 is independently selected from hydrogen, deuterium, -Crealkyl, -Crealkenyl, -Crealkynyl, -Crehaloalkyl, -Crealkyl N (R')2, -C(O)R', -C(O)N(R')2, -C(O)OR’, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycle alkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl; wherein the -Crealkyl, -Crealkenyl, -Crealkynyl, -Crehaloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12-membered heteroaryl groups are each independently optionally substituted by one or more (such as 1, 2, 3, 4, 5, or 6) substituents selected from: deuterium, halogen, -Crealkyl, -C2ealkcnyl, -C2ealkynyl, -Crehaloalkyl, -CN, oxo, -OR', -SR', -C(O)R', -C(O )N(R')2, - C(O)OR’, -OC(O)R’, -OC(O)N(R')2, -N(R')2, -NR’C(O )R', -NR’C(O)OR’, -NR'C(O)N(R')2, -S(O)R', - S(O)N(R')2, -NR’S (O)R’, -NR'S(O)N(R')2, -S(O)2R', -S(O)2N(R')2, -NR’S(O)2R’, -NR'S(O)2N(R')2, - PO(R')2, -PO2, optionally substituted 3-12 membered cycloalkyl, optionally substituted 3-12 membered cycloalkenyl, optionally substituted 3-12 membered heterocycloalkyl, optionally substituted 3-12 membered heterocycloalkenyl, optionally substituted 6-12 membered aryl, and 5-12 membered heteroaryl; each occurrence of R' is independently selected from hydrogen, deuterium, halogen, -OH, - CN, oxo, -NH2, -NHCrealkyl, -N(Crealkyl)2, -Crealkyl, -Crealkyl-NC realkyl, -Crehaloalkyl, -OCr ealkyl, -C3- ucycloalkyl, -C3 uheterocycloalkyl, - C2e alkenyl, -Crealkynyl, 6-12 membered aryl, and 5-12 membered heteroaryl; the -C3- ucycloalkyl, -C3 uheterocycloalkyl, 6- 12-membered aryl and 5- 12-membered heteroaryl are each independently optionally substituted by one or more (such as 1, 2, 3, 4, 5, or 6) substituents selected from: deuterium, halogen, -CN, NH2, -NO2, oxo, -PO3H2, -OH, -SH, -SO2H, -SO3H, -SO2NH2, -COOH, -CONH2, -CHO, -Crealkyl, -C2-6alkenyl, -C2-6alkynyl, -Cr ehaloalkyl, -OCrealkyl, -SCrealkyl, -C(O)C realkyl, -C(O)NHC realkyl, -C(O)N(C1-6alkyl)2, - C(O)OC1-6alkyl, -OC(O)C realkyl, -OC(O)NHC realkyl, -OC(O)N(C1-6alkyl)2, -NHCrealkyl, -N(Cr6alkyl)2, -NHC(O)C realkyl, -N( Cr6alkyl)C(O)C realkyl, -S(O)Cr6alkyl, -S(O)NHCre alkyl, - S(O)N(Crealkyl)2, -NHS(O)C realkyl, -N(Cr6alkyl)S(O)C realkyl, -S(O)2Cr6alkyl, -S(O)2NHC realkyl, -S(O)2N(Crealkyl)2, -NHS(O)2Cr6alkyl, -N(Crealkyl)S(O)2Crealkyl, -P(O)(OCr6alkyl)2, and -PO(Cr6alkyl)2; wherein said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain1, 2, or 3 heteroatoms selected from N, O, and S;wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0234] In certain embodiments, B is any compound described in International Patent Application No. PCT / CN2022 / 111050, which is incorporated herein by reference. In certain embodiments, B is of the formula:wherein:Y is selected from O, S, NR’, S=O, -S(=O)(=NR’), and O=S=O; one of Xi, X2, X3 and X4 is selected from CR2, and the others of Xi, X2, X3 and X4 are each independently selected from N and CR4;X5 is selected from N and CRi ;Ri is independently selected from hydrogen, deuterium, halogen, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C1-6haloalkyl, -CN, -OR’, -SR’, -C(O)R’, -C(O)N (R’)2, -C(O)OR’, -OC(O)R’, - OC(O)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, -S(O)N(R’)2, - NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, 3- 12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl and 5-12 membered heteroaryl; said -C1-6alkyl, - C2-6alkenyl, -C2-6alkynyl, -C1-6haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3- 12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from deuterium, halogen, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -Ci- ehaloalkyl, -CN, oxo, -OR’, -SR’, -C(O)R’, -C(O)N(R’)2, -C(O)OR’, -OC(O)R’, -OC(O)N(R’)2, - N(R’)2, -NR’C(O)R’, -NR’C(O) OR’, -NR’C(O)N(R’)2, -S(O)R’, -S(O)N(R’)2, -NR’S(O)R’, - NR’S(O)N(R’)2, -S (O)2R’, -S(O)2N (R’)2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl;R2is -NR5IR52, -OR53 or -SR54;R3 is selected from hydrogen, deuterium, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -Ci- ehaloalkyl, -C(O)R’, -C(O)N(R’)2, -C(O)OR’, -S(O)R’, -S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, - PO(R’)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl; said -Ci-ealkyl, -C2-ealkenyl, -C2-6alkynyl, -C1-6haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) R2a; each Rga is independently selected from deuterium, halogen, -C1-6alkyl, -C2-6alkenyl, -C26alkynyl, -C1-6haloalkyl, -CN, oxo, -OR’, -SR’, -C(O)R’, -C(O)N(R’)2, -C(O)OR’, -OC(O)R’, - OC(O)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, -S(O)N(R’)2, - NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2(R’)2, -S(=O)(=NR’)R’, -NR’S(O)2R’, - NR’S(O)2N(R’)2, -PO(R’)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl; said -C1-6alkyl, -C2-ealkenyl, -C2-ealkynyl, -C1-6haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl are each independently optionally substituted with one or more substituents Pie, each R3bis independently selected from deuterium, halogen, -C1-6alkyl, -C2-ealkenyl, -C26alkynyl, -C1-6haloalkyl, -CN, oxo, -OR’, -SR’, -C(O)R’, -C(O)N(R’)2, -C(O)OR’, -OC(O)R’, - OC(O)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, -S (O)N(R’)2, - NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -S(=O)(=NR’)R’, -NR’S(O)2R’, - NR’S(O)2N(R’)2, and -PO(R’)2;R4 at each occurrence is independently selected from hydrogen, deuterium, halogen, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C1-6haloalkyl, -CN, -OR’, -SR’, -C(O)R’, -C(O)N(R’)2, -C(O)OR’, -OC(O)R’, -OC(O)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, - S(O)N(R’)2, -NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl; said -Ci- ealkyl, -C2-ealkenyl, -C2-ealkynyl, -C1-6haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from deuterium, halogen, -C1-6alkyl, -C2-ealkenyl, -C26alkynyl, -C1-6haloalkyl, -CN, oxo, -OR’, -SR’, -C(O)R’, -C(O)N(R’)2, -C(O)OR’, -OC(O)R’, - OC(O)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, -S(O)N(R’)2, - NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -S(=O)(=NR’)R’, -NR’S(O)2R’, - NR’S(O)2N(R’)2, -PO(R’)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl and 5-12 membered heteroaryl;R51, RS2, R53 and R54 are each independently selected from hydrogen, deuterium, -Ci-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C1-6haloalkyl, -C(O)R’, -C(O)N(R’)2, -C(O)OR’, -S(O)R’, -S(0)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -P0(R’)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl; said -C1-6alkyl, -C2-6alkenyl, -C2-6.alkynyl, -C1-6.haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from deuterium, halogen, -C1-6alkyl, -C2-6alkenyl, -C2ealkynyl, -C1-6.haloalkyl, -CN, oxo, =NR’, -Ci-6alkyl-CH(R’)2, -OR’, -SR’, -C(O)R’, -C(O)N(R’)2, -C(O)OR’, -OC(O)R’, -OC(O)N(R’)2, -N(R’)2, - NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, -S(O)N(R’)2, -NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -S(=O)(=NR’)R’, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl;Rn and RJ2are independently selected from hydrogen, deuterium, -OH, halogen, -CN, oxo, -C1-6alkyl, -C1-6 haloalkyl, -C1-6.alkoxy, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2and 3-6 membered cycloalkyl; wherein said -C1-6alkyl, -C1-6.alkoxy and 3-6 membered cycloalkyl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from deuterium, -OH, halogen, -CN, oxo, -C1-6.alkoxy, -NH-C1-6alkyl, -N(Ci-4alkyl)2, and 3-6 membered cycloalkyl;R13 is selected from hydrogen, deuterium, -C1-6.alkyl and 3-6 membered cycloalkyl; wherein said -C1-6.alkyl and 3-6 membered cycloalkyl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from deuterium, -OH, halogen, -CN, oxo, -C1-6.alkoxy, -NH2, -NHC1-6alkyl, and -N(Ci-4alkyl)2; each R’ is independently selected from hydrogen, deuterium, halogen, -OH, -CN, oxo, - NH2, -NHCrealkyl, -N (C1-6alkyl)2, -C1-6alkyl, -C1-6alkylOC1-6alkyl, -C1-6alkyl-NHC1-6alkyl, -Ci- 6alkyl-N(C1-6alkyl)2, -C1-6.haloalkyl, -OC1-6alkyl, -C3- ucycloalkyl, -C3 uheterocycloalkyl, -C2-ealkenyl, -C2-6alkynyl, 6-12 membered aryl, and 5-12 membered heteroaryl; wherein said -C1-6alkyl, -OCi ealkyl, -C3- ucycloalkyl, -C3 uheterocycloalkyl, -C2-ealkenyl, -C2-ealkynyl, 6-12 membered aryl, and 5- 12 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, -CN, -Ci-salkyl, oxo, -OH, -OCi-3alkyl, -NH2, -NHCnsalkyl, -N (Ci-3alkyl)2, -C(=O)NH2, -C(=O)NH(C1-3alkyl), -C(=O)N(C1-3alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-3alkyl), -S(=O)2C1-3alkyl, -S(=O)2N(C1-3alkyl)2, -S(=O)(=NH)C1-3alkyl, -S(=O)(=NC1-3alkyl)C1-3alkyl, and 3-6 membered cycloalkyl; said heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contains 1 , 2 or 3 heteroatoms selected from N, O, P and S; m is selected from 1, 2, 3, 4, 5 and 6; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0235] In certain embodiments, B is any compound described in Chinese Patent Application No.202211503396, which is incorporated herein by reference. In certain embodiments, B is of the formula:wherein:Y is selected from NR', O, S, S=O, and O=S=O; one of Xi, X2, X3 and X4 is selected from CR2, and the other Xi, X2, X3 and X4 are each independently selected from N and CR4;X5 is selected from N and CRi ;E is a substituted or unsubstituted ring;Ri is independently selected from hydrogen, deuterium, halogen, -Crealkyl, -C2-6alkenyl, -C26alkynyl, -Crehaloalkyl, -CN, -OR’, -SR', -C(O)R’, -C(O)N(R’)2, -C(O)OR’, -OC(O)R’, -OC(O)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, -S (O)N(R’)2, -NR’S(O)R’, - NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, -PO2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl and 5-12 membered heteroaryl; wherein the -Crealkyl, -C2-6.alkenyl, -Crealkynyl, -Crehaloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl groups are each independently optionally substituted by one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from: deuterium, halogen, -C1-6 alkyl, -C2-6.alkenyl, -C2-6.alkynyl, -Crehaloalkyl, -CN, oxo, -OR', -SR', -C(O)R', -C (O)N(R')2, - C(O)OR’, -OC(O)R’, -OC(O)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, - S(O)N(R’)2, -NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, - PO(R')2, -PO2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered Heterocycloalkenyl, 6-12 membered aryl and 5-12 membered heteroaryl;R2is -NR51 RS2, -OR53 or -SR54;R3 is selected from hydrogen, -Crealkyl, -C2-6.alkenyl, -C2-6.alkynyl, -Crehaloalkyl, -C(O)R', - C(O)N(R’)2, -C(O)OR’, -S(O)R’, -S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -PO(R’)2, -PO2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl; said -Crealkyl, -C2-6.alkenyl, -C2-6.alkynyl, -Crehaloalkyl, 3-12 membered cycloalkyl, 3-12-membered cycloalkenyl, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkenyl, 6-12-membered aryl, and 5-12- membered heteroaryl are each independently optionally replaced by one or more (such as 1, 2, 3, 4, 5 or 6) R3a substituents; each R3a is independently selected from deuterium, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C1-6haloalkyl, -CN, oxo, -OR’, - SR', -C(O)R', -C(O)N(R')2, -C(O)OR', -OC(O)R’, - 0C(0)N(R')2, -N(R')2, -NR'C(O)R', -NR’C(O)OR’, -NR'C(0)N(R')2, -S(O)R' , -S(O)N(R')2, - NR'S(O)R', -NR'S(O)N(R')2, -S(O)2R’, -S(O)2N(R’)2, -NR'S(O)2R', -NR'S(O)2N(R')2, -PO(R')2, -PO2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl; wherein the -C1-6alkyl, -C2-ealkenyl, -C2-ealkynyl, -C1-6haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 member aryl, and 5-12 member heteroaryl are each independently optionally substituted by one or more (such as 1, 2, 3, 4, 5 or 6) R3t>; each R3bis independently selected from deuterium, halogen, -C1-6alkyl, -C2-ealkenyl, -C2.6alkynyl, -C1-6haloalkyl, -CN, oxo, -OR’, - SR’, -C(O)R’, -C(O)N(R’)2, -C(O)OR’, -OC(O)R’, - OC(O)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’ , -S(O)N(R’)2, - NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’ )2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, and - PO2; each occurrence of R4 is independently selected from hydrogen, deuterium, halogen, -C1-6 alkyl, -C2-6alkenyl, -C2.6alkynyl, -C1-6haloalkyl, -CN, -OR’, -SR’, -C(O)R’, -C(O)N(R’)2, -C(O)OR’, - OC(O)R’, -OC(O)N(R')2. -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, -S(O)N(R’)2, -NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, -PO(R’)2, -PO2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl and 5-12 membered heteroaryl; wherein the -C1-6alkyl, -C2-ealkenyl, -C2-ealkynyl, -C1-6haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12-membered aryl group, and the 5-12-membered heteroaryl group are each independently optionally substituted by one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from: deuterium, halogen, -C1-6alkyl, -C2-ealkenyl, -C2-ealkynyl, -C1-6haloalkyl, -CN, oxo, -OR', -SR', -C(O)R ', - C(O)N(R’)2, -C(O)OR’, -OC(O)R’, -OC(O)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, - NR’C(O)N(R’)2, -S(O)R’, -S(O)N(R ’)2, -NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, - NR'S(O)2R ', -NR'S(O)2N(R')2, -PO(R')2, -PO2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl and 5-12 membered heteroaryl;R51, RS2, R53 and R54 are each independently selected from: hydrogen, -C1-6 alkyl, -C2-ealkenyl, -C2-6alkynyl, -C1-6haloalkyl, -C(O)R’ , -C(O)N(R’)2, -C(O)OR’, -S(O)R’, -S(O)N(R’)2, -S(O)2R’, -S(O)2N(R')2, -P0(R')2, -PO2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocyclenyl, 6-12 membered aryl, and 5-12 membered heteroaryl; wherein the -C1-6alkyl, -C2-6alkenyl, -C2-ealkynyl, -C1-6haloalkyl , 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl each is independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from: deuterium, halogen, -Ci ealkyl, -C2-6 alkenyl, -C2-6alkynyl, -C1-6haloalkyl, -CN, oxo, -C1-6alkyl-CH(R')2, -OR', -SR', -C(O)R', -C(0)N(R')2, -C(O)OR’, -OC(O)R’, -OC(O)N(R’)2, -N(R’)2, -NR’C(O)R’, -NR’C(O)OR’, -NR’C(O)N(R’)2, -S(O)R’, - S(O)N(R’)2, -NR’S(O)R’, -NR’S(O)N(R’)2, -S(O)2R’, -S(O)2N(R’)2, -NR’S(O)2R’, -NR’S(O)2N(R’)2, - PO(R')2, -PO2, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, and 5-12 membered heteroaryl;Rn and RJ2are independently selected from: hydrogen, -OH, deuterium, halogen, -CN, oxo, - C1-6alkyl, -C1-6haloalkyl, -C1-6.alkoxy, -NH2, -NHC1-6alkyl, -N(C1-6alkyl)2or 3-6 membered cycloalkyl; wherein said -C1-6alkyl, -C1-6.alkoxy and 3-6 membered cycloalkyl independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from:-OH, deuterium, halogen, -CN, oxo, -Ci- 6 alkoxy, -NH-C1-6 alkyl, -N(Ci-4alkyl)2, and 3-6 membered cycloalkyl;R13 is hydrogen, -C1-6.alkyl or 3-6 membered cycloalkyl; wherein said -C1-6.alkyl and 3-6 membered cycloalkyl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents: -OH, deuterium, halogen, -CN, oxo, -C1-6 alkoxy, -NH2, -NHC1-6 alkyl, or - N(Ci-4alkyl)2; each occurrence of R' is independently selected from hydrogen, deuterium, halogen, -OH, - CN, oxo, -NH2, -NHCrealkyl, -N(C1-6alkyl)2, -C1-6alkyl, -C1-6alkylOC1-6alkyl, -Crealkyl-NHCre alkyl, -C1-6alkyl-N(C1-6alkyl)2, -Ci r.haloalkyl, -OC1-6alkyl, -C3 ucycloalkyl, -C3 uheterocycloalkyl, -C2. ealkenyl, -C2-6alkynyl, 6-12 membered aryl, and 5-12 membered heteroaryl, and each occurrence of each R' is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of deuterium, halogen, -CN, optionally substituted -C1-6 alkyl, optionally substituted - C1-6> haloalkyl, oxo, -OH, optionally substituted -OC1-6alkyl, -NH2, optionally substituted -NHC1-6 alkyl, optionally substituted -N(C1-6alkyl)2, -C(=O)NH2, optionally substituted -C(=O)NHC1-6alkyl, optionally substituted -C(=O)N(Ci=ealkyl)2, optionally substituted -C(=O)OC1-6alkyl, -S(=O)2NH2, optionally substituted -S(=O)2NHC1-6alkyl, optionally substituted-S(=O)2C1-6alkyl, optionally substituted-S(=O)2N(C1-6alkyl)2, optionally substituted 3-6 membered cycloalkyl, optionally substituted -C1-6alkyl-(3-6 membered cycloalkyl), optionally substituted 3-6 membered heterocycloalkyl, optionally substituted -C1-6 alkyl-(3-6 membered heterocycloalkyl), and optionally substituted -PO(C1-6alkane)2;wherein the optionally substituted comprises optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from the group consisting of: -OH, deuterium, halogen, -CN, oxo, -C1-6alkyl, -C1-6haloalkyl, -C1-6.alkoxy, -C1-6haloalkoxy, -C1-6.alkyl-C1-6.alkoxy base, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2, -COOH, -COOC1-6alkyl, -C(=O)NH2, -C(=O)NH( C1-6alkyl), -C (=O)N(C,.6alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-6alkyl), -S(=O)2C1-6alkyl, -S(=O)2N(C1-6alkyl)2, -PO(C1-6alkyl)2, 3-6 membered cycloalkyl, -C1-6 alkyl-(3-6 membered cycloalkyl), 3-6 membered heterocycloalkyl, and -C1-6alkyl-(3-6 membered heterocycloalkyl); wherein the heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contain 1, 2, or 3 heteroatoms selected from N, O, P, and S; m is selected from 0, 1, 2, 3, 4, 5 or 6; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0236] In certain embodiments, B is any compound described in International Patent Application No. PCT / CN2022 / 115635 (published March 2, 2023), which is incorporated herein by reference. In certain embodiments, B is of the formula:wherein,Ring A is aryl or heteroaryl;Ring B is aryl or heteroaryl;C ring is C3-8 cycloalkyl or 4-to- 12-membered heterocyclic group;D is a chemical bond, -C=C-, -CRa=CRa-, or a C3-6 cyclic group;E is chemical bond, -(CRaRa)q-, -O-, -NRb-, C3-6 cyclic group, or 3-to-6-membered heterocyclic group;F is a chemical bond, -NRb-, -O-, or -(CRaRa)q-;U is chemical bond, -NRC-, -O-, -NRCC(O)RC-, or -NRCC(O)-; each of the above Rais independently selected from hydrogen, halogen, C1-4 alkyl, ORb, CN, and NRbRb; each Rband Rcare independently selected from hydrogen, C1-4 alkyl, Ci .4 haloalkyl, C3-6 cycloalkyl, and 3 -to- 8 -membered heterocyclic group; in addition to one substituent, the cycloalkyl or heterocyclic group is optionally substituted by =M;M is O or CReRe; or two Rband the nitrogen atoms connected to them together form an optionally substituted 4-to-8-membered ring structure, which may additionally contain 0-1 heteroatoms selected from N, O, and S;R1is hydrogen, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, 3 -to- 8 -membered heterocyclyl, aryl, heteroaryl, C(O)Rd, or S(O)2Rd; wherein the alkyl, cycloalkyl, heterocyclyl are optionally substituted by one or more groups selected from the group: halogen, CN, ORb, SRb,and NRbRb; the cycloalkyl and heterocyclic groups are optionally substituted by =M;M is selected from O or CReRe; each Reis independently hydrogen, fluorine, or C1-4 alkyl; wherein the alkyl in the Reis optionally substituted with CN, ORb, SRb, NRbRb, or C(O)ORb;Rdis C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C36 cycloalkyl, 3 -to- 8 -membered heterocyclic group, aryl group, or heteroaryl group; in addition to general substituents, the cycloalkyl or heterocyclic group is optionally substituted by =M; M is selected from O or CReRe; Rbis as defined above; each R2 is independently hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C2 4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3-to-6-membered heterocyclyl, CN, ORb, SRb, or NRbRb;Rbis as defined above;R3 is hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3 -to- 8 -membered heterocyclyl, aryl , heteroaryl, CN, ORb, SRb, NRbRb, C(O)Rd, C(O)ORb, C(O)NRbRb, C(O)N(ORb)Rb, NRbC(O)Rd, NRbS(O)2Rd, S(O)2Rd, S(O)(NRb)Rd, S(O)Rd, NRbS(O)2Rd, S(O)2NRbRb, NRbS(O)2NRbRb, P(O)RfRf, P(O)(NRbRb)Rf, or P(O)(ORb)Rf; the definitions of each Rband Rdare as stated above; or two Rbtogether with the nitrogen atoms connected to them form any substituted 4-to-8- membered ring structure; wherein the ring structure can additionally contain 0-1 heteroatoms optionally selected from N, O, and S; the ring structure is optionally substituted by =M;M is selected from O or CReRe; each Rfis each independently C1-4 alkyl, C3 6 cycloalkyl, 3 -to- 8 -membered heterocyclyl, aryl, heteroaryl, ORb, NRbRb; or two Rftogether with the phosphorus atom connected to them to form an optionally substituted 4-to- 8 -membered ring structure, which may additionally contain 0-1 heteroatoms optionally selected from N, O, and S; the alkyl, cycloalkyl, heterocyclyl, or ring structures in Rfare optionally substituted with hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3- 6cycloalkyl, 3-to-6- membered heterocyclyl, CN, ORb, SRb, NRbRb, or =0;Rbis as defined above; each R4is independently selected from hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, hydroxyl, C1-4 alkoxy, C1-4 haloalkoxy, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, C2-4 haloalkynyl, C3 6 cycloalkyl, 3 -to- 8 -membered heterocyclyl, C2-4 alkenyl-O-, C2-4 haloalkenyl -O-, C2-4 alkynyl-O-, C2-4 haloalkynyl-O-, C3-6 cycloalkyl-O-, 3 -to- 8 -membered heterocyclyl-O-, CN, SRb, NRbRb, C(O)Rd, C(O)ORb, and C(O)NRbRb; the alkyl, alkoxy, cycloalkyl, and heterocyclyl are optionally substituted with one or more of halogen, CN, ORb, SRb, and NRbRb; or the cycloalkyl and heterocyclic group is optionally substituted by =M;M is selected from O or CReRe; each Reis independently selected from hydrogen, fluorine, and C1-4 alkyl; the alkyl of Reis optionally substituted with CN, ORb, SRb, NRbRb, or C(O)ORb; the definitions of each Rband Rdare as above; or the Rain R4and E and the ring atoms on the F and B rings connected to it together form an optionally substituted 6-to- 8 -membered ring structure; or R4and Rbin F and the ring atoms on the B ring to which it is connected together form an optionally substituted 6-to- 8 -membered ring structure;R5is hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3 -to- 8 -membered heterocyclyl, CN, ORb, SRb, NRbRb, C(O)Rd, C(O)ORb, C(O)NRbRb, C(O)NRb(ORb), NRbC(O)Rd, NRbS(O)2Rd, S(O)2Rd, S(O)(NRb)Rd, S(O)Rd, NRbS(O)2Rd, or S(O)2NRbRb; each Rbis independently hydrogen, C1-4 alkyl, or C1-4 haloalkyl; or two Rbtogether with the nitrogen atoms connected to them form an optionally substituted 4-to=8-membered ring structure, which can additionally contain 0-1 heteroatoms optionally selected from N, O, and S;Rdis selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, and 3-to-6- membered heterocyclyl;R5, Rb, Rdin the alkyl, cycloalkyl and heterocyclyl are optionally substituted by one or more groups selected from the group consisting of halogen, C1-4 alkyl, C3-6 cycloalkyl, 3-to-6-membered heterocyclyl, CN , ORb, SRb, and NRbRb; or the cycloalkyl and heterocyclyl in R5are optionally substituted by C=M;M is selected from O or CReRe; each Reis independently hydrogen, fluorine, or C1-4 alkyl group; the alkyl group of Reis optionally substituted with CN, ORb, SRb, NRbRb, or C(O)ORb; the definition of each Rbis as stated above; each R6is independently hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, hydroxyl, C1-4 alkoxy, C1-4 haloalkoxy, C3 6 cycloalkyl, 3-to-6-membered heterocyclyl, CN, SRb, NRbRb;each Rbis defined as above; m is selected from 0, 1, 2, 3, or 4; n is selected from 0, 1, 2, 3, or 4; p is selected from 0, 1, 2, 3, or 4; q is selected from 0, 1, 2, or 3; wherein, each of the above-mentioned alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups is optionally and independently replaced by 1-3 substituents independently selected from the halogen, Ci-4 alkyl, Ci-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-8 cycloalkyl, 3 -to- 8 -membered heterocyclyl, aryl, heteroaryl base, CN, NO2, ORb, SRb, NRbRb, C(O)Rd, C(O)ORb, C(O)NRbRb, NRbC(O)Rd, NRbS(O)2Rd, and S(O)2Rd, provided that the formed chemical structure is stable; wherein each Rbis independently hydrogen, C1-4 alkyl, or C1-4 haloalkyl; or two Rband the nitrogen atom connected to them together form an optionally substituted 4-to-8-membered ring structure, which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; each Rdis independently selected from C1-4 alkane base, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3-to-8- membered heterocyclyl, aryl, or heteroaryl; unless otherwise specified, the above-mentioned aryl group is an aromatic group containing 6-12 carbon atoms; the heteroaryl group is a 5 -to- 15 -membered (preferably 5 -to- 12- membered) heteroaromatic group; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0237] In certain embodiments, B is any compound described in Chinese Patent Application No. 202211077205, which is incorporated herein by reference. In certain embodiments, B is of the of formula:wherein:* and # are used to denote bond connection positions; ring D is:in ring Di and ring D2, each of Ai, A2, A3 and A4 is independently N or CH; in ring D3, Bi, B3 and B4 are each independently CH, N, NH, O or S; B2 and B5 are each independently C or N; each R is independently F, Cl, Br, I, -CN, C1-4 alkyl, C1-4 alkoxy or halogenated C1-4 alkyl;M isZ, is C(R3), N, O or N(R4);Z2is C(R5), N, O or N(R6);Z3 is CH or N;Z4 is CH or N; each L2 is independently -NH-, -CH2-, -O- or -S-; ring Qi and ring Q2 are each independently a saturated or partially unsaturated 5-10 membered carbocyclic ring, a saturated or partially unsaturated 5-10 membered heterocyclic ring, a 6- 10 membered aromatic ring, a 5-10 membered heteroaromatic ring, or 8-10 membered bicyclic rings; one ring in the 8-10 membered bicyclic rings is a saturated or partially unsaturated 5-6 membered carbocyclic ring, or a saturated or partially unsaturated 5-6 membered heterocyclic ring, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring; in ring D3 and ring C, the" bond is a double bond or a single bond, provided that ring D3 and ring C are aromatic rings;R3, R4, R5 and Re are each independently H, C1-4 alkyl or halogenated C1-4 alkyl;RAand RBare independently H, halogen or C1-4 alkyl;Li is absent or -C(O)-; ring B is a saturated or partially unsaturated 3 -to- 10-membered carbocyclic ring, a saturated or partially unsaturated 3 -to- 10-membered heterocyclic ring, a 6-to- 10-membered aromatic ring, a 5- to- 10-membered heteroaromatic ring, or a 6-to- 10-membered bicyclic fused ring; one ring in the 6-10membered bicyclic fused ring is a saturated or partially unsaturated 5-6 membered carbocyclic ring or a saturated or partially unsaturated 5-6 membered heterocyclic ring, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring; each R2 is independently F, Cl, Br, I, =0, -CN, -NH2, -NHRd, -NRdRe, C1-4 alkyl, C1-4 alkyl substituted by 1, 2 or 3 Rc, C1-4 alkoxy, C1-4 alkoxy substituted by 1, 2 or 3 Rc, halogenated C1-4 alkyl, - C(0)NHRd, -C(0)NRdRe, -C(0)0Rdor -SO2Rd; each Ri is independently F, Cl, Br, I, -NH2, =0, -NHRd, -NRdRe, C1-4 alkyl, C1-4 alkyl substituted by 1, 2 or 3 Rh, C1-4 alkoxy, C1-4 alkoxy substituted by 1, 2 or 3 Rh, halogenated C1-4 alkyl, 3-10 membered cycloalkyl, or 3-10 membered heterocycloalkyl (for exampleeach Rd and Reis independently H, C1-4 alkyl, or C1-4 alkyl substituted by 1, 2 or 3 Rt>; each Rc, Rb and Rh is independently -OH, -ORf, -NH2, -NHRf or -NRfRg; each Rf and Rgis independently C1-4 alkyl or -Boc; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; the number of heteroatoms in the heterocycle, heterocycloalkyl, heteroaryl ring and heteroaryl is 1, 2 or 3, and each heteroatom is N, O, or S; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0238] In certain embodiments, B is any compound described in International Patent Application No. PCT / CN2023 / 079047, which is incorporated herein by reference. In certain embodiments, B is of the formula:wherein:* and # are used to bond connection positions; ring D isin ring Di and ring D2, each Ai, A2, A3 and A4 are independently N or CH; in ring D3, Bi, B3 and B4 are each independently CH, N, NH, O or S; B2 and B5 are each independently C or N; each Rais independently F, Cl, Br, I, C1-4 alkyl, C1-4 alkoxy or halo C1-4 alkyl;Z, is C(R3), N, O or N(R4);Z2is C(R5), N, O or N(R6);Z3 is CH or N;Z4, Z5 and Ze are independently C(R?) or N; each L2 is independently -NH-, -CH2-, -O-, or -S-; ring Qi and ring Q2 are each independently a saturated or partially unsaturated 5-10-membered carbocyclic ring, a saturated or partially unsaturated 5-10-membered heterocyclic ring, a 6-10- membered aromatic ring, a 5-10-membered heteroaromatic ring, or 8-10 membered bicyclic ring; one of the 8-10 membered bicyclic ring is a saturated or partially unsaturated 5-6 membered carbocyclic ring, or a saturated or partially unsaturated 5-6 membered heterocyclic ring, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring; in ring D3 and ring C, the “ — "bond is a double bond or a single bond, provided that ring D3 and ring C are aromatic rings;R3, R4, R5 and Re are each independently H, C1-4 alkyl or halogenated C1-4 alkyl; each R7 is independently -H, -F, -Cl, C1-4 alkyl, haloCi-4 alkyl, C1-4 alkoxy, -OH or -CN;Li does not exist; ring B is a saturated or partially unsaturated 3-10-membered carbocyclic ring, a saturated or partially unsaturated 3-10-membered heterocyclic ring, a 6-10-membered aromatic ring, a 5-10- membered heteroaromatic ring or a 6-10-membered bicyclic ring; one of the 6-10 membered bicyclic rings is a saturated or partially unsaturated 5-6 membered carbocyclic ring, or a saturated or partiallyunsaturated 5-6 membered heterocyclic ring, and the other ring is a benzene ring or 5-6 membered heteroaromatic ring; each R2 is independently F, Cl, Br, I, -NH2, -NHRd, -NRdRe, C1-4 alkyl, C1-4 alkyl substituted by 1, 2 or 3 Rc, C1-4 alkoxy, C1-4 alkoxy substituted by 1, 2 or 3 Rc, halogenated C1-4 alkyl, C3-10 cycloalkyl, C3 10 cycloalkyl substituted by 1, 2 or 3 Rc , -C(O)NHRd, -C(O)NRdRe, -C(O)ORd or -SO2K1; each Ri is independently F, Cl, Br, I, -NH2, =0, -NHRd, -NRdRe, C1-4 alkyl, C1-4 alkyl substituted by 1, 2 or 3 Rh, C1-4 alkoxy, C1-4 alkoxy substituted by 1, 2 or 3 Rh, halogenated C1-4 alkyl, 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl (such aseach Rd and Reare independently C35 cycloalkyl, C1-4 alkyl, or C1-4 alkyl substituted by 1, 2 or 3 Rt>; each Rc, Rb and Rh are independently -OH, -ORf, -NH2, -NHRf or -NRfRg; each Rf and Rgis independently a C1-4 alkyl group; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; the number of heteroatoms in the heterocycle, heterocycloalkyl, heteroaromatic ring and heteroaryl is 1, 2 or 3, and each heteroatom is independently N, O or S; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0239] In certain embodiments, B is any compound described in U.S. Patent Application U.S.S.N.18 / 160,060, which is incorporated herein by reference. In certain embodiments, B is of the formula:wherein:R1is selected from aryl, heteroaryl, and heterocyclyl, each of which is independently unsubstituted or substituted with one, two or three substituents selected from a hydroxyl group, sulfhydryl group, halogen, amino group, nitro group, nitroso group, cyano group, azido group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine group, alkyl group, halo-alkyl group, alkenyl group, halo-alkenyl group, alkynyl group, halo-alkynyl group, alkoxy group, aryl group, aryloxy group, aralkyl group, arylalkoxy group, heterocyclyl group, acyl group, acyloxy group, carbamate group, amide group, ureido group, epoxy group, -P(O)R2i , and an ester group;R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently unsubstituted or substituted with one, two or three substituents selected from a hydroxyl group, sulfhydryl group, halogen, amino group, nitro group, nitroso group, cyano group, azido group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine group, alkyl group, haloalkyl group, alkenyl group, halo-alkenyl group, alkynyl group, halo-alkynyl group, alkoxy group, aryl group, aryloxy group, aralkyl group, arylalkoxy group, heterocyclyl group, acyl group, acyloxy group, carbamate group, amide group, ureido group, epoxy group, -P(0)R2i, and an ester group; or hydrogen, -C(0)R2i, -C(0)0R2i, -C(O)NR2iR22, -OR21, -SR21, -NR21R22, -NR2IC(O)R22, or -0C(0)R2i;R3is H;R4 is heterocyclyl substituted with one, two, or three substituents selected from a halogen group, a hydroxyl group, sulfhydryl group, halogen, amino group, nitro group, nitroso group, cyano group, azido group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine group, alkyl group, halo-alkyl group, alkenyl group, halo-alkenyl group, alkynyl group, halo-alkynyl group, alkoxy group, aryl group, aryloxy group, aralkyl group, arylalkoxy group, heterocyclyl group, acyl group, acyloxy group, carbamate group, amide group, ureido group, epoxy group, -P(0)R2i, and an ester group; and each R21 and R22 is independently hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, wherein the compound is optionally substituted with at least one deuterium; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0240] In certain embodiments, B is of the of formula:wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

[0241] In certain embodiments, B binds p53 with a Kd of less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

[0242] In certain embodiments, B selectively binds p53 as compared to another substrate (e.g., protein). In certain embodiments, the selectivity is from about 2-fold to about 5-fold. In certain embodiments, the selectivity is from about 5 -fold to about 10-fold. In certain embodiments, the selectivity is from about 10-fold to about 20-fold. In certain embodiments, the selectivity is from about 20-fold to about 50-fold. In certain embodiments, the selectivity is from about 50-fold to about 100-fold. In certain embodiments, the selectivity is from about 100-fold to about 200-fold. In certain embodiments, the selectivity is from about 200-fold to about 500-fold. In certain embodiments, the selectivity is from about 500-fold to about 1000-fold. In certain embodiments, the selectivity is at least about 1000-fold.IL KB

[0243] As described herein, KB is a kinase binding moiety or a detectable moiety.

[0244] In certain embodiments, KB is a kinase binding moiety. In certain embodiments, KB is a kinase inhibitor or kinase activator. In certain embodiments, KB is a kinase inhibitor. In certain embodiments, KB is a kinase activator. In certain embodiments, KB is a serine / threonine kinase. In certain embodiments, KB is a serine / threonine kinase expressed in the cell nucleus.

[0245] In certain embodiments, KB is a Protein Kinase C (PKC (e.g., PKC-Q); AMPK; ABL; ABL1; SRC; BTK; ATM; ATR; DNA-PK; PDPK1; PK; MAPK (e.g., MAPK1, MAPK11, MAPK12, MAPK13, MAPK14, p38a MAPK); EGFR; FGFR; NGFR; TrkA; ABL; CDK (e.g., CDK2, CDK4, CDK8); PI3K; VEGFR; BRAF; MEK (e.g., MEK1 / 2, MEK5); AKT; ALK; BTK; BCKDK; FLT3; JAK2; AURKA; c-MET; DDR; INSR; JNK; IK|3; IKK; Lyn; mTOR (e.g., mTORC-1); PAK; PDK (e.g., PDK1 or PDK2); PTK2 / FAK; pyruvate kinases; RAC-a; RIPK; TYK2; SHP; NOP; GPC family (e.g., p opioid receptor or 5 opioid receptor); UMPK; SphK; or GSK-3 binding moiety.

[0246] In certain embodiments, KBis a PKC, AMPK, ATM, ATR, DNA-PK, PDPK1, MAPKs, CDK, PI3K, MEK, AKT, AURKA, JNK, IK|3 (IKK), mTOR, PAK, PDK, RAC-a, RIPK, GSK-3 binding moiety.

[0247] In certain embodiments, KBis an AMPK, ATM, ATR, DNA-PK, MAPKs, CDK, PI3K, AKT, AURKA, PAK, PDK, RAC-a, GSK-3 binding moiety.

[0248] In certain embodiments, KB is a PKC binding moiety, an AMPK binding moiety, a PDPK1 binding moiety, or an ABL1 binding moiety.

[0249] In certain embodiments, KB is a PKC binding moiety, an AMPK binding moiety, or a PDPK1 binding moiety.

[0250] In certain embodiments, KB is a PKC binding moiety. In certain embodiments, KB is an AMPK binding moiety. In certain embodiments, KB is a PDPK1 binding moiety. In certain embodiments, KB is an ABL1 binding moiety.

[0251] In certain embodiments, KB is any kinase binding moiety in International Patent Application No. PCT / US2022 / 080175, incorporated herein by reference.a. KB-1

[0252] In certain embodiments, KB is an AMPK binding moiety. In certain embodiments, KB is of formula:wherein:Rlkis -C(=O)ORA, -C(=O)N(RA)2, -C(=O)NRAS(O)2RA, -S(O)2ORA, -S(O)2N(RA)2, -S(O)2NHC(O)RA, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl; each of R2k, R3k, and R4kis independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, -N(RA)2, -ORA, or -SRA;R5kis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group;R6kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, -N(RA)2, -ORA, -SRA, -C(=O)ORA, -C(=O)N(RA)2, - NRAC(=O)RA, -C(=O)RA, -NRAC(=O)ORA, -NRAC(=O)N(RA)2, -OC(=O)RA, -OC(=O)ORA, - OC(=O)N(RA)2, -S(O)2N(RA)2, or -NRAS(O)2RA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.Rlk

[0253] As described herein, Rlkis -C(=O)ORA, -C(=O)N(RA)2, -C(=O)NRAS(O)2RA, -S(O)2ORA, - S(O)2N(RA)2, -S(O)2NHC(O)RA, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.

[0254] In certain embodiments, Rlkis -C(=O)ORA, -C(=O)N(RA)2, -C(=O)NRAS(O)2RA, - S(O)2ORA, -S(O)2N(RA)2, or -S(O)2NHC(O)RA. In certain embodiments, Rlkis -C(=O)ORA. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis hydrogen or substituted or unsubstituted alkyl. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis substituted or unsubstituted alkyl. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis substituted or unsubstituted Ci-4 alkyl. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis unsubstituted Ci-4 alkyl. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis t-butyl. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis t- butyl or hydrogen. In certain embodiments, Rlkis -C(=O)OH.R2k

[0255] As described herein, R2kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, - N(RA)2, -ORA, or -SRA.

[0256] In certain embodiments, R2kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, R2kis hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R2kis hydrogen.R3k

[0257] As described herein, R3kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, - N(RA)2, -ORA, or -SRA.

[0258] In certain embodiments, R3kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, R3kis hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R3kis halogen. In certain embodiments, R3kis chloro.R4k

[0259] As described herein, R4kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, - N(RA)2, -ORA, or -SRA.

[0260] In certain embodiments, R4kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, R4kis hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R4kis hydrogen.RlkR2kR3kmd R4k

[0261] In certain embodiments, Rlkis -C(=O)ORA; and R2k, R3k, and R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, Rlkis -C(=O)OH; and R2k, R3k, and R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl.

[0262] In certain embodiments, Rlkis -C(=O)ORA; R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis halogen. In certain embodiments, Rlkis - C(=O)ORA; R2kand R4kare each hydrogen; and R3kis halogen. In certain embodiments, Rlkis - C(=O)ORA, wherein RAis substituted or unsubstituted C1-4 alkyl (e.g., unsubstituted Ci-4 alkyl, e.g., t- butyl); R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis halogen. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis substituted or unsubstituted Ci-4 alkyl (e.g., unsubstituted C1-4 alkyl, e.g., t-butyl); R2kand R4kare each hydrogen; and R3kis halogen. In certain embodiments, Rlkis -C(=O)OH; R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis halogen. In certain embodiments, Rlkis -C(=O)OH; R2kand R4kare each hydrogen; and R3kis halogen.

[0263] In certain embodiments, Rlkis -C(=O)ORA; R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis chloro. In certain embodiments, Rlkis - C(=O)ORA; R2kand R4kare each hydrogen; and R3kis chloro. In certain embodiments, Rlkis - C(=O)ORA, wherein RAis substituted or unsubstituted C1-4 alkyl (e.g., unsubstituted CM alkyl, e.g., t- butyl); R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis chloro. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis substituted or unsubstituted C1-4 alkyl (e.g., unsubstituted C1-4 alkyl, e.g., t-butyl); R2kand R4kare each hydrogen; and R3kis chloro. In certain embodiments, Rlkis -C(=O)OH; R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis chloro. In certain embodiments, Rlkis -C(=O)OH; R2kand R4kare each hydrogen; and R3kis chloro.R5k

[0264] As described herein, R5kis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group. In certain embodiments, R5kis hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted alkyl. In certain embodiments, R5kis hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R5kis hydrogen.R6k

[0265] As described herein, R6kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, -N(RA)2, -ORA, -SRA, -C(=O)ORA, - C(=O)N(RA)2, -NRAC(=O)RA, -C(=O)RA, -NRAC(=O)ORA, -NRAC(=O)N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)N(RA)2, -S(O)2N(RA)2, or -NRAS(O)2RA. In certain embodiments, R6kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl. In certain embodiments, R6kis hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R6kis hydrogen.Embodiments of KB- 1

[0266] In certain embodiments, KB is of formula:(KB-la).

[0267] In certain embodiments, KB is of formula:

[0268] In certain embodiments, KB is of formula:(KB-1C).

[0269] In certain embodiments, KB is of formula:b. KB-2

[0270] In certain embodiments, KB is an AMPK binding moiety. In certain embodiments, KB is of formula:wherein:V1is CR2kor N;V2is CR3kor N;V3is CR6kor N; provided that at least one of V1, V2, or V3is N;Rlkis -C(=O)ORA, -C(=O)N(RA)2, -C(=O)NRAS(O)2RA, -S(O)2ORA, -S(O)2N(RA)2, -S(O)2NHC(O)RA, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl; each of R2k, R3k, and R4kis independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, -N(RA)2, -ORA, or -SRA;R5kis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group;R6kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, -N(RA)2, -ORA, -SRA, -C(=O)ORA, -C(=O)N(RA)2, -NRAC(=O)RA, -C(=O)RA, -NRAC(=O)ORA, -NRAC(=O)N(RA)2, -OC(=O)RA, -OC(=O)ORA, - OC(=O)N(RA)2, -S(O)2N(RA)2, or -NRAS(O)2RA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.V1, V2, and V'

[0271] As described herein, V1is CR2kor N; V2is CR3kor N; and V3kis CR6kor N; provided that at least one of V1, V2, or V3is N.

[0272] In certain embodiments, V1is CR2k. In certain embodiments, V1is N. In certain embodiments, V2is CR2k. In certain embodiments, V2is N. In certain embodiments, V3is CR2k. In certain embodiments, V3is N. In certain embodiments, V1is N; V2is CR3k; and V3is CR6k. In certain embodiments, V1is CR2k; V2is N; and V3is CR6k. In certain embodiments, V1is CR2k; V2is CR3k; and V3is N.Rlk

[0273] As described herein, Rlkis -C(=O)ORA, -C(=O)N(RA)2, -C(=O)NRAS(O)2RA, -S(O)2ORA, - S(O)2N(RA)2, -S(O)2NHC(O)RA, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.

[0274] In certain embodiments, Rlkis -C(=O)ORA, -C(=O)N(RA)2, -C(=O)NRAS(O)2RA, - S(O)2ORA, -S(O)2N(RA)2, or -S(O)2NHC(O)RA. In certain embodiments, Rlkis -C(=O)ORA. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis hydrogen or substituted or unsubstituted alkyl. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis substituted or unsubstituted alkyl. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis substituted or unsubstituted Ci-4 alkyl. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis unsubstituted Ci-4 alkyl. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis t-butyl or hydrogen. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis t-butyl. In certain embodiments, Rlkis -C(=O)OH.R2k

[0275] As described herein, R2kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, - N(RA)2, -ORA, or -SRA.

[0276] In certain embodiments, R2kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, R2kis hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R2kis hydrogen, halogen, or unsubstituted alkyl. In certain embodiments, R2kis fluoro. In certain embodiments, R2kis hydrogen.R3k

[0277] As described herein, R3kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, - N(RA)2, -ORA, or -SRA.

[0278] In certain embodiments, R3kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, R3kis hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R3kis hydrogen. In certain embodiments, R3kis halogen. In certain embodiments, R3kis fluoro. In certain embodiments, R3kis bromo. In certain embodiments, R3kis chloro.R4k

[0279] As described herein, R4kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, - N(RA)2, -ORA, or -SRA.

[0280] In certain embodiments, R4kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, R4kis hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R4kis hydrogen, halogen, or unsubstituted alkyl. In certain embodiments, R4kis halogen. In certain embodiments, R4kis fluoro. In certain embodiments, R4kis hydrogen.RIk, R2k, R3k, and RJk

[0281] In certain embodiments, Rlkis -C(=O)ORA; and R2k, R3k, and R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, Rlkis -C(=O)OH; and R2k, R3k, and R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl.

[0282] In certain embodiments, Rlkis -C(=O)ORA; R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis halogen. In certain embodiments, Rlkis - C(=O)ORA; R2kand R4kare each hydrogen; and R3kis halogen. In certain embodiments, Rlkis - C(=O)ORA, wherein RAis substituted or unsubstituted C1-4 alkyl (e.g., unsubstituted CM alkyl, e.g., t- butyl); R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis halogen. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis substituted or unsubstituted C1-4 alkyl (e.g., unsubstituted C1-4 alkyl, e.g., t-butyl); R2kand R4kare each hydrogen; and R3kis halogen. In certain embodiments, Rlkis -C(=O)OH; R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis halogen. In certain embodiments, Rlkis -C(=O)OH; R2kand R4kare each hydrogen; and R3kis halogen.

[0283] In certain embodiments, Rlkis -C(=O)ORA; R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis chloro. In certain embodiments, Rlkis - C(=O)ORA; R2kand R4kare each hydrogen; and R3kis chloro. In certain embodiments, Rlkis - C(=O)ORA, wherein RAis substituted or unsubstituted C1-4 alkyl (e.g., unsubstituted CM alkyl, e.g., t- butyl); R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis chloro. In certain embodiments, Rlkis -C(=O)ORA, wherein RAis substituted or unsubstituted C1-4 alkyl (e.g., unsubstituted C1-4 alkyl, e.g., t-butyl); R2kand R4kare each hydrogen; and R3kis chloro. In certain embodiments, Rlkis -C(=O)OH; R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis chloro. In certain embodiments, Rlkis -C(=O)OH; R2kand R4kare each hydrogen; and R3kis chloro.R5k

[0284] As described herein, R5kis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group. In certain embodiments, R5kis hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted alkyl. In certain embodiments, R5kis hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R5kis hydrogen or unsubstituted alkyl. In certain embodiments, R5kis hydrogen.R6

[0285] As described herein, R6kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, -N(RA)2,-ORA, -SRA, -C(=O)ORA, -C(=O)N(RA)2, -NRAC(=O)RA, -C(=O)RA, -NRAC(=O)ORA, - NRAC(=O)N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)N(RA)2, -S(O)2N(RA)2, or -NRAS(O)2RA. In certain embodiments, R6kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl. In certain embodiments, R6kis hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R6kis hydrogen, halogen, or unsubstituted alkyl. In certain embodiments, R6kis halogen. In certain embodiments, R6kis fluoro. In certain embodiments, R6kis methyl. In certain embodiments, R6kis hydrogen.Embodiments of KB-2

[0286] In certain embodiments, KB is of formula:(KB-2a).

[0287] In certain embodiments, KB is of formula:(KB-2b).

[0288] In certain embodiments, KB is of formula:(KB-2C).

[0289] In certain embodiments, KB is of formula:(KB-2d).

[0290] In certain embodiments, KB is of formula:

[0291] In certain embodiments, KB is of formula:(KB-2f).

[0292] In certain embodiments, KB is of formula:(KB-2g).

[0293] In certain embodiments, KB is of formula:(KB-2h).

[0294] In certain embodiments, KB is of formula:(KB-2i).

[0295] In certain embodiments, KB is of formula:(KB-2j).

[0296] In certain embodiments, KB is of formula:b. KB-3

[0297] In certain embodiments, KB is of formula:wherein:V1is CR2kor N; each of R2k, R3k, and R4kis independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, -CN, -N(RA)2, -ORA, or -SRA;R5kis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group;R6kis -ORC, -N(RB)2, or substituted or unsubstituted alkyl; each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; each occurrence of RBis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group, or two RBgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic ring; andRcis substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group.V1

[0298] As described herein, V1is CR2kor N. In certain embodiments, V1is CR2k. In certain embodiments, V1is N.R2k

[0299] As described herein, R2kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, -CN, - N(RA)2, -ORA, or -SRA.

[0300] In certain embodiments, R2kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, R2kis hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R2kis hydrogen, halogen, or unsubstituted alkyl. In certain embodiments, R2kis halogen. In certain embodiments, R2kis fluoro. In certain embodiments, R2kis hydrogen.R3k

[0301] As described herein, R3kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, -CN, - N(RA)2, -ORA, or -SRA.

[0302] In certain embodiments, R3kis hydrogen, -CN, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, R3kis hydrogen, -CN, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R3kis substituted or unsubstituted alkyl. In certain embodiments, R3kis -CH3 or -CF3. In certain embodiments, R3kis -CH3. In certain embodiments, R3kis -CF3. In certain embodiments, R3kis hydrogen. In certain embodiments, R3kis halogen. In certain embodiments, R3kis fluoro. In certain embodiments, R3kis bromo. In certain embodiments, R3kis chloro. In certain embodiments, R3kis - CN. / Cz'

[0303] As described herein, R4kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, -CN - N(RA)2, -ORA, or -SRA.

[0304] In certain embodiments, R4kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, R4kis hydrogen, halogen, or substituted or unsubstituted alkyl. In certainembodiments, R4kis hydrogen, halogen, or unsubstituted alkyl. In certain embodiments, R4kis halogen. In certain embodiments, R4kis fluoro. In certain embodiments, R4kis hydrogen.R2k, R3k, andR4k

[0305] In certain embodiments, R2k, R3k, and R4kare each independently hydrogen, -CN, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R2k, R3k, and R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl.

[0306] In certain embodiments, R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis halogen. In certain embodiments, R2kand R4kare each hydrogen; and R3kis halogen. In certain embodiments, R4kis hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis halogen. In certain embodiments, R4kis hydrogen; and R3kis halogen.

[0307] In certain embodiments, R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis chloro. In certain embodiments, R2kand R4kare each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis -CN. In certain embodiments, R2kand R4kare each hydrogen; and R3kis chloro. In certain embodiments, R2kand R4kare each hydrogen; and R3kis -CN. In certain embodiments, R4kis hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis chloro. In certain embodiments, R4kis hydrogen, halogen, or substituted or unsubstituted alkyl; and R3kis -CN. In certain embodiments, R4kis hydrogen; and R3kis chloro. In certain embodiments, R4kis hydrogen; and R3kis -CN.R5k

[0308] As described herein, R5kis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group. In certain embodiments, R5kis hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted alkyl. In certain embodiments, R5kis hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R5kis hydrogen or unsubstituted alkyl. In certain embodiments, R5kis hydrogen. In certain embodiments, R5kis a nitrogen protecting group. In certain embodiments, R5kis 2-(trimethylsilyl)ethoxymethyl (SEM).R6k

[0309] As described herein, R6kis -ORC, -N(RB)2, or substituted or unsubstituted alkyl. In certain embodiments, R6kis -ORCor substituted or unsubstituted alkyl.

[0310] In certain embodiments, R6kis substituted or unsubstituted alkyl. In certain embodiments, R6kis unsubstituted alkyl. In certain embodiments, R6kis unsubstituted C1-4 alkyl.

[0311] In certain embodiments, R6kis -N(RB)2- In certain embodiments, R6kis -N(RB)2, wherein each occurrence of RBis, independently, substituted or unsubstituted alkyl, or two RBgroups areattached to the same atom to form a substituted or unsubstituted heterocyclic ring. In certain embodiments,

[0312] In certain embodiments, R6kis -ORC. In certain embodiments, R6kis -ORC, wherein Rcis substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl. In certain embodiments, R6kis -ORC, wherein Rcis substituted or unsubstituted C3-6 cycloalkyl, or substituted or unsubstituted 4-10 membered heterocyclyl.

[0313] In certain embodiments, R6kis -ORC, wherein Rcis substituted or unsubstituted C3-6

[0314] In certain embodiments, R6kis -ORC, wherein Rcis substituted or unsubstituted 4-10 membered heterocyclyl. In certain embodiments, R6kis -ORC, wherein Rcis substituted or unsubstituted 4-6 membered heterocyclyl or a sugar moiety. In certain embodiments, R6kis

[0315] In certain embodiments, R6kis methyl, ethyl, isopropyl,In certain embodiments, R6kis methyl, ethyl, isopropyl,

[0316] In certain embodiments, R6kis methyl. In certain embodiments, R6kis ethyl. In certain embodiments, R6kis isopropyl. In certain embodiments,certain embodiments,certain embodiments, R6kiscertain embodiments, R6kis. In certainembodiments, R6kisIn certain embodiments,certain em ib-od riments,certain embodiments, R6kisIn certain embodiments, R6kis, certain embodiments, R6kis -N(CH3)2- In certain embodiments,

[0317] In certain embodiments, R6kis notcertain embodiments, R6kis notcertain embodiments, R6kis notEmbodiments of KB-3

[0318] In certain embodiments, KB is of formula:(KB-3a).

[0319] In certain embodiments, KB is of formula:(KB-3b).

[0320] In certain embodiments, KB is of formula:(KB-3C).

[0321] In certain embodiments, KB is of formula:(KB-3d).

[0322] In certain embodiments, KB is of formula:(KB-3e).

[0323] In certain embodiments, KB is of formula:(KB-3f).

[0324] In certain embodiments, KB is of formula:(KB-3g).

[0325] In certain embodiments, KB is of formula:(KB-3h).

[0326] In certain embodiments, KB is of formula:

[0327] In certain embodiments, KB is of formula:d. KB-4, KB-5, and KB-6

[0328] In certain embodiments, KB is an PDPK1 binding moiety. In certain embodiments, KB is of formula:wherein:Rlkis substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, or a bond;R2kis substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2kais hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2and R2atogether with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;R3kis -C(=O)ORA, -C(=O)N(RA)2, -C(=O)NRAS(O)2RA, -SO2N(RA)2, -ORA, -N(RA)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;R3kais hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;X is a bond, substituted or unsubstituted methylene, or -NRB-;Y is substituted or unsubstituted methylene or -NRB-; each RBis independently hydrogen, substituted or unsubstituted acyl, -C(=O)N(RA)2, -SO2RA, substituted or unsubstituted alkyl, or a nitrogen protecting group; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

[0329] In certain embodiments, KB is of formula:wherein:Rlkis substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, or a bond;A2is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2kis substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2kais hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2and R2atogether with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;R3kis -C(=O)ORA, -C(=O)N(RA)2, -C(=O)NRAS(O)2RA, -SO2N(RA)2, -ORA, -N(RA)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;R3kais hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;X is a bond, substituted or unsubstituted methylene, or -NRB-;Y is substituted or unsubstituted methylene or -NRB-; each RBis independently hydrogen, substituted or unsubstituted acyl, -C(=O)N(RA)2, -SO2RA, substituted or unsubstituted alkyl, or a nitrogen protecting group; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, anoxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

[0330] In certain embodiments, KB is of formula:

[0331] In certain embodiments, KB is of formula:Rlk

[0332] As described herein, Rlkis substituted or unsubstituted alkylene substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, or a bond.

[0333] In certain embodiments, Rlkis unsubstituted alkylene. In certain embodiments, Rlkis unsubstituted Cwalkylene. In certain embodiments, Rlkis unsubstituted C2-3alkylene. In certain embodiments, Rlkis unsubstituted methylene. In certain embodiments, Rlkis unsubstituted ethylene. In certain embodiments, Rlkis unsubstituted propylene. In certain embodiments, Rlkis unsubstituted butylene.

[0334] In certain embodiments, Rlkis alkylene substituted with alkyl, halogen, or two alkyl substituents on the same carbon of the alkylene form a substituted or unsubstituted cycloalkyl. In certain embodiments, Rlkis alkylene substituted with alkyl, fluoro (e.g., gem- difluoro), or two alkyl substituents on the same carbon of the alkylene form a substituted or unsubstituted cycloalkyl. In certain embodiments, Rlkis alkylene substituted with alkyl, or two alkyl substituents on the same carbon of the alkylene form a substituted or unsubstituted cycloalkyl. In certain embodiments, Rlkis Ci-4alkylene substituted with alkyl, or two alkyl substituents on the same carbon of the alkylene form a substituted or unsubstituted cycloalkyl. In certain embodiments, Rlkis C2-3alkylene substituted with alkyl, or two alkyl substituents on the same carbon of the alkylene form a substituted or unsubstituted cycloalkyl. In certain embodiments, Rlkis C2alkylene substituted with alkyl, or two alkyl substituents on the same carbon of the alkylene form a substituted or unsubstitutedcycloalkyl. In certain embodiments, Rlkis, ,

[0335] In certain embodiments, Rlkis cycloalkyl. In certain embodiments, Rlkis C3- certain embodiments, Rlkiscei-(ajnembodiments, Rlkis

[0336] In certain embodiments, Rlkis substituted or unsubstituted alkenylene, or unsubstituted alkynylene. In certain embodiments, Rlkis substituted or unsubstituted alkenylene. In certain embodiments, Rlkis unsubstituted alkenylene. In certain embodiments, Rlkis unsubstituted ethenylene. In certain embodiments, Rlkis substituted or unsubstituted alkynylene. In certain embodiments, Rlkis unsubstituted alkynylene. In certain embodiments, Rlkis unsubstituted ethynylene.R2k

[0338] As described herein, R2kis substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0339] In certain embodiments, R2kis substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R2kis substituted or unsubstituted heteroaryl.

[0340] In certain embodiments, R2kis unsubstituted heteroaryl or heteroaryl substituted with one or more instances of substituted or unsubstituted alkyl. In certain embodiments, R2kis unsubstituted heteroaryl or heteroaryl substituted with one or more instances ofunsubstituted alkyl. In certain embodiments, R2kis unsubstituted heteroaryl or heteroaryl substituted with one or more instances of unsubstituted Ci-2alkyl.

[0341] In certain embodiments, R2kis unsubstituted monocyclic heteroaryl or monocyclic heteroaryl substituted with one or more instances of substituted or unsubstituted alkyl. In certain embodiments, R2kis unsubstituted monocyclic heteroaryl or monocyclic heteroaryl substituted with one or more instances of unsubstituted alkyl. In certain embodiments, R2kis unsubstituted monocyclic heteroaryl or monocyclic heteroaryl substituted with one or more instances of unsubstituted Ci-2alkyl. In certain embodiments,

[0342] In certain embodiments, R2kis unsubstituted bicyclic heteroaryl or bicyclic heteroaryl substituted with one or more instances of substituted or unsubstituted alkyl. In certain embodiments, R2kis unsubstituted bicyclic heteroaryl or bicyclic heteroaryl substituted with one or more instances of unsubstituted alkyl. In certain embodiments, R2kis unsubstituted bicyclic heteroaryl or bicyclic heteroaryl substituted with one or more instances of unsubstituted Ci-2alkyl.

[0345] In certain embodiments, R2kis substituted or unsubstituted aryl. In certain embodiments, R2kis unsubstituted aryl or aryl substituted with one or more instances of halogen, -CN, cycloalkyl, -ORA, or substituted or unsubstituted alkyl, or wherein two substituents together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl. In certain embodiments, R2kis aryl substituted with one or more instances of halogen, -CN, cycloalkyl, -ORA, or substituted or unsubstituted alkyl, or wherein two substituents together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl. In certain embodiments, R2kis phenyl substituted with one or more instances of halogen, -CN, cycloalkyl, -ORA, or substituted or unsubstituted alkyl, or wherein two substituents together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl. In certain embodiments, R2kis phenyl substituted with one or more instances of -Cl, -F, -CN, cycloalkyl, -OCH3, -OCF3, -CH3, -CF3, or cyclopropyl, or wherein two substituents together with the atoms to which they are attached form a substituted 5-membered heterocyclyl.

[0346] In certain embodiments, R2kis unsubstituted aryl. In certain embodiments, R2kis unsubstituted naphthyl. In certain embodiments,

[0349] In certain embodiments, R2kis of formula:?wherein each REis independently halogen, -CN, cycloalkyl, -ORA, or substituted or unsubstituted alkyl, or two instances of RE, together with the atoms to which they are attached, form a substituted or unsubstituted aryl, heteroaryl, carbocyclyl, or heterocyclyl ring; and m is 0, 1, 2, or 3.

[0350] In certain embodiments, R2kis of formula:?wherein each REis independently -Cl, -F, -CN, cycloalkyl, -OCH3, -OCF3, -CH3, -CF3, or cyclopropyl, or wherein two substituents, or two instances of RE, together with the atoms to which they are attached, form a together with the atoms to which they are attached form a substituted 5- membered heterocyclyl; and m is 0, 1, 2, or 3.

[0352] In certain embodiments, R2kis notj^2ka

[0353] As described herein, R2kais hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2kand R2katogether with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl.

[0354] In certain embodiments, R2kais hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R2kais hydrogen. In certain embodiments, R2kais substituted or unsubstituted alkyl. In certain embodiments, R2kais substituted or unsubstituted Ci-4alkyl. In certain embodiments, R2kais substituted or unsubstituted Ci-2alkyl. In certain embodiments, R2kais substituted or unsubstituted methyl. In certain embodiments, R2kais unsubstituted alkyl. In certain embodiments, R2kais unsubstituted Ci-4alkyl. In certain embodiments, R2kais unsubstituted Ci-2alkyl. In certain embodiments, R2kais unsubstituted methyl.

[0355] In certain embodiments, R2kand R2katogether with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl.

[0356] In certain embodiments, R2kand R2katogether with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl. In certain embodiments, R2kand R2katogether with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl.R3k

[0357] As described herein,SO2N(RA)2, -ORA, -N(RA)2, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In certain embodiments, R3kis any carboxylic acid bioisostere.

[0358] In certain embodiments, R3kis -C(=O)ORA. In certain embodiments, R3kis -C(=O)N(RA)2. In certain embodiments, R3kis -C(=O)NRAS(O)2RA. In certain embodiments, R3kis -SO2N(RA)2. In certain embodiments, R3kis -ORA. In certain embodiments, R3kis - N(RA)2. In certain embodiments, R3kis substituted or unsubstituted alkyl. In certain embodiments, R3kis substituted or unsubstituted heteroalkyl. In certain embodiments, R3kis substituted or unsubstituted heterocyclyl. In certain embodiments, R3kis substituted or unsubstituted, 5-membered heterocyclyl. In certain embodiments, R3kis or substituted or unsubstituted, 5-membered heteroaryl.

[0361] In certain embodiments, R3kis -C(=O)OH. In certain embodiments, R3kis -SO2NH2. In certain embodiments, R3kis. in certain embodiments, R3kis, ,certain embodiments, R3kis 0 . In certain embodiments, R3kis 0 . In certaincertain embodiments,certain embodiments, R3kis. In certain embodiments, R3kis. In certain embodiments,certainembodiments, R3kis 0 . In certain embodiments, R3kis 0 . In certain embodiments,

[0362] In certain embodiments, R3kis not -C(=O)OH.

[0363] In certain embodiments, R2kand R3khave a trans stereochemical relationship. In certain embodiments, R2kand R3khave a cis stereochemical relationship. In certain embodiments, the carbon to which R2kis attached is in an (S) configuration and the carbon to which R3kis attached is in an (R) configuration. In certain embodiments, the carbon to which R2kis attached is in an (S) configuration and the carbon to which R3kis attached is in an (S) configuration. In certain embodiments, the carbon to which R2kis attached is in an (R) configuration and the carbon to which R3kis attached is in an (R) configuration. In certain embodiments, the carbon to which R2kis attached is in an (R) configuration and the carbon to which R3kis attached is in an (S) configuration.

[0364] In certain embodiments, the carbon to which R2kis attached is in an (S) configuration and the carbon to which R3kis attached is in an (R) configuration, wherein R2kand R3khave a trans stereochemical relationship. In certain embodiments, the carbon to which R2kis attached is in an (S) configuration and the carbon to which R3kis attached is in an (S) configuration, wherein R2kand R3khave a trans stereochemical relationship. In certain embodiments, the carbon to which R2kis attached is in an (R) configuration and the carbon to which R3kis attached is in an (R) configuration, wherein R2kand R3khave a trans stereochemical relationship. In certain embodiments, the carbon to which R2kis attached is in the (R) configuration and the carbon to which R3kis attached is in an (S) configuration, wherein R2kand R3khave a trans stereochemical relationship.

[0365] In certain embodiments, the carbon to which R2kis attached is in an (S) configuration and the carbon to which R3kis attached is in an (R) configuration, wherein R2kand R3khave a cis stereochemical relationship. In certain embodiments, the carbon to which R2kis attached is in an (S) configuration and the carbon to which R3kis attached is in an (S) configuration, wherein R2kand R3khave a cis stereochemical relationship. In certain embodiments, the carbon to which R2kis attached is in an (R) configuration and the carbon towhich R3kis attached is in an (R) configuration, wherein R2kand R3khave a cis stereochemical relationship. In certain embodiments, the carbon to which R2kis attached is in the (R) configuration and the carbon to which R3kis attached is in an (S) configuration, wherein R2kand R3khave a cis stereochemical relationship. ^3ka

[0366] As described herein, R3kais hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0367] In certain embodiments, R3kais hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R3kais hydrogen. In certain embodiments, R3kais substituted or unsubstituted alkyl. In certain embodiments, R3kais substituted or unsubstituted Ci-4alkyl. In certain embodiments, R3kais substituted or unsubstituted Ci-2alkyl. In certain embodiments, R3kais substituted or unsubstituted methyl. In certain embodiments, R3kais unsubstituted alkyl. In certain embodiments, R3kais unsubstituted Ci-4alkyl. In certain embodiments, R3kais unsubstituted Ci-2alkyl. In certain embodiments, R3kais unsubstituted methyl.

[0368] In certain embodiments, R3kais hydrogen, R2kais hydrogen, and R2kand R3khave a trans stereochemical relationship. In certain embodiments, R3kais hydrogen, R2kais hydrogen, and R2kand R3khave a cis stereochemical relationship.X and Y

[0369] As described herein, X is a bond, substituted or unsubstituted methylene, or -NRB-; and Y is substituted or unsubstituted methylene or -NRB-.

[0370] In certain embodiments, X is -C(Ra)2-, wherein each Rais independently hydrogen or unsubstituted alkyl, or both instances of Ratogether with the atoms to which they are attached form a substituted or unsubstituted cycloalkyl. In certain embodiments, X is -C(Ra)2- , wherein each Rais independently hydrogen or unsubstituted alkyl. In certain embodiments, X is -C(Ra)2-, wherein each Rais independently unsubstituted alkyl, or both instances of Ratogether with the atoms to which they are attached form a substituted or unsubstituted cycloalkyl. In certain embodiments, X is -CH2-. In certain embodiments, X is -NRB-. In certain embodiments, X is -NRB-, wherein RBis substituted or unsubstituted alkyl, - C(=O)N(RA)2, -SO2RA, or a nitrogen protecting group. In certain embodiments, X is -NRB-, wherein RBis substituted or unsubstituted alkyl or a nitrogen protecting group. In certain embodiments, X is -NRB-, wherein RBis substituted or unsubstituted alkyl, or a nitrogen protecting group. In certain embodiments, X is -NRB-, wherein RBis substituted orunsubstituted alkyl. In certain embodiments, X is -NRB-, wherein RBis unsubstituted alkyl. In certain embodiments, X is -NRB-, wherein RBis unsubstituted Cwalkyl. In certain embodiments, X is -NRB-, wherein RBis unsubstituted Ci-2alkyl. In certain embodiments, X is -NRB-, wherein RBis unsubstituted methyl. In certain embodiments, X is -NRB-, wherein RBis -C(=O)N(RA)2. In certain embodiments, X is -NRB-, wherein RBis -C(=O)NHCH3. In certain embodiments, X is -NRB-, wherein RBis -SO2RA. In certain embodiments, X is -NRB- , wherein RBis -SO2CH3. In certain embodiments, X is a bond.

[0371] In certain embodiments, Y is -C(Ra)2-, wherein each Rais independently hydrogen or unsubstituted alkyl, or both instances of Ratogether with the atoms to which they are attached form a substituted or unsubstituted cycloalkyl. In certain embodiments, Y is -C(Ra)2- , wherein each Rais independently hydrogen or unsubstituted alkyl. In certain embodiments, Y is -C(Ra)2-, wherein each Rais independently unsubstituted alkyl, or both instances of Ratogether with the atoms to which they are attached form a substituted or unsubstituted cycloalkyl. In certain embodiments, Y is -CH2-. In certain embodiments, Y is -NRB-. In certain embodiments, Y is -NRB-, wherein RBis substituted or unsubstituted alkyl, - C(=O)N(RA)2, -SO2RA, or a nitrogen protecting group. In certain embodiments, Y is -NRB-, wherein RBis substituted or unsubstituted alkyl or a nitrogen protecting group. In certain embodiments, Y is -NRB-, wherein RBis substituted or unsubstituted alkyl. In certain embodiments, Y is -NRB-, wherein RBis unsubstituted alkyl. In certain embodiments, Y is - NRB-, wherein RBis unsubstituted Ci-4alkyl. In certain embodiments, Y is -NRB-, wherein RBis unsubstituted Ci-2alkyl. In certain embodiments, Y is -NRB-, wherein RBis unsubstituted methyl. In certain embodiments, Y is -NRB-, wherein RBis -C(=O)N(RA)2. In certain embodiments, Y is -NRB-, wherein RBis -C(=O)NHCH3. In certain embodiments, Y is - NRB-, wherein RBis -SO2RA. In certain embodiments, Y is -NRB-, wherein RBis -SO2CH3. In certain embodiments, Y is a bond.

[0372] In certain embodiments, X is -CH2-; and Y is -NRB-. In certain embodiments, X is - CH2-; and Y is -NRB-, wherein RBis substituted or unsubstituted alkyl or a nitrogen protecting group. In certain embodiments, X is -CH2-; and Y is -NRB-, wherein RBis substituted or unsubstituted alkyl.

[0373] In certain embodiments, X is a bond; and Y is -NRB-. In certain embodiments, X is a bond; and Y is -CH2-. In certain embodiments, X is -CH2-; and Y is -CH2-. In certain embodiments, X is -NRB-; and Y is -CH2-.A2

[0374] As described herein, A2is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In certain embodiments, A2is substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0375] In certain embodiments, A2is substituted or unsubstituted heteroarylene. In certain embodiments, A2is substituted or unsubstituted 5-membered heteroarylene. In certain embodiments, A2is substituted or unsubstituted pyrazole or imidazole. In certain embodiments, A2is substituted 5-membered heteroarylene, wherein A2is substituted with one or more instances of substituted or unsubstituted alkyl. In certain embodiments, A2is substituted 5-membered heteroarylene, wherein A2is substituted with one or more instances of unsubstituted alkyl. In certain embodiments, A2is substituted or unsubstituted pyrazole or imidazole. In certain embodiments, A2is substituted pyrazole or imidazole, wherein A2is substituted with one or more instances of substituted or unsubstituted alkyl. In certain embodiments, A2is substituted pyrazole or imidazole, wherein A2is substituted with one or more instances of unsubstituted alkyl. In certain embodiments, A2is:

[0376] In certain embodiments, A2is substituted or unsubstituted arylene. In certain embodiments, A2is substituted arylene. In certain embodiments, A2is substituted or unsubstituted phenylene. In certain embodiments, A2is substituted phenylene.

[0377] In certain embodiments, A2is phenylene substituted with one or more instances of deuterium, halogen, -CN, -N(RA)2, -ORA, -SRA, -C(=O)ORA, -C(=O)N(RA)2, -NRAC(=O), - NRAS(O)2RA, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, or wherein two substituents together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl.

[0378] In certain embodiments, A2is phenylene substituted with one or more instances of halogen, -CN, -ORA, -C(=O)ORA, -C(=O)N(RA)2, -N(RA)2, -NRAC(=O), -NRAS(O)2RA, unsubstituted alkyl, haloalkyl, or unsubstituted cycloalkyl, or wherein two substituentstogether with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl; wherein each RAis independently hydrogen, unsubstituted alkyl, or haloalkyl.

[0379] In certain embodiments, A2is phenylene substituted with one or more instances of - F, -Cl, -Br, -CN, -CH3, -CF3, cyclopropyl, -NH2, -NHCH3, -NHC(=O)CH3, -NHS(O)2CH3, - OCH3, -OCHF2, -OCH2F, -OCF3, or -C(=O)OH, or wherein two substituents together with the atoms to which they are attached form a substituted 5-membered heterocyclyl.

[0380] In certain embodiments, A2is phenylene substituted with one or more instances of halogen. In certain embodiments, A2is phenylene substituted with one or more instances of - Cl or -Br.

[0381] In certain embodiments, A2is of formula:each RDis independently deuterium, halogen, -CN, -N(RA)2, -ORA, -SRA, -C(=O)ORA, -C(=O)N(RA)2, -NRAC(=O), - NRAS(O)2RA, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, or wherein two substituents together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and n is 0, 1, or 2.

[0382] In certain embodiments, A2is of formula:each RDis independently halogen, -CN, -ORA, -C(=O)ORA, -C(=O)N(RA)2, -N(RA)2, -NRAC(=O), -NRAS(O)2RA, unsubstituted alkyl, haloalkyl, or unsubstituted cycloalkyl, or wherein two substituents together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl; wherein each RAis independently hydrogen, unsubstituted alkyl, or haloalkyl; and n is 0, 1, or 2.

[0383] In certain embodiments, A2is of formula:each RDis independently -F, -Cl, -Br, -CN, -CH3, -CF3, cyclopropyl, -NH2, -NHCH3, -NHC(=O)CH3, -NHS(O)2CH3, -OCH3, -OCHF2, -OCH2F, -OCF3, or -C(=O)OH, or wherein two substituents together withthe atoms to which they are attached form a substituted 5-membered heterocyclyl; and n is 0, l, or 2.Embodiments of KB-4

[0387] In certain embodiments, KB is of formula:(KB-4a).

[0388] In certain embodiments, KB is of formula:(KB-4b).

[0389] In certain embodiments, KB is of formula:

[0390] In certain embodiments, KB is of formula:(KB-4d).

[0391] In certain embodiments, KB is of formula:(KB-4e).

[0392] In certain embodiments, KB is of formula:(KB-4f), wherein each REis independently halogen, -CN, cycloalkyl, -ORA, or substituted or unsubstituted alkyl, or two instances of RE, together with the atoms to which they are attached, form a substituted or unsubstituted aryl, heteroaryl, carbocyclyl, or heterocyclyl ring; and m is 0, 1, 2, or 3.

[0393] (KB-4g).

[0394] In certain embodiments, KB is of formula:

[0395] (KB-4i).

[0396] In certain embodiments, KBis of formula:

[0397] (KB-4k).

[0398] In certain embodiments, KB is of formula:(KB-41).

[0399] In certain embodiments, KB is of formula:(KB-4m).

[0400] In certain embodiments, KB is of formula:(KB-4n).

[0401] In certain embodiments, KB is of formula:(KB-4O), wherein each REis independently halogen, -CN, cycloalkyl, -ORA, or substituted or unsubstituted alkyl, or two instances of RE, together with the atoms to which they are attached, form a substituted or unsubstituted aryl, heteroaryl, carbocyclyl, or heterocyclyl ring; and m is 0, 1, 2, or 3.

[0402] In certain embodiments, KB is of formula:

[0403] In certain embodiments, KB is of formula:(KB-4q).

[0404] In certain embodiments, KB is of formula:(KB-4r).

[0405] In certain embodiments, KB is of formula:(KB-4S).

[0406] In certain embodiments, KB is of formula:(KB-4t).

[0407] In certain embodiments, KB is of formula:(KB-4U).

[0408] In certain embodiments, KB is of formula:

[0409] In certain embodiments, KB is of formula:Embodiments of KB- 5

[0410] In certain embodiments, KB is of formula:(KB-5a).

[0411] In certain embodiments, KB is of formula:Embodiments O / KB-6

[0412] In certain embodiments, KB is of formula:(KB-6a).

[0413] In certain embodiments, KB is of formula:(KB-6b).

[0414] In certain embodiments, KB is of formula:(KB-6C).

[0415] In certain embodiments, KB is of formula:(KB-6d).

[0416] In certain embodiments, KB is of formula:wherein each RDis independently deuterium, halogen, -CN, -N(RA)2, -ORA, -SRA, -C(=O)ORA, - C(=O)N(RA)2, -NRAC(=O), -NRAS(O)2RA, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, or wherein two substituents together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and n is 0, 1 , or 2.

[0417] In certain embodiments, KB is of formula:wherein each RDis independently deuterium, halogen, -CN, -N(RA)2, -ORA, -SRA, -C(=O)ORA, - C(=0)N(RA)2, -NRAC(=O), -NRAS(0)2RA, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, or wherein two substituents together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and n is 0, 1 , or 2.

[0418] In certain embodiments, KB is of formula:(KB-6g), wherein each RDis independently deuterium, halogen, -CN, -N(RA)2, -ORA, -SRA, -C(=O)ORA, - C(=O)N(RA)2, -NRAC(=O), -NRAS(O)2RA, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, or wherein two substituents together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and n is 0, 1 , or 2.

[0419] In certain embodiments, KB is of formula:(KB-6h), wherein RDis deuterium, halogen, -CN, -N(RA)2, -ORA, -SRA, -C(=O)ORA, -C(=O)N(RA)2, - NRAC(=O), -NRAS(O)2RA, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, or wherein two substituents together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and n is 0, 1, or 2..

[0420] In certain embodiments, KB is of formula:(KB-6i).

[0421] In certain embodiments, KB is of formula:(KB-6j).

[0422] In certain embodiments, KB is of formula:(KB-6k), wherein each REis independently halogen, -CN, cycloalkyl, -ORA, or substituted or unsubstituted alkyl, or two instances of RE, together with the atoms to which they are attached, form a substituted or unsubstituted aryl, heteroaryl, carbocyclyl, or heterocyclyl ring; and m is 0, 1, 2, or 3.

[0423] In certain embodiments, KB is of formula:(KB-61), wherein each REis independently halogen, -CN, cycloalkyl, -ORA, or substituted or unsubstituted alkyl, or two instances of RE, together with the atoms to which they are attached, form a substituted or unsubstituted aryl, heteroaryl, carbocyclyl, or heterocyclyl ring; and m is 0, 1, 2, or 3.

[0424] In certain embodiments, KB is of formula:(KB-6m).

[0425] In certain embodiments, KB is of formula:(KB-6n).

[0426] In certain embodiments, KB is of formula:(KB-6O).

[0427] In certain embodiments, KB is of formula:(KB-6p).

[0428] In certain embodiments, KB is of formula:(KB-6q).

[0429] In certain embodiments, KB is of formula:(KB-6r).

[0430] In certain embodiments, KB is of formula:(KB-6S).

[0431] In certain embodiments, KB is of formula:(KB-6t).

[0432] In certain embodiments, KB is of formula:e. KB-7 and KB-8

[0433] In certain embodiments, KB is an ABL1 binding moiety. In certain embodiments, KB is of formula:wherein:Rlkis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 0, 1, 2, 3, 4, and 5;R2kis hydrogen, or substituted or unsubstituted alkyl;R3kis hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

[0434] In certain embodiments, KB is of formula:wherein:Rlkis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN,-SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2;n is an integer selected from 0, 1, 2, 3, 4, and 5;R2kis hydrogen, halogen, or substituted or unsubstituted alkyl;R3kis hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.RIk

[0435] As described herein, Rlkis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2.

[0436] In certain embodiments, Rlkis hydrogen, substituted or unsubstituted alkyl, halogen, hydroxy, or -O-(substituted or unsubstituted alkyl). In certain embodiments, Rlkis substituted or unsubstituted alkyl, halogen, hydroxy, or -O-(substituted or unsubstituted alkyl). In certain embodiments, Rlkis chloro, methyl, fluoro, bromo, trifluoromethyl, or trifluoromethoxy.

[0437] In certain embodiments, Rlkis hydrogen. In certain embodiments, Rlkis halogen. In certain embodiments, Rlkis substituted or unsubstituted alkyl. In certain embodiments, Rlkis haloalkyl. In certain embodiments, Rlkis hydroxy. In certain embodiments, Rlkis or -O-(unsubstituted alkyl). In certain embodiments, Rlkis or -O-(haloalkyl).

[0438] In certain embodiments, Rlkis hydrogen or halogen. In certain embodiments, Rlkis substituted or unsubstituted alkyl or hydrogen. In certain embodiments, Rlkis substituted or unsubstituted alkyl or halogen.

[0439] In certain embodiments,s bromophenyl, chlorophenyl, iodophenyl, fluorophenyl, methylphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, hydroxyphenyl, methoxyphenyl, dibromophenyl, dichlorophenyl, diiodophenyl, difluorophenyl, dimethylphenyl, (methyl)(chloro)phenyl, (methyl)(iodo)phenyl, (methyl)(bromo)phenyl, (methyl)(fluoro)phenyl,(chloro)(fluoro)phenyl, (bromo)(chloro)phenyl, (chloro)(iodo)phenyl, (bromo)(fluoro)phenyl, (iodo)(fluoro)phenyl, or (bromo)(iodo)phenyl.

[0440] In certain embodiments,-dichlorophenyl, 3-methyl-4-chlorophenyl,3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 3 -bromophenyl, 2-fluoro-5-chlorophenyl, 3,5- dichlorophenyl, 2,4-dichlorophenyl,3-fluoro-4-chlorophenyl, 3-chloro-5-fluorophenyl, 2,5- dichlorophenyl, 2-fluoro-3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4- trifluoromethoxyphenyl, or 2,3-dichlorophenyl.n

[0443] As provided herein, n is an integer selected from 0, 1, 2, 3, 4, and 5. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 0, 1, or 2.

[0444] As described herein, R2kis hydrogen or substituted or unsubstituted alkyl, or R2kis hydrogen, halogen, substituted or unsubstituted alkyl, -ORA, or -SRA.

[0445] In certain embodiments, R2kis hydrogen.

[0446] In certain embodiments, R2kis halogen. In certain embodiments, R2kis chloro, bromo, iodo, or fluoro. In certain embodiments, R2kis bromo.

[0447] In certain embodiments, R2kis substituted or unsubstituted alkyl. In certain embodiments, R2kis substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted orunsubstituted propyl, or substituted or unsubstituted butyl. In certain embodiments, R2kis substituted or unsubstituted methyl. In certain embodiments, R2kis substituted or unsubstituted ethyl. In certain embodiments, R2kis substituted or unsubstituted propyl (e.g., n-propyl, iso-propyl). In certain embodiments, R2kis substituted or unsubstituted butyl (n-butyl, tert-butyl, .vec-butyl ).

[0448] In certain embodiments, R2kis hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, or substituted or unsubstituted butyl. In certain embodiments, R2kis hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted butyl. In certain embodiments, R2kis hydrogen, substituted methyl, substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R2kis hydrogen, methyl, 2- hydroxyethyl, sec-butyl, or isopropyl. In certain embodiments, R2kis hydrogen or unsubstituted methyl.

[0449] In certain embodiments, R2kis -ORA. In certain embodiments, R2kis -OH. In certain embodiments, R2kis -O(substituted or unsubstituted C1-6 alkyl). In certain embodiments, R2kis -O(Ci 6 alkyl).

[0450] In certain embodiments, R2kis -SRA. In certain embodiments, R2kis -SH. In certain embodiments, R2kis -S(substituted or unsubstituted C1-6 alkyl). In certain embodiments, R2kis -S(C1-6 alkyl).

[0451] In certain embodiments, the carbon to which R2kis attached is in an (R) configuration. In certain embodiments, the carbon to which R2kis attached is in an (S) configuration.R3k

[0452] As described herein, R3kis hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group. In certain embodiments, R3kis hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R3kis hydrogen or substituted or unsubstituted methyl.

[0453] In certain embodiments, R3kis hydrogen.

[0454] In certain embodiments, R3kis substituted or unsubstituted alkyl. In certain embodiments, R3kis substituted or unsubstituted methyl. In certain embodiments, R3kis substituted methyl. In certain embodiments, R3kis unsubstituted methyl.

[0455] In certain embodiments, R3kis nitrogen protecting group.Embodiments of KB-7

[0456] In certain embodiments, KB is of formula:(KB-7a).

[0457] In certain embodiments, KB is of formula:(KB-7b).

[0458] In certain embodiments, KB is of formula:(KB-7C).

[0459] In certain embodiments, KB is of formula:Embodiments of KB-8

[0460] In certain embodiments, KB is of formula:

[0461] In certain embodiments, KB is of formula:(KB-8b). f. KB-9

[0462] In certain embodiments, KB is a PKC binding moiety. In certain embodiments, KB is of formula:wherein:Rlk, R3k, and R4kare each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;R2k is -O-, -O(substituted or unsubstituted alkylene)-, -S-, -NH-, -N(C1-6alkyl)-, - C(=O)N(RA)-, -C(=O)(substituted or unsubstituted heterocyclylene)-, substituted or unsubstituted alkylene, substituted or unsubstituted alkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or a combination thereof;R5kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, - C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

[0463] In certain embodiments, R2k is -O-, -S-, -NH-, -N(C1-6alkyl)-, -C(=O)N(RA)-, substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or a combination thereof.

[0464] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group.Rlk, R3k, andR4k

[0465] As described herein, Rlk, R3k, and R4kare each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0466] In certain embodiments, Rlk, R3k, and R4kare each independently substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, or substituted or unsubstituted C2-6 alkynyl. In certain embodiments, Rlk, R3k, and R4kare each independently substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, or substituted or unsubstituted C2-4 alkynyl. In certain embodiments, Rlk, R3k, and R4kare each independently substituted or unsubstituted C1-2 alkyl, substituted or unsubstituted C2-3 alkenyl, or substituted or unsubstituted C2-3 alkynyl.

[0467] In certain embodiments, Rlk, R3k, and R4kare each independently substituted or unsubstituted alkyl. In certain embodiments, Rlk, R3k, and R4kare each independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, Rlk, R3k, and R4kare each independently substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rlk, R3k, and R4kare each independently substituted or unsubstituted C1-2 alkyl. In certain embodiments, Rlk, R3k, and R4kare each independently substituted or unsubstituted -CH3.

[0468] In certain embodiments, Rlk, R3k, and R4kare each independently unsubstituted alkyl. In certain embodiments, Rlk, R3k, and R4kare each independently unsubstituted C1-6 alkyl. In certain embodiments, Rlk, R3k, and R4kare each independently unsubstituted C1-4 alkyl. In certain embodiments, Rlk, R3k, and R4kare each independently unsubstituted C1-2 alkyl. In certain embodiments, Rlk, R3k, and R4kare each -CH3.R2k

[0469] As described herein, R2k is -O-, -O(substituted or unsubstituted alkylene)-, -S-, -NH-, - N(C1-6alkyl)-, -C(=O)N(RA)-, -C(=O)(substituted or unsubstituted heterocyclylene)-, substituted or unsubstituted alkylene, substituted or unsubstituted alkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or a combination thereof. In certain embodiments, R2k is -O-. In certain embodiments, R2k is - □(substituted or unsubstituted alkylene)-. In certain embodiments, R2k is -C(=O)(substituted or unsubstituted heterocyclylene)-. In certain embodiments, R2k is substituted or unsubstituted alkylene. In certain embodiments, R2k is substituted or unsubstituted alkynylene.

[0470] In certain embodiments, R2kis -O-, -S-, -NH-, -N(C1-6alkyl)-, substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or a combination thereof.

[0471] In certain embodiments, R2kis -O-, -O(substituted or unsubstituted alkylene)-, substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstitutedheterocyclylene. In certain embodiments, R2kis -O-. In certain embodiments, R2kis -O(substituted or unsubstituted alkylene)-. In certain embodiments, R2kis substituted or unsubstituted alkylene. In certain embodiments, R2kis substituted or unsubstituted cycloalkylene. In certain embodiments, R2kis substituted or unsubstituted heterocyclylene. In certain embodiments, R2k is -C(=O)N(RA)-. In certain embodiments, R2k is -C(=O) (substituted or unsubstituted heterocyclylene)-. In certain embodiments, R2k is substituted or unsubstituted alkynylene, In certain embodiments, R2kis substituted or unsubstituted heteroalkylene.

[0472] In certain embodiments, R2kis -O-, -NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, or a combination thereof. In certain embodiments, R2kis -O-, -NH-, substituted or unsubstituted alkylene, substituted or unsubstituted arylene, or a combination thereof. In certain embodiments, R2kis -O-, -NH-, substituted or unsubstituted methylene, substituted or unsubstituted phenylene, or a combination thereof.

[0473] In certain embodiments, R2kis a combination of -O-, -NH-, substituted or unsubstituted alkylene, and substituted or unsubstituted arylene. In certain embodiments, R2kis a combination of - O-, -NH-, substituted or unsubstituted methylene, and substituted or unsubstituted phenylene. In certain embodiments, R2kis a combination of -O-, -NH-, unsubstituted methylene, and unsubstituted phenylene.

[0474] In certain embodiments, R2kis of formula:, wherein R2kais substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and R2kbis hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R2kis of formula:, wherein R2kais substituted or unsubstituted arylene; and R2kbis hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R2kis of formula:, wherein R2kais substituted or unsubstituted phenylene; and R2kbis hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R2kis of formula:, wherein R2kais unsubstituted phenylene; and R2kbis hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R2kis of formula:

[0475] In certain embodiments, R2kis of formula:certain embodiments, R2kis, . In certain embodiments, R2kis of formula:. In certain embodiments, R2kis of formula:. In certain embodiments, R2kis of formula:certain embodiments, R2kis of formula:certain embodiments, R2kis of, embodiments, R2kis of formula:certain embodiments, R2kis of formula:certain embodiments, R2kis of formula:certain embodiments, R2kis of formula:In certain embodiments, R2kis of formula:certain embodiments, R2kis of, embodiments, R2kis of formula:. In certain embodiments, R2kis of formula:In certain embodiments, R2kis of formula:In certain embodiments, R2kis of formula:. In certain embodiments, R2kis of formula:. In certain embodiments,R2kis of formula:. In certain embodiments, R2kis of formula:In certain embodiments, R2kis of formula:In certain embodiments, R2kis of formula:In certain embodiments, R2kis of formula:. In certain embodiments, R2kis of formula:. In certain embodiments, R2kis of formula:. In certain embodiments, R2kis of formula:In certain embodiments, R2kis of formula:In certain embodiments, R2kis of formula:.R5k

[0476] As described herein, R5kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA,-SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2.

[0477] In certain embodiments, R5kis hydrogen, substituted or unsubstituted alkyl, halogen, hydroxy, or -O-(substituted or unsubstituted alkyl). In certain embodiments, R5kis substituted orunsubstituted alkyl, halogen, hydroxy, or -O-(substituted or unsubstituted alkyl). In certain embodiments, R5kis chloro, methyl, fluoro, bromo, trifluoromethyl, or trifluoromethoxy. In certain embodiments, R5kis hydrogen. In certain embodiments, R5kis halogen. In certain embodiments, R5kis -Br. In certain embodiments, R5kis -F. In certain embodiments, R5kis substituted or unsubstituted alkyl. In certain embodiments, R5kis haloalkyl. In certain embodiments, R5kis hydroxy. In certain embodiments, R5kis or -O-(unsubstituted alkyl). In certain embodiments, R5kis or -O-(haloalkyl).

[0478] In certain embodiments, R5kis hydrogen or halogen. In certain embodiments, R5kis substituted or unsubstituted alkyl or hydrogen. In certain embodiments, R5kis substituted or unsubstituted alkyl or halogen.Embodiments of KB-9

[0479] In certain embodiments, KB is of formula:

[0480] In certain embodiments, KB is of formula:

[0481] In certain embodiments, KB is of formula:

[0482] In certain embodiments, KB is of formula:(KB-9d).

[0483] In certain embodiments, KB is of formula:

[0484] In certain embodiments, KB is of formula:(KB-9f).

[0485] In certain embodiments, KB is of formula:

[0486] In certain embodiments, KB is of formula:Detectable moiety

[0487] In certain embodiments, KB is a detectable moiety (e.g., a chromophore, dye, fluorophore, luminophore or luminescent material, or radioactive material). In certain embodiments, the luminescent material is a phosphorescent agent.

[0488] In certain embodiments, KB is a chromophore. In certain embodiments, KB is a dye. In certain embodiments, KB is a fluorophore. In certain embodiments, KB is a luminophore. In certain embodiments, KB is a luminescent material. In certain embodiments, KB is a radioactive material.

[0489] In certain embodiments, KB is a dye. In certain embodiments, KB is a fluorescent dye. In certain embodiments, KB is of formula:III. A - Orienting moiety

[0490] As described herein, A is a bond or an orienting moiety. An orienting moiety is a group that acts as a spacer between KB and L. The orienting moiety spatially orients or establishes the position and direction from which the linker attaches to KB (i.e., the orientation in space into which the linker extends), thus having an impact on the overall geometry of the compound.

[0491] In certain embodiments of any compound described herein. In certain embodiments, when KB is of Formula (KB-5), A is a bond. In certain embodiments, when KB is of Formula (KB-6), A is a bond. In certain embodiments, when KB is of Formula (KB-9), A is a bond.

[0492] In certain embodiments of any compound described herein, A is substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -N(RA)-, -O-, -S-, -C(=O)O-, -OC(=O)-, - C(=O)NRA-, -NRAC(=O)-, -C(=O)-, -NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)O-, -OC(=O)N(RA)- , -S(O)2N(RA)-, -NRAS(O)2-, or a combination thereof; and each occurrence of RAis, independently,hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group.

[0493] In certain embodiments of any compound described herein, A is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted arylene, - N(RA)-, -O-, -C(=O)NRA-, -NRAC(=O)-, -C(=O)-, or a combination thereof; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group.Compounds where KB is of Formula (KB-1), (KB-2), and (KB-3)

[0494] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and Y is a bond, -NRA-, -O-, -S-, -S(O)2-, -S(O)-, -C=C-, substituted or unsubstituted -C=C-heterocyclylene, substituted or unsubstituted C1-2 alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted carbocyclylene.

[0495] For certain instances herein where A is of formula -X-Y-, X is bound to KB and Y is bound to L.

[0496] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and Y is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted -C=C-heterocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted arylene.

[0497] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted arylene; and Y is a bond, substituted or unsubstituted -C=C-heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heterocyclylene.

[0498] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted phenylene; and Y is a bond, substituted or unsubstituted -C=C-heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heterocyclylene.

[0499] In certain embodiments, A is of formula:A is of formula:certain embodiments, A is of formula:

[0502] In certain embodiments, A is not of formula:

[0503] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and Y is a bond, substituted or unsubstituted methylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted carbocyclylene.

[0504] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted arylene; and Y is a bond, substituted or unsubstituted methylene, or substituted or unsubstituted carbocyclylene.

[0505] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted phenylene; and Y is a bond, substituted or unsubstituted methylene, or substituted or unsubstituted carbocyclylene.

[0506] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted arylene; and Y is a bond.

[0507] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted phenylene; and Y is a bond.

[0508] certain embodiments, A is of formula:formula:embodiments, A is of formula:. In certain embodiments, A is oIn certain embodiments, A is of formula:

[0509] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted arylene; and Y is substituted or unsubstituted methylene or substituted or unsubstituted carbocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted orunsubstituted phenylene; and Y is substituted or unsubstituted methylene or substituted or unsubstituted carbocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted arylene; and Y is substituted or unsubstituted methylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted arylene; and Y is substituted or unsubstituted carbocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted phenylene; and Y is substituted or unsubstituted methylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted phenylene; and Y is substituted or unsubstituted carbocyclylene. In certain embodiments, A is of formula:; wherein n is 0 or 1; m is 0 or 1; Rylis hydrogen, C1-6 alkyl, or halogen; and Ry2is hydrogen, C1-6 alkyl, or halogen. In certain embodiments, A is of formula: herein n is 0 or 1; m is 0 or 1. In certain embodiments, A is of formula:hydrogen, C1-6 alkyl, or halogen; and Ry2is hydrogen, C1-6 alkyl, or halogen.In certain embodiments, A is of formula:; wherein n is 0 or1; m is 0 or 1; Rylis C1-6 alkyl or halogen; and Ry2is C1-6 alkyl or halogen. In certain embodiments, A is of formula:wherein n is 0 or 1; m is 0 or 1. In certain embodiments, A is of formula:; wherein Rylis C1-6 alkyl or halogen; and Ry2is C1-6 alkyl or halogen. In certain embodiments, A is of formula:wherein n is 0 or 1 ;m is 0 or 1; Rylis C1-6 alkyl; and Ry2is C1-6 alkyl. In certain embodiments, A is of formula:ula:wherein n is 0 or 1; m is 0 or 1; Rylis C1-3 alkyl; and Ry2is Cm alkyl. In certain embodiments, A is of formula:wherein n is 0 or 1; m is 0 or 1. In certain embodiments, A is of formula:alkyl; and Ry2is Cm alkyl. In certain embodiments, A is of formula:wherein n is 0 or 1 ; m is 0 or 1 ; Rylis C1-2 alkyl;and Ry2is C1-2 alkyl. In certain embodiments, A is of formula:wherein n is 0 or; ; . ,certain embodiments, A is of formula:certain embodiments, A is of formula:

[0510] In certain embodiments, A is of formula: X is substituted or unsubstituted carbocyclylene; and Y is a bond. In certain embodiments, A is of formula:certain embodiments, A is of formula:. In certain embodiments, A is of formula:certain embodiments, A is of formula:certain embodiments, A is of formula:In certain embodiments, A is of formula:

[0511] In certain embodiments, A is of formula: -X-Y-; X is substituted or unsubstituted heterocyclylene; and Y is a bond or substituted or unsubstituted arylene. In certain embodiments, A iscertain embodiments, A is of formula:

[0512] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted heteroarylene; and Y is a bond or substituted or unsubstituted heterocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted 6-membered heteroarylene; and Y is a bond or substituted or unsubstituted heterocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, or substituted or unsubstituted pyrazine; and Y is a bond or substituted or unsubstituted heterocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine, or substituted or unsubstituted pyrimidine; and Y is a bond or substituted or unsubstituted heterocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine; and Y is a bond or substituted or unsubstituted heterocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrazine; and Y is a bond or substituted or unsubstituted heterocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrimidine; and Y is a bond or substituted or unsubstituted heterocyclylene.

[0513] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, or substituted or unsubstituted pyrazine, substituted or unsubstituted pyridine, or substituted or unsubstituted pyrimidine; and Y is a bond or substituted or unsubstituted 6-7 membered heterocyclylene. In certain embodiments, A is of formula: -X-Y-,wherein: X is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, or substituted or unsubstituted pyrazine; and Y is a bond or substituted or unsubstituted 6-7 membered heterocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine, or substituted or unsubstituted pyrimidine; and Y is a bond or substituted or unsubstituted 6-7 membered heterocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine; and Y is a bond or substituted or unsubstituted 6-7 membered heterocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrimidine; and Y is a bond or substituted or unsubstituted 6-7 membered heterocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrazine; and Y is a bond or substituted or unsubstituted 6-7 membered heterocyclylene.

[0514] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, or substituted or unsubstituted pyrazine; and Y is a bond, substituted or unsubstituted piperidine, substituted or unsubstituted piperazine, or substituted or unsubstituted 2,6-diazaspiro[3.3]heptane.

[0515] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine, or substituted or unsubstituted pyrimidine; and Y is a bond, substituted or unsubstituted piperidine, substituted or unsubstituted piperazine, or substituted or unsubstituted 2,6- diazaspiro[3.3]heptane. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine, or substituted or unsubstituted pyrimidine; and Y is a bond. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine, or substituted or unsubstituted pyrimidine; and Y is substituted or unsubstituted piperidine. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine, or substituted or unsubstituted pyrimidine; and Y is substituted or unsubstituted piperazine. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine, or substituted or unsubstituted pyrimidine; and Y is substituted or unsubstituted 2,6- diazaspiro[3.3]heptane.

[0516] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine; and Y is a bond, substituted or unsubstituted piperidine, substituted or unsubstituted piperazine, or substituted or unsubstituted 2,6-diazaspiro[3.3]heptane. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine; and Y is a bond. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine; and Y is substituted or unsubstituted piperidine. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine; and Y is substituted or unsubstituted piperazine. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyridine; and Y is substituted or unsubstituted 2,6-diazaspiro[3.3]heptane.

[0517] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrimidine; and Y is a bond, substituted or unsubstituted piperidine, substituted or unsubstituted piperazine, or substituted or unsubstituted 2,6-diazaspiro[3.3]heptane. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrimidine; and Y is a bond. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrimidine; and Y is substituted or unsubstituted piperidine. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrimidine; and Y is substituted or unsubstituted piperazine. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrimidine; and Y is substituted or unsubstituted 2,6-diazaspiro[3.3]heptane.

[0518] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrazine; and Y is a bond, substituted or unsubstituted piperidine, substituted or unsubstituted piperazine, or substituted or unsubstituted 2,6-diazaspiro[3.3]heptane. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrazine; and Y is a bond. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrazine; and Y is substituted or unsubstituted piperidine. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrazine; and Y is substituted or unsubstituted piperazine. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted pyrazine; and Y is substituted or unsubstituted 2,6-diazaspiro[3.3]heptane.

[0519] In certain embodiments, A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4 alkyl.

[0520] In certain embodiments, A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted CM alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4 alkyl.

[0521] In certain embodiments, A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4 alkyl.

[0522] In certain embodiments, A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted CM alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4 alkyl.

[0523] In certain embodiments, A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted CM alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4 alkyl.

[0524] In certain embodiments, A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted CM alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4 alkyl.

[0525] In certain embodiments, A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4 alkyl.

[0526] In certain embodiments, A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted CM alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4 alkyl.

[0527] In certain embodiments, A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4 alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4 alkyl.

[0528] In certain embodiments, A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or ...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I) :KB-A-L-B(I), or a pharmaceutically acceptable salt thereof, wherein:KB is a kinase binding moiety or a detectable moiety;A is a bond or an orienting moiety;L is a bond or linker; andB is a p53 binding moiety.

2. A compound of Formula (II):T-A-L-B(II), or a pharmaceutically acceptable salt thereof, wherein:T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle;A is a bond or an orienting moiety;L is a linker; andB is a p53 binding moiety.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein KB is a kinase binding moiety.

4. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein B is of formula:(B-l) wherein: each = is independently a single bond or a double bond;X1is C, CR5, CR5R6, N, NR5, O, S, C=O, C=S;X2is C, CR7, CR7R8, N, NR7, O, S, C=O, C=S;X3is C, CR9, CR9R10, N, NR9, O, S, C=O, C=S;X4is C, CR", CR"R12, N, NR", O, S, C=O, C=S;X5is C or N;X6is C or N;X7is CR13, N, S, O, or NR13;X8is C, CR5, or N; wherein at least one of X1, X2, X3, and X4is a carbon atom connected to Q1;A1is a linking group;Q1is C=O, C=S, C=CR14R15, C=NR14, alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted, or a bond; m is 1, 2, 3, or 4;Y is N, O, or absent;R1is -C(O)R16, -C(O)OR16, -C(O)NR16R17, -OR16, -SR16, -NR16R17, -NR16C(O)R16, -OC(O)R16, -SiR16R17R18, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, each of which is independently substituted or unsubstituted, or halogen, or hydrogen; each R3and R4is independently -C(O)R19, -C(O)OR19, -C(O)NR19R20, -SOR19, -SO2R19, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted, or R3is absent; each R2, R5, R6, R7, R8, R9, R10, R", R12, R13, R14, R15, R16, R17, and R18is independently - C(O)R21, -C(O)OR21, -C(O)NR21R22, -OR21, -SR21, -NR21R22, -NR21C(O)R22, -OC(O)R21, alkyl,alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen, or R2is absent; each R19and R20is independently -C(O)R23, -C(O)OR23, -C(O)NR23R24, -OR23, -SR23, -NR23R24, -NR23C(O)R24, -OC(O)R23, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; each R21and R22is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen; and each R23and R24is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

5. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein B is of formula:wherein: each = is independently a single bond or a double bond;X1is C, CR5, CR5R6, N, NR5, O, S, C=O, or C=S;X2is C, CR7, CR7R8, N, NR7, O, S, C=O, or C=S;X3is C, CR9, CR9R10, N, NR9, O, S, C=O, or C=S;X4is C, CR", CR"R12, N, NR11, O, S, C=O, or C=S;X7is CR13, N, or NR13; wherein at least one of X1, X2, X3, and X4is a carbon atom connected to Q1;A1is a linking group;Q1is C=O, C=S, C=CR14R15, C=NR14, alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted, or a bond; m is 1, 2, 3, or 4;Y is N, O, or absent;R1is -C(O)R16, -C(O)OR16, -C(O)NR16R17, -OR16, -SR16, -NR16R17, -NR16C(O)R16, -OC(O)R16, -SiR16R17R18, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, or halo, each of which is independently substituted or unsubstituted, or hydrogen; each R3and R4is independently -C(O)R19, -C(O)OR19, -C(O)NR19R20, -SOR19, -SO2R19, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted, or R3is absent; each R2, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18is independently - C(O)R21, -C(O)OR21, -C(O)NR21R22, -OR21, -SR21, -NR21R22, -NR21C(O)R22, -OC(O)R21, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; each R19and R20is independently -C(O)R23, -C(O)OR23, -C(O)NR23R24, -OR23, -SR23, -NR23R24, -NR23C(O)R24, -OC(O)R23, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; each R21and R22is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen; and each R23and R24is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

6. The compound of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein A1is substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heteroalkenylene, or substituted or unsubstituted heteroalkynylene.

7. The compound of any of claims 4-6, or a pharmaceutically acceptable salt thereof, wherein B is of formula:-lc).

8. The compound of any of claims 4-7, or a pharmaceutically acceptable salt thereof, wherein B is of formula:ld).

9. The compound of any of claims 4-8, or a pharmaceutically acceptable salt thereof, wherein B is of formula:

10. The compound of any of claims 4-9, or a pharmaceutically acceptable salt thereof, wherein B is of formula:

11. The compound of any of claims 4-10, or a pharmaceutically acceptable salt thereof, wherein B is of formula:wherein: each RQis independently, hydrogen, halogen, or substituted or unsubstituted alkyl.

12. The compound of any of claims 4-11, or a pharmaceutically acceptable salt thereof, wherein B is of formula:wherein: each RQis independently, hydrogen, halogen, or substituted or unsubstituted alkyl; each RNis independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; andRN1is substituted or unsubstituted alkylene, substituted or unsubstituted acyl, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene.

13. The compound of any of claims 4-12, or a pharmaceutically acceptable salt thereof, wherein B is of formula:-lk-2),wherein: each RQis independently, hydrogen, halogen, or substituted or unsubstituted alkyl; each Rpis independently, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or -C(=O)N(RX1)2; andRP1is -O-, substituted or unsubstituted -O-alkylene,, substituted or unsubstituted alkylene, -C(=O)O-, -C(=O)S-, or -C(=O)N(RX1)-; andRX1is hydrogen or substituted or unsubstituted alkyl.

14. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein B is of formula:wherein:Hy is a substituted or unsubstituted heteroarylene.

15. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein B is of formula:-lm-2).

16. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein B is of formula:

17. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein B is of formula:-lo-1).

18. The compound of any of claims 4-13, or a pharmaceutically acceptable salt thereof, wherein B is of formula:

19. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is of formula:wherein:R2is independently halogen, -CX23, -CHX22, -CH2X2. -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NR2CNR2AR2B, -ONR2AR2B, -NHC(O)NR2CNR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -SF5, -N3, -NS(O)F2,-NS(O)FNR2AR2B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2A, R2B, R2C, and R2Dare independently hydrogen, -CCI3, -CBn. -CF3, -CI3, -CHQ2, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1Aand R2Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;X2is independently -F, -Cl, -Br, or -I; n2 is independently an integer from 0 to 4; m2 and v2 are independently 1 or 2; z2 is an integer from 0 to 7 ; andR3is an electrophilic group or a substituted or unsubstituted alkyl; wherein L is attached to B by replacing a substituent of B with a bond to L on any substitutable atom of B.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein B is of formula:

21. The compound of claim 19 or 20, or a pharmaceutically acceptable salt thereof, wherein B is of formula:wherein:

22. The compound of any of claims 19-21, or a pharmaceutically acceptable salt thereof, wherein B is of formula:

23. The compound of any of claims 19-22, or a pharmaceutically acceptable salt thereof, wherein B is of formula:

24. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein B is of formula:

25. The compound of claim 19 or 24, or a pharmaceutically acceptable salt thereof, wherein B is of formula:wherein:each R2is independently substituted or unsubstituted alkyl,26. The compound of claim 19, 24, or 25, or a pharmaceutically acceptable salt thereof, whereinB is of formula:

27. The compound of any of claims 15 or 22-24, or a pharmaceutically acceptable salt thereof, wherein B is of formula:

28. The compound of any of claims 1 or 3-27, or a pharmaceutically acceptable salt thereof, wherein KBis a PKC (e.g., PKC-0; AMPK; ABL; ABL1; SRC; BTK; ATM; ATR; DNA-PK; PDPK1; PK; MAPK (e.g., MAPK1, MAPK11, MAPK12, MAPK13, MAPK14, p38a MAPK); EGFR; FGFR; NGFR; TrkA; ABL; CDK (e.g., CDK2, CDK4, CDK8); PI3K; VEGFR; BRAF; MEK (e.g., MEK1 / 2, MEK5); AKT; ALK; BTK; BCKDK; FLT3; JAK2; AURKA; c-MET; DDR; INSR; JNK; IKP; IKK; Lyn; mTOR (e.g., mTORC-1); PAK; PDK (e.g., PDK1 or PDK2); PTK2 / FAK; pyruvate kinases; RAC-a; RIPK; TYK2; SHP; NOP; GPC family (e.g., p opioid receptor or 5 opioid receptor); UMPK; SphK; or GSK-3 binding moiety.

29. The compound of any of claims 1 or 3-28, wherein KB is a PKC, AMPK, ATM, ATR, DNA- PK, PDPK1, MAPKs, CDK, PI3K, MEK, AKT, AURKA, JNK, IKP (IKK), mTOR, PAK, PDK, RAC-a, RIPK, or GSK-3 binding moiety.

30. The compound of any of claims 1 or 3-29, wherein KB is an AMPK, ATM, ATR, DNA-PK, MAPKs, CDK, PI3K, AKT, AURKA, PAK, PDK, RAC-a, GSK-3 binding moiety.

31. The compound of any of claims 1 or 3-28, wherein KB is a PKC binding moiety, an AMPK binding moiety, or a PDPK1 binding moiety.

32. The compound of any of claims 1 or 3-28, wherein KB is an ABL1 binding moiety.

33. The compound of any of claims 1 or 3-32, wherein KB is a kinase inhibitor or kinase activator.

34. The compound of any of claims 1 or 3-30, wherein KB is of formula:wherein:Rlkis -C(=O)ORA, -C(=O)N(RA)2, -C(=O)NRAS(O)2RA, -S(O)2ORA, -S(O)2N(RA)2, -S(O)2NHC(O)RA, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl; each of R2k, R3k, and R4kis independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, -N(RA)2, -ORA, or -SRA;R5kis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group;R6kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, -N(RA)2, -ORA, -SRA, -C(=O)ORA, -C(=O)N(RA)2, -NRAC(=O)RA, -C(=O)RA, -NRAC(=O)ORA, -NRAC(=O)N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)N(RA)2, -S(O)2N(RA)2, or -NRAS(O)2RA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

35. The compound of any of claims 1 or 3-33, wherein KB is of formula:wherein:V1is CR2kor N;V2is CR3kor N;V3is CR6kor N; provided that at least one of V1, V2, or V3is N;Rlkis -C(=O)ORA, -C(=O)N(RA)2, -C(=O)NRAS(O)2RA, -S(O)2ORA, -S(O)2N(RA)2, -S(0)2NHC(0)RA, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl; each of R2k, R3k, and R4kis independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, -N(RA)2, -ORA, or -SRA;R5kis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group;R6kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, -N(RA)2, -ORA, -SRA, -C(=O)ORA, -C(=0)N(RA)2, - NRAC(=O)RA, -C(=O)RA, -NRAC(=O)ORA, -NRAC(=O)N(RA)2, -OC(=O)RA, -OC(=O)ORA, - OC(=O)N(RA)2, -S(O)2N(RA)2, or -NRAS(O)2RA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

36. The compound of any of claims 1 or 3-33, wherein KB is of formula:wherein:V1is CR2kor N; each of R2k, R3k, and R4kis independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroalkyl, -CN, -N(RA)2, -ORA, or -SRA;R5kis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group;R6kis -ORC, -N(RB)2, or substituted or unsubstituted alkyl; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroupsare attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; each occurrence of RBis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group, or two RBgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic ring; andRcis substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group.

37. The compound of any of claims 1 or 3-33, wherein KB is of formula:or a pharmaceutically acceptable salt thereof, wherein:Rlkis substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, or a bond;R2kis substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2kais hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2and R2atogether with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;R3kis -C(=O)ORA, -C(=O)N(RA)2, -C(=O)NRAS(O)2RA, -SO2N(RA)2, -ORA, -N(RA)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;R3kais hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;X is a bond, substituted or unsubstituted methylene, or -NRB-;Y is substituted or unsubstituted methylene or -NRB-; each RBis independently hydrogen, substituted or unsubstituted acyl, -C(=O)N(RA)2, -SO2RA, substituted or unsubstituted alkyl, or a nitrogen protecting group; andeach occurrence of RAis, independently, hydrogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

38. The compound of any of claims 1 or 3-33, wherein KB is of formula:wherein:Rlkis substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, or a bond;A2is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2kis substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R2kais hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R2and R2atogether with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;R3kis -C(=O)ORA, -C(=O)N(RA)2, -C(=O)NRAS(O)2RA, -SO2N(RA)2, -ORA, -N(RA)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;R3kais hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;X is a bond, substituted or unsubstituted methylene, or -NRB-;Y is substituted or unsubstituted methylene or -NRB-; each RBis independently hydrogen, substituted or unsubstituted acyl, -C(=O)N(RA)2, -SO2RA, substituted or unsubstituted alkyl, or a nitrogen protecting group; andeach occurrence of RAis, independently, hydrogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

39. The compound of any of claims 1 or 3-33, wherein KB is of formula:wherein:Rlkis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 0, 1, 2, 3, 4, and 5;R2kis hydrogen, or substituted or unsubstituted alkyl;R3kis hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

40. The compound of any of claims 1 or 3-33, wherein KB is of formula:wherein:Rlkis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN,n is an integer selected from 0, 1, 2, 3, 4, and 5;R2kis hydrogen, halogen, or substituted or unsubstituted alkyl;R3kis hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

41. The compound of any of claims 1 or 3-33, wherein KB is of formula:wherein:Rlk, R3k, and R4kare each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;R2kis -O-, -O(substituted or unsubstituted alkylene)-, -S-, -NH-, -N(C1-6alkyl)-, -C(=O)N(RA)- , -C(=O)(substituted or unsubstituted heterocyclylene)-, substituted or unsubstituted alkylene, substituted or unsubstituted alkynylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or a combination thereof;R5kis hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

42. The compound of any of claims 1 or 3-30, or a pharmaceutically acceptable salt thereof, wherein KB is of formula:

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein:A is of formula: -X-Y-;X is bound to KB and Y is bound to L;X is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; andY is a bond, -NRA-, -O-, -S-, -S(O)2-, -S(O)-, -C=C-, substituted or unsubstituted -C=C- heterocyclylene, substituted or unsubstituted C1-2 alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted carbocyclylene.

44. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein:A is a bond.

45. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein:A is -X'-X2-X3-X4-;XIis a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene;X2is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene;X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; andX4is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene.

46. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein:A is -X’-X2-X3-X4-;X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene;X2is a substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, or substituted or unsubstituted pyrazinylene;X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; andX4is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene.

47. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein:A is -X’-X2-X3-X4-;X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene;X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene;X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; andX4is a bond, -N(RA)-, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene.

48. The compound of any of claims 1 or 3-47, or a pharmaceutically acceptable salt thereof,49. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:L is a chain of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous atoms.

50. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:L is substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, , substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -N(RA)-, -O-, -S-, - C(=O)O-, -OC(=O)-, -C(=O)NRA-, -NRAC(=O)-, -C(=O)-, -NRAC(=O)O-, -NRAC(=O)N(RA)-, - OC(=O)O-, -OC(=O)N(RA)-, -S(O)2N(RA)-, -NRAS(O)2-, or a combination thereof; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group.

51. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:L is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted heteroarylene, -N(RA)-, -O-, -C(=O)NRA-, -NRAC(=O)-, -C(=O)-, or a combination thereof; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group.

52. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:L is substituted or unsubstituted alkylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene,-N(CH3)C(=0)-, -C(=O)-, or a combination thereof.

53. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:L is of formula:wherein:Z1is a bond, -0-, -N(RA)-, -C(=0)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;Z2is a bond, -N(RA)-, -NRAC(=O)-, -C(=O)-, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted alkylene;Q is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene;Q1is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene;Z3is a bond, -C(=O)-, -O-, or -N(RA)-;Z4is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-30; and u is 0-30; provided that L comprises at least one atom.

54. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:L is of formula:wherein:Z1is a bond, -O-, -N(RA)-, unsubstituted C1-6 alkylene,Z3is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.

55. The compound of claim 51 or 52, or a pharmaceutically acceptable salt thereof, wherein:L is of formula:

56. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:L is any one of formula L1-L57 and L158-L177:

57. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:L is any one of formula L58-L239:

58. The compound of claim 34, wherein the compound is of Formula (I-a) or (I-b):or a pharmaceutically acceptable salt thereof.

59. The compound of claim 35, wherein the compound is of Formula (I-c) or (I-d):or a pharmaceutically acceptable salt thereof.

60. The compound of claim 36, wherein the compound is of Formula (I-e) or (I-f):or a pharmaceutically acceptable salt thereof.

61. The compound of claim 36, wherein the compound is of Formula (I-g) or (I-h):or a pharmaceutically acceptable salt thereof.

62. The compound of claim 38, wherein the compound is of Formula (I-i) or (I-j):or a pharmaceutically acceptable salt thereof.

63. The compound of claim 38, wherein the compound is of Formula (I-k) or (1-1):or a pharmaceutically acceptable salt thereof.

64. The compound of claim 39, wherein the compound is of Formula (I-m) or (I-n):or a pharmaceutically acceptable salt thereof.

65. The compound of claim 40, wherein the compound is of Formula (I-o) or (I-p):or a pharmaceutically acceptable salt thereof.

66. The compound of claim 39, wherein the compound is of Formula (I-q), (I-r), (I-kk), (1-11), (I- mm), (I-nn), (I-oo), (I-pp), (I-qq), (I-rr), or (I-ss):or a pharmaceutically acceptable salt thereof.

67. The compound of claim 34, wherein the compound is of Formula (I-s):or a pharmaceutically acceptable salt thereof.

68. The compound of claim 35, wherein the compound is of Formula (I-t):or a pharmaceutically acceptable salt thereof.

69. The compound of claim 36, wherein the compound is of Formula (I-u):or a pharmaceutically acceptable salt thereof.

70. The compound of claim 37, wherein the compound is of Formula (I-v):or a pharmaceutically acceptable salt thereof.

71. The compound of claim 38, wherein the compound is of Formula (I-w):or a pharmaceutically acceptable salt thereof.

72. The compound of claim 38, wherein the compound is of Formula (I-x):or a pharmaceutically acceptable salt thereof.

73. The compound of claim 39, wherein the compound is of Formula (I-y):or a pharmaceutically acceptable salt thereof.

74. The compound of claim 40, wherein the compound is of Formula (I-z):or a pharmaceutically acceptable salt thereof.

75. The compound of claim 41, wherein the compound is of Formula (I-aa):or a pharmaceutically acceptable salt thereof.

76. The compound of claim 34, wherein the compound is of Formula (I-bb):-bb), or a pharmaceutically acceptable salt thereof.

77. The compound of claim 35, wherein the compound is of Formula (I-cc):or a pharmaceutically acceptable salt thereof.

78. The compound of claim 36, wherein the compound is of Formula (I-dd):or a pharmaceutically acceptable salt thereof.

79. The compound of claim 37, wherein the compound is of Formula (I-ee):or a pharmaceutically acceptable salt thereof.

80. The compound of claim 38, wherein the compound is of Formula (I-ff):or a pharmaceutically acceptable salt thereof.

81. The compound of claim 38, wherein the compound is of Formula (I-gg):or a pharmaceutically acceptable salt thereof.

82. The compound of claim 39, wherein the compound is of Formula (I-hh):-hh), or a pharmaceutically acceptable salt thereof.

83. The compound of claim 40, wherein the compound is of Formula (I-ii):or a pharmaceutically acceptable salt thereof.

83. The compound of claim 41, wherein the compound is of Formula (I-jj):or a pharmaceutically acceptable salt thereof.

85. The compound of claim 1, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

86. The compound of any of claims 1, 3-27, 43-47, or 49-57, or a pharmaceutically acceptable salt thereof, wherein:KB is a detectable moiety.

87. The compound of any of claims 1, 3-27, 43-47, 49-57, or 86, or a pharmaceutically acceptable salt thereof, wherein:KB is a dye.

88. The compound of any of claims 1, 3-27, 43-47, 49-47, 86, or 87, or a pharmaceutically acceptable salt thereof, wherein:KB is a fluorescent dye.

89. The compound of any of claims 1, 3-27, 43-47, 49-57, or 86-88, or a pharmaceutically acceptable salt thereof, wherein:KB is of formula:

90. The compound of any of claims 1, 3-27, 43-47, 49-57, or 86-89, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

91. The compound of claim 9, wherein the compound of Formula (II) is of formula:or a pharmaceutically acceptable salt thereof.

92. The compound of claim 19, wherein the compound of Formula (II) is of formula:or a pharmaceutically acceptable salt thereof.

93. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:T is hydrogen, -ORA, -Ns, -COORA, -C=CH, halogen, or a nitrogen protecting group; andRAis hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group.

94. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

95. A method of phosphorylating p53, the method comprising administering a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 94, to a mixture that comprises a kinase and p53.

96. The method of claim 95, wherein the compound causes phosphorylation of p53 at a rate or amount that is increased over the rate or amount of phosphorylation in the same mixture comprising the kinase and p53 but without the compound.

97. The method of claim 95 or 96, wherein the amount of phosphorylation is measured at a specified time.

98. A method of promoting the phosphorylation of p53, the method comprising contacting the target substrate with a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 94.

99. A method of modulating a kinase, the method comprising contacting the protein kinase with a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 94.

100. The method of claim 99, wherein the kinase is PKC (e.g., PKC-Q; AMPK; ABL; ABL1; SRC; BTK; ATM; ATR; DNA-PK; PDPK1; PK; MAPK (e.g., MAPK1, MAPK11, MAPK12, MAPK13, MAPK14, p38a MAPK); EGFR; FGFR; NGFR; TrkA; ABL; CDK (e.g., CDK2, CDK4, CDK8); PI3K; VEGFR; BRAF; MEK (e.g., MEK1 / 2, MEK5); AKT; ALK; BTK; BCKDK; FLT3; JAK2; AURKA; c-MET; DDR; INSR; JNK; IKP; IKK; Lyn; mTOR (e.g., mTORC-1); PAK; PDK (e.g., PDK1 or PDK2); PTK2 / FAK; pyruvate kinases; RAC-a; RIPK; TYK2; SHP; NOP; GPC family (e.g., p opioid receptor or 5 opioid receptor); UMPK; SphK; or GSK-3.

101. The method of claim 99, wherein the kinase is PKC, AMPK, PDPK1, or ABLE102. The method of claim 99, wherein the kinase is PKC.

103. The method of any of claims 96-101, wherein the phosphorylation, promotion, or modulation is in a cell.

104. The method of any of claims 95-103, wherein the phosphorylation, promotion, or modulation is in a biological sample.

105. The method of any of claims 95-104, wherein the phosphorylation, promotion, or modulation is in a subject.

106. A method of treating a disease or condition in a subject in need thereof, the method comprising administering a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 94, to the subject.

107. The method of claim 106, wherein the disease or condition is cancer.

108. The method of claim 107, wherein the cancer is ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, colon cancer, endometrial cancer, head and neck cancer, small cell lung cancer, germ cell cancer, or Li-Fraumeni syndrome.

109. The method of claim 107 or 108, wherein the cancer is associated with a Y220C, Y220S, or Y220N p53 mutation.

110. A kit comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 94; and instructions for use.

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