Bifunctional kinase binding compounds and uses thereof

Abstract

Provided herein are bifunctional compounds that bind 5 '-AMP-activated protein kinase (AMPK) and / or promote targeted phosphorylation of a substrate. The induced phosphorylation of the target substrate can alter the substrate's structure and function, thus providing compounds which enable phosphorylation of target substrates, including those that may not otherwise be substrates for AMPK, and providing new modes for inducing strategic phosphorylation. Also provided are pharmaceutical compositions comprising the bifunctional compounds and methods of promoting the phosphorylation of target substrates in a biological sample by administering a compound or composition described herein.

Description

BIFUNCTIONAL KINASE BINDING COMPOUNDS AND USES THEREOF RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N.63 / 514,055, filed July 17, 2023, the contents of which are incorporated herein by reference in their entirety. BACKGROUND

[0002] Protein kinases regulate critical substrates (e.g., protein) and cellular functions like substrate half-life, substrate engagement with various biomolecules, metabolismR , 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.

[0003] 5'-AMP-activated protein kinase (AMPK) is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It is expressed in a number of cell types and tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation includes stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic β-cells.

[0004] Recently, a new strategy to phosphorylate 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 may then dissociate from the target substrate and initiate another catalytic cycle.SUMMARY

[0005] Phosphorylation (native or neo) 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 substrate-of-interest. Provided herein are PHICS compounds which enable a kinase (e.g., AMPK) to phosphorylate target substrates, including substrates that may not normally be substrates for the kinase, thus providing new modes to induce substrate alterations via strategic phosphorylation in a variety of settings. Also provided are bifunctional compounds that comprise a first functional moiety that engages AMPK 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 a target substrate (e.g., protein) via proximity-induced engagement between AMPK and a target substrate.

[0006] In one aspect, provided herein are compounds of Formula (I):(I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein: V1is CR2or N; each of R2, R3, and R4is 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; R5is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group; R6is -ORC, -N(RB)2, or substituted or unsubstituted alkyl; A is a bond or an orienting moiety; L is a bond or a linker; B is a targeting moiety or a detectable moiety; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted 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; RCis 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; provided that the compound is not of formula:

[0007] In another aspect, provided herein are compounds of Formula (II):and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrug thereof, wherein: V1is N or CR2; each of R2, R3, and R4is 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; R5is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group; R6is -ORC, -N(RB)2, or substituted or unsubstituted alkyl; A is a bond or an orienting moiety; L is a bond or a linker; T is hydrogen, a protecting group, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle; 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; 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;RCis 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; provided that the compound is not of formula:

[0008] In another aspect, provided are pharmaceutical compositions comprising a compound (e.g., PHICS) 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.

[0009] In another aspect, provided are methods of phosphorylating a target substrate (e.g., protein), 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 AMPK and the target substrate.

[0010] In another aspect, provided are methods of promoting the phosphorylation of a target substrate (e.g., protein) with AMPK, the method comprising contacting the target substrate 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.

[0011] 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 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 protein kinase is AMPK.

[0012] 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.

[0013] 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. DEFINITIONS Chemical definitions

[0014] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in 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 Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0015] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be preparedby asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions, p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0016] In a formula, is 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, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[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 (“C1-10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n- butyl, tert-butyl, sec-butyl, iso-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 instanceof an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10 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 C1-6alkyl, 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 some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms some embodiments, the haloalkyl moiety has 1 to 3 carbon atomssome embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2haloalkyl”). Examples of haloalkyl groups include –CHF2, −CH2F, −CF3, −CH2CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, 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 (“heteroC1-20alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-18 alkyl”). In some 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 some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-14alkyl”). In some 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 some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-10alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and 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 heteroC1-10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 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 some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some 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 C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified ()-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 (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 heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3alkenyl”). In some embodiments, a heteroalkenyl group has 2 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 heteroC2-10alkenyl.

[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 some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2carbon 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 C2-4alkynyl 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 C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10alkynyl. 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 (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 heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3alkynyl”). In some embodiments, a heteroalkynyl group has 2 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 heteroC2-10alkynyl.

[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 zeroheteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include, 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 (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0028] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl.

[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 the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0030] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen,and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[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-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6- dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3- c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7- tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydro- thieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-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 (“C6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g.,phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 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 C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14 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 be on 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 some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 memberedheteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[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), C1-10alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, 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, C1-10 alkyl, C1-10 perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1-6 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, C6-10 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 =O 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, C6-10aryl, 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, C1-6alkyl, C1-6perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; 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(C1-6alkyl)+X−, −NH3+X−, −N(OC1-6alkyl)(C1-6alkyl), −N(OH)(C1-6alkyl), −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(C1-6alkyl), −C(=O)NH2, −C(=O)N(C1-6alkyl)2, −OC(=O)NH(C1-6alkyl), −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(=O)NH2, −C(=NH)O(C1-6 alkyl), −OC(=NH)(C1-6 alkyl), −OC(=NH)OC1-6alkyl, −C(=NH)N(C1-6alkyl)2, −C(=NH)NH(C1-6alkyl), −C(=NH)NH2, −OC(=NH)N(C1-6 alkyl)2, −OC(=NH)NH(C1-6 alkyl), −OC(=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(C1-6alkyl), −SO2O(C1-6alkyl), −OSO2(C1-6alkyl), −SO(C1-6alkyl), −Si(C1-6alkyl)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)(C1-6alkyl)2, −OP(=O)(OC1-6alkyl)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O 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, −NHCO2Raa, −NHC(=O)N(Rbb)2, −NHC(=NRbb)N(Rbb)2, −NHSO2Raa, −NHP(=O)(ORcc)2, and −NHP(=O)(N(Rbb)2)2, wherein Raa, 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, andincludes 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 or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0051] The term “carbonyl” refers a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen (i.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 =O, 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, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rcc, and Rddare as defined herein.

[0055] In certain embodiments, the substituent present on the nitrogen atom is an 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, C1-10alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[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), 1-(1-adamantyl)-1- methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1- methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2¢- and 4¢-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N- hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2- phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1- dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5- dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1- phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[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), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4¢,8¢-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0059] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)- acyl derivative, N¢-p-toluenesulfonylaminoacyl derivative, N¢-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 1,3-dimethyl-1,3,5- triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5- dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N’- oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N’,N’-dimethylaminomethylene)amine, N,N’-isopropylidenediamine, N-p- nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1- cyclohexenyl)amine, N-borane 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 phosphoramidate, benzenesulfenamide, o- nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (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, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin- 4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a- octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o- nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5- dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1- 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, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S- dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p- methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p- nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4- (methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1- dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2- methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). 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 notlimited 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–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO − 3 , HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p– toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO 3− 4 , 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, N,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 aMitsunobu 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 exemplary leaving 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 invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4−salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[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 R×x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R×0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R×2 H2O) and hexahydrates (R×6 H2O)).

[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 its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[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 particularprodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C1-8alkyl, C2-8alkenyl, C2-8alkynyl, 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 a vascular 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 some embodiments, the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, the plant is a legume, e.g., a bean plant, e.g., soybean plant. In some 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 anabnormal 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 least about 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 byreference. 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 “bioactive moiety” refers to an agent or moiety that can influence (i.e., effect a change in) a biological system, such as in an organism, tissue, or cell. In some embodiments, the bioactive moiety is a small molecule. In some embodiments, the bioactive moiety is a peptide or protein.

[0087] 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.

[0088] 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.

[0089] The term “orienting moiety” refers to a chemical entity that acts as a spacing group in a molecule to spatially orient or establish the position and direction from which it joins one or more other moieties. BRIEF DESCRIPTION OF THE DRAWINGS

[0090] FIG.1 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 105.

[0091] FIG.2 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 106.

[0092] FIG.3 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 107.

[0093] FIG.4 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 109.

[0094] FIG.5 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 111.

[0095] FIG.6 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 112.

[0096] FIG.7 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 122.

[0097] FIG.8 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 124.

[0098] FIG.9 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 126.

[0099] FIG.10 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 128.

[0100] FIG.11 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 129.

[0101] FIG.12 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 130.

[0102] FIG.13 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 131.

[0103] FIG.14 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 132.

[0104] FIG.15 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 133.

[0105] FIG.16 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 134.

[0106] FIG.17 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 135.

[0107] FIG.18 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 136.

[0108] FIG.19 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 137.

[0109] FIG.20 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 138.

[0110] FIG.21 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 139.

[0111] FIG.22 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 140.

[0112] FIG.23 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 141.

[0113] FIG.24 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 142.

[0114] FIG.25 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 144.

[0115] FIG.26 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 145.

[0116] FIG.27 shows a plot of compound-mediated phosphorylation of KRAS by AMPK with exemplary compound 146.

[0117] FIG.28 shows a plot of compound-mediated phosphorylation of BRD4 by AMPK with exemplary compound 147.

[0118] FIG.29 shows a plot of compound-mediated phosphorylation of BRD4 by AMPK with exemplary compound 148.

[0119] FIG.30 shows a plot of compound-mediated phosphorylation of BRD4 by AMPK with exemplary compound 47.

[0120] FIG.31 shows a plot of compound-mediated phosphorylation of BRD4 by AMPK with exemplary compound 149.

[0121] FIG.32 shows a plot of compound-mediated phosphorylation of BRD4 by AMPK with exemplary compound 150.

[0122] FIG.33 shows a plot of compound-mediated phosphorylation of BRD4 by AMPK with exemplary compound 151.

[0123] FIG.34 shows a plot of compound-mediated phosphorylation of BRD4 by AMPK with exemplary compound 152.

[0124] FIG.35 shows a plot of compound-mediated phosphorylation of BRD4 by AMPK with exemplary compound 153. DETAILEDDESCRIPTION OFCERTAINEMBODIMENTS

[0125] Provided herein are bifunctional compounds that bind a target substrate (e.g., protein) and recruit a kinase (e.g., AMPK) to promote the phosphorylation of the target substrate (e.g., protein). Also provided are compounds that act as chemical probes having a detectable moiety (e.g., luminescent materials, such as dyes) that bind AMPK. Also provided are compounds useful in the production and manufacture of the bifunctional compounds and probes described herein.

[0126] 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 some embodiments, provided herein are compounds of Formula (I):and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystal,s tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein: V1is CR2or N; each of R2, R3, and R4is 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; R5is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group; R6is -ORC, -N(RB)2, or substituted or unsubstituted alkyl; A is a bond or an orienting moiety; L is a bond or a linker; B is a targeting moiety or a detectable moiety; 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; 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, ortwo RBgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic ring; and RCis 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.

[0127] In certain embodiments, the compound of Formula (I) is not of formula:.

[0128] In certain embodiments, the compound of Formula (I) is not of formula:

[0129] In certain embodiments, the compound of Formula (I) is not of formula: ;.

[0130] In some embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers, and pharmaceutical compositions thereof. In some embodiments, the disclosureprovides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, tautomers, and stereoisomers, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, and tautomers, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, and pharmaceutical compositions thereof.

[0131] In another aspect, the disclosure provides compounds that may be useful as intermediates in the preparation of the compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. In this aspect, disclosed are compounds of Formula (II):(II), and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof, wherein: V1is N or CR2; each of R2, R3, and R4is 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; R5is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group; R6is -ORC, -N(RB)2, or substituted or unsubstituted alkyl; A is a bond or an orienting moiety; L is a bond or a linker; T is hydrogen, a protecting group, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle; 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 unsubstitutedcarbocyclyl, 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; and RCis 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.

[0132] In certain embodiment, the compound of Formula (II) is not of formula:

[0133] In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, tautomers, and stereoisomers, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, and tautomers, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, and pharmaceutical compositions thereof. V1

[0134] As described herein, V1is CR2or N. In certain embodiments, V1is CR2. In certain embodiments, V1is N. R2

[0135] As described herein, R2is 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.

[0136] In certain embodiments, R2is 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, R2is hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R2is hydrogen, halogen, or unsubstituted alkyl. In certain embodiments, R2is halogen. In certain embodiments, R2is fluoro. In certain embodiments, R2is hydrogen.R3

[0137] As described herein, R3is 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.

[0138] In certain embodiments, R3is 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, R3is hydrogen, -CN, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R3is substituted or unsubstituted alkyl. In certain embodiments, R3is -CH3or -CF3. In certain embodiments, R3is -CH3. In certain embodiments, R3is -CF3. In certain embodiments, R3is hydrogen. In certain embodiments, R3is halogen. In certain embodiments, R3is fluoro. In certain embodiments, R3is bromo. In certain embodiments, R3is chloro. In certain embodiments, R3is -CN. R4

[0139] As described herein, R4is 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.

[0140] In certain embodiments, R4is 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, R4is hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R4is hydrogen, halogen, or unsubstituted alkyl. In certain embodiments, R4is halogen. In certain embodiments, R4is fluoro. In certain embodiments, R4is hydrogen. R2, R3, and R4

[0141] In certain embodiments, R2, R3, and R4are each independently hydrogen, -CN, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R2, R3, and R4are each independently hydrogen, halogen, or substituted or unsubstituted alkyl.

[0142] In certain embodiments, R2and R4are each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3is halogen. In certain embodiments, R2and R4are each hydrogen; and R3is halogen. In certain embodiments, R4is hydrogen, halogen, or substituted orunsubstituted alkyl; and R3is halogen. In certain embodiments, R4is hydrogen; and R3is halogen.

[0143] In certain embodiments, R2and R4are each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3is chloro. In certain embodiments, R2and R4are each independently hydrogen, halogen, or substituted or unsubstituted alkyl; and R3is -CN. In certain embodiments, R2and R4are each hydrogen; and R3is chloro. In certain embodiments, R2and R4are each hydrogen; and R3is -CN. In certain embodiments, R4is hydrogen, halogen, or substituted or unsubstituted alkyl; and R3is chloro. In certain embodiments, R4is hydrogen, halogen, or substituted or unsubstituted alkyl; and R3is -CN. In certain embodiments, R4is hydrogen; and R3is chloro. In certain embodiments, R4is hydrogen; and R3is -CN. R5

[0144] As described herein, R5is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group. In certain embodiments, R5is hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted alkyl. In certain embodiments, R5is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R5is hydrogen or unsubstituted alkyl. In certain embodiments, R5is hydrogen. In certain embodiments, R5is a nitrogen protecting group. In certain embodiments, R5is 2-(trimethylsilyl)ethoxymethyl (SEM). R6

[0145] As described herein, R6is -ORC, -N(RB)2, or substituted or unsubstituted alkyl. In certain embodiments, R6is -ORCor substituted or unsubstituted alkyl.

[0146] In certain embodiments, R6is substituted or unsubstituted alkyl. In certain embodiments, R6is unsubstituted alkyl. In certain embodiments, R6is unsubstituted C1-4alkyl.

[0147] In certain embodiments, R6is -N(RB)2. In certain embodiments, R6is -N(RB)2, wherein each occurrence of RBis, independently, substituted or unsubstituted alkyl, or two RBgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, R6is -N(CH3)2or .

[0148] In certain embodiments, R6is -ORC. In certain embodiments, R6is -ORC, wherein RCis substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aryl. In certain embodiments, R6is - ORC, wherein RCis substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl. In certain embodiments, R6is -ORC, wherein RCis substituted or unsubstituted C3-6cycloalkyl, or substituted or unsubstituted 4-10 membered heterocyclyl.

[0149] In certain embodiments, R6is -ORC, wherein RCis substituted or unsubstituted C3-6cycloalkyl. In certain embodiments,,

[0150] In certain embodiments, R6is -ORC, wherein RCis substituted or unsubstituted 4-10 membered heterocyclyl. In certain embodiments,R6is -ORC, wherein RCis substituted or unsubstituted 4-6 membered heterocyclyl or a sugar moiety. In certain embodiments, R6is,

[0151] In certain embodiments, R6is -ORC, wherein RCis substituted or unsubstituted aryl. In certain embodiments, R6is -ORC, wherein RCis substituted or unsubstituted phenyl. In.

[0152] In certain embodiments, R6is -ORC, wherein RCis substituted or unsubstituted alkyl. In certain embodiments, R6is -ORC, wherein RCis substituted alkyl. In certain embodiments, R6is -ORC, wherein RCis substituted C1-4alkyl. In certain embodiments, R6is.

[0153] In certain embodiments, R6is methyl, ethyl, isopropyl,,[

[0155] In certain embodiments, R6is methyl. In certain embodiments, R6is ethyl. In certain embodiments, R6is isopropyl. In certain embodiments, R6is. In certain embodiments, R6is. In certain embodiments, R6is. In certain embodiments, R6is. In certain embodiments, R6is. In certain embodiments, R6is. In certain embodiments,certain embodiments,certain embodiments,R6is.In certain embodiments, R6is. In certain embodiments, R6is. In certain embodiments,. In certain embodiments, R6is. In certain embodiments, R6is. In certain embodiments, R6is. In certain embodiments,In certain embodiments,certain embodiments, R6is. In certain embodiments,certain embodiments,certain embodiments,. In certain embodiments, R6is In certain embodiments, R6is In certain embodiments, R6is. In certain embodiments, R6is. In certain embodiments,certain embodiments,embodiments,certain embodiments,embodiments,certain embodiments,certainembodiments, R6isembodiments,certain embodiments,. In certain embodiments,embodiments,certain embodiments, R6is. In certain embodiments, R6is -N(CH3)2. In certain embodiments,.

[0156] In certain embodiments, R6is notcertain embodiments, R6is notcertain embodiments, R6is not. A

[0157] As described herein, A is a bond or an orienting moiety. An orienting moiety is a group that acts as a spacer between the bicyclic kinase-binding moiety (e.g., AMPK-binding moiety) and L, the linker of the disclosed compounds. The orienting moiety spatially orients or establishes the position and direction from which the linker attaches to the AMPK-binding moiety (i.e., the orientation in space into which the linker extends), thus having an impact on the overall geometry of the compound.

[0158] In certain embodiments, A is a bond.

[0159] 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.

[0160] For certain instances herein where A is of formula -X-Y-, X is bound to the bicyclic moiety and Y is bound to the linker (L).

[0161] 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.

[0162] 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.

[0163] 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.

[0164] In certain embodiments, A is of formula:, ,[ ,

[0166] In certain embodiments, A is of formula:certain embodiments, A is of formula:certain embodiments, A is of formula:.

[0167] In certain embodiments, A is of formula: -X-Y-, wherein: X 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; and Y is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is -C≡C-; and Y is substituted or unsubstituted arylene. In certain embodiments, A is of formula.

[0168] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted arylene; and Y is substituted or unsubstituted heteroarylene. In certain

[0169] In certain embodiments, A is not of formula:.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted arylene; and Y is a bond.

[0174] In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted phenylene; and Y is a bond.

[0175] In certain embodiments, A is of formula:. In certain embodiments, A is of formula:. In certain embodiments, A i. In certain embodiments, A is of formula:embodiments, A is of formula:. In certain embodiments, A is of formula:. In certain embodiments, A is of formula:.

[0176] 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 orunsubstituted carbocyclylene. In certain embodiments, A is of formula: -X-Y-, wherein: X is substituted or unsubstituted 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; Ry1is hydrogen, C1-6alkyl, or halogen; and Ry2is hydrogen, C1-6alkyl, 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:hydrogen, C1-6alkyl, or halogen; and Ry2is hydrogen, C1-6alkyl, or halogen. In certain embodiments, A is of formula:wherein n is 0 or 1; m is 0 or 1; Ry1is C1-6 alkyl or halogen; and Ry2is C1-6alkyl 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 Ry1is C1-6 alkyl or halogen; and Ry2is C1-6 alkyl or halogen. In certainembodiments, A is of formula:; wherein n is 0 or 1; m is 0 or 1; Ry1is C1-6alkyl; and Ry2is C1-6alkyl. In certain embodiments, A is of formula: i iwherein n is 0 or 1; m is 0 or 1; Ry1is C1-3 alkyl; and Ry2is C1-3 alkyl. In certain embodiments, A is of formula:; wherein n is 0 or 1; m is 0 or 1. In certain embodiments, A iscertain embodiments, A is of formula:certain embodiments, A is of formula:. In certain embodiments, A is of formula:. In certain embodiments, A is of formula:certain embodiments, A is of formula:.

[0177] In certain embodiments, A is of formula -X-Y-, wherein: 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:. In certain embodiments, A is of formula:. In certain embodiments, A is of formula:.

[0178] In certain embodiments, A is of formula -XO-X-Y-, wherein XOis a bond, -NRA-, -O-, -S-, -S(O)2-, or -S(O)-; 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 C1-2alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted carbocyclylene. In certain embodiments, A is of formula -XO-X-Y-, wherein XOis -NRA-, -O-, -S-, -S(O)2-, or -S(O)-; X is substituted or unsubstituted carbocyclylene; and Y is a bond. In certain embodiments, A is of formula:.

[0179] 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 certainembodiments, A is of formula:. In certain embodiments, A is of formula:embodiments, A is of formula:certain embodiments, A is of formula:certain embodiments, A is of formula:. In certain embodiments, A is of formula:. In certain embodiments, A is of formula:.

[0180] 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.

[0181] 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 substitutedor 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] In certain embodiments, A is of formula:, wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4alkyl.

[0188] In certain embodiments, A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4alkyl.

[0189] In certain embodiments, A is of formula:, wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4alkyl.

[0190] In certain embodiments, A is of formula:, wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4alkyl.

[0191] In certain embodiments, A is of formula:, wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; andeach occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4alkyl.

[0192] In certain embodiments, A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4alkyl.

[0193] In certain embodiments, A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4alkyl.

[0194] In certain embodiments, A is of formula:, wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA. In certainembodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4alkyl.

[0195] In certain embodiments, A is of formula:, wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4alkyl.

[0196] In certain embodiments, A is of formula:, wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA. In certain embodiments, Rxis -ORA, wherein RAis substituted or unsubstituted C1-4alkyl. In certain embodiments, Rxis -ORA, wherein RAis unsubstituted C1-4alkyl.

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

[0201] In certain embodiments, A is of formula:. L

[0202] As described herein, L is a bond or a linker. In certain embodiments, L is a bond. In certain embodiments, L is a linker. In certain embodiments, 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. In certain embodiments, L is a chain of at least 1 atom. In certain embodiments, L is a chain of at least 2 contiguous atoms. In certain embodiments, L is a chain of at least 3 contiguous atoms. In certain embodiments, L is a chain of at least 4 contiguous atoms. In certain embodiments, L is a chain of at least 5 contiguous atoms. In certain embodiments, L is a chain of at least 6 contiguous atoms. In certain embodiments, L is a chain of at least 7 contiguous atoms. In certain embodiments, L is a chain of at least 8 contiguous atoms. In certain embodiments, L is a chain of at least 9 contiguous atoms. In certain embodiments, L is a chain of at least 10 contiguous atoms. In certain embodiments, L is a chain of at least 11 contiguous atoms. In certain embodiments, L is a chain of at least 12 contiguous atoms. In certain embodiments, L is a chain of at least 13 contiguous atoms. In certain embodiments, L is a chain of at least 14 contiguous atoms. In certain embodiments, L is a chain of at least 15 contiguous atoms. In certain embodiments, L is a chain of any range of from 1 to 15 contiguous atoms.

[0203] In certain embodiments of L disclosed herein where L is depicted as a chemical structure, the lefthand attachment point is to A and the righthand attachment point is to B when B is present; or the lefthand attachment point is to A and the righthand attachment point is to T when T is present.

[0204] In certain embodiments of L disclosed herein where L is depicted as a chemical structure, the lefthand attachment point is to B and the righthand attachment point is to A when B is present; or the lefthand attachment point is to T and the righthand attachment point is to A when T is present.

[0205] In certain embodiments, L is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, 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)-, or -NRAS(O)2-, or a combination thereof.

[0206] In certain embodiments, 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)-, or -C(=O)-, or a combination thereof.

[0207] In certain embodiments, L is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, -N(RA)-, -O-, or -C(=O)-, or a combination thereof. In certain embodiments, L is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In certain embodiments, L is substituted or unsubstituted heteroalkylene.

[0208] In certain embodiments, L is substituted or unsubstituted alkylene, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene,, , , -N(RA)-, -O-, - N(RA)C(=O)-, or -C(=O)-, or a combination thereof. In certain embodiments, L is a combination of two or more of substituted or unsubstituted alkylene, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene,, , , -N(RA)-, -O-, -N(RA)C(=O)-, and -C(=O)-.

[0209] In certain embodiments, L is substituted or unsubstituted alkylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene,, , , -N(RA)-, -O-, -N(RA)C(=O)-, or -C(=O)-, or a combination thereof. In certain embodiments, L is a combination of two or more of substituted or unsubstituted alkylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene,and -C(=O)-.

[0210] In certain embodiments, L is substituted or unsubstituted alkylene, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene,, , , -N(H)-, - N(CH3)-, -O-, -N(H)C(=O)-, -N(CH3)C(=O)-, or -C(=O)-, or a combination thereof. In certain embodiments, L is a combination of two or more of substituted or unsubstituted alkylene, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene, , ,, -N(H)-, -N(CH3)-, -O-, -N(H)C(=O)-, -N(CH3)C(=O)-, and -C(=O)-.

[0211] In certain embodiments, L is substituted or unsubstituted alkylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene,- N(CH3)-, -O-, -N(H)C(=O)-, -N(CH3)C(=O)-, or -C(=O)-, or a combination thereof. In certain embodiments, L is a combination of two or more of substituted or unsubstituted alkylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene,, , , -N(H)-, -N(CH3)-, -O-, -N(H)C(=O)-, -N(CH3)C(=O)-, and -C(=O)-.

[0212] In some embodiments, L is of formula:, wherein: Z1is a bond, -O-, -N(RA)-, -C(=O)-, 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.

[0213] In certain embodiments, L is of formula:, wherein: Z1is a bond, -O-, -N(RA)-, or substituted or unsubstituted heteroalkylene; Z2is a bond, -NRAC(=O)-, -N(RA)-, -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; Z3is a bond, -C(=O)-, or -N(RA)-; t is 0-30; and u is 0-30; provided that L comprises at least one atom.

[0214] In certain embodiments, L is of formula:, wherein:Z1is a bond, -O-, -N(RA)-, -C(=O)-, unsubstituted C1-6alkylene, ,Z3is a bond, -C(=O)-, -O-, or -N(RA)-; Z4is 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.

[0215] In certain embodiments, L is of formula:, wherein:Z1is a bond, -O-, -N(RA)-, -C(=O)-, unsubstituted C1-6alkylene, ,Z3is a bond, -C(=O)-, -O-, or -N(RA)-; Z4is 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.

[0216] In certain embodiments, L is of formula:, wherein:t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[0217] In certain embodiments, L is of formula:t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[0218] In certain embodiments, L is of formula:, wherein:Z2is a bond, -NRAC(=O)-, -C(=O)-, or -CH2-;Z3is a bond, -C(=O)-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[0219] In certain embodiments, L is of formula:, wherein:; Z3is a bond, -C(=O)-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[0220] In certain embodiments, L is of formula:, wherein:t is 0-20; andu is 0-6; provided that L comprises at least one atom.

[0221] In certain embodiments, L is of formula:, wherein:t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[0222] In certain embodiments, L is of formula:Z3is a bond or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[0223] In certain embodiments, L is of formula:, wherein:Z3is a bond or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[0224] In certain embodiments, L is of formula:, wherein:t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[0225] In certain embodiments, L is of formula:, wherein: Z1is a bond,Z2is a bond, -Q is a bond,Z3is a bond, -C(=O)-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[0226] In certain embodiments, L is of formula:, wherein:t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[0227] In certain embodiments, L is of formula:, wherein:t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[0228] In certain embodiments, L is of formula:

[0229] In certain embodiments, L is of formula:

[0230] In certain embodiments, L is of formula:.

[0231] In certain embodiments, L is of formula:.

[0232] In certain embodiments, L is of formula:.

[0233] In certain embodiments, L is of formula:.

[0234] In certain embodiments, L is of formula:.

[0235] In certain embodiments, L is of formula:.

[0236] In certain embodiments, L is of formula:.

[0237] In certain embodiments, L is of formula:.

[0238] In certain embodiments, L is of formula:.

[0239] In certain embodiments, L is of formula:.

[0240] In certain embodiments, L is of formula:.

[0241] In certain embodiments, L is of formula:.

[0242] In certain embodiments, L is of formula:.

[0243] In certain embodiments, L is of formula:.

[0244] In certain embodiments, L is of formula:.

[0245] In certain embodiments, L is of formula:.

[0246] In certain embodiments, L is of formula:.

[0247] In certain embodiments, L is of formula: .

[0248] In some embodiments, L is of formula: ,, , or .

[0249] In certain embodiments, L is selected from any one of L1-L73:

[0250] In certain embodiments, L is of formula L2, L4, L10, L12, L13, L16, L17, L18, L20, L21, L23, L27, L28, L29, L30, L32, L37, L40, L46, L47, L51, L52, L53, L54, L55, L56, L57, L58, L59, L60, L68, L69, L70, L71, L72, or L73. In certain embodiments, L is of formula L2, L4, L12, L16, L17, L18, L20, L23, L27, L28, L29, L32, L37, L40, L46, L47, L51, L52, L53, L54, L68, L69, L70, L71, L72, or L73. In certain embodiments, L is of formula L2. In certain embodiments, L is of formula L4. In certain embodiments, L is of formula L10. In certain embodiments, L is of formula L12. In certain embodiments, L is of formula L13. In certain embodiments, L is of formula L16. In certain embodiments, L is of formula L17. In certain embodiments, L is of formula L18. In certain embodiments, L is of formula L20. In certain embodiments, L is of formula L21. In certain embodiments, L is of formula L23. In certain embodiments, L is of formula L27. In certain embodiments, L is of formula L28. In certain embodiments, L is of formula L29. In certain embodiments, L is of formula L32. In certain embodiments, L is of formula L37. In certain embodiments, L is of formula L40. In certain embodiments, L is of formula L46. In certain embodiments, L is of formula L47. In certain embodiments, L is of formula L50. In certain embodiments, L is of formula L51. In certain embodiments, L is of formula L52. In certain embodiments, L is of formula L53. In certainembodiments, L is of formula L54. In certain embodiments, L is of formula L55. In certain embodiments, L is of formula L56. In certain embodiments, L is of formula L57. In certain embodiments, L is of formula L58. In certain embodiments, L is of formula L59.. In certain embodiments, L is of formula L60. In certain embodiments, L is of formula L67. In certain embodiments, L is of formula L68. In certain embodiments, L is of formula L69. In certain embodiments, L is of formula L70. In certain embodiments, L is of formula L71. In certain embodiments, L is of formula L72. In certain embodiments, L is of formula L73.

[0251] In certain embodiments, L is of formula:.

[0252] In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula: . In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:embodiments, L is of formula:. In some embodiments, L is of formula: . In some embodiments, L is of formula:mula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula: . In some embodiments, L is of formula:mula:. In some embodiments, L is of formula:. In someembodiments, L is of formula:. In some embodiments, L is of f. n some em o ments, s o ormua: . In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:some embodiments, L is of formula:. In some embodiments, L is of f. ,. n some em o ments, s o ormua: .

[0253] In certain embodiments, L is of formula:.

[0255] In certain embodiments, t is 1-20, 1-10, 1-8, 1-6, 1-5, 1-4, 1-3, or 1-2. In certain embodiments, t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, u is 1-6, 1-5, 1-4, 1-3, or 1-2. In certain embodiments, u is 1, 2, 3, 4, 5, or 6.

[0256] In some embodiments, L is selected from any one of L74-L232:

[0257] In certain embodiments, L is selected from any one of L1-L232.

[0258] In certain embodiments, L is of formula L75, L76, L79, L80, L82, L83, L84, L87, L88, L89, L90, L92, L93, L94, L95, L96, L97, L99, L101, L102, L103, L105, L106, L107, L108, L109, L110, L111, L112, L113, L115, L116, L117, L118, L119, L120, L137, L138, L139, L140, L141, L149, L153, L182, L187, L189, L191, L192, L193, L194, L195, L196, L197, L198, L199, L200, L201, L202, L203, L214, L215, L216, L217, L218, L222, L223, L224, L225, L226, L227, L228, L229, L230, L231, or L232.

[0259] In certain embodiments, L is of formula L75, L76, L79, L80, L87, L88, L93, L94, L95, L96, L97, L99, L101, L102, L103, L105, L106, L107, L108, L109, L110, L111, L112, L113, L137, L138, L139, L140, L141, L149, L153, L182, L187, L189, L191, L192, L193, L194, L195, L196, L197, L198, L200, L201, L202, L203, L223, L224, L225, L226, L227, L228, L229, L230, L231, or L232.

[0260] In certain embodiments, L is of formula L75, L76, L79, L80, L87, L88, L93, L94, L95, L96, L97, L99, L101, L102, L103, L105, L106, L107, L108, L109, L110, L111, L112, L113, L137, L138, L139, L140, L141, L149, L153, L182, L187, L189, L191, L192, L193, L194, L195, L196, L197, L198, L200, L201, L202, L203, L223, L224, L225, L226, L227, L228, L229, L230, or L231.

[0261] In certain embodiments, L is of formula L75. In certain embodiments, L is of formula L76. In certain embodiments, L is of formula L79. In certain embodiments, L is of formula L80. In certain embodiments, L is of formula L82. In certain embodiments, L is of formula L83. In certain embodiments, L is of formula L84. In certain embodiments, L is of formula L87. In certain embodiments, L is of formula L88. In certain embodiments, L is of formula L89. In certain embodiments, L is of formula L90. In certain embodiments, L is of formula L92. In certain embodiments, L is of formula L93. In certain embodiments, L is of formula L94. In certain embodiments, L is of formula L95. In certain embodiments, L is of formula L96. In certain embodiments, L is of formula L97. In certain embodiments, L is of formula L99. In certain embodiments, L is of formula L101. In certain embodiments, L is of formula L102. In certain embodiments, L is of formula L103. In certain embodiments, L is of formula L105. Incertain embodiments, L is of formula L106. In certain embodiments, L is of formula L107. In certain embodiments, L is of formula L108. In certain embodiments, L is of formula L109. In certain embodiments, L is of formula L110. In certain embodiments, L is of formula L111. In certain embodiments, L is of formula L112. In certain embodiments, L is of formula L113. In certain embodiments, L is of formula L115. In certain embodiments, L is of formula L116. In certain embodiments, L is of formula L117. In certain embodiments, L is of formula L118. In certain embodiments, L is of formula L119. In certain embodiments, L is of formula L120. In certain embodiments, L is of formula L137. In certain embodiments, L is of formula L138. In certain embodiments, L is of formula L139. In certain embodiments, L is of formula L140. In certain embodiments, L is of formula L141. In certain embodiments, L is of formula L149. In certain embodiments, L is of formula L153. In certain embodiments, L is of formula L182. In certain embodiments, L is of formula L187. In certain embodiments, L is of formula L189. In certain embodiments, L is of formula L191. In certain embodiments, L is of formula L192. In certain embodiments, L is of formula L193. In certain embodiments, L is of formula L194. In certain embodiments, L is of formula L195. In certain embodiments, L is of formula L196. In certain embodiments, L is of formula L197. In certain embodiments, L is of formula L198. In certain embodiments, L is of formula L199. In certain embodiments, L is of formula L200. In certain embodiments, L is of formula L201. In certain embodiments, L is of formula L202. In certain embodiments, L is of formula L203. In certain embodiments, L is of formula L214. In certain embodiments, L is of formula L215. In certain embodiments, L is of formula L216. In certain embodiments, L is of formula L217. In certain embodiments, L is of formula L218. In certain embodiments, L is of formula L222. In certain embodiments, L is of formula L223. In certain embodiments, L is of formula L224. In certain embodiments, L is of formula L225. In certain embodiments, L is of formula L226. In certain embodiments, L is of formula L227. In certain embodiments, L is of formula L228. In certain embodiments, L is of formula L229. In certain embodiments, L is of formula L230. In certain embodiments, L is of formula L231. In certain embodiments, L is of formula L232.

[0262] In certain embodiments, L is of formula:.

[0263] In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:some embodiments, L is of formula:. In some embodiments, L is offormula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula: mbodiments, L is of formula:. In some embodiments, L is oormu a: . In some embodiments, L is of formula:some embodiments, L is of formula:. In some embodiments, L is ofsome embodiments, L is of formula:. In some embodiments, L is of. ,. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula: bodiments, L is of formula:. In some embodiments, L is. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula: . In some embodiments, L is of formula:. In some rmula:. In some embodiments, L is of formula:. n some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:In some embodiments, L is of formula:. In some embodiments,L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:In some embodiments, L is of formula:some embodiments, L is of formula:. In some embodiments, L is of formula:some embodiments, L is of formula:some embodiments, L is of formula: some embodiments, L is of formula:ormula:. In some embodiments, L is of formula:. me embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:embodiments, L is of formula:. In some embodiments, L is offormula:. In some embodiments, L is of formula:. In some embodiments, L is of formula:. In some embodiments, L is of.

[0264] In certain embodiments, L is of formula:[.

[0266] In certain embodiments, L is (e.g., for Formula (II)): L95, L107, L232, a bond (L73), -O-, -OCH2-, -N(CH3)-, -NH-, -C(=O)-, -C(=O)CH2, -CH2-, -CH2CH2-,

[0267] In certain embodiments, L is not one or more of the following:.

[0268] In certain embodiments, L is not:.

[0269] In certain embodiments, L is not:.

[0271] In certain embodiments, L is not one or more of the following:

[0272] In certain embodiments, L is not. In certain embodiments, L iRA

[0273] As described herein, 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.

[0274] In some 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, 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 joined to form a substituted or unsubstituted heterocyclic ring.

[0275] 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 two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

[0276] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygen atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring.

[0277] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring.

[0278] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 5-6 membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring.

[0279] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-30 heteroalkyl, substituted or unsubstituted 5-6 membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring.

[0280] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C1-30 heteroalkyl.

[0281] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C1-20heteroalkyl.

[0282] In certain embodiments, each occurrence of RAis, independently, hydrogen, or substituted or unsubstituted C1-6alkyl. In certain embodiments, RAis hydrogen or substituted or unsubstituted alkyl. In certain embodiments, RAis substituted or unsubstituted alkyl. In certain embodiments, RAis substituted or unsubstituted C1-4alkyl. In certain embodiments, RAis unsubstituted C1-4alkyl. In certain embodiments, RAis t-butyl. In certain embodiments, RAis methyl. In certain embodiments, RAis t-butyl, n-butyl, n-propyl, iso-propyl, ethyl, methyl, or hydrogen In certain embodiments, RAis methyl. In certain embodiments, RAis t-butyl, methyl, or hydrogen. In certain embodiments, RAis t-butyl or hydrogen. In certain embodiments, RAis hydrogen. B

[0283] As described herein, B is a targeting moiety or detectable moiety (e.g., a chromophore, dye, fluorophore, luminophore or luminescent material, or radioactive material). In certain embodiments, B is a detectable moiety (e.g., a chromophore, dye, fluorophore, luminophore or luminescent material, or radioactive material). In certain embodiments, B is a dye. In certainembodiments, B is a targeting moiety. In certain embodiments, the targeting moiety is a bioactive moiety. In certain embodiments, the targeting moiety is a protein-binding moiety. In certain embodiments, the targeting moiety binds an enzyme. In some embodiments, the luminescent material is a phosphorescent agent.

[0284] The targeting moiety provides a means for recruiting, binding, modulating, modifying, inhibiting, and / or associating the compound with a target substrate. In certain embodiments, the target substrate is a biomolecule. In certain embodiments, the target substrate is a polypeptide, a polynucleotide, or a polysaccharide. In certain embodiments, the target substrate is a protein. In certain embodiments, B is a ligand, binder, modulator, modifier, and / or inhibitor of a protein. In certain embodiments, B is a protein-binding moiety. In certain embodiments, B is an inhibitor of a protein. In certain embodiments, B is an inhibitor of an enzyme.

[0285] The compounds disclosed herein may bind to a kinase, such as AMPK, and to a target substrate associated with the targeting moiety in order to alter the function of the kinase or the target substrate. In certain embodiments, a compound recruits, binds, modulates, modifies, inhibits, activates, and / or associates with a kinase, such as AMPK, to phosphorylate the target substrate associated with the targeting moiety. In an embodiment, the target substrate (e.g., protein) is not a natural substrate of the kinase to which the compound also binds.

[0286] In certain embodiments, the compounds disclosed herein include a moiety that binds to a kinase, such as AMPK, and a targeting moiety that binds to a second kinase. In certain embodiments, the compounds disclosed herein include a moiety that binds to a kinase, such as AMPK, and a targeting moiety that binds to a phosphatase.

[0287] In some embodiments, B is a BTK-binding moiety, bromodomain and extra-terminal domain (BET)-binding moiety, BRD2-binding moiety, BRD3-binding moiety, BRD4-binding moiety, BRDT-binding moiety, a kinase-binding moiety, KRAS-binding moiety, TRIM24- binding moiety, CAII-binding moiety, or a phosphatase-binding moiety. In some embodiments, B is a BTK-binding moiety. In some embodiments, B is a bromodomain and extra-terminal domain (BET)-binding moiety. In some embodiments, B is a BRD2-binding moiety. In some embodiments, B is a BRD3-binding moiety. In some embodiments, B is a BRD4-binding moiety. In some embodiments, B is a BRDT-binding moiety. In some embodiments, B is a kinase-binding moiety. In some embodiments, B is a KRAS-binding moiety. In some embodiments, B is a phosphatase-binding moiety. In some embodiments, B is a TRIM24-binding moiety. In some embodiments, B is a CAII-binding moiety.

[0288] In certain embodiments, B is a moiety that recruits, binds, modulates, modifies, inhibits, activates, and / or associates with 5'-AMP-activated protein kinase (AMPK) or isoforms of AMPK, a bromodomain-containing protein (e.g., BRD2, BRD3, BRD4, BRDT); histoneacetyltransferase (e.g., CREBBP, GCN5, PCAF, TAFII250); methyltransferase (e.g., ASH1L, MLL); Swi2 / Snf2; estrogen receptor; p53; Max; beta-catenin; BTK; BCR-ABL; KRAS (K-Ras protein or Kirsten rat sarcoma virus protein) or KRAS mutant; TRIM24 (Tripartite motif- containing 24); MDM2; EGFR; CDK4; CDK6; C-MET; PSENEN (presenilin enhancer 2 homolog (C. elegans)); CTSB (cathepsin B); PSEN1 (presenilin 1); APP (amyloid beta (A4) precursor protein); APH1B (anterior pharynx defective 1 homolog B (C. elegans)); PSEN2 (presenilin 2); BACE1 (beta-site APP-cleaving enzyme 1); ITM2B (integral membrane protein 2B); CTSD (cathepsin D); NOTCH1 (Notch homolog 1, translocation-associated); TNF (tumor necrosis factor (TNF superfamily, member 2)); INS (insulin); DYT10 (dystonia 10); ADAM17 (ADAM metallopeptidase domain 17); APOE (apolipoprotein E); ACE (angiotensin I converting enzyme (peptidyl-dipeptidase A) 1); STN (statin); TP53 (tumor protein p53); IL6 (interleukin 6 (interferon, beta 2)); NGFR (nerve growth factor receptor (TNFR superfamily, member 16)); IL1B (interleukin 1, beta); ACHE (acetylcholinesterase (Yt blood group)); CTNNB1 (catenin (cadherin-associated protein); beta 1, 88kDa); IGF1 (insulin-like growth factor 1 (somatomedin C)); IFNG (interferon, gamma); NRG1 (neuregulin 1); CASP3 (caspase 3, apoptosis-related cysteine peptidase); MAPK1 (mitogen-activated protein kinase 1); CDH1 (cadherin 1, type 1, E- cadherin (epithelial)); APBB1 (amyloid beta (A4) precursor protein-binding, family B, member 1 (Fe65)); HMGCR (3- hydroxy-3-methylglutaryl-Coenzyme A reductase); CREB1 (cAMP responsive element binding protein 1); PTGS2 (prostaglandin-endoperoxide synthase 2 (prostaglandin G / H synthase and cyclooxygenase)); HES1 (hairy and enhancer of split 1); CAT (catalase); TGFB1 (transforming growth factor, beta 1); EN02 (enolase 2 (gamma, neuronal)); ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4); TRAPPC10 (trafficking protein particle complex 10); MAOB (monoamine oxidase B); NGF (nerve growth factor (beta polypeptide)); MMP12 (matrix metallopeptidase 12 (macrophage elastase)); JAG1 (jagged 1 (Alagille syndrome)); CD40LG (CD40 ligand); PPARG (peroxisome proliferator-activated receptor gamma); FGF2 (fibroblast growth factor 2 (basic)); IL3 (interleukin 3 (colony- stimulating factor, multiple)); LRPl (low density lipoprotein receptor-related protein 1); NOTCH4 (Notch homolog 4); MAPK8 (mitogen-activated protein kinase 8); PREP (prolyl endopeptidase); NOTCH3 (Notch homolog 3); PRNP (prion protein); CTSG (cathepsin G); EGF (epidermal growth factor (beta-urogastrone)); REN (renin); CD44 (CD44 molecule); SELP (selectin P (granule membrane protein 140 kDa, antigen CD62)); GHR (growth hormone receptor); ADCYAP1 (adenylate cyclase activating polypeptide 1); INSR (insulin receptor); GFAP (glial fibrillary acidic protein); MMP3 (matrix metallopeptidase 3); MAPK10 (mitogen- activated protein kinase 10); SP1 (Spl transcription factor); MYC (v-myc myelocytomatosis viral oncogene homolog); CTSE (cathepsin E); PPARA (peroxisome proliferator-activated receptoralpha); JUN (jun oncogene); TIMP1 (TIMP metallopeptidase inhibitor 1); IL5 (interleukin 5 (colony-stimulating factor, eosinophil)); ILIA (interleukin 1, alpha); MMP9 (matrix metallopeptidase 9); HTR4 (5- hydroxytryptamine (serotonin) receptor 4); HSPG2 (heparan sulfate proteoglycan 2); CYCS (cytochrome c, somatic); SMG1 (SMG1 homolog, phosphatidylinositol 3-kinase-related kinase); IL1R1 (interleukin 1 receptor, type I); PROK1 (prokineticin 1); MAPK3 (mitogen-activated protein kinase 3); NTRK1 (neurotrophic tyrosine kinase, receptor, type 1); IL13 (interleukin 13); MME (membrane metallo-endopeptidase); TKT (transketolase); CXCR2 (chemokine (C-X-C motif) receptor 2); IGF1R (insulin-like growth factor 1 receptor); RARA (retinoic acid receptor, alpha); CREBBP (CREB binding protein); PTGS1 (prostaglandin-endoperoxide synthase 1 (prostaglandin G / H synthase and cyclooxygenase)); GALT (galactose-1-phosphate uridylyltransferase); CHRM1 (cholinergic receptor, muscarinic 1); ATXN1 (ataxin 1); PAWR (PRKC, apoptosis, WT1, regulator); NOTCH2 (Notch homolog 2); M6PR (mannose-6-phosphate receptor (cation dependent)); CYP46A1 (cytochrome P450, family 46, subfamily A, polypeptide 1); CSNK1 D (casein kinase 1, delta); MAPK14 (mitogen-activated protein kinase 14, also called p38-a); PRG2 (proteoglycan 2, bone marrow); PRKC A (protein kinase C, alpha); LI CAM (LI cell adhesion molecule); CD40 (CD40 molecule); NR1I2 (nuclear receptor subfamily 1, group I, member 2); JAG2 (jagged 2); CTNND1 (catenin (cadherin-associated protein), delta 1); CDH2 (cadherin 2, type 1, N- cadherin); CMA1 (chymase 1); SORT1 (sortilin 1); DLK1 (delta-like 1 homolog); THEM4 (thioesterase superfamily member 4); JUP (junction plakoglobin); CD46 (CD46 molecule, complement regulatory protein); CCL11 (chemokine (C-C motif) ligand 11); CAV3 (caveolin 3); RNASE3 (ribonuclease, RNase A family, 3); HSPA8 (heat shock 70kDa protein 8); CASP9 (caspase 9); CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4); CCR3 (chemokine (C-C motif) receptor 3); TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)); SCP2 (sterol carrier protein 2); CDK4 (cyclin-dependent kinase 4); HIF1A (hypoxia inducible factor 1, alpha subunit); TCF7L2 (transcription factor 7- like 2); IL1R2 (interleukin 1 receptor, type II); B3GALTL (beta 1,3-galactosyltransferase-like); MDM2 (Mdm2 p53 binding protein homolog); RELA (v-rel reticuloendotheliosis viral oncogene homolog A); CASP7 (caspase 7); IDE (insulin-degrading enzyme); FABP4 (fatty acid binding protein 4, adipocyte); CASK (calcium / calmodulin-dependent serine protein kinase (MAGUK family)); ADCYAPIRI (adenylate cyclase activating polypeptide 1 (pituitary) receptor type I); ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)); PDGFA (platelet-derived growth factor alpha polypeptide); C21 or f33 (chromosome 21 open reading frame 33); SCG5 (secretogranin V (7B2 protein)); RNF123 (ring finger protein 123); NFKBl (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1); ERBB2 (v-erb-b2erythroblastic leukemia viral oncogene homolog 2, neuro / glioblastoma derived oncogene homolog); CAV1 (caveolin 1, caveolae protein, 22 kDa); MMP7 (matrix metallopeptidase 7); TGFA (transforming growth factor, alpha); RXRA (retinoid X receptor, alpha); STX1A (syntaxin 1A); PSMC4 (proteasome (prosome, macropain) 26S subunit, ATPase, 4); P2RY2 (purinergic receptor P2Y, G-protein coupled, 2); TNFRSF21 (tumor necrosis factor receptor superfamily, member 21); DLG1 (discs, large homolog 1); NUMBL (numb homolog); SPN (sialophorin); PLSCR1 (phospholipid scramblase 1); UBQLN2 (ubiquilin 2); UBQLN1 (ubiquilin 1); PCSK7 (proprotein convertase subtilisin / kexin type 7); SPON1 (spondin 1, extracellular matrix protein); SILV (silver homolog); QPCT (glutaminyl-peptide cyclotransferase); HESS (hairy and enhancer of split 5); GCC1 (GRIP and coiled-coil domain containing 1); Angiopoietin-like 4 (ANGPTL4); Apolipoprotein C3 (APOCIII); Recombination Activating Gene 1 (RAG1); BCL11 A; PCSK9; laminin; alpha 2 (lama2); ATXN3; alanine-glyoxylate aminotransferase (AGXT); collagen type vii alpha 1 chain (COL7al); spinocerebellar ataxia type 1 protein (ATXN1); Angiopoietin-like 3 (ANGPTL3); Frataxin (FXN); Superoxidase Dismutase 1 (SOD1); Synuclein Alpha (SNCA); Sodium Channel, Voltage Gated, Type X Alpha Subunit (SCN10A); Spinocerebellar Ataxia Type 2 Protein (ATXN2); Dystrophia Myotonica-Protein Kinase (DMPK); beta globin locus on chromosome 11; acyl-coenzyme A dehydrogenase for medium chain fatty acids (ACADM); long- chain 3-hydroxyl-coenzyme A dehydrogenase for long chain fatty acids (HADHA); acyl- coenzyme A dehydrogenase for very long-chain fatty acids (ACADVL); Transthyretin (TTR); Angiopoietin-like 4 (ANGPTL4); Sodium Voltage-Gated Channel Alpha Subunit 9 (SCN9A); Interleukin-7 receptor (IL7R); glucose-6-phosphatase; catalytic (G6PC); haemochromatosis (HFE); SERPINAl; C90RF72; β-globin; dystrophin; g-globin; an AAVS1 (PPPIR12C) gene; an ALB gene; an Angptl3 gene; an ApoC3 gene; an ASGR2 gene; a CCR5 gene; a FIX (F9) gene; a G6PC gene; a Gys2 gene; an HGD gene; a Lp(a) gene; a Pcsk9 gene; a Serpinal gene; a TF gene; a TTR gene; B2M; CD247; CD3D; CD3E; CD3G; TRAC; TRBC1; TRBC2; HLA-A; HLA-B; HLA-C; DCK; CD52; FKBP1A; CIITA; NLRC5; RFXANK; RFX5; RFXAP; or NR3C1; HAVCR2; LAG3; PDCD1; PD-L2; CTLA4; CEACAM (CEACAM-1, CEACAM-3 and / or CEACAM-5); VISTA; BTLA; TIGIT; LAIR1; CD 160; 2B4; CD80; CD86; B7-H3 (CD113); B7-H4 (VTCN1); HVEM (TNFRSF14 or CD 107); KIR; A2aR; MHC class I; MHC class II; GAL9; adenosine; TGF beta; PTPN11; DCK; CD52; NR3C1; LILRBl; CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRvIII); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2- 3)bDGalp(l-4)bDGlcp(l-l)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAca-Ser / Thr)); prostate-specific membrane antigen (PSMA); Receptortyrosine kinase-like orphan receptor 1 (ROR1); Fms-Like Tyrosine Kinase 3 (FLT3); Tumor- associated glycoprotein 72 (TAG72); CD38; CD44v6; Carcinoembryonic antigen (CEA); Epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); Interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); Mesothelin; Interleukin 11 receptor alpha (IL- llRa); prostate stem cell antigen (PSCA); Protease Serine 21 (Testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis(Y) antigen; CD24; Platelet-derived growth factor receptor beta (PDGFR-beta); Stage-specific embryonic antigen-4 (S SEA-4); CD20; Folate receptor alpha; Receptor tyrosine-protein kinase ERBB2 (Her2 / neu); n kinase ERBB2 (Her2 / neu); Mucin 1; cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); Prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); Ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor); carbonic anhydrase IX (CAIX); carbonic anhydrase II (CAII); Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2); glycoprotein 100 (gplOO); oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr- abl); tyrosinase; ephrin type- A receptor 2 (EphA2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bDGalp(l-4)bDGlcp(l-l)Cer); transglutaminase 5 (TGS5); high molecular weight- melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); Folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); Polysialic acid; placenta- specific 1 (PLAC1); hexasaccharide portion of globoH glycoceramide (GloboH); mammary gland differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); Hepatitis A virus cellular receptor 1 (HAVCR1); adrenoceptor beta 3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K 9 (LY6K); Olfactory receptor 51E2 (OR51E2); TCR Gamma Alternate Reading Frame Protein (TARP); Wilms tumor protein (WT1); Cancer / testis antigen 1 (NY-ESO-1); Cancer / testis antigen 2 (LAGE-la); Melanoma- associated antigen 1 (MAGE-A1); ETS translocation-variant gene 6, located on chromosome 12p (ETV6- AML); sperm protein 17 (SPA17); X Antigen Family, Member 1A (XAGE1); angiopoietin- binding cell surface receptor 2 (Tie 2); melanoma cancer testis antigen-1 (MAD-CT-1); melanoma cancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; wild-type p53-induced phosphatase 1 (Wip1); prostein; surviving; telomerase; prostate carcinoma tumor antigen-1 (PCTA-1 or Galectin 8); melanoma antigen recognized by T cells 1 (MelanA or MARTI); Rat sarcoma (Ras) mutant; human Telomerase reverse transcriptase(hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-Acetyl glucosaminyl- transferase V (NA17); paired box protein Pax-3 (PAX3); Androgen receptor; Cyclin Bl; v- myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN); Ras Homolog Family Member C (RhoC); Tyrosinase-related protein 2 (TRP-2); Cytochrome P4501B1 (CYP1B1); CCCTC-Binding Factor (Zinc Finger Protein)-Like (BORIS or Brother of the Regulator of Imprinted Sites); Squamous Cell Carcinoma Antigen Recognized By T Cells 3 (SART3); Paired box protein Pax-5 (PAX5); proacrosin binding protein sp32 (OY- TES1); lymphocyte-specific protein tyrosine kinase (LCK); Janus kinase 2 (JAK2); large tumor suppressor kinase 1 (LATS1); large tumor suppressor kinase 2 (LATS2); A kinase anchor protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 (SSX2); Receptor for Advanced Glycation Endproducts (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papilloma virus E6 (HPV E6); human papilloma virus E7 (HPV E7); intestinal carboxyl esterase; heat shock protein 70-2 mutated (mut hsp70-2); CD79a; CD79b; CD72; Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89); Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule- like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module- containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); Glypican-3 (GPC3); Fc receptor-like 5 (FCRLS); and immunoglobulin lambda-like polypeptide 1 (IGLL1); CD 19; BCMA; CD70; G6PC; Dystrophin, including modification of exon 51 by deletion or excision; DMPK; CFTR (cystic fibrosis transmembrane conductance regulator); the SCNN1A gene; acetyl-CoA carboxylase; fatty acid synthase; 3-ketoacyl acyl- carrier protein synthase III; glycerol-3-phospate dehydrogenase (G3PDH); Enoyl-acyl carrier protein reductase (Enoyl-ACP-reductase); glycerol- 3-phosphate acyltransferase; lysophosphatidic acyl transferase; diacylglycerol acyltransferase; phoshatidate phosphatase; fatty acid thioesterase such as palmitoyi protein thioesterase or malic enzyme; acyl-CoA synthetase; 3-ketoacyl-CoA thiolase; acyl-CoA oxidase activity; phosphoglucomutase; Arylsulfatase A; Wiskott-Aldrich Syndrome protein; ATP- binding cassette DI; receptor type 5- C-C chemokine or CXCR4 gene; Hemoglobin beta subunit; interelukin-2 receptor subunit gamma; cystinosin; Ribosomal protein S19; Fanconi anemia complementation groups (e.g., FNACA, FNACB, FANCC, FANCD1, FANCD2, FANCE, FANCF, RAD51C); Shwachman syndrome gene; Glucocerebrosidase; Anti-hemophiliac factor OR Factor VIII; Christmas factor; Serine protease; Factor Hemophilia B IX; Adenosine deaminase; beta- galactosidase; alpha-glucosidase; sphingomyelinase; galactercerebrosidease; Human leukocyte antigens DR-15; DQ-6; DRB1; RSI, RL2 and / or LAT genes; PreC, C, X, PreSl, PreS2, S, Pand / or SP gene(s); Chromosomal Sequence Encoded Protein, Delta-aminolevulinate synthase 2 (ALAS2); ATP-binding cassette transporter (ABCA1); Angiotensin I converting enzyme (ACE); Apolipoprotein E precursor (APOE); amyloid precursor protein (APP); aquaporin 1 protein (AQP1); Myc box-dependent- interacting protein 1 or bridging integrator 1 protein (BIN1); brain- derived neurotrophic factor (BDNF); Butyrophilin-like protein 8 (BTNL8); chromosome 1 open reading frame 49 (C10RF49); CDH4 (Cadherin-4 CHRNB2 Neuronal acetylcholine receptor subunit beta-2); CKLF-like MARVEL transmembrane domain- containing protein 2 (CKLFSF2); C-type lectin domain family 4, member e (CLEC4E); CLU clusterin protein (also known as apoplipoprotein J); Erythrocyte complement receptor 1 (CR1, also known as CD35, C3b / C4b receptor and immune adherence receptor); Erythrocyte complement receptor 1 (CR1L); granulocyte colony-stimulating factor 3 receptor (CSF3R); CST3 (Cystatin C or cystatin 3); CYP2C (Cytochrome P4502C); Death-associated protein kinase 1 (DAPK1); Estrogen receptor 1 (ESR1); fragment of IgA receptor (FCAR, also known as CD89); Fc fragment of IgG, low affinity Illb, receptor (FCGR3B or CD16b); Free fatty acid receptor 2 (FFA2); FGA Fibrinogen (Factor I); GRB2-associated-binding protein 2 (GAB2); Galanin-like peptide (GALP); Glyceraldehyde-3- phosphate dehydrogenase, spermatogenic (GAPDHS); Haptoglobin (HP); serotonin receptor 7; Insulin degrading enzyme (IDE); IF 127; IFI6 Interferon, alpha-inducible protein 6 (IFI6); Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2); interleukin-1 receptor antagonist (IL-1RA); Interleukin 8 receptor, alpha (IL8RA or CD181); Interleukin 8 receptor, beta (IL8RB); Jagged 1 (JAG1); Potassium inwardly-rectifying channel, subfamily J, member 15 (KCNJ15); Low-density lipoprotein receptor-related protein 6 (LRP6); microtubule- associated protein tau (MAPT); MAP / microtubule affinity-regulating kinase 4 (MARK4); M- phase phosphoprotein 1 (MPHOSPH1); 5,10-methylenetetrahydrofolate reductase (MTHFR); Interferon- induced GTP-binding protein Mx2 (MX2); Nibrin (NBN); Nicastrin (NCSTN); Niacin receptor 2 (NIACR2, also known as GPR109B); nicotinamide nucleotide adenylyltransferase 3 (NMNAT3); Neurotrimin (NTM or HNT); Orosmucoid 1 (ORM1); Alpha- 1-acid glycoprotein 1; P2Y purinoceptor 13 (P2RY13); Nicotinamide phosphoribosyltransferase (NAmPRTase or Nampt) also known as pre-B-cell colony-enhancing factor 1 (PBEF1); visfatin; Phosphoenolpyruvate carboxy kinase (PCK1); phosphatidylinositol binding clathrin assembly protein (PICALM); Urokinase-type plasminogen activator (PLAU); Plexin Cl (PLXNC1); Prion protein (PRNP); PSEN1 presenilin 1 protein (PSEN1); presenilin 2 protein (PSEN2); protein tyrosine phosphatase receptor type A protein (PTPRA); Ral GEF with PH domain and SH3 binding motif 2 (RALGPS2); regulator of G-protein signaling like 2 (RGSL2); Selenium binding protein 1 (SELNBP1); SLC25A37 Mitoferrin-1, sortilin-related receptor L(DLR class) A repeats- containing protein (SORLl); Transferrin; Mitochondrial transcription factor A (TFAM); Tumornecrosis factor (TNF); Tumor necrosis factor receptor superfamily member 10C (TNFRSF10C); Tumor necrosis factor receptor superfamily, (TRAIL) member 10a (TNFSF10); ubiquitin-like modifier activating enzyme 1 (UBA1); NEDD8-activating enzyme El catalytic subunit protein (UBE1C); ubiquitin B protein (UBB); Ubiquilin-1 (UBQLN1); ubiquitin carboxyl-terminal esterase LI protein (UCHL1); ubiquitin carboxyl-terminal hydrolase isozyme L3 protein (UCHL3); very low density lipoprotein receptor protein (VLDLR); low density lipoprotein receptor protein (VLDLR) encoded by the VLDLR gene; the ubiquitin-like modifier activating enzyme 1 (UBA1) encoded by the UBA1 gene; the NEDD8-activating enzyme El catalytic subunit protein (UBE1C) encoded by the UBA3 gene; the aquaporin 1 protein (AQP1) encoded by the AQP1 gene; the ubiquitin carboxyl-terminal esterase LI protein (UCHL1) encoded by the UCHL1 gene; the ubiquitin carboxyl-terminal hydrolase isozyme L3 protein (UCHL3) encoded by the UCHL3 gene; the ubiquitin B protein (UBB) encoded by the UBB gene; the microtubule- associated protein tau (MAPT) encoded by the MAPT gene; the protein tyrosine phosphatase receptor type A protein (PTPRA) encoded by the PTPRA gene; the phosphatidylinositol binding clathrin assembly protein (PICALM) encoded by the PICALM gene; the clusterin protein (also known as apoplipoprotein J) encoded by the CLU gene; the presenilin 1 protein encoded by the PSEN1 gene; the presenilin 2 protein encoded by the PSEN2 gene; the sortilin-related receptor L(DLR class) A repeats-containing protein (SORLl) protein encoded by the SORLl gene; the amyloid precursor protein (APP) encoded by the APP gene; the Apolipoprotein E precursor (APOE) encoded by the APOE gene; the brain-derived neurotrophic factor (BDNF) encoded by the BDNF gene; cell surface receptors; cell surface receptors on cancer cells; TfRs; folate receptors (FRs); VCAM (vascular endothelium); E- and P-selectins; VCAM-1; ICAMs; TIMP1- 4; MT1-MMP; MMP-2; an RGD peptide; phospholipase A2; alkaline phosphatase; transglutaminase; phosphatidylinositol-specific phospholipase C; cell-penetrating peptides (CPPs); amphipathic helical peptides; transportan; MAP; TATp; Antennapedia; penetratin; or VP22; or any combination thereof.

[0289] In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with KRAS or KRAS mutant, BRD4, CAII, TRIM24, BTK, BET, BRD2, BRD3, or BRDT. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with a kinase or phosphatase. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with KRAS or KRAS mutant, BRD4, CAII, TRIM24, or BTK. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with BRD4 or BTK. In certain embodiments, B is a ligand, recruiter, binder, modulator, modifier, inhibitor, activator, and / or associator of KRAS or KRAS mutant, BRD4, CAII, TRIM24, or BTK. In certain embodiments, B is a ligand, recruiter, binder,modulator, modifier, inhibitor, activator, and / or associator of BRD4 or BTK. In certain embodiments, B is an inhibitor of KRAS or KRAS mutant, BRD4, CAII, TRIM24, or BTK. In certain embodiments, B is an inhibitor of BRD4 or BTK. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with KRAS or KRAS mutant. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with BRD4. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with CAII. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with TRIM24. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with BTK. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with BET. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with BRD2. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with BRD3. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with BRDT. In certain embodiments, B is an inhibitor of KRAS or KRAS mutant. In certain embodiments, B is an inhibitor of BRD4. In certain embodiments, B is an inhibitor of CAII. In certain embodiments, B is an inhibitor of TRIM24. In certain embodiments, B is an inhibitor of BTK. In certain embodiments, B is an inhibitor of BET. In certain embodiments, B is an inhibitor of BRD2. In certain embodiments, B is an inhibitor of BRD3. In certain embodiments, B is an inhibitor of BRDT.

[0290] In certain embodiments, B is a KRAS-binding moiety, a kinase-binding moiety or a phosphatase-binding moiety. [[or a pharmaceutically acceptable salt thereof.

[0293] In certain embodiments, B is of formula:, or a pharmaceutically acceptable salt thereof.

[0294] In certain embodiments, B is of formula:, or a pharmaceutically acceptable salt thereof.

[0295] In certain embodiments, B is of formula:, or a pharmaceutically acceptable salt thereof.

[0296] In certain embodiments, B is of formula:, or a pharmaceutically acceptable salt thereof.

[0297] In certain embodiments, B is of formula:, or a pharmaceutically acceptable salt thereof.

[0298] In certain embodiments, B is of formula:

[0299] In certain embodiments, B is a detectable moiety. In certain embodiments, B is a chromophore. In certain embodiments, B is a dye. In certain embodiments, B is a fluorophore. In certain embodiments, B is a luminophore. In certain embodiments, B is a luminescent material. In certain embodiments, B is a radioactive material.

[0300] In certain embodiments, B is a dye. In certain embodiments, B is a fluorescent dye. In certain embodiments, B is of formula:

[0301] In certain embodiments, B is of formula:or a pharmaceutically acceptable salt thereof.

[0302] In certain embodiments, B is of formula:, or a pharmaceutically acceptable salt thereof.

[0303] In certain embodiments, the targeting moiety B (e.g., protein-binding moiety) binds a target substrate (e.g., protein) 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.

[0304] In certain embodiments, the targeting moiety B (e.g., protein-binding moiety) selectively binds a target substrate (e.g., protein) 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. T

[0305] As described herein, T is hydrogen, a protecting group, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle. In certain embodiments, T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, a nitrogen protecting group, an oxygen protecting group, or a click chemistry handle. In certain embodiments, T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle

[0306] In certain embodiments, T is a click chemistry handle. “Click chemistry” refers to a chemical approach to conjugation introduced by Sharpless in 2001 and describes chemistry tailored to generate substances quickly and reliably by joining units together. See, e.g., Kolb, Finn and Sharpless Angewandte Chemie International Edition 200140, 2004–2021; Evans,Australian Journal of Chemistry 200760, 384–395). Exemplary coupling reactions (some of which may be classified as “click chemistry”) include, but are not limited to, formation of esters, thioesters, amides (e.g., such as peptide coupling) from activated acids or acyl halides; nucleophilic displacement reactions (e.g., such as nucleophilic displacement of a halide or ring opening of strained ring systems); azide–alkyne Huisgen cycloaddition; thiol–yne addition; imine formation; Michael additions (e.g., maleimide addition reactions); and Diels–Alder reactions (e.g., tetrazine [4 + 2] cycloaddition). Examples of click chemistry reactions and click-chemistry handles can be found in, e.g., Kolb, H. C.; Finn, M. G. and Sharpless, K. B., Angew. Chem. Int. Ed.2001, 40, 2004-2021. Kolb, H. C. and Sharless, K. B. Drug Disc. Today, 2003, 8, 112-1137; Rostovtsev, V. V.; Green L. G.; Fokin, V. V. and Shrapless, K. B. Angew. Chem. Int. Ed.2002, 41, 2596-2599; Tomoe, C. W.; Christensen, C. and Meldal, M. J. Org. Chem.2002, 67, 3057- 3064. Wang, Q. et al. J. Am. Chem. Soc.2003, 125, 3192-3193; Lee, L. V. et al., J. Am. Chem. Soc.2003125, 9588-9589; Lewis, W. G. et al., Angew. Chem. Int. Ed.2002, 41, 1053- 41057; Manetsch, R. et al., J. Am. Chem. Soc.2004, 126, 12809- 12818; Mocharla, V. P. et al., Angew. Chem., Int. Ed.2005, 44, 116-120.

[0307] In some embodiments, click chemistry handles are used that can react to form covalent bonds in the absence of a metal catalyst. Such click chemistry handles are known to those of skill in the art and include the click chemistry handles described in Becer, Hoogenboom, and Schubert, Click Chemistry beyond Metal-Catalyzed Cycloaddition, Angewandte Chemie International Edition (2009) 48: 4900 – 4908.

[0308] In certain embodiments, the click-chemistry handle comprises an alkenylene group or alkynylene group. In certain embodiments, the click-chemistry handle comprises an internal alkenylene group or alkynylene group. In certain embodiments, the click-chemistry handle comprises a terminal alkenylene group or alkynylene group. In certain embodiments, the click- chemistry handle is –CºCH, substituted or unsubstituted cyclooctynyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, substituted or unsubstituted cyclopropenyl, substituted or unsubstituted cyclobutenyl, substituted or unsubstituted trans-cyclooctenyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, or substituted or unsubstituted. In certain embodiments, the click chemistry handle is an azide, tetrazine, tetrazole, dithioester, anthracene, amine, or thiol.

[0309] In some embodiments, T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle. In certain embodiments, T is hydrogen, a nucleophilic group, a leaving group, a nitrogen protecting group, or an oxygen protecting group. In certainembodiments, T is hydrogen, a nucleophilic group, a leaving group, or a nitrogen protecting group. In some embodiments, T is hydrogen, -ORA, -N3, -COORA, -C≡CH, halogen, or a nitrogen protecting group. In some embodiments, T is hydrogen, an amine, a carboxylic acid, an aldehyde, an alkyne, an alkene, an azide, an alcohol, a halogen, or a nitrogen protecting group. In some embodiments, T is -ORA, -Br, -Cl, -F, -COORA, -NHRA, -C(=O)H, -C≡CH, -N3, or a nitrogen protecting group. In certain embodiments, T is hydrogen, halogen, -OH, -OMe, -OtBu, -OMs (mesylate), -OTs (tosylate), or -C≡CH. In certain embodiments, T is -C≡CH. In certain embodiments, T is hydrogen or a halogen (e.g., -Br). In certain embodiment, T is halogen. In certain embodiments, T is -Cl or -Br. In certain embodiments, T is -Br. In certain embodiments, T is hydrogen, -OH, -OMe, -OtBu, -OMs (mesylate), -OTs (tosylate), -C≡CH, -Br, or a nitrogen protecting group (e.g., Boc). In certain embodiments, T is a nitrogen protecting group (e.g., Boc). In certain embodiments, T is hydrogen, -OH, -OMe, or -OtBu. In certain embodiments, T is -OH or -OMe. In certain embodiments, T is -OH. In certain embodiments, T is hydrogen. In certain embodiments, T is -NHRA. In certain embodiments, T is -NH2. In certain embodiments, T is -Cl. Further Embodiments of Formula (I)

[0310] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a):(I-a), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein A, L, B, R3, R4, R5, and R6are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a), wherein L is any one of L1-L232, or a pharmaceutically acceptable salt thereof.

[0311] The following embodiments of this paragraph relate to embodiments of the compound of Formula (I-a). In certain embodiments, L is of formula L1. In certain embodiments, L is of formula L2. In certain embodiments, L is of formula L3. In certain embodiments, L is of formula L4. In certain embodiments, L is of formula L5. In certain embodiments, L is of formula L6. In certain embodiments, L is of formula L7. In certain embodiments, L is of formula L8. In certain embodiments, L is of formula L9. In certain embodiments, L is of formula L10. In certain embodiments, L is of formula L11. In certain embodiments, L is of formula L12. In certain embodiments, L is of formula L13. In certain embodiments, L is of formula L14. In certain embodiments, L is of formula L15. In certainembodiments, L is of formula L16. In certain embodiments, L is of formula L17. In certain embodiments, L is of formula L18. In certain embodiments, L is of formula L19. In certain embodiments, L is of formula L20. In certain embodiments, L is of formula L21. In certain embodiments, L is of formula L22. In certain embodiments, L is of formula L23. In certain embodiments, L is of formula L24. In certain embodiments, L is of formula L25. In certain embodiments, L is of formula L26. In certain embodiments, L is of formula L27. In certain embodiments, L is of formula L28. In certain embodiments, L is of formula L29. In certain embodiments, L is of formula L30. In certain embodiments, L is of formula L31. In certain embodiments, L is of formula L32. In certain embodiments, L is of formula L33. In certain embodiments, L is of formula L34. In certain embodiments, L is of formula L35. In certain embodiments, L is of formula L36. In certain embodiments, L is of formula L37. In certain embodiments, L is of formula L38. In certain embodiments, L is of formula L39. In certain embodiments, L is of formula L40. In certain embodiments, L is of formula L41. In certain embodiments, L is of formula L42. In certain embodiments, L is of formula L43. In certain embodiments, L is of formula L44. In certain embodiments, L is of formula L45. In certain embodiments, L is of formula L46. In certain embodiments, L is of formula L47. In certain embodiments, L is of formula L48. In certain embodiments, L is of formula L49. In certain embodiments, L is of formula L50. In certain embodiments, L is of formula L51. In certain embodiments, L is of formula L52. In certain embodiments, L is of formula L53. In certain embodiments, L is of formula L54. In certain embodiments, L is of formula L55. In certain embodiments, L is of formula L56. In certain embodiments, L is of formula L57. In certain embodiments, L is of formula L58. In certain embodiments, L is of formula L59. In certain embodiments, L is of formula L60. In certain embodiments, L is of formula L61. In certain embodiments, L is of formula L62. In certain embodiments, L is of formula L63. In certain embodiments, L is of formula L64. In certain embodiments, L is of formula L65. In certain embodiments, L is of formula L66. In certain embodiments, L is of formula L67. In certain embodiments, L is of formula L68. In certain embodiments, L is of formula L69. In certain embodiments, L is of formula L70. In certain embodiments, L is of formula L71. In certain embodiments, L is of formula L72. In certain embodiments, L is of formula L73. In certain embodiments, L is of formula L74. In certain embodiments, L is of formula L75. In certain embodiments, L is of formula L76. In certain embodiments, L is of formula L77. In certain embodiments, L is of formula L78. In certain embodiments, L is of formula L79. In certain embodiments, L is of formula L80. In certain embodiments, L is of formula L81. In certain embodiments, L is of formula L82. In certain embodiments, L is of formula L83. In certainembodiments, L is of formula L84. In certain embodiments, L is of formula L85. In certain embodiments, L is of formula L86. In certain embodiments, L is of formula L87. In certain embodiments, L is of formula L88. In certain embodiments, L is of formula L89. In certain embodiments, L is of formula L90. In certain embodiments, L is of formula L91. In certain embodiments, L is of formula L92. In certain embodiments, L is of formula L93. In certain embodiments, L is of formula L94. In certain embodiments, L is of formula L95. In certain embodiments, L is of formula L96. In certain embodiments, L is of formula L97. In certain embodiments, L is of formula L98. In certain embodiments, L is of formula L99. In certain embodiments, L is of formula L100. In certain embodiments, L is of formula L101. In certain embodiments, L is of formula L102. In certain embodiments, L is of formula L103. In certain embodiments, L is of formula L104. In certain embodiments, L is of formula L105. In certain embodiments, L is of formula L106. In certain embodiments, L is of formula L107. In certain embodiments, L is of formula L108. In certain embodiments, L is of formula L109. In certain embodiments, L is of formula L110. In certain embodiments, L is of formula L111. In certain embodiments, L is of formula L112. In certain embodiments, L is of formula L113. In certain embodiments, L is of formula L114. In certain embodiments, L is of formula L115. In certain embodiments, L is of formula L116. In certain embodiments, L is of formula L117. In certain embodiments, L is of formula L118. In certain embodiments, L is of formula L119. In certain embodiments, L is of formula L120. In certain embodiments, L is of formula L121. In certain embodiments, L is of formula L122. In certain embodiments, L is of formula L123. In certain embodiments, L is of formula L124. In certain embodiments, L is of formula L125. In certain embodiments, L is of formula L126. In certain embodiments, L is of formula L127. In certain embodiments, L is of formula L128. In certain embodiments, L is of formula L129. In certain embodiments, L is of formula L130. In certain embodiments, L is of formula L131. In certain embodiments, L is of formula L132. In certain embodiments, L is of formula L133. In certain embodiments, L is of formula L134. In certain embodiments, L is of formula L135. In certain embodiments, L is of formula L136. In certain embodiments, L is of formula L137. In certain embodiments, L is of formula L138. In certain embodiments, L is of formula L139. In certain embodiments, L is of formula L140. In certain embodiments, L is of formula L141. In certain embodiments, L is of formula L142. In certain embodiments, L is of formula L143. In certain embodiments, L is of formula L144. In certain embodiments, L is of formula L145. In certain embodiments, L is of formula L146. In certain embodiments, L is of formula L147. In certain embodiments, L is of formula L148. In certain embodiments, L is of formula L149. In certain embodiments, L is of formula L150. In certain embodiments, L is of formula L151. In certainembodiments, L is of formula L152. In certain embodiments, L is of formula L153. In certain embodiments, L is of formula L154. In certain embodiments, L is of formula L155. In certain embodiments, L is of formula L156. In certain embodiments, L is of formula L157. In certain embodiments, L is of formula L158. In certain embodiments, L is of formula L159. In certain embodiments, L is of formula L160. In certain embodiments, L is of formula L161. In certain embodiments, L is of formula L162. In certain embodiments, L is of formula L163. In certain embodiments, L is of formula L164. In certain embodiments, L is of formula L165. In certain embodiments, L is of formula L166. In certain embodiments, L is of formula L167. In certain embodiments, L is of formula L168. In certain embodiments, L is of formula L169. In certain embodiments, L is of formula L170. In certain embodiments, L is of formula L171. In certain embodiments, L is of formula L172. In certain embodiments, L is of formula L173. In certain embodiments, L is of formula L174. In certain embodiments, L is of formula L175. In certain embodiments, L is of formula L176. In certain embodiments, L is of formula L177. In certain embodiments, L is of formula L178. In certain embodiments, L is of formula L179. In certain embodiments, L is of formula L180. In certain embodiments, L is of formula 181. In certain embodiments, L is of formula L182. In certain embodiments, L is of formula L183. In certain embodiments, L is of formula L184. In certain embodiments, L is of formula L185. In certain embodiments, L is of formula L186. In certain embodiments, L is of formula L187. In certain embodiments, L is of formula L188. In certain embodiments, L is of formula L189. In certain embodiments, L is of formula L190. In certain embodiments, L is of formula L191. In certain embodiments, L is of formula L192. In certain embodiments, L is of formula L193. In certain embodiments, L is of formula L194. In certain embodiments, L is of formula L195. In certain embodiments, L is of formula L196. In certain embodiments, L is of formula L197. In certain embodiments, L is of formula L198. In certain embodiments, L is of formula L199. In certain embodiments, L is of formula L200. In certain embodiments, L is of formula L201. In certain embodiments, L is of formula L202. In certain embodiments, L is of formula L203. In certain embodiments, L is of formula L204. In certain embodiments, L is of formula L205. In certain embodiments, L is of formula L206. In certain embodiments, L is of formula L207. In certain embodiments, L is of formula L208. In certain embodiments, L is of formula L209. In certain embodiments, L is of formula L210. In certain embodiments, L is of formula L211. In certain embodiments, L is of formula L212. In certain embodiments, L is of formula L213. In certain embodiments, L is of formula L214. In certain embodiments, L is of formula L215. In certain embodiments, L is of formula L216. In certain embodiments, L is of formula L217. In certain embodiments, L is of formula L218. In certain embodiments, L is of formula L219. In certainembodiments, L is of formula L220. In certain embodiments, L is of formula L221. In certain embodiments, L is of formula L222. In certain embodiments, L is of formula L223. In certain embodiments, L is of formula L224. In certain embodiments, L is of formula L225. In certain embodiments, L is of formula L226. In certain embodiments, L is of formula L227. In certain embodiments, L is of formula L228. In certain embodiments, L is of formula L229. In certain embodiments, L is of formula L230. In certain embodiments, L is of formula L231. In certain embodiments, L is of formula L232.

[0312] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a- 1):(I-a-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein A, L, B, R3, and R6are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a-1), wherein L is any one of L1-L232, or a pharmaceutically acceptable salt thereof.

[0313] The following embodiments of this paragraph relate to embodiments of the compound of Formula (I-a-1). In certain embodiments, L is of formula L1. In certain embodiments, L is of formula L2. In certain embodiments, L is of formula L3. In certain embodiments, L is of formula L4. In certain embodiments, L is of formula L5. In certain embodiments, L is of formula L6. In certain embodiments, L is of formula L7. In certain embodiments, L is of formula L8. In certain embodiments, L is of formula L9. In certain embodiments, L is of formula L10. In certain embodiments, L is of formula L11. In certain embodiments, L is of formula L12. In certain embodiments, L is of formula L13. In certain embodiments, L is of formula L14. In certain embodiments, L is of formula L15. In certain embodiments, L is of formula L16. In certain embodiments, L is of formula L17. In certain embodiments, L is of formula L18. In certain embodiments, L is of formula L19. In certain embodiments, L is of formula L20. In certain embodiments, L is of formula L21. In certain embodiments, L is of formula L22. In certain embodiments, L is of formula L23. In certain embodiments, L is of formula L24. In certain embodiments, L is of formula L25. In certain embodiments, L is of formula L26. In certain embodiments, L is of formula L27. In certain embodiments, L is of formula L28. In certain embodiments, L is of formula L29. In certain embodiments, L is of formula L30. In certain embodiments, L is of formula L31. In certainembodiments, L is of formula L32. In certain embodiments, L is of formula L33. In certain embodiments, L is of formula L34. In certain embodiments, L is of formula L35. In certain embodiments, L is of formula L36. In certain embodiments, L is of formula L37. In certain embodiments, L is of formula L38. In certain embodiments, L is of formula L39. In certain embodiments, L is of formula L40. In certain embodiments, L is of formula L41. In certain embodiments, L is of formula L42. In certain embodiments, L is of formula L43. In certain embodiments, L is of formula L44. In certain embodiments, L is of formula L45. In certain embodiments, L is of formula L46. In certain embodiments, L is of formula L47. In certain embodiments, L is of formula L48. In certain embodiments, L is of formula L49. In certain embodiments, L is of formula L50. In certain embodiments, L is of formula L51. In certain embodiments, L is of formula L52. In certain embodiments, L is of formula L53. In certain embodiments, L is of formula L54. In certain embodiments, L is of formula L55. In certain embodiments, L is of formula L56. In certain embodiments, L is of formula L57. In certain embodiments, L is of formula L58. In certain embodiments, L is of formula L59. In certain embodiments, L is of formula L60. In certain embodiments, L is of formula L61. In certain embodiments, L is of formula L62. In certain embodiments, L is of formula L63. In certain embodiments, L is of formula L64. In certain embodiments, L is of formula L65. In certain embodiments, L is of formula L66. In certain embodiments, L is of formula L67. In certain embodiments, L is of formula L68. In certain embodiments, L is of formula L69. In certain embodiments, L is of formula L70. In certain embodiments, L is of formula L71. In certain embodiments, L is of formula L72. In certain embodiments, L is of formula L73. In certain embodiments, L is of formula L74. In certain embodiments, L is of formula L75. In certain embodiments, L is of formula L76. In certain embodiments, L is of formula L77. In certain embodiments, L is of formula L78. In certain embodiments, L is of formula L79. In certain embodiments, L is of formula L80. In certain embodiments, L is of formula L81. In certain embodiments, L is of formula L82. In certain embodiments, L is of formula L83. In certain embodiments, L is of formula L84. In certain embodiments, L is of formula L85. In certain embodiments, L is of formula L86. In certain embodiments, L is of formula L87. In certain embodiments, L is of formula L88. In certain embodiments, L is of formula L89. In certain embodiments, L is of formula L90. In certain embodiments, L is of formula L91. In certain embodiments, L is of formula L92. In certain embodiments, L is of formula L93. In certain embodiments, L is of formula L94. In certain embodiments, L is of formula L95. In certain embodiments, L is of formula L96. In certain embodiments, L is of formula L97. In certain embodiments, L is of formula L98. In certain embodiments, L is of formula L99. In certainembodiments, L is of formula L100. In certain embodiments, L is of formula L101. In certain embodiments, L is of formula L102. In certain embodiments, L is of formula L103. In certain embodiments, L is of formula L104. In certain embodiments, L is of formula L105. In certain embodiments, L is of formula L106. In certain embodiments, L is of formula L107. In certain embodiments, L is of formula L108. In certain embodiments, L is of formula L109. In certain embodiments, L is of formula L110. In certain embodiments, L is of formula L111. In certain embodiments, L is of formula L112. In certain embodiments, L is of formula L113. In certain embodiments, L is of formula L114. In certain embodiments, L is of formula L115. In certain embodiments, L is of formula L116. In certain embodiments, L is of formula L117. In certain embodiments, L is of formula L118. In certain embodiments, L is of formula L119. In certain embodiments, L is of formula L120. In certain embodiments, L is of formula L121. In certain embodiments, L is of formula L122. In certain embodiments, L is of formula L123. In certain embodiments, L is of formula L124. In certain embodiments, L is of formula L125. In certain embodiments, L is of formula L126. In certain embodiments, L is of formula L127. In certain embodiments, L is of formula L128. In certain embodiments, L is of formula L129. In certain embodiments, L is of formula L130. In certain embodiments, L is of formula L131. In certain embodiments, L is of formula L132. In certain embodiments, L is of formula L133. In certain embodiments, L is of formula L134. In certain embodiments, L is of formula L135. In certain embodiments, L is of formula L136. In certain embodiments, L is of formula L137. In certain embodiments, L is of formula L138. In certain embodiments, L is of formula L139. In certain embodiments, L is of formula L140. In certain embodiments, L is of formula L141. In certain embodiments, L is of formula L142. In certain embodiments, L is of formula L143. In certain embodiments, L is of formula L144. In certain embodiments, L is of formula L145. In certain embodiments, L is of formula L146. In certain embodiments, L is of formula L147. In certain embodiments, L is of formula L148. In certain embodiments, L is of formula L149. In certain embodiments, L is of formula L150. In certain embodiments, L is of formula L151. In certain embodiments, L is of formula L152. In certain embodiments, L is of formula L153. In certain embodiments, L is of formula L154. In certain embodiments, L is of formula L155. In certain embodiments, L is of formula L156. In certain embodiments, L is of formula L157. In certain embodiments, L is of formula L158. In certain embodiments, L is of formula L159. In certain embodiments, L is of formula L160. In certain embodiments, L is of formula L161. In certain embodiments, L is of formula L162. In certain embodiments, L is of formula L163. In certain embodiments, L is of formula L164. In certain embodiments, L is of formula L165. In certain embodiments, L is of formula L166. In certain embodiments, L is of formula L167. In certainembodiments, L is of formula L168. In certain embodiments, L is of formula L169. In certain embodiments, L is of formula L170. In certain embodiments, L is of formula L171. In certain embodiments, L is of formula L172. In certain embodiments, L is of formula L173. In certain embodiments, L is of formula L174. In certain embodiments, L is of formula L175. In certain embodiments, L is of formula L176. In certain embodiments, L is of formula L177. In certain embodiments, L is of formula L178. In certain embodiments, L is of formula L179. In certain embodiments, L is of formula L180. In certain embodiments, L is of formula 181. In certain embodiments, L is of formula L182. In certain embodiments, L is of formula L183. In certain embodiments, L is of formula L184. In certain embodiments, L is of formula L185. In certain embodiments, L is of formula L186. In certain embodiments, L is of formula L187. In certain embodiments, L is of formula L188. In certain embodiments, L is of formula L189. In certain embodiments, L is of formula L190. In certain embodiments, L is of formula L191. In certain embodiments, L is of formula L192. In certain embodiments, L is of formula L193. In certain embodiments, L is of formula L194. In certain embodiments, L is of formula L195. In certain embodiments, L is of formula L196. In certain embodiments, L is of formula L197. In certain embodiments, L is of formula L198. In certain embodiments, L is of formula L199. In certain embodiments, L is of formula L200. In certain embodiments, L is of formula L201. In certain embodiments, L is of formula L202. In certain embodiments, L is of formula L203. In certain embodiments, L is of formula L204. In certain embodiments, L is of formula L205. In certain embodiments, L is of formula L206. In certain embodiments, L is of formula L207. In certain embodiments, L is of formula L208. In certain embodiments, L is of formula L209. In certain embodiments, L is of formula L210. In certain embodiments, L is of formula L211. In certain embodiments, L is of formula L212. In certain embodiments, L is of formula L213. In certain embodiments, L is of formula L214. In certain embodiments, L is of formula L215. In certain embodiments, L is of formula L216. In certain embodiments, L is of formula L217. In certain embodiments, L is of formula L218. In certain embodiments, L is of formula L219. In certain embodiments, L is of formula L220. In certain embodiments, L is of formula L221. In certain embodiments, L is of formula L222. In certain embodiments, L is of formula L223. In certain embodiments, L is of formula L224. In certain embodiments, L is of formula L225. In certain embodiments, L is of formula L226. In certain embodiments, L is of formula L227. In certain embodiments, L is of formula L228. In certain embodiments, L is of formula L229. In certain embodiments, L is of formula L230. In certain embodiments, L is of formula L231. In certain embodiments, L is of formula L232.

[0314] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a- 2):(I-a-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein A, L, B, and R6are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a-2), wherein L is any one of L1-L232, or a pharmaceutically acceptable salt thereof.

[0315] The following embodiments of this paragraph relate to embodiments of the compound of Formula (I-a-2). In certain embodiments, L is of formula L1. In certain embodiments, L is of formula L2. In certain embodiments, L is of formula L3. In certain embodiments, L is of formula L4. In certain embodiments, L is of formula L5. In certain embodiments, L is of formula L6. In certain embodiments, L is of formula L7. In certain embodiments, L is of formula L8. In certain embodiments, L is of formula L9. In certain embodiments, L is of formula L10. In certain embodiments, L is of formula L11. In certain embodiments, L is of formula L12. In certain embodiments, L is of formula L13. In certain embodiments, L is of formula L14. In certain embodiments, L is of formula L15. In certain embodiments, L is of formula L16. In certain embodiments, L is of formula L17. In certain embodiments, L is of formula L18. In certain embodiments, L is of formula L19. In certain embodiments, L is of formula L20. In certain embodiments, L is of formula L21. In certain embodiments, L is of formula L22. In certain embodiments, L is of formula L23. In certain embodiments, L is of formula L24. In certain embodiments, L is of formula L25. In certain embodiments, L is of formula L26. In certain embodiments, L is of formula L27. In certain embodiments, L is of formula L28. In certain embodiments, L is of formula L29. In certain embodiments, L is of formula L30. In certain embodiments, L is of formula L31. In certain embodiments, L is of formula L32. In certain embodiments, L is of formula L33. In certain embodiments, L is of formula L34. In certain embodiments, L is of formula L35. In certain embodiments, L is of formula L36. In certain embodiments, L is of formula L37. In certain embodiments, L is of formula L38. In certain embodiments, L is of formula L39. In certain embodiments, L is of formula L40. In certain embodiments, L is of formula L41. In certain embodiments, L is of formula L42. In certain embodiments, L is of formula L43. In certain embodiments, L is of formula L44. In certain embodiments, L is of formula L45. In certainembodiments, L is of formula L46. In certain embodiments, L is of formula L47. In certain embodiments, L is of formula L48. In certain embodiments, L is of formula L49. In certain embodiments, L is of formula L50. In certain embodiments, L is of formula L51. In certain embodiments, L is of formula L52. In certain embodiments, L is of formula L53. In certain embodiments, L is of formula L54. In certain embodiments, L is of formula L55. In certain embodiments, L is of formula L56. In certain embodiments, L is of formula L57. In certain embodiments, L is of formula L58. In certain embodiments, L is of formula L59. In certain embodiments, L is of formula L60. In certain embodiments, L is of formula L61. In certain embodiments, L is of formula L62. In certain embodiments, L is of formula L63. In certain embodiments, L is of formula L64. In certain embodiments, L is of formula L65. In certain embodiments, L is of formula L66. In certain embodiments, L is of formula L67. In certain embodiments, L is of formula L68. In certain embodiments, L is of formula L69. In certain embodiments, L is of formula L70. In certain embodiments, L is of formula L71. In certain embodiments, L is of formula L72. In certain embodiments, L is of formula L73. In certain embodiments, L is of formula L74. In certain embodiments, L is of formula L75. In certain embodiments, L is of formula L76. In certain embodiments, L is of formula L77. In certain embodiments, L is of formula L78. In certain embodiments, L is of formula L79. In certain embodiments, L is of formula L80. In certain embodiments, L is of formula L81. In certain embodiments, L is of formula L82. In certain embodiments, L is of formula L83. In certain embodiments, L is of formula L84. In certain embodiments, L is of formula L85. In certain embodiments, L is of formula L86. In certain embodiments, L is of formula L87. In certain embodiments, L is of formula L88. In certain embodiments, L is of formula L89. In certain embodiments, L is of formula L90. In certain embodiments, L is of formula L91. In certain embodiments, L is of formula L92. In certain embodiments, L is of formula L93. In certain embodiments, L is of formula L94. In certain embodiments, L is of formula L95. In certain embodiments, L is of formula L96. In certain embodiments, L is of formula L97. In certain embodiments, L is of formula L98. In certain embodiments, L is of formula L99. In certain embodiments, L is of formula L100. In certain embodiments, L is of formula L101. In certain embodiments, L is of formula L102. In certain embodiments, L is of formula L103. In certain embodiments, L is of formula L104. In certain embodiments, L is of formula L105. In certain embodiments, L is of formula L106. In certain embodiments, L is of formula L107. In certain embodiments, L is of formula L108. In certain embodiments, L is of formula L109. In certain embodiments, L is of formula L110. In certain embodiments, L is of formula L111. In certain embodiments, L is of formula L112. In certain embodiments, L is of formula L113. In certainembodiments, L is of formula L114. In certain embodiments, L is of formula L115. In certain embodiments, L is of formula L116. In certain embodiments, L is of formula L117. In certain embodiments, L is of formula L118. In certain embodiments, L is of formula L119. In certain embodiments, L is of formula L120. In certain embodiments, L is of formula L121. In certain embodiments, L is of formula L122. In certain embodiments, L is of formula L123. In certain embodiments, L is of formula L124. In certain embodiments, L is of formula L125. In certain embodiments, L is of formula L126. In certain embodiments, L is of formula L127. In certain embodiments, L is of formula L128. In certain embodiments, L is of formula L129. In certain embodiments, L is of formula L130. In certain embodiments, L is of formula L131. In certain embodiments, L is of formula L132. In certain embodiments, L is of formula L133. In certain embodiments, L is of formula L134. In certain embodiments, L is of formula L135. In certain embodiments, L is of formula L136. In certain embodiments, L is of formula L137. In certain embodiments, L is of formula L138. In certain embodiments, L is of formula L139. In certain embodiments, L is of formula L140. In certain embodiments, L is of formula L141. In certain embodiments, L is of formula L142. In certain embodiments, L is of formula L143. In certain embodiments, L is of formula L144. In certain embodiments, L is of formula L145. In certain embodiments, L is of formula L146. In certain embodiments, L is of formula L147. In certain embodiments, L is of formula L148. In certain embodiments, L is of formula L149. In certain embodiments, L is of formula L150. In certain embodiments, L is of formula L151. In certain embodiments, L is of formula L152. In certain embodiments, L is of formula L153. In certain embodiments, L is of formula L154. In certain embodiments, L is of formula L155. In certain embodiments, L is of formula L156. In certain embodiments, L is of formula L157. In certain embodiments, L is of formula L158. In certain embodiments, L is of formula L159. In certain embodiments, L is of formula L160. In certain embodiments, L is of formula L161. In certain embodiments, L is of formula L162. In certain embodiments, L is of formula L163. In certain embodiments, L is of formula L164. In certain embodiments, L is of formula L165. In certain embodiments, L is of formula L166. In certain embodiments, L is of formula L167. In certain embodiments, L is of formula L168. In certain embodiments, L is of formula L169. In certain embodiments, L is of formula L170. In certain embodiments, L is of formula L171. In certain embodiments, L is of formula L172. In certain embodiments, L is of formula L173. In certain embodiments, L is of formula L174. In certain embodiments, L is of formula L175. In certain embodiments, L is of formula L176. In certain embodiments, L is of formula L177. In certain embodiments, L is of formula L178. In certain embodiments, L is of formula L179. In certain embodiments, L is of formula L180. In certain embodiments, L is of formula 181. In certainembodiments, L is of formula L182. In certain embodiments, L is of formula L183. In certain embodiments, L is of formula L184. In certain embodiments, L is of formula L185. In certain embodiments, L is of formula L186. In certain embodiments, L is of formula L187. In certain embodiments, L is of formula L188. In certain embodiments, L is of formula L189. In certain embodiments, L is of formula L190. In certain embodiments, L is of formula L191. In certain embodiments, L is of formula L192. In certain embodiments, L is of formula L193. In certain embodiments, L is of formula L194. In certain embodiments, L is of formula L195. In certain embodiments, L is of formula L196. In certain embodiments, L is of formula L197. In certain embodiments, L is of formula L198. In certain embodiments, L is of formula L199. In certain embodiments, L is of formula L200. In certain embodiments, L is of formula L201. In certain embodiments, L is of formula L202. In certain embodiments, L is of formula L203. In certain embodiments, L is of formula L204. In certain embodiments, L is of formula L205. In certain embodiments, L is of formula L206. In certain embodiments, L is of formula L207. In certain embodiments, L is of formula L208. In certain embodiments, L is of formula L209. In certain embodiments, L is of formula L210. In certain embodiments, L is of formula L211. In certain embodiments, L is of formula L212. In certain embodiments, L is of formula L213. In certain embodiments, L is of formula L214. In certain embodiments, L is of formula L215. In certain embodiments, L is of formula L216. In certain embodiments, L is of formula L217. In certain embodiments, L is of formula L218. In certain embodiments, L is of formula L219. In certain embodiments, L is of formula L220. In certain embodiments, L is of formula L221. In certain embodiments, L is of formula L222. In certain embodiments, L is of formula L223. In certain embodiments, L is of formula L224. In certain embodiments, L is of formula L225. In certain embodiments, L is of formula L226. In certain embodiments, L is of formula L227. In certain embodiments, L is of formula L228. In certain embodiments, L is of formula L229. In certain embodiments, L is of formula L230. In certain embodiments, L is of formula L231. In certain embodiments, L is of formula L232.

[0316] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a- 3):(I-a-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein A, L, B, and RBare asdefined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a-3), wherein L is any one of L1-L232, or a pharmaceutically acceptable salt thereof.

[0317] The following embodiments of this paragraph relate to embodiments of the compound of Formula (I-a-3). In certain embodiments, L is of formula L1. In certain embodiments, L is of formula L2. In certain embodiments, L is of formula L3. In certain embodiments, L is of formula L4. In certain embodiments, L is of formula L5. In certain embodiments, L is of formula L6. In certain embodiments, L is of formula L7. In certain embodiments, L is of formula L8. In certain embodiments, L is of formula L9. In certain embodiments, L is of formula L10. In certain embodiments, L is of formula L11. In certain embodiments, L is of formula L12. In certain embodiments, L is of formula L13. In certain embodiments, L is of formula L14. In certain embodiments, L is of formula L15. In certain embodiments, L is of formula L16. In certain embodiments, L is of formula L17. In certain embodiments, L is of formula L18. In certain embodiments, L is of formula L19. In certain embodiments, L is of formula L20. In certain embodiments, L is of formula L21. In certain embodiments, L is of formula L22. In certain embodiments, L is of formula L23. In certain embodiments, L is of formula L24. In certain embodiments, L is of formula L25. In certain embodiments, L is of formula L26. In certain embodiments, L is of formula L27. In certain embodiments, L is of formula L28. In certain embodiments, L is of formula L29. In certain embodiments, L is of formula L30. In certain embodiments, L is of formula L31. In certain embodiments, L is of formula L32. In certain embodiments, L is of formula L33. In certain embodiments, L is of formula L34. In certain embodiments, L is of formula L35. In certain embodiments, L is of formula L36. In certain embodiments, L is of formula L37. In certain embodiments, L is of formula L38. In certain embodiments, L is of formula L39. In certain embodiments, L is of formula L40. In certain embodiments, L is of formula L41. In certain embodiments, L is of formula L42. In certain embodiments, L is of formula L43. In certain embodiments, L is of formula L44. In certain embodiments, L is of formula L45. In certain embodiments, L is of formula L46. In certain embodiments, L is of formula L47. In certain embodiments, L is of formula L48. In certain embodiments, L is of formula L49. In certain embodiments, L is of formula L50. In certain embodiments, L is of formula L51. In certain embodiments, L is of formula L52. In certain embodiments, L is of formula L53. In certain embodiments, L is of formula L54. In certain embodiments, L is of formula L55. In certain embodiments, L is of formula L56. In certain embodiments, L is of formula L57. In certain embodiments, L is of formula L58. In certain embodiments, L is of formula L59. In certain embodiments, L is of formula L60. In certain embodiments, L is of formula L61. In certainembodiments, L is of formula L62. In certain embodiments, L is of formula L63. In certain embodiments, L is of formula L64. In certain embodiments, L is of formula L65. In certain embodiments, L is of formula L66. In certain embodiments, L is of formula L67. In certain embodiments, L is of formula L68. In certain embodiments, L is of formula L69. In certain embodiments, L is of formula L70. In certain embodiments, L is of formula L71. In certain embodiments, L is of formula L72. In certain embodiments, L is of formula L73. In certain embodiments, L is of formula L74. In certain embodiments, L is of formula L75. In certain embodiments, L is of formula L76. In certain embodiments, L is of formula L77. In certain embodiments, L is of formula L78. In certain embodiments, L is of formula L79. In certain embodiments, L is of formula L80. In certain embodiments, L is of formula L81. In certain embodiments, L is of formula L82. In certain embodiments, L is of formula L83. In certain embodiments, L is of formula L84. In certain embodiments, L is of formula L85. In certain embodiments, L is of formula L86. In certain embodiments, L is of formula L87. In certain embodiments, L is of formula L88. In certain embodiments, L is of formula L89. In certain embodiments, L is of formula L90. In certain embodiments, L is of formula L91. In certain embodiments, L is of formula L92. In certain embodiments, L is of formula L93. In certain embodiments, L is of formula L94. In certain embodiments, L is of formula L95. In certain embodiments, L is of formula L96. In certain embodiments, L is of formula L97. In certain embodiments, L is of formula L98. In certain embodiments, L is of formula L99. In certain embodiments, L is of formula L100. In certain embodiments, L is of formula L101. In certain embodiments, L is of formula L102. In certain embodiments, L is of formula L103. In certain embodiments, L is of formula L104. In certain embodiments, L is of formula L105. In certain embodiments, L is of formula L106. In certain embodiments, L is of formula L107. In certain embodiments, L is of formula L108. In certain embodiments, L is of formula L109. In certain embodiments, L is of formula L110. In certain embodiments, L is of formula L111. In certain embodiments, L is of formula L112. In certain embodiments, L is of formula L113. In certain embodiments, L is of formula L114. In certain embodiments, L is of formula L115. In certain embodiments, L is of formula L116. In certain embodiments, L is of formula L117. In certain embodiments, L is of formula L118. In certain embodiments, L is of formula L119. In certain embodiments, L is of formula L120. In certain embodiments, L is of formula L121. In certain embodiments, L is of formula L122. In certain embodiments, L is of formula L123. In certain embodiments, L is of formula L124. In certain embodiments, L is of formula L125. In certain embodiments, L is of formula L126. In certain embodiments, L is of formula L127. In certain embodiments, L is of formula L128. In certain embodiments, L is of formula L129. In certainembodiments, L is of formula L130. In certain embodiments, L is of formula L131. In certain embodiments, L is of formula L132. In certain embodiments, L is of formula L133. In certain embodiments, L is of formula L134. In certain embodiments, L is of formula L135. In certain embodiments, L is of formula L136. In certain embodiments, L is of formula L137. In certain embodiments, L is of formula L138. In certain embodiments, L is of formula L139. In certain embodiments, L is of formula L140. In certain embodiments, L is of formula L141. In certain embodiments, L is of formula L142. In certain embodiments, L is of formula L143. In certain embodiments, L is of formula L144. In certain embodiments, L is of formula L145. In certain embodiments, L is of formula L146. In certain embodiments, L is of formula L147. In certain embodiments, L is of formula L148. In certain embodiments, L is of formula L149. In certain embodiments, L is of formula L150. In certain embodiments, L is of formula L151. In certain embodiments, L is of formula L152. In certain embodiments, L is of formula L153. In certain embodiments, L is of formula L154. In certain embodiments, L is of formula L155. In certain embodiments, L is of formula L156. In certain embodiments, L is of formula L157. In certain embodiments, L is of formula L158. In certain embodiments, L is of formula L159. In certain embodiments, L is of formula L160. In certain embodiments, L is of formula L161. In certain embodiments, L is of formula L162. In certain embodiments, L is of formula L163. In certain embodiments, L is of formula L164. In certain embodiments, L is of formula L165. In certain embodiments, L is of formula L166. In certain embodiments, L is of formula L167. In certain embodiments, L is of formula L168. In certain embodiments, L is of formula L169. In certain embodiments, L is of formula L170. In certain embodiments, L is of formula L171. In certain embodiments, L is of formula L172. In certain embodiments, L is of formula L173. In certain embodiments, L is of formula L174. In certain embodiments, L is of formula L175. In certain embodiments, L is of formula L176. In certain embodiments, L is of formula L177. In certain embodiments, L is of formula L178. In certain embodiments, L is of formula L179. In certain embodiments, L is of formula L180. In certain embodiments, L is of formula 181. In certain embodiments, L is of formula L182. In certain embodiments, L is of formula L183. In certain embodiments, L is of formula L184. In certain embodiments, L is of formula L185. In certain embodiments, L is of formula L186. In certain embodiments, L is of formula L187. In certain embodiments, L is of formula L188. In certain embodiments, L is of formula L189. In certain embodiments, L is of formula L190. In certain embodiments, L is of formula L191. In certain embodiments, L is of formula L192. In certain embodiments, L is of formula L193. In certain embodiments, L is of formula L194. In certain embodiments, L is of formula L195. In certain embodiments, L is of formula L196. In certain embodiments, L is of formula L197. In certainembodiments, L is of formula L198. In certain embodiments, L is of formula L199. In certain embodiments, L is of formula L200. In certain embodiments, L is of formula L201. In certain embodiments, L is of formula L202. In certain embodiments, L is of formula L203. In certain embodiments, L is of formula L204. In certain embodiments, L is of formula L205. In certain embodiments, L is of formula L206. In certain embodiments, L is of formula L207. In certain embodiments, L is of formula L208. In certain embodiments, L is of formula L209. In certain embodiments, L is of formula L210. In certain embodiments, L is of formula L211. In certain embodiments, L is of formula L212. In certain embodiments, L is of formula L213. In certain embodiments, L is of formula L214. In certain embodiments, L is of formula L215. In certain embodiments, L is of formula L216. In certain embodiments, L is of formula L217. In certain embodiments, L is of formula L218. In certain embodiments, L is of formula L219. In certain embodiments, L is of formula L220. In certain embodiments, L is of formula L221. In certain embodiments, L is of formula L222. In certain embodiments, L is of formula L223. In certain embodiments, L is of formula L224. In certain embodiments, L is of formula L225. In certain embodiments, L is of formula L226. In certain embodiments, L is of formula L227. In certain embodiments, L is of formula L228. In certain embodiments, L is of formula L229. In certain embodiments, L is of formula L230. In certain embodiments, L is of formula L231. In certain embodiments, L is of formula L232.

[0318] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a- 4):(I-a-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein A, L, B, and RCare as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a-4), wherein L is any one of L1-L232, or a pharmaceutically acceptable salt thereof.

[0319] The following embodiments of this paragraph relate to embodiments of the compound of Formula (I-a-4). In certain embodiments, L is of formula L1. In certain embodiments, L is of formula L2. In certain embodiments, L is of formula L3. In certain embodiments, L is of formula L4. In certain embodiments, L is of formula L5. In certain embodiments, L is of formula L6. In certain embodiments, L is of formula L7. In certain embodiments, L is of formula L8. In certain embodiments, L is of formula L9. In certainembodiments, L is of formula L10. In certain embodiments, L is of formula L11. In certain embodiments, L is of formula L12. In certain embodiments, L is of formula L13. In certain embodiments, L is of formula L14. In certain embodiments, L is of formula L15. In certain embodiments, L is of formula L16. In certain embodiments, L is of formula L17. In certain embodiments, L is of formula L18. In certain embodiments, L is of formula L19. In certain embodiments, L is of formula L20. In certain embodiments, L is of formula L21. In certain embodiments, L is of formula L22. In certain embodiments, L is of formula L23. In certain embodiments, L is of formula L24. In certain embodiments, L is of formula L25. In certain embodiments, L is of formula L26. In certain embodiments, L is of formula L27. In certain embodiments, L is of formula L28. In certain embodiments, L is of formula L29. In certain embodiments, L is of formula L30. In certain embodiments, L is of formula L31. In certain embodiments, L is of formula L32. In certain embodiments, L is of formula L33. In certain embodiments, L is of formula L34. In certain embodiments, L is of formula L35. In certain embodiments, L is of formula L36. In certain embodiments, L is of formula L37. In certain embodiments, L is of formula L38. In certain embodiments, L is of formula L39. In certain embodiments, L is of formula L40. In certain embodiments, L is of formula L41. In certain embodiments, L is of formula L42. In certain embodiments, L is of formula L43. In certain embodiments, L is of formula L44. In certain embodiments, L is of formula L45. In certain embodiments, L is of formula L46. In certain embodiments, L is of formula L47. In certain embodiments, L is of formula L48. In certain embodiments, L is of formula L49. In certain embodiments, L is of formula L50. In certain embodiments, L is of formula L51. In certain embodiments, L is of formula L52. In certain embodiments, L is of formula L53. In certain embodiments, L is of formula L54. In certain embodiments, L is of formula L55. In certain embodiments, L is of formula L56. In certain embodiments, L is of formula L57. In certain embodiments, L is of formula L58. In certain embodiments, L is of formula L59. In certain embodiments, L is of formula L60. In certain embodiments, L is of formula L61. In certain embodiments, L is of formula L62. In certain embodiments, L is of formula L63. In certain embodiments, L is of formula L64. In certain embodiments, L is of formula L65. In certain embodiments, L is of formula L66. In certain embodiments, L is of formula L67. In certain embodiments, L is of formula L68. In certain embodiments, L is of formula L69. In certain embodiments, L is of formula L70. In certain embodiments, L is of formula L71. In certain embodiments, L is of formula L72. In certain embodiments, L is of formula L73. In certain embodiments, L is of formula L74. In certain embodiments, L is of formula L75. In certain embodiments, L is of formula L76. In certain embodiments, L is of formula L77. In certainembodiments, L is of formula L78. In certain embodiments, L is of formula L79. In certain embodiments, L is of formula L80. In certain embodiments, L is of formula L81. In certain embodiments, L is of formula L82. In certain embodiments, L is of formula L83. In certain embodiments, L is of formula L84. In certain embodiments, L is of formula L85. In certain embodiments, L is of formula L86. In certain embodiments, L is of formula L87. In certain embodiments, L is of formula L88. In certain embodiments, L is of formula L89. In certain embodiments, L is of formula L90. In certain embodiments, L is of formula L91. In certain embodiments, L is of formula L92. In certain embodiments, L is of formula L93. In certain embodiments, L is of formula L94. In certain embodiments, L is of formula L95. In certain embodiments, L is of formula L96. In certain embodiments, L is of formula L97. In certain embodiments, L is of formula L98. In certain embodiments, L is of formula L99. In certain embodiments, L is of formula L100. In certain embodiments, L is of formula L101. In certain embodiments, L is of formula L102. In certain embodiments, L is of formula L103. In certain embodiments, L is of formula L104. In certain embodiments, L is of formula L105. In certain embodiments, L is of formula L106. In certain embodiments, L is of formula L107. In certain embodiments, L is of formula L108. In certain embodiments, L is of formula L109. In certain embodiments, L is of formula L110. In certain embodiments, L is of formula L111. In certain embodiments, L is of formula L112. In certain embodiments, L is of formula L113. In certain embodiments, L is of formula L114. In certain embodiments, L is of formula L115. In certain embodiments, L is of formula L116. In certain embodiments, L is of formula L117. In certain embodiments, L is of formula L118. In certain embodiments, L is of formula L119. In certain embodiments, L is of formula L120. In certain embodiments, L is of formula L121. In certain embodiments, L is of formula L122. In certain embodiments, L is of formula L123. In certain embodiments, L is of formula L124. In certain embodiments, L is of formula L125. In certain embodiments, L is of formula L126. In certain embodiments, L is of formula L127. In certain embodiments, L is of formula L128. In certain embodiments, L is of formula L129. In certain embodiments, L is of formula L130. In certain embodiments, L is of formula L131. In certain embodiments, L is of formula L132. In certain embodiments, L is of formula L133. In certain embodiments, L is of formula L134. In certain embodiments, L is of formula L135. In certain embodiments, L is of formula L136. In certain embodiments, L is of formula L137. In certain embodiments, L is of formula L138. In certain embodiments, L is of formula L139. In certain embodiments, L is of formula L140. In certain embodiments, L is of formula L141. In certain embodiments, L is of formula L142. In certain embodiments, L is of formula L143. In certain embodiments, L is of formula L144. In certain embodiments, L is of formula L145. In certainembodiments, L is of formula L146. In certain embodiments, L is of formula L147. In certain embodiments, L is of formula L148. In certain embodiments, L is of formula L149. In certain embodiments, L is of formula L150. In certain embodiments, L is of formula L151. In certain embodiments, L is of formula L152. In certain embodiments, L is of formula L153. In certain embodiments, L is of formula L154. In certain embodiments, L is of formula L155. In certain embodiments, L is of formula L156. In certain embodiments, L is of formula L157. In certain embodiments, L is of formula L158. In certain embodiments, L is of formula L159. In certain embodiments, L is of formula L160. In certain embodiments, L is of formula L161. In certain embodiments, L is of formula L162. In certain embodiments, L is of formula L163. In certain embodiments, L is of formula L164. In certain embodiments, L is of formula L165. In certain embodiments, L is of formula L166. In certain embodiments, L is of formula L167. In certain embodiments, L is of formula L168. In certain embodiments, L is of formula L169. In certain embodiments, L is of formula L170. In certain embodiments, L is of formula L171. In certain embodiments, L is of formula L172. In certain embodiments, L is of formula L173. In certain embodiments, L is of formula L174. In certain embodiments, L is of formula L175. In certain embodiments, L is of formula L176. In certain embodiments, L is of formula L177. In certain embodiments, L is of formula L178. In certain embodiments, L is of formula L179. In certain embodiments, L is of formula L180. In certain embodiments, L is of formula 181. In certain embodiments, L is of formula L182. In certain embodiments, L is of formula L183. In certain embodiments, L is of formula L184. In certain embodiments, L is of formula L185. In certain embodiments, L is of formula L186. In certain embodiments, L is of formula L187. In certain embodiments, L is of formula L188. In certain embodiments, L is of formula L189. In certain embodiments, L is of formula L190. In certain embodiments, L is of formula L191. In certain embodiments, L is of formula L192. In certain embodiments, L is of formula L193. In certain embodiments, L is of formula L194. In certain embodiments, L is of formula L195. In certain embodiments, L is of formula L196. In certain embodiments, L is of formula L197. In certain embodiments, L is of formula L198. In certain embodiments, L is of formula L199. In certain embodiments, L is of formula L200. In certain embodiments, L is of formula L201. In certain embodiments, L is of formula L202. In certain embodiments, L is of formula L203. In certain embodiments, L is of formula L204. In certain embodiments, L is of formula L205. In certain embodiments, L is of formula L206. In certain embodiments, L is of formula L207. In certain embodiments, L is of formula L208. In certain embodiments, L is of formula L209. In certain embodiments, L is of formula L210. In certain embodiments, L is of formula L211. In certain embodiments, L is of formula L212. In certain embodiments, L is of formula L213. In certainembodiments, L is of formula L214. In certain embodiments, L is of formula L215. In certain embodiments, L is of formula L216. In certain embodiments, L is of formula L217. In certain embodiments, L is of formula L218. In certain embodiments, L is of formula L219. In certain embodiments, L is of formula L220. In certain embodiments, L is of formula L221. In certain embodiments, L is of formula L222. In certain embodiments, L is of formula L223. In certain embodiments, L is of formula L224. In certain embodiments, L is of formula L225. In certain embodiments, L is of formula L226. In certain embodiments, L is of formula L227. In certain embodiments, L is of formula L228. In certain embodiments, L is of formula L229. In certain embodiments, L is of formula L230. In certain embodiments, L is of formula L231. In certain embodiments, L is of formula L232..

[0320] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a- 5):(I-a-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein L, B, and RCare as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a-5), wherein L is any one of L1-L232, or a pharmaceutically acceptable salt thereof.

[0321] The following embodiments of this paragraph relate to embodiments of the compound of Formula (I-a-5). In certain embodiments, L is of formula L1. In certain embodiments, L is of formula L2. In certain embodiments, L is of formula L3. In certain embodiments, L is of formula L4. In certain embodiments, L is of formula L5. In certain embodiments, L is of formula L6. In certain embodiments, L is of formula L7. In certain embodiments, L is of formula L8. In certain embodiments, L is of formula L9. In certain embodiments, L is of formula L10. In certain embodiments, L is of formula L11. In certain embodiments, L is of formula L12. In certain embodiments, L is of formula L13. In certain embodiments, L is of formula L14. In certain embodiments, L is of formula L15. In certain embodiments, L is of formula L16. In certain embodiments, L is of formula L17. In certain embodiments, L is of formula L18. In certain embodiments, L is of formula L19. In certain embodiments, L is of formula L20. In certain embodiments, L is of formula L21. In certain embodiments, L is of formula L22. In certain embodiments, L is of formula L23. In certain embodiments, L is of formula L24. In certain embodiments, L is of formula L25. In certainembodiments, L is of formula L26. In certain embodiments, L is of formula L27. In certain embodiments, L is of formula L28. In certain embodiments, L is of formula L29. In certain embodiments, L is of formula L30. In certain embodiments, L is of formula L31. In certain embodiments, L is of formula L32. In certain embodiments, L is of formula L33. In certain embodiments, L is of formula L34. In certain embodiments, L is of formula L35. In certain embodiments, L is of formula L36. In certain embodiments, L is of formula L37. In certain embodiments, L is of formula L38. In certain embodiments, L is of formula L39. In certain embodiments, L is of formula L40. In certain embodiments, L is of formula L41. In certain embodiments, L is of formula L42. In certain embodiments, L is of formula L43. In certain embodiments, L is of formula L44. In certain embodiments, L is of formula L45. In certain embodiments, L is of formula L46. In certain embodiments, L is of formula L47. In certain embodiments, L is of formula L48. In certain embodiments, L is of formula L49. In certain embodiments, L is of formula L50. In certain embodiments, L is of formula L51. In certain embodiments, L is of formula L52. In certain embodiments, L is of formula L53. In certain embodiments, L is of formula L54. In certain embodiments, L is of formula L55. In certain embodiments, L is of formula L56. In certain embodiments, L is of formula L57. In certain embodiments, L is of formula L58. In certain embodiments, L is of formula L59. In certain embodiments, L is of formula L60. In certain embodiments, L is of formula L61. In certain embodiments, L is of formula L62. In certain embodiments, L is of formula L63. In certain embodiments, L is of formula L64. In certain embodiments, L is of formula L65. In certain embodiments, L is of formula L66. In certain embodiments, L is of formula L67. In certain embodiments, L is of formula L68. In certain embodiments, L is of formula L69. In certain embodiments, L is of formula L70. In certain embodiments, L is of formula L71. In certain embodiments, L is of formula L72. In certain embodiments, L is of formula L73. In certain embodiments, L is of formula L74. In certain embodiments, L is of formula L75. In certain embodiments, L is of formula L76. In certain embodiments, L is of formula L77. In certain embodiments, L is of formula L78. In certain embodiments, L is of formula L79. In certain embodiments, L is of formula L80. In certain embodiments, L is of formula L81. In certain embodiments, L is of formula L82. In certain embodiments, L is of formula L83. In certain embodiments, L is of formula L84. In certain embodiments, L is of formula L85. In certain embodiments, L is of formula L86. In certain embodiments, L is of formula L87. In certain embodiments, L is of formula L88. In certain embodiments, L is of formula L89. In certain embodiments, L is of formula L90. In certain embodiments, L is of formula L91. In certain embodiments, L is of formula L92. In certain embodiments, L is of formula L93. In certainembodiments, L is of formula L94. In certain embodiments, L is of formula L95. In certain embodiments, L is of formula L96. In certain embodiments, L is of formula L97. In certain embodiments, L is of formula L98. In certain embodiments, L is of formula L99. In certain embodiments, L is of formula L100. In certain embodiments, L is of formula L101. In certain embodiments, L is of formula L102. In certain embodiments, L is of formula L103. In certain embodiments, L is of formula L104. In certain embodiments, L is of formula L105. In certain embodiments, L is of formula L106. In certain embodiments, L is of formula L107. In certain embodiments, L is of formula L108. In certain embodiments, L is of formula L109. In certain embodiments, L is of formula L110. In certain embodiments, L is of formula L111. In certain embodiments, L is of formula L112. In certain embodiments, L is of formula L113. In certain embodiments, L is of formula L114. In certain embodiments, L is of formula L115. In certain embodiments, L is of formula L116. In certain embodiments, L is of formula L117. In certain embodiments, L is of formula L118. In certain embodiments, L is of formula L119. In certain embodiments, L is of formula L120. In certain embodiments, L is of formula L121. In certain embodiments, L is of formula L122. In certain embodiments, L is of formula L123. In certain embodiments, L is of formula L124. In certain embodiments, L is of formula L125. In certain embodiments, L is of formula L126. In certain embodiments, L is of formula L127. In certain embodiments, L is of formula L128. In certain embodiments, L is of formula L129. In certain embodiments, L is of formula L130. In certain embodiments, L is of formula L131. In certain embodiments, L is of formula L132. In certain embodiments, L is of formula L133. In certain embodiments, L is of formula L134. In certain embodiments, L is of formula L135. In certain embodiments, L is of formula L136. In certain embodiments, L is of formula L137. In certain embodiments, L is of formula L138. In certain embodiments, L is of formula L139. In certain embodiments, L is of formula L140. In certain embodiments, L is of formula L141. In certain embodiments, L is of formula L142. In certain embodiments, L is of formula L143. In certain embodiments, L is of formula L144. In certain embodiments, L is of formula L145. In certain embodiments, L is of formula L146. In certain embodiments, L is of formula L147. In certain embodiments, L is of formula L148. In certain embodiments, L is of formula L149. In certain embodiments, L is of formula L150. In certain embodiments, L is of formula L151. In certain embodiments, L is of formula L152. In certain embodiments, L is of formula L153. In certain embodiments, L is of formula L154. In certain embodiments, L is of formula L155. In certain embodiments, L is of formula L156. In certain embodiments, L is of formula L157. In certain embodiments, L is of formula L158. In certain embodiments, L is of formula L159. In certain embodiments, L is of formula L160. In certain embodiments, L is of formula L161. In certainembodiments, L is of formula L162. In certain embodiments, L is of formula L163. In certain embodiments, L is of formula L164. In certain embodiments, L is of formula L165. In certain embodiments, L is of formula L166. In certain embodiments, L is of formula L167. In certain embodiments, L is of formula L168. In certain embodiments, L is of formula L169. In certain embodiments, L is of formula L170. In certain embodiments, L is of formula L171. In certain embodiments, L is of formula L172. In certain embodiments, L is of formula L173. In certain embodiments, L is of formula L174. In certain embodiments, L is of formula L175. In certain embodiments, L is of formula L176. In certain embodiments, L is of formula L177. In certain embodiments, L is of formula L178. In certain embodiments, L is of formula L179. In certain embodiments, L is of formula L180. In certain embodiments, L is of formula 181. In certain embodiments, L is of formula L182. In certain embodiments, L is of formula L183. In certain embodiments, L is of formula L184. In certain embodiments, L is of formula L185. In certain embodiments, L is of formula L186. In certain embodiments, L is of formula L187. In certain embodiments, L is of formula L188. In certain embodiments, L is of formula L189. In certain embodiments, L is of formula L190. In certain embodiments, L is of formula L191. In certain embodiments, L is of formula L192. In certain embodiments, L is of formula L193. In certain embodiments, L is of formula L194. In certain embodiments, L is of formula L195. In certain embodiments, L is of formula L196. In certain embodiments, L is of formula L197. In certain embodiments, L is of formula L198. In certain embodiments, L is of formula L199. In certain embodiments, L is of formula L200. In certain embodiments, L is of formula L201. In certain embodiments, L is of formula L202. In certain embodiments, L is of formula L203. In certain embodiments, L is of formula L204. In certain embodiments, L is of formula L205. In certain embodiments, L is of formula L206. In certain embodiments, L is of formula L207. In certain embodiments, L is of formula L208. In certain embodiments, L is of formula L209. In certain embodiments, L is of formula L210. In certain embodiments, L is of formula L211. In certain embodiments, L is of formula L212. In certain embodiments, L is of formula L213. In certain embodiments, L is of formula L214. In certain embodiments, L is of formula L215. In certain embodiments, L is of formula L216. In certain embodiments, L is of formula L217. In certain embodiments, L is of formula L218. In certain embodiments, L is of formula L219. In certain embodiments, L is of formula L220. In certain embodiments, L is of formula L221. In certain embodiments, L is of formula L222. In certain embodiments, L is of formula L223. In certain embodiments, L is of formula L224. In certain embodiments, L is of formula L225. In certain embodiments, L is of formula L226. In certain embodiments, L is of formula L227. In certain embodiments, L is of formula L228. In certain embodiments, L is of formula L229. In certainembodiments, L is of formula L230. In certain embodiments, L is of formula L231. In certain embodiments, L is of formula L232.

[0322] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a- 5a):(I-a-5a), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein L and B are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a-5a), wherein L is any one of L1-L232, or a pharmaceutically acceptable salt thereof.

[0323] The following embodiments of this paragraph relate to embodiments of the compound of Formula (I-a-5a). In certain embodiments, L is of formula L1. In certain embodiments, L is of formula L2. In certain embodiments, L is of formula L3. In certain embodiments, L is of formula L4. In certain embodiments, L is of formula L5. In certain embodiments, L is of formula L6. In certain embodiments, L is of formula L7. In certain embodiments, L is of formula L8. In certain embodiments, L is of formula L9. In certain embodiments, L is of formula L10. In certain embodiments, L is of formula L11. In certain embodiments, L is of formula L12. In certain embodiments, L is of formula L13. In certain embodiments, L is of formula L14. In certain embodiments, L is of formula L15. In certain embodiments, L is of formula L16. In certain embodiments, L is of formula L17. In certain embodiments, L is of formula L18. In certain embodiments, L is of formula L19. In certain embodiments, L is of formula L20. In certain embodiments, L is of formula L21. In certain embodiments, L is of formula L22. In certain embodiments, L is of formula L23. In certain embodiments, L is of formula L24. In certain embodiments, L is of formula L25. In certain embodiments, L is of formula L26. In certain embodiments, L is of formula L27. In certain embodiments, L is of formula L28. In certain embodiments, L is of formula L29. In certain embodiments, L is of formula L30. In certain embodiments, L is of formula L31. In certain embodiments, L is of formula L32. In certain embodiments, L is of formula L33. In certain embodiments, L is of formula L34. In certain embodiments, L is of formula L35. In certain embodiments, L is of formula L36. In certain embodiments, L is of formula L37. In certain embodiments, L is of formula L38. In certain embodiments, L is of formula L39. In certainembodiments, L is of formula L40. In certain embodiments, L is of formula L41. In certain embodiments, L is of formula L42. In certain embodiments, L is of formula L43. In certain embodiments, L is of formula L44. In certain embodiments, L is of formula L45. In certain embodiments, L is of formula L46. In certain embodiments, L is of formula L47. In certain embodiments, L is of formula L48. In certain embodiments, L is of formula L49. In certain embodiments, L is of formula L50. In certain embodiments, L is of formula L51. In certain embodiments, L is of formula L52. In certain embodiments, L is of formula L53. In certain embodiments, L is of formula L54. In certain embodiments, L is of formula L55. In certain embodiments, L is of formula L56. In certain embodiments, L is of formula L57. In certain embodiments, L is of formula L58. In certain embodiments, L is of formula L59. In certain embodiments, L is of formula L60. In certain embodiments, L is of formula L61. In certain embodiments, L is of formula L62. In certain embodiments, L is of formula L63. In certain embodiments, L is of formula L64. In certain embodiments, L is of formula L65. In certain embodiments, L is of formula L66. In certain embodiments, L is of formula L67. In certain embodiments, L is of formula L68. In certain embodiments, L is of formula L69. In certain embodiments, L is of formula L70. In certain embodiments, L is of formula L71. In certain embodiments, L is of formula L72. In certain embodiments, L is of formula L73. In certain embodiments, L is of formula L74. In certain embodiments, L is of formula L75. In certain embodiments, L is of formula L76. In certain embodiments, L is of formula L77. In certain embodiments, L is of formula L78. In certain embodiments, L is of formula L79. In certain embodiments, L is of formula L80. In certain embodiments, L is of formula L81. In certain embodiments, L is of formula L82. In certain embodiments, L is of formula L83. In certain embodiments, L is of formula L84. In certain embodiments, L is of formula L85. In certain embodiments, L is of formula L86. In certain embodiments, L is of formula L87. In certain embodiments, L is of formula L88. In certain embodiments, L is of formula L89. In certain embodiments, L is of formula L90. In certain embodiments, L is of formula L91. In certain embodiments, L is of formula L92. In certain embodiments, L is of formula L93. In certain embodiments, L is of formula L94. In certain embodiments, L is of formula L95. In certain embodiments, L is of formula L96. In certain embodiments, L is of formula L97. In certain embodiments, L is of formula L98. In certain embodiments, L is of formula L99. In certain embodiments, L is of formula L100. In certain embodiments, L is of formula L101. In certain embodiments, L is of formula L102. In certain embodiments, L is of formula L103. In certain embodiments, L is of formula L104. In certain embodiments, L is of formula L105. In certain embodiments, L is of formula L106. In certain embodiments, L is of formula L107. In certainembodiments, L is of formula L108. In certain embodiments, L is of formula L109. In certain embodiments, L is of formula L110. In certain embodiments, L is of formula L111. In certain embodiments, L is of formula L112. In certain embodiments, L is of formula L113. In certain embodiments, L is of formula L114. In certain embodiments, L is of formula L115. In certain embodiments, L is of formula L116. In certain embodiments, L is of formula L117. In certain embodiments, L is of formula L118. In certain embodiments, L is of formula L119. In certain embodiments, L is of formula L120. In certain embodiments, L is of formula L121. In certain embodiments, L is of formula L122. In certain embodiments, L is of formula L123. In certain embodiments, L is of formula L124. In certain embodiments, L is of formula L125. In certain embodiments, L is of formula L126. In certain embodiments, L is of formula L127. In certain embodiments, L is of formula L128. In certain embodiments, L is of formula L129. In certain embodiments, L is of formula L130. In certain embodiments, L is of formula L131. In certain embodiments, L is of formula L132. In certain embodiments, L is of formula L133. In certain embodiments, L is of formula L134. In certain embodiments, L is of formula L135. In certain embodiments, L is of formula L136. In certain embodiments, L is of formula L137. In certain embodiments, L is of formula L138. In certain embodiments, L is of formula L139. In certain embodiments, L is of formula L140. In certain embodiments, L is of formula L141. In certain embodiments, L is of formula L142. In certain embodiments, L is of formula L143. In certain embodiments, L is of formula L144. In certain embodiments, L is of formula L145. In certain embodiments, L is of formula L146. In certain embodiments, L is of formula L147. In certain embodiments, L is of formula L148. In certain embodiments, L is of formula L149. In certain embodiments, L is of formula L150. In certain embodiments, L is of formula L151. In certain embodiments, L is of formula L152. In certain embodiments, L is of formula L153. In certain embodiments, L is of formula L154. In certain embodiments, L is of formula L155. In certain embodiments, L is of formula L156. In certain embodiments, L is of formula L157. In certain embodiments, L is of formula L158. In certain embodiments, L is of formula L159. In certain embodiments, L is of formula L160. In certain embodiments, L is of formula L161. In certain embodiments, L is of formula L162. In certain embodiments, L is of formula L163. In certain embodiments, L is of formula L164. In certain embodiments, L is of formula L165. In certain embodiments, L is of formula L166. In certain embodiments, L is of formula L167. In certain embodiments, L is of formula L168. In certain embodiments, L is of formula L169. In certain embodiments, L is of formula L170. In certain embodiments, L is of formula L171. In certain embodiments, L is of formula L172. In certain embodiments, L is of formula L173. In certain embodiments, L is of formula L174. In certain embodiments, L is of formula L175. In certainembodiments, L is of formula L176. In certain embodiments, L is of formula L177. In certain embodiments, L is of formula L178. In certain embodiments, L is of formula L179. In certain embodiments, L is of formula L180. In certain embodiments, L is of formula 181. In certain embodiments, L is of formula L182. In certain embodiments, L is of formula L183. In certain embodiments, L is of formula L184. In certain embodiments, L is of formula L185. In certain embodiments, L is of formula L186. In certain embodiments, L is of formula L187. In certain embodiments, L is of formula L188. In certain embodiments, L is of formula L189. In certain embodiments, L is of formula L190. In certain embodiments, L is of formula L191. In certain embodiments, L is of formula L192. In certain embodiments, L is of formula L193. In certain embodiments, L is of formula L194. In certain embodiments, L is of formula L195. In certain embodiments, L is of formula L196. In certain embodiments, L is of formula L197. In certain embodiments, L is of formula L198. In certain embodiments, L is of formula L199. In certain embodiments, L is of formula L200. In certain embodiments, L is of formula L201. In certain embodiments, L is of formula L202. In certain embodiments, L is of formula L203. In certain embodiments, L is of formula L204. In certain embodiments, L is of formula L205. In certain embodiments, L is of formula L206. In certain embodiments, L is of formula L207. In certain embodiments, L is of formula L208. In certain embodiments, L is of formula L209. In certain embodiments, L is of formula L210. In certain embodiments, L is of formula L211. In certain embodiments, L is of formula L212. In certain embodiments, L is of formula L213. In certain embodiments, L is of formula L214. In certain embodiments, L is of formula L215. In certain embodiments, L is of formula L216. In certain embodiments, L is of formula L217. In certain embodiments, L is of formula L218. In certain embodiments, L is of formula L219. In certain embodiments, L is of formula L220. In certain embodiments, L is of formula L221. In certain embodiments, L is of formula L222. In certain embodiments, L is of formula L223. In certain embodiments, L is of formula L224. In certain embodiments, L is of formula L225. In certain embodiments, L is of formula L226. In certain embodiments, L is of formula L227. In certain embodiments, L is of formula L228. In certain embodiments, L is of formula L229. In certain embodiments, L is of formula L230. In certain embodiments, L is of formula L231. In certain embodiments, L is of formula L232.

[0324] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a- 6):(I-a-6), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein L, B, and RCare as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a-6), wherein L is any one of L1-L232, or a pharmaceutically acceptable salt thereof.

[0325] The following embodiments of this paragraph relate to embodiments of the compound of Formula (I-a-6). In certain embodiments, L is of formula L1. In certain embodiments, L is of formula L2. In certain embodiments, L is of formula L3. In certain embodiments, L is of formula L4. In certain embodiments, L is of formula L5. In certain embodiments, L is of formula L6. In certain embodiments, L is of formula L7. In certain embodiments, L is of formula L8. In certain embodiments, L is of formula L9. In certain embodiments, L is of formula L10. In certain embodiments, L is of formula L11. In certain embodiments, L is of formula L12. In certain embodiments, L is of formula L13. In certain embodiments, L is of formula L14. In certain embodiments, L is of formula L15. In certain embodiments, L is of formula L16. In certain embodiments, L is of formula L17. In certain embodiments, L is of formula L18. In certain embodiments, L is of formula L19. In certain embodiments, L is of formula L20. In certain embodiments, L is of formula L21. In certain embodiments, L is of formula L22. In certain embodiments, L is of formula L23. In certain embodiments, L is of formula L24. In certain embodiments, L is of formula L25. In certain embodiments, L is of formula L26. In certain embodiments, L is of formula L27. In certain embodiments, L is of formula L28. In certain embodiments, L is of formula L29. In certain embodiments, L is of formula L30. In certain embodiments, L is of formula L31. In certain embodiments, L is of formula L32. In certain embodiments, L is of formula L33. In certain embodiments, L is of formula L34. In certain embodiments, L is of formula L35. In certain embodiments, L is of formula L36. In certain embodiments, L is of formula L37. In certain embodiments, L is of formula L38. In certain embodiments, L is of formula L39. In certain embodiments, L is of formula L40. In certain embodiments, L is of formula L41. In certain embodiments, L is of formula L42. In certain embodiments, L is of formula L43. In certain embodiments, L is of formula L44. In certain embodiments, L is of formula L45. In certainembodiments, L is of formula L46. In certain embodiments, L is of formula L47. In certain embodiments, L is of formula L48. In certain embodiments, L is of formula L49. In certain embodiments, L is of formula L50. In certain embodiments, L is of formula L51. In certain embodiments, L is of formula L52. In certain embodiments, L is of formula L53. In certain embodiments, L is of formula L54. In certain embodiments, L is of formula L55. In certain embodiments, L is of formula L56. In certain embodiments, L is of formula L57. In certain embodiments, L is of formula L58. In certain embodiments, L is of formula L59. In certain embodiments, L is of formula L60. In certain embodiments, L is of formula L61. In certain embodiments, L is of formula L62. In certain embodiments, L is of formula L63. In certain embodiments, L is of formula L64. In certain embodiments, L is of formula L65. In certain embodiments, L is of formula L66. In certain embodiments, L is of formula L67. In certain embodiments, L is of formula L68. In certain embodiments, L is of formula L69. In certain embodiments, L is of formula L70. In certain embodiments, L is of formula L71. In certain embodiments, L is of formula L72. In certain embodiments, L is of formula L73. In certain embodiments, L is of formula L74. In certain embodiments, L is of formula L75. In certain embodiments, L is of formula L76. In certain embodiments, L is of formula L77. In certain embodiments, L is of formula L78. In certain embodiments, L is of formula L79. In certain embodiments, L is of formula L80. In certain embodiments, L is of formula L81. In certain embodiments, L is of formula L82. In certain embodiments, L is of formula L83. In certain embodiments, L is of formula L84. In certain embodiments, L is of formula L85. In certain embodiments, L is of formula L86. In certain embodiments, L is of formula L87. In certain embodiments, L is of formula L88. In certain embodiments, L is of formula L89. In certain embodiments, L is of formula L90. In certain embodiments, L is of formula L91. In certain embodiments, L is of formula L92. In certain embodiments, L is of formula L93. In certain embodiments, L is of formula L94. In certain embodiments, L is of formula L95. In certain embodiments, L is of formula L96. In certain embodiments, L is of formula L97. In certain embodiments, L is of formula L98. In certain embodiments, L is of formula L99. In certain embodiments, L is of formula L100. In certain embodiments, L is of formula L101. In certain embodiments, L is of formula L102. In certain embodiments, L is of formula L103. In certain embodiments, L is of formula L104. In certain embodiments, L is of formula L105. In certain embodiments, L is of formula L106. In certain embodiments, L is of formula L107. In certain embodiments, L is of formula L108. In certain embodiments, L is of formula L109. In certain embodiments, L is of formula L110. In certain embodiments, L is of formula L111. In certain embodiments, L is of formula L112. In certain embodiments, L is of formula L113. In certainembodiments, L is of formula L114. In certain embodiments, L is of formula L115. In certain embodiments, L is of formula L116. In certain embodiments, L is of formula L117. In certain embodiments, L is of formula L118. In certain embodiments, L is of formula L119. In certain embodiments, L is of formula L120. In certain embodiments, L is of formula L121. In certain embodiments, L is of formula L122. In certain embodiments, L is of formula L123. In certain embodiments, L is of formula L124. In certain embodiments, L is of formula L125. In certain embodiments, L is of formula L126. In certain embodiments, L is of formula L127. In certain embodiments, L is of formula L128. In certain embodiments, L is of formula L129. In certain embodiments, L is of formula L130. In certain embodiments, L is of formula L131. In certain embodiments, L is of formula L132. In certain embodiments, L is of formula L133. In certain embodiments, L is of formula L134. In certain embodiments, L is of formula L135. In certain embodiments, L is of formula L136. In certain embodiments, L is of formula L137. In certain embodiments, L is of formula L138. In certain embodiments, L is of formula L139. In certain embodiments, L is of formula L140. In certain embodiments, L is of formula L141. In certain embodiments, L is of formula L142. In certain embodiments, L is of formula L143. In certain embodiments, L is of formula L144. In certain embodiments, L is of formula L145. In certain embodiments, L is of formula L146. In certain embodiments, L is of formula L147. In certain embodiments, L is of formula L148. In certain embodiments, L is of formula L149. In certain embodiments, L is of formula L150. In certain embodiments, L is of formula L151. In certain embodiments, L is of formula L152. In certain embodiments, L is of formula L153. In certain embodiments, L is of formula L154. In certain embodiments, L is of formula L155. In certain embodiments, L is of formula L156. In certain embodiments, L is of formula L157. In certain embodiments, L is of formula L158. In certain embodiments, L is of formula L159. In certain embodiments, L is of formula L160. In certain embodiments, L is of formula L161. In certain embodiments, L is of formula L162. In certain embodiments, L is of formula L163. In certain embodiments, L is of formula L164. In certain embodiments, L is of formula L165. In certain embodiments, L is of formula L166. In certain embodiments, L is of formula L167. In certain embodiments, L is of formula L168. In certain embodiments, L is of formula L169. In certain embodiments, L is of formula L170. In certain embodiments, L is of formula L171. In certain embodiments, L is of formula L172. In certain embodiments, L is of formula L173. In certain embodiments, L is of formula L174. In certain embodiments, L is of formula L175. In certain embodiments, L is of formula L176. In certain embodiments, L is of formula L177. In certain embodiments, L is of formula L178. In certain embodiments, L is of formula L179. In certain embodiments, L is of formula L180. In certain embodiments, L is of formula 181. In certainembodiments, L is of formula L182. In certain embodiments, L is of formula L183. In certain embodiments, L is of formula L184. In certain embodiments, L is of formula L185. In certain embodiments, L is of formula L186. In certain embodiments, L is of formula L187. In certain embodiments, L is of formula L188. In certain embodiments, L is of formula L189. In certain embodiments, L is of formula L190. In certain embodiments, L is of formula L191. In certain embodiments, L is of formula L192. In certain embodiments, L is of formula L193. In certain embodiments, L is of formula L194. In certain embodiments, L is of formula L195. In certain embodiments, L is of formula L196. In certain embodiments, L is of formula L197. In certain embodiments, L is of formula L198. In certain embodiments, L is of formula L199. In certain embodiments, L is of formula L200. In certain embodiments, L is of formula L201. In certain embodiments, L is of formula L202. In certain embodiments, L is of formula L203. In certain embodiments, L is of formula L204. In certain embodiments, L is of formula L205. In certain embodiments, L is of formula L206. In certain embodiments, L is of formula L207. In certain embodiments, L is of formula L208. In certain embodiments, L is of formula L209. In certain embodiments, L is of formula L210. In certain embodiments, L is of formula L211. In certain embodiments, L is of formula L212. In certain embodiments, L is of formula L213. In certain embodiments, L is of formula L214. In certain embodiments, L is of formula L215. In certain embodiments, L is of formula L216. In certain embodiments, L is of formula L217. In certain embodiments, L is of formula L218. In certain embodiments, L is of formula L219. In certain embodiments, L is of formula L220. In certain embodiments, L is of formula L221. In certain embodiments, L is of formula L222. In certain embodiments, L is of formula L223. In certain embodiments, L is of formula L224. In certain embodiments, L is of formula L225. In certain embodiments, L is of formula L226. In certain embodiments, L is of formula L227. In certain embodiments, L is of formula L228. In certain embodiments, L is of formula L229. In certain embodiments, L is of formula L230. In certain embodiments, L is of formula L231. In certain embodiments, L is of formula L232.

[0326] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a- 6a):(I-a-6a),or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein L and B are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a-6a), wherein L is any one of L1-L232, or a pharmaceutically acceptable salt thereof.

[0327] The following embodiments of this paragraph relate to embodiments of the compound of Formula (I-a-6a). In certain embodiments, L is of formula L1. In certain embodiments, L is of formula L2. In certain embodiments, L is of formula L3. In certain embodiments, L is of formula L4. In certain embodiments, L is of formula L5. In certain embodiments, L is of formula L6. In certain embodiments, L is of formula L7. In certain embodiments, L is of formula L8. In certain embodiments, L is of formula L9. In certain embodiments, L is of formula L10. In certain embodiments, L is of formula L11. In certain embodiments, L is of formula L12. In certain embodiments, L is of formula L13. In certain embodiments, L is of formula L14. In certain embodiments, L is of formula L15. In certain embodiments, L is of formula L16. In certain embodiments, L is of formula L17. In certain embodiments, L is of formula L18. In certain embodiments, L is of formula L19. In certain embodiments, L is of formula L20. In certain embodiments, L is of formula L21. In certain embodiments, L is of formula L22. In certain embodiments, L is of formula L23. In certain embodiments, L is of formula L24. In certain embodiments, L is of formula L25. In certain embodiments, L is of formula L26. In certain embodiments, L is of formula L27. In certain embodiments, L is of formula L28. In certain embodiments, L is of formula L29. In certain embodiments, L is of formula L30. In certain embodiments, L is of formula L31. In certain embodiments, L is of formula L32. In certain embodiments, L is of formula L33. In certain embodiments, L is of formula L34. In certain embodiments, L is of formula L35. In certain embodiments, L is of formula L36. In certain embodiments, L is of formula L37. In certain embodiments, L is of formula L38. In certain embodiments, L is of formula L39. In certain embodiments, L is of formula L40. In certain embodiments, L is of formula L41. In certain embodiments, L is of formula L42. In certain embodiments, L is of formula L43. In certain embodiments, L is of formula L44. In certain embodiments, L is of formula L45. In certain embodiments, L is of formula L46. In certain embodiments, L is of formula L47. In certain embodiments, L is of formula L48. In certain embodiments, L is of formula L49. In certain embodiments, L is of formula L50. In certain embodiments, L is of formula L51. In certain embodiments, L is of formula L52. In certain embodiments, L is of formula L53. In certain embodiments, L is of formula L54. In certain embodiments, L is of formula L55. In certain embodiments, L is of formula L56. In certain embodiments, L is of formula L57. In certainembodiments, L is of formula L58. In certain embodiments, L is of formula L59. In certain embodiments, L is of formula L60. In certain embodiments, L is of formula L61. In certain embodiments, L is of formula L62. In certain embodiments, L is of formula L63. In certain embodiments, L is of formula L64. In certain embodiments, L is of formula L65. In certain embodiments, L is of formula L66. In certain embodiments, L is of formula L67. In certain embodiments, L is of formula L68. In certain embodiments, L is of formula L69. In certain embodiments, L is of formula L70. In certain embodiments, L is of formula L71. In certain embodiments, L is of formula L72. In certain embodiments, L is of formula L73. In certain embodiments, L is of formula L74. In certain embodiments, L is of formula L75. In certain embodiments, L is of formula L76. In certain embodiments, L is of formula L77. In certain embodiments, L is of formula L78. In certain embodiments, L is of formula L79. In certain embodiments, L is of formula L80. In certain embodiments, L is of formula L81. In certain embodiments, L is of formula L82. In certain embodiments, L is of formula L83. In certain embodiments, L is of formula L84. In certain embodiments, L is of formula L85. In certain embodiments, L is of formula L86. In certain embodiments, L is of formula L87. In certain embodiments, L is of formula L88. In certain embodiments, L is of formula L89. In certain embodiments, L is of formula L90. In certain embodiments, L is of formula L91. In certain embodiments, L is of formula L92. In certain embodiments, L is of formula L93. In certain embodiments, L is of formula L94. In certain embodiments, L is of formula L95. In certain embodiments, L is of formula L96. In certain embodiments, L is of formula L97. In certain embodiments, L is of formula L98. In certain embodiments, L is of formula L99. In certain embodiments, L is of formula L100. In certain embodiments, L is of formula L101. In certain embodiments, L is of formula L102. In certain embodiments, L is of formula L103. In certain embodiments, L is of formula L104. In certain embodiments, L is of formula L105. In certain embodiments, L is of formula L106. In certain embodiments, L is of formula L107. In certain embodiments, L is of formula L108. In certain embodiments, L is of formula L109. In certain embodiments, L is of formula L110. In certain embodiments, L is of formula L111. In certain embodiments, L is of formula L112. In certain embodiments, L is of formula L113. In certain embodiments, L is of formula L114. In certain embodiments, L is of formula L115. In certain embodiments, L is of formula L116. In certain embodiments, L is of formula L117. In certain embodiments, L is of formula L118. In certain embodiments, L is of formula L119. In certain embodiments, L is of formula L120. In certain embodiments, L is of formula L121. In certain embodiments, L is of formula L122. In certain embodiments, L is of formula L123. In certain embodiments, L is of formula L124. In certain embodiments, L is of formula L125. In certainembodiments, L is of formula L126. In certain embodiments, L is of formula L127. In certain embodiments, L is of formula L128. In certain embodiments, L is of formula L129. In certain embodiments, L is of formula L130. In certain embodiments, L is of formula L131. In certain embodiments, L is of formula L132. In certain embodiments, L is of formula L133. In certain embodiments, L is of formula L134. In certain embodiments, L is of formula L135. In certain embodiments, L is of formula L136. In certain embodiments, L is of formula L137. In certain embodiments, L is of formula L138. In certain embodiments, L is of formula L139. In certain embodiments, L is of formula L140. In certain embodiments, L is of formula L141. In certain embodiments, L is of formula L142. In certain embodiments, L is of formula L143. In certain embodiments, L is of formula L144. In certain embodiments, L is of formula L145. In certain embodiments, L is of formula L146. In certain embodiments, L is of formula L147. In certain embodiments, L is of formula L148. In certain embodiments, L is of formula L149. In certain embodiments, L is of formula L150. In certain embodiments, L is of formula L151. In certain embodiments, L is of formula L152. In certain embodiments, L is of formula L153. In certain embodiments, L is of formula L154. In certain embodiments, L is of formula L155. In certain embodiments, L is of formula L156. In certain embodiments, L is of formula L157. In certain embodiments, L is of formula L158. In certain embodiments, L is of formula L159. In certain embodiments, L is of formula L160. In certain embodiments, L is of formula L161. In certain embodiments, L is of formula L162. In certain embodiments, L is of formula L163. In certain embodiments, L is of formula L164. In certain embodiments, L is of formula L165. In certain embodiments, L is of formula L166. In certain embodiments, L is of formula L167. In certain embodiments, L is of formula L168. In certain embodiments, L is of formula L169. In certain embodiments, L is of formula L170. In certain embodiments, L is of formula L171. In certain embodiments, L is of formula L172. In certain embodiments, L is of formula L173. In certain embodiments, L is of formula L174. In certain embodiments, L is of formula L175. In certain embodiments, L is of formula L176. In certain embodiments, L is of formula L177. In certain embodiments, L is of formula L178. In certain embodiments, L is of formula L179. In certain embodiments, L is of formula L180. In certain embodiments, L is of formula 181. In certain embodiments, L is of formula L182. In certain embodiments, L is of formula L183. In certain embodiments, L is of formula L184. In certain embodiments, L is of formula L185. In certain embodiments, L is of formula L186. In certain embodiments, L is of formula L187. In certain embodiments, L is of formula L188. In certain embodiments, L is of formula L189. In certain embodiments, L is of formula L190. In certain embodiments, L is of formula L191. In certain embodiments, L is of formula L192. In certain embodiments, L is of formula L193. In certainembodiments, L is of formula L194. In certain embodiments, L is of formula L195. In certain embodiments, L is of formula L196. In certain embodiments, L is of formula L197. In certain embodiments, L is of formula L198. In certain embodiments, L is of formula L199. In certain embodiments, L is of formula L200. In certain embodiments, L is of formula L201. In certain embodiments, L is of formula L202. In certain embodiments, L is of formula L203. In certain embodiments, L is of formula L204. In certain embodiments, L is of formula L205. In certain embodiments, L is of formula L206. In certain embodiments, L is of formula L207. In certain embodiments, L is of formula L208. In certain embodiments, L is of formula L209. In certain embodiments, L is of formula L210. In certain embodiments, L is of formula L211. In certain embodiments, L is of formula L212. In certain embodiments, L is of formula L213. In certain embodiments, L is of formula L214. In certain embodiments, L is of formula L215. In certain embodiments, L is of formula L216. In certain embodiments, L is of formula L217. In certain embodiments, L is of formula L218. In certain embodiments, L is of formula L219. In certain embodiments, L is of formula L220. In certain embodiments, L is of formula L221. In certain embodiments, L is of formula L222. In certain embodiments, L is of formula L223. In certain embodiments, L is of formula L224. In certain embodiments, L is of formula L225. In certain embodiments, L is of formula L226. In certain embodiments, L is of formula L227. In certain embodiments, L is of formula L228. In certain embodiments, L is of formula L229. In certain embodiments, L is of formula L230. In certain embodiments, L is of formula L231. In certain embodiments, L is of formula L232.

[0328] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a- 7):(I-a-7), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein L, B, and RCare as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a-7), wherein L is any one of L1-L232, or a pharmaceutically acceptable salt thereof.

[0329] The following embodiments of this paragraph relate to embodiments of the compound of Formula (I-a-7). In certain embodiments, L is of formula L1. In certain embodiments, L is of formula L2. In certain embodiments, L is of formula L3. In certainembodiments, L is of formula L4. In certain embodiments, L is of formula L5. In certain embodiments, L is of formula L6. In certain embodiments, L is of formula L7. In certain embodiments, L is of formula L8. In certain embodiments, L is of formula L9. In certain embodiments, L is of formula L10. In certain embodiments, L is of formula L11. In certain embodiments, L is of formula L12. In certain embodiments, L is of formula L13. In certain embodiments, L is of formula L14. In certain embodiments, L is of formula L15. In certain embodiments, L is of formula L16. In certain embodiments, L is of formula L17. In certain embodiments, L is of formula L18. In certain embodiments, L is of formula L19. In certain embodiments, L is of formula L20. In certain embodiments, L is of formula L21. In certain embodiments, L is of formula L22. In certain embodiments, L is of formula L23. In certain embodiments, L is of formula L24. In certain embodiments, L is of formula L25. In certain embodiments, L is of formula L26. In certain embodiments, L is of formula L27. In certain embodiments, L is of formula L28. In certain embodiments, L is of formula L29. In certain embodiments, L is of formula L30. In certain embodiments, L is of formula L31. In certain embodiments, L is of formula L32. In certain embodiments, L is of formula L33. In certain embodiments, L is of formula L34. In certain embodiments, L is of formula L35. In certain embodiments, L is of formula L36. In certain embodiments, L is of formula L37. In certain embodiments, L is of formula L38. In certain embodiments, L is of formula L39. In certain embodiments, L is of formula L40. In certain embodiments, L is of formula L41. In certain embodiments, L is of formula L42. In certain embodiments, L is of formula L43. In certain embodiments, L is of formula L44. In certain embodiments, L is of formula L45. In certain embodiments, L is of formula L46. In certain embodiments, L is of formula L47. In certain embodiments, L is of formula L48. In certain embodiments, L is of formula L49. In certain embodiments, L is of formula L50. In certain embodiments, L is of formula L51. In certain embodiments, L is of formula L52. In certain embodiments, L is of formula L53. In certain embodiments, L is of formula L54. In certain embodiments, L is of formula L55. In certain embodiments, L is of formula L56. In certain embodiments, L is of formula L57. In certain embodiments, L is of formula L58. In certain embodiments, L is of formula L59. In certain embodiments, L is of formula L60. In certain embodiments, L is of formula L61. In certain embodiments, L is of formula L62. In certain embodiments, L is of formula L63. In certain embodiments, L is of formula L64. In certain embodiments, L is of formula L65. In certain embodiments, L is of formula L66. In certain embodiments, L is of formula L67. In certain embodiments, L is of formula L68. In certain embodiments, L is of formula L69. In certain embodiments, L is of formula L70. In certain embodiments, L is of formula L71. In certainembodiments, L is of formula L72. In certain embodiments, L is of formula L73. In certain embodiments, L is of formula L74. In certain embodiments, L is of formula L75. In certain embodiments, L is of formula L76. In certain embodiments, L is of formula L77. In certain embodiments, L is of formula L78. In certain embodiments, L is of formula L79. In certain embodiments, L is of formula L80. In certain embodiments, L is of formula L81. In certain embodiments, L is of formula L82...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: V1is CR2or N; each of R2, R3, and R4is 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; R5is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group; R6is -ORC, -N(RB)2, or substituted or unsubstituted alkyl; A is a bond or an orienting moiety; L is a bond or a linker; B is a targeting moiety or a detectable moiety; 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; 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; provided that the compound is not of formula:(II), or a pharmaceutically acceptable salt thereof, wherein: V1is N or CR2; each of R2, R3, and R4is 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; R5is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group;R6is -ORC, -N(RB)2, or substituted or unsubstituted alkyl; A is a bond or an orienting moiety; L is a bond or a linker; T is hydrogen, a protecting group, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle; 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; 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; RCis 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; provided that the compound is not of formula:

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: V1is CR2.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: V1is N.

5. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R2is 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.

6. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R2is hydrogen, halogen, or substituted or unsubstituted alkyl.

7. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R2is hydrogen.

8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R2is halogen.

9. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:R3is 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.

10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R3is hydrogen, -CN, halogen, or substituted or unsubstituted alkyl.

11. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R3is halogen.

12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R3is chloro.

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R4is 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.

14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R4is hydrogen, halogen, or substituted or unsubstituted alkyl.

15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R4is hydrogen.

16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R5is hydrogen or substituted or unsubstituted alkyl.

17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R5is hydrogen.

18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R5is a nitrogen protecting group.

19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R5is 2-(trimethylsilyl)ethoxymethyl (SEM).

20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R6is -ORCor -N(RB)2.

21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R6is -ORC.

22. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R6is -ORC, wherein RCis substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aryl.

23. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R6is -ORC, wherein RCis substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl.

24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R6is -ORC, wherein RCis substituted or unsubstituted C3-6 cycloalkyl, or substituted or unsubstituted 4-10 membered heterocyclyl.

25. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R6is -ORC, wherein RCis substituted or unsubstituted C3-6 cycloalkyl.

26. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:

27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: ,28. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R6is -ORC, wherein RCis substituted or unsubstituted 4-10 membered heterocyclyl.

29. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R6is -ORC, wherein RCis substituted or unsubstituted 4-6 membered heterocyclyl or a sugar moiety.

30. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:

31. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:

32. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R6is methyl, ethyl, isopropyl,33. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:.

34. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula: -X-Y-; X is bound to the bicyclic moiety, 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; and Y is a bond, -NRA-, -O-, -S-, -S(O)2-, -S(O)-, -C≡C-, substituted or unsubstituted -C≡C-heterocyclylene, substituted or unsubstituted C1-2alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted carbocyclylene.

35. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula: -X-Y-; X is bound to the bicyclic moiety, 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; 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.

36. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula: -X-Y-; X is bound to the bicyclic moiety, and Y is bound to L; 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.

37. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula: -X-Y-, wherein: X is bound to the bicyclic moiety, and Y is bound to L; X is substituted or unsubstituted phenylene; andY is a bond, substituted or unsubstituted -C≡C-heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heterocyclylene.

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

39. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula: -X-Y-; X is bound to the bicyclic moiety, and Y is bound to L; X is substituted or unsubstituted arylene; and Y is substituted or unsubstituted heteroarylene.

40. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula:

41. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula: -X-Y-; X is bound to the bicyclic moiety, and Y is bound to L; X is substituted or unsubstituted carbocyclylene; and Y is a bond.

42. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula:.

43. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula: -X-Y-; X is bound to the bicyclic moiety, and Y is bound to L; X is substituted or unsubstituted heterocyclylene; and Y is a bond or substituted or unsubstituted arylene.

44. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula:

45. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula: -X-Y-; X is substituted or unsubstituted heteroarylene; and Y is a bond or substituted or unsubstituted heterocyclylene.

46. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula: -X-Y-; X is bound to the bicyclic moiety, and Y is bound to L; X is substituted or unsubstituted 6-membered heteroarylene; and Y is a bond or substituted or unsubstituted heterocyclylene.

47. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula: -X-Y-; X is bound to the bicyclic moiety, and Y is bound to L; 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.

48. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula: -X-Y-; X is bound to the bicyclic moiety, and Y is bound to L; 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.

49. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula: -X-Y-; X is bound to the bicyclic moiety, and Y is bound to L; 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.

50. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula:, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

51. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula:wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

52. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula:wherein Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

53. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A is of formula:, , , ,54. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:

55. 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.

56. 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 carbocyclylene, 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)-, or -NRAS(O)2-, or a combination thereof.

57. 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)-, or -C(=O)-, or a combination thereof.

58. 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(=O)-, -C(=O)-, or a combination thereof.

59. 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 azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene,N(CH3)C(=O)-, or -C(=O)-, or a combination thereof.

60. 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)-, -C(=O)-, 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.

61. 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)-, 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; Z3is a bond, -C(=O)-, or -N(RA)-; t is 0-30; and u is 0-30; provided that L comprises at least one atom.

62. 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)-, -C(=O)-, unsubstituted C1-6alkylene,,Z3is a bond, -C(=O)-, -O-, or -N(RA)-; Z4is 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.

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

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

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

66. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: L is selected from any one of L1-L73:

67. The compound of claim 66, or a pharmaceutically acceptable salt thereof, wherein: L is of formula L2, L4, L10, L12, L13, L16, L17, L18, L20, L21, L23, L27, L28, L32, L37, L40, L46, L47, L51, L52, L53, L54, L55, L56, L57, L58, L59, L60, L68, L69, L70, L71, L72, or L73: or L is of formula L2, L4, L12, L16, L17, L18, L20, L23, L27, L28, L32, L37, L40, L46, L47, L51, L52, L53, L54, L68, L69, L70, L71, L72, or L73.

68. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: L is selected from any one of L74-L232:

69. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: L is of formula L75, L76, L79, L80, L82, L83, L84, L87, L88, L89, L90, L92, L93, L94, L95, L96, L97, L99, L101, L102, L103, L105, L106, L107, L108, L109, L110, L111, L112, L113, L115, L116, L117, L118, L119, L120, L137, L138, L139, L140, L141, L149, L153, L182, L187, L189, L191, L192, L193, L194, L195, L196, L197, L198, L199, L200, L201, L202, L203, L214, L215, L216, L217, L218, L222, L223, L224, L225, L226, L227, L228, L229, L230, L231, or L232; or L is of formula L75, L76, L79, L80, L87, L88, L93, L94, L95, L96, L97, L99, L101, L102, L103, L105, L106, L107, L108, L109, L110, L111, L112, L113, L137, L138, L139, L140, L141, L149, L153, L182, L187, L189, L191, L192, L193, L194, L195, L196, L197, L198, L200, L201, L202, L203, L223, L224, L225, L226, L227, L228, L229, L230, L231, or L232; or L is of formula L75, L76, L79, L80, L87, L88, L93, L94, L95, L96, L97, L99, L101, L102, L103, L105, L106, L107, L108, L109, L110, L111, L112, L113, L137, L138, L139, L140, L141, L149, L153, L182, L187, L189, L191, L192, L193, L194, L195, L196, L197, L198, L200, L201, L202, L203, L223, L224, L225, L226, L227, L228, L229, L230, or L231.

70. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: B is a targeting moiety.

71. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: B is a bioactive moiety.

72. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: B is a protein-binding moiety.

73. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: B is a KRAS-binding moiety, a kinase-binding moiety, or a phosphatase-binding moiety.

74. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein B is of formula:

75. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: B is a detectable moiety.

76. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: B is a dye.

77. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: B is a fluorescent dye.

78. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: B is of formula:.

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

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

81. The compound of claim 1, wherein the compound is of Formula (I-a-2):(I-a-2), or a pharmaceutically acceptable salt thereof.

82. The compound of claim 1, wherein the compound is of Formula (I-a-3):(I-a-3), or a pharmaceutically acceptable salt thereof.

83. The compound of claim 1, wherein the compound is of Formula (I-a-4):(I-a-4), or a pharmaceutically acceptable salt thereof.

84. The compound of claim 1, wherein the compound is of Formula (I-a-5):(I-a-5), or a pharmaceutically acceptable salt thereof.

85. The compound of claim 1, wherein the compound is of Formula (I-a-5a):(I-a-5a), or a pharmaceutically acceptable salt thereof.

86. The compound of claim 1, wherein the compound is of Formula (I-a-6):(I-a-6), or a pharmaceutically acceptable salt thereof.

87. The compound of claim 1, wherein the compound is of Formula (I-a-6a):(I-a-6a), or a pharmaceutically acceptable salt thereof.

88. The compound of claim 1, wherein the compound is of Formula (I-a-7):or a pharmaceutically acceptable salt thereof.

89. The compound of claim 1, wherein the compound is of Formula (I-a-7a):(I-a-7a), or a pharmaceutically acceptable salt thereof.

90. The compound of claim 1, wherein the compound is of Formula (I-a-7b):(I-a-7b), or a pharmaceutically acceptable salt thereof.

91. The compound of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

92. The compound of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof 93. The compound of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

94. The compound of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

95. The compound of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

96. The compound of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

97. The compound of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

98. The compound of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

99. The compound of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

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

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

102. The compound of claim 1, wherein the compound is of Formula (I-b-2):(I-b-2), or a pharmaceutically acceptable salt thereof.

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

104. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: T is hydrogen, a nucleophilic group, a leaving group, or a nitrogen protecting group.

105. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: T is hydrogen, -ORA, -N3, -COORA, -C≡CH, halogen, or a nitrogen protecting group.

106. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:T is hydrogen, -OH, -OMe, -OtBu, -OMs, -OTs, -C≡CH, -F, -Br, or a nitrogen protecting group.

107. The compound of claim 2, wherein the compound is of Formula (II-a):(II-a), or a pharmaceutically acceptable salt thereof.

108. The compound of claim 2, wherein the compound is of Formula (II-a-1):(II-a-1), or a pharmaceutically acceptable salt thereof.

109. The compound of claim 2, wherein the compound is of Formula (II-a-2):(II-a-2), or a pharmaceutically acceptable salt thereof.

110. The compound of claim 2, wherein the compound is of Formula (II-a-3):(II-a-3), or a pharmaceutically acceptable salt thereof.

111. The compound of claim 2, wherein the compound is of Formula (II-a-4):(II-a-4), or a pharmaceutically acceptable salt thereof.

112. The compound of claim 2, wherein the compound is of Formula (II-a-5):(II-a-5), or a pharmaceutically acceptable salt thereof.

113. The compound of claim 2, wherein the compound is of Formula (II-a-6):(II-a-6), or a pharmaceutically acceptable salt thereof.

114. The compound of claim 2, wherein the compound is of Formula (II-a-7):or a pharmaceutically acceptable salt thereof.

115. The compound of claim 2, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein:Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

116. The compound of claim 2, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

117. The compound of claim 2, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

118. The compound of claim 2, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

119. The compound of claim 2, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

120. The compound of claim 2, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

121. The compound of claim 2, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

122. The compound of claim 2, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof, wherein:Rxis hydrogen, halogen, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, -N(RA)2, -ORA, or -SRA; and each occurrence of RAis, independently, hydrogen, substituted or unsubstituted acyl, or substituted or unsubstituted C1-4alkyl.

123. The compound of claim 2, wherein the compound is of Formula (II-b):(II-b), or a pharmaceutically acceptable salt thereof.

124. The compound of claim 2, wherein the compound is of Formula (II-c-1):(II-b-1), or a pharmaceutically acceptable salt thereof.

125. The compound of claim 2, wherein the compound is of Formula (II-b-2):(II-b-2), or a pharmaceutically acceptable salt thereof.

126. The compound of claim 2, wherein the compound is:or a pharmaceutically acceptable salt thereof.

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

128. A method of phosphorylating a target substrate, 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 127, to a mixture that comprises AMPK and the target substrate.

129. The method of claim 128, wherein the compound causes phosphorylation of the target substrate at a rate or amount that is increased over the rate or amount of phosphorylation in the same mixture comprising the AMPK and the target substrate but without the compound.

130. The method of claim 128 or 129, wherein the amount of phosphorylation is measured at a specified time.

131. A method of promoting the phosphorylation of a target substrate, 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 127.

132. The method of any one of claims 128-131, wherein the target substrate is a protein.

133. A method of modulating a protein 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 127.

134. The method of claim 133, wherein the protein kinase is AMPK.

135. The method of any of claims 128-134, wherein the phosphorylation or modulation is in a cell.

136. The method of any of claims 128-135, wherein the phosphorylation or modulation is in a biological sample.

137. The method of any of claims 128-136, wherein the target substate is a kinase or a phosphatase.

138. The method of any of claims 128-137, wherein the target substate is KRAS or KRAS mutant, BRD4, BRD2, BRD3, BET, BRDT, CAII, TRIM24, or BTK.

139. The method of any of claims 128-137, wherein the target substate is KRAS or KRAS mutant, BRD4, CAII, TRIM24, or BTK.

140. A kit comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 127; and instructions for use.

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