Bifunctional ABL1-binding compounds and uses thereof

Abstract

Provided herein are compounds that bind 3-phosphoinositide-dependent protein kinase-1 (ABL1) 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 ABL1, and providing new modes for inducing strategic phosphorylation. Also provided are compounds that are intermediates of the bifunctional compounds. Also provided are compounds that bind an allosteric site of ABL1I and inhibit the phosphorylation of a target substrate. Also provided are pharmaceutical compositions comprising the disclosed compounds and methods of promoting the phosphorylation of target substrates in a biological sample by administering a compound or composition described herein.

Description

BIFUNCTIONAL ABL1-BINDING COMPOUNDS AND USES THEREOFRELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N. 63 / 607,902, filed December 8, 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, metabolism, differentiation, proliferation, and apoptosis. Kinase dysfunction is also associated with a variety of human diseases, including, but not limited to, cancer, inflammatory conditions, autoimmune disorders, and cardiovascular diseases. Agents that block protein phosphorylation via kinase inhibition have had a transformative impact in basic science and medicine. However, agents that can both engage a kinase and one or more other target substrates of interest (e.g., proteins) to be phosphorylated may also be useful as a means of evoking desired attributes or responses from those target substrates.

[0003] Tyrosine-protein kinase ABL1 (referred herein as ABL1, formerly known as ABL) is a protein that has been implicated in cell differentiation, cell division, cell adhesion, and stress response. The activity of ABL1 protein is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABL1 into an oncogene. The ubiquitously expressed protein has DNA- binding activity that is regulated by CDC2-mediated phosphorylation, suggesting a cell cycle function.

[0004] Recently, a new strategy for promoting the phosphorylation of target proteins of interest, PHICS (phosphorylation-inducing chimeric small molecules), was introduced. PHICS are bifunctional molecules containing two small molecule binding moieties, joined together by a linker. One of the small molecule moieties is designed to bind to a target protein while the other small molecule moiety binds to a protein kinase. The PHICS selectively binds to the target substrate of interest and simultaneously binds to and recruits a specific kinase to phosphorylate the target substrate. The PHICS then dissociate from the target substrate and initiate another catalytic cycle.SUMMARY

[0005] Phosphorylation of any given target substrate (e.g., a protein) can alter its structure, activity, localization, and / or function. Such modifications may be accomplished by compounds that bring a kinase in proximity to a target substrate. Provided herein are PHICS compoundswhich enable a kinase (e.g., ABL1) to phosphorylate target substrates, including substrates that may not normally be substrates for the kinase. The compounds provide new modes for inducing substrate alterations via strategic phosphorylation in a variety of settings. Also provided are bifunctional compounds that comprise a first functional moiety that engages / binds ABL1 and a second functional moiety that comprises a detectable moiety (e.g., a chromophore, dye, fluorophore, luminophore or luminescent material, or radioactive material) joined together by a linker. Also provided are compounds that are useful as synthetic intermediates in methods of preparing the aforementioned bifunctional compounds. Accordingly, the present disclosure provides new compounds, compositions, kits, uses, and methods for modulating (e.g., phosphorylating) a target substrate (e.g. , protein) via proximity-induced engagement between ABL1 and a target substrate.

[0006] In one aspect, provided herein are compounds of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, n, R2, R3, A, and L are as provided herein and B is a targeting moiety or a detectable moiety.

[0007] In another aspect, provided herein are compounds of Formula (II):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, n, R2, R3, A, and L are as provided herein and T is hydrogen, a nucleophilic group, an electrophilic group, a protecting group, a leaving group, or a click chemistry handle.

[0008] In another aspect, provided herein are compounds of Formula (III):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Y1, R1, n, R3, A, and L are as provided herein and B is a targeting moiety or a detectable moiety.

[0009] In another aspect, provided herein are compounds of Formula (IV):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Y1, R1, n, R3, A, and L are as provided herein and T is hydrogen, a nucleophilic group, an electrophilic group, a protecting group, a leaving group, or a click chemistry handle.

[0010] In another, provided herein are compounds of Formula (V):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, R1, n, R2, R3, A, and L are as provided herein and B is a targeting moiety or a detectable moiety.

[0011] In another aspect, provided herein are compounds of Formula (VI):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, n, R2, R3, A, and L are as provided herein and T is hydrogen, a nucleophilic group, an electrophilic group, a protecting group, a leaving group, or a click chemistry handle.

[0012] 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.

[0013] 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 ABL1 and the target substrate.

[0014] In another aspect, provided are methods of promoting the phosphorylation of a target substrate (e.g., protein) with ABL1, 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.

[0015] 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 ABL1.

[0016] 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.

[0017] 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1 depicts Abl phosphorylation for a variety of PHICS: (3)-(9) and (13)-(20). To assess phosphorylation, the measured mass of BRD4 after incubation with Abl+ / - PHICS was compared to the mass of BRD4 alone. Quantification of the modification was performed using deconvoluted peak height. Each phosphorylation state is expressed as a percentage of the total BRD4 protein detected in the LCMS run.

[0019] FIG. 2 depicts Abl phosphorylation for a variety of PHICS: (21)-(34, (48), (50), (51), and (54). To assess phosphorylation, the measured mass of BRD4 after incubation with Abl+ / - PHICS was compared to the mass of BRD4 alone. Quantification of the modification was performed using deconvoluted peak height. Each phosphorylation state is expressed as a percentage of the total BRD4 protein detected in the LCMS run.

[0020] FIG.3 depicts Abl phosphorylation for a variety of PHICS: (35)-(46). To assess phosphorylation, the measured mass of TRIM24 after incubation with Abl+ / - PHICS was compared to the mass of TRIM24 alone. Quantification of the modification was performed using deconvoluted peak height. Each phosphorylation state is expressed as a percentage of the total TRIM24 protein detected in the LCMS run. DEFINITIONSChemical definitions

[0021] 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.

[0022] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions, p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0023] Where compound structures are depicted, stereocenters labeled with “abs” indicate known absolute stereochemistry, stereocenters labeled with “&1” indicate a mixture of the two trans or cis stereoisomers, and stereocenters labeled with “or1” indicate a single stereoisomer with unknown absolute stereochemistry.

[0024] 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, andis a single or double bond.

[0025] 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.

[0026] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-6alkyl” 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.

[0027] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0028] 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 (“C1-9alkyl”). 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 (“C1alkyl”). 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 instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10alkyl (such as unsubstituted C1-6alkyl, e.g., −CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl(i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10alkyl (such as substituted C1-6alkyl, e.g., −CF3, Bn).

[0029] 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 (“C1-8haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3haloalkyl”). In some 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.

[0030] 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 (“heteroC1-18alkyl”). 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 (“heteroC1-16alkyl”). 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 (“heteroC1-12alkyl”). 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 (“heteroC1-8alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 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 (“heteroC1-3alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1alkyl”). In some embodiments, the heteroalkyl groupdefined 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 heteroC1-20alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl.

[0031] 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 (“C2-9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). 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 (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). 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 (“C2-3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). 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 C2-6alkenyl 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 C2-10alkenyl. 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 (e.g., −CH=CHCH3ormay be an (E)- or (Z)-double bond.

[0032] 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(“heteroC2-10alkenyl”). 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 (“heteroC2-8alkenyl”). 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 (“heteroC2-7alkenyl”). 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 (“heteroC2-5alkenyl”). 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 (“heteroC2-6alkenyl”). 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 heteroC2-10alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10alkenyl.

[0033] 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) (“C2-10alkynyl”). 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 (“C2-6alkynyl”). 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 (“C2-3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). 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 C2-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”)with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10alkynyl.

[0034] 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 (“heteroC2-9alkynyl”). 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 (“heteroC2-7alkynyl”). 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 (“heteroC2-6alkynyl”). 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 (“heteroC2-5alkynyl”). 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 (“heteroC2-6alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10alkynyl.

[0035] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms 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 (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ringcarbon 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 C3-8carbocyclyl 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 C3-14carbocyclyl.

[0036] 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 (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl 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 C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl 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 oneor 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14aryl. In certain embodiments, the aryl group is a substituted C6-14aryl.

[0041] “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.

[0042] 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 π 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).

[0043] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the5-6 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.

[0044] 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.

[0045] “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.

[0046] The term “unsaturated bond” refers to a double or triple bond.

[0047] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0048] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0049] 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.

[0050] 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.

[0051] 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, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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 C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each 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, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; each instance of Rccis, independently, selected from hydrogen, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 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 C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 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, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl 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, −OC1-6alkyl, −ON(C1-6alkyl)2, −N(C1-6alkyl)2, −N(C1-6alkyl)3+X−, −NH(C1-6alkyl)2+X−, −NH2(C1-6alkyl)+X−, −NH3+X−, −N(OC1-6alkyl)(C1-6alkyl), −N(OH)(C1-6alkyl), −NH(OH), −SH, −SC1-6alkyl, −SS(C1-6alkyl), −C(=O)(C1-6alkyl), −CO2H, −CO2(C1-6alkyl), −OC(=O)(C1-6alkyl), −OCO2(C1-6alkyl), −C(=O)NH2, −C(=O)N(C1-6alkyl)2, −OC(=O)NH(C1-6alkyl), −NHC(=O)(C1-6alkyl), −N(C1-6alkyl)C(=O)( C1-6alkyl), −NHCO2(C1-6alkyl), −NHC(=O)N(C1-6alkyl)2, −NHC(=O)NH(C1-6alkyl), −NHC(=O)NH2, −C(=NH)O(C1-6alkyl), −OC(=NH)(C1-6alkyl), −OC(=NH)OC1-6alkyl, −C(=NH)N(C1-6alkyl)2, −C(=NH)NH(C1-6alkyl), −C(=NH)NH2, −OC(=NH)N(C1-6alkyl)2, −OC(=NH)NH(C1-6alkyl), −OC(=NH)NH2, −NHC(=NH)N(C1-6alkyl)2, −NHC(=NH)NH2, −NHSO2(C1-6alkyl), −SO2N(C1-6alkyl)2, −SO2NH(C1-6alkyl),−SO2NH2, −SO2(C1-6alkyl), −SO2O(C1-6alkyl), −OSO2(C1-6alkyl), −SO(C1-6alkyl), −Si(C1-6alkyl)3, −OSi(C1-6alkyl)3−C(=S)N(C1-6alkyl)2, C(=S)NH(C1-6alkyl), C(=S)NH2, −C(=O)S(C1-6alkyl), −C(=S)SC1-6alkyl, −SC(=S)SC1-6alkyl, −P(=O)(OC1-6alkyl)2, −P(=O)(C1-6alkyl)2, −OP(=O)(C1-6alkyl)2, −OP(=O)(OC1-6alkyl)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 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.

[0052] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0053] 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.

[0054] 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.

[0055] 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.

[0056] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from −N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −NRbbSO2Raa, −NRbbP(=O)(ORcc)2, and −NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0057] 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.

[0058] 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).

[0059] 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)-).

[0060] The term “silyl” refers to the group –Si(Raa)3, wherein Raais as defined herein.

[0061] The term “oxo” refers to the group =O, and the term “thiooxo” refers to the group =S.

[0062] 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, C2-10 alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rcc, and Rddare as defined herein.

[0063] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1-10alkyl (e.g., aralkyl, heteroaralkyl), C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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).

[0068] 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.

[0069] 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).

[0070] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine- sulfenyl, or triphenylmethyl.

[0071] 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–, HCO3−, HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p– toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−, B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0072] 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 a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non- limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Further 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).

[0073] 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.

[0074] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0075] 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

[0076] The following definitions are more general terms used throughout the present application.

[0077] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.

[0078] 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.

[0079] 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.

[0080] 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)).

[0081] 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.

[0082] 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”.

[0083] 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”.

[0084] 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.

[0085] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C1-8alkyl, C2-8alkenyl, C2-8alkynyl, aryl, C7-12substituted aryl, and C7-12arylalkyl esters of the compounds described herein may be preferred.

[0086] The terms “composition” and “formulation” are used interchangeably.

[0087] 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.

[0088] 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.

[0089] The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is the object to which a compound and / or composition of the disclosure is delivered. A tissue may be an abnormal or unhealthy tissue. A tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy.

[0090] 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.

[0091] 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 amountof 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.

[0092] 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 by reference. All listed drugs are considered acceptable for use in accordance with the present invention.

[0093] The term “targeting moiety” refers to any chemical entity that serves to bind or otherwise direct the compound to a particular location or association.

[0094] The term “detectable moiety” refers to a chemical entity that can be used to produce a detectable signal that indicates the presence or concentration of the compound having the detectable moiety in a sample.

[0095] 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. In some embodiments, the bioactive moiety is an FDA-approved drug.

[0096] 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.

[0097] 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. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0098] Provided herein are bifunctional compounds that bind a target substrate (e.g., protein) and recruit a kinase (e.g., ABL1) 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 ABL1. Also provided are compounds useful in the production and manufacture of the bifunctional compounds and probes described herein.

[0099] 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):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN,-SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 1, 2, 3, 4, and 5; R2is hydrogen, or substituted or unsubstituted alkyl; R3is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; A is -X1-X2-X3-X4-; X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X2is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene; X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X4is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; 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.

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

[0101] In one aspect, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. In some embodiments, provided herein are compounds of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 1, 2, 3, 4, and 5; R2is hydrogen, or substituted or unsubstituted alkyl; R3is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; A is -X1-X2-X3-X4-; X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X2is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene; X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X4is a bond, substituted or unsubstituted heterocyclyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl;L is a bond or a linker; T is hydrogen, 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.

[0102] In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, and tautomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

[0103] In one aspect, the disclosure provides compounds of Formula (III), 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 (III):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN,-SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 1, 2, 3, 4, and 5; Y1isR2is hydrogen, halogen, substituted or unsubstituted alkyl, -ORA, or -SRA; R3is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; A is -X1-X2-X3-X4-; X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X4is a bond, -N(RA)-, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; 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.

[0104] In some embodiments, the disclosure provides compounds of Formula (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (III), and pharmaceutically acceptable salts, solvates,hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (III), and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (III), and pharmaceutically acceptable salts, and tautomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (III), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

[0105] In one aspect, the disclosure provides compounds of Formula (IV), 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 (IV):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 1, 2, 3, 4, and 5; Y1isR2is hydrogen, halogen, substituted or unsubstituted alkyl, -ORA, or -SRA; R3is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; A is -X1-X2-X3-X4-; X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene;X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X4is a bond, -N(RA)-, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; L is a bond or a linker; T is hydrogen, 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.

[0106] In some embodiments, the disclosure provides compounds of Formula (IV), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (IV), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (IV), and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (IV), and pharmaceutically acceptable salts, and tautomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (IV), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

[0107] In one aspect, the disclosure provides compounds of Formula (V), 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 (V):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 1, 2, 3, 4, and 5; R2is hydrogen, or substituted or unsubstituted alkyl; R3is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; A is -X1-X2-X3-X4-; X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X2is a substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, or substituted or unsubstituted pyrazinylene; X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X4is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; 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 groupwhen 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; provided that the compound is not of the following formula, or stereoisomer thereof:

[0108] In some embodiments, the disclosure provides compounds of Formula (V), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (V), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (V), and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (V), and pharmaceutically acceptable salts, and tautomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (V), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

[0109] In one aspect, the disclosure provides compounds of Formula (VI), 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 (VI):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 1, 2, 3, 4, and 5; R2is hydrogen, or substituted or unsubstituted alkyl; R3is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; A is -X1-X2-X3-X4-; X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X2is a substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, or substituted or unsubstituted pyrazinylene; X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X4is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; L is a bond or a linker; T is hydrogen, 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; provided that the compound is not of the following formula:

[0110] In some embodiments, the disclosure provides compounds of Formula (VI), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (VI), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (VI), and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (VI), and pharmaceutically acceptable salts, and tautomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (VI), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

[0111] In certain embodiments, the disclosure provides additional compounds (i.e., not of Formula (I), (II), (III), (IV), (V), (VI)), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure provides additional compounds (i.e., not of Formula (I), (II), (III), (IV), (V), (VI)), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure provides additional compounds (i.e., not of Formula (I), (II), (III), (IV), (V), (VI)), and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure provides additional compounds (i.e., not of Formula (I), (II), (III), (IV), (V), (VI)), and pharmaceutically acceptablesalts and tautomers thereof, and pharmaceutical compositions thereof. In certain embodiments, the disclosure provides additional compounds (i.e., not of Formula (I), (II), (III), (IV), (V), (VI)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

[0112] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), or otherwise as provided herein) bind ABL1 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. R1

[0113] As described herein, R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2.

[0114] In some embodiments, R1is hydrogen, substituted or unsubstituted alkyl, halogen, hydroxy, or -O-(substituted or unsubstituted alkyl). In some embodiments, R1is substituted or unsubstituted alkyl, halogen, hydroxy, or -O-(substituted or unsubstituted alkyl). In certain embodiments, R1is chloro, methyl, fluoro, bromo, trifluoromethyl, or trifluoromethoxy.

[0115] In certain embodiments, R1is hydrogen. In certain embodiments, R1is halogen. In some embodiments, R1is substituted or unsubstituted alkyl. In some embodiments, R1is haloalkyl. In some embodiments, R1is hydroxy. In some embodiments, R1is or -O-(unsubstituted alkyl). In some embodiments, R1is or -O-(haloalkyl).

[0116] In certain embodiments, R1is hydrogen or halogen. In some embodiments, R1is substituted or unsubstituted alkyl or hydrogen. In some embodiments, R1is substituted or unsubstituted alkyl or halogen.

[0117] In some embodiments,is bromophenyl, chlorophenyl, iodophenyl, fluorophenyl, methylphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, hydroxyphenyl, methoxyphenyl, dibromophenyl, dichlorophenyl, diiodophenyl, difluorophenyl, dimethylphenyl, (methyl)(chloro)phenyl, (methyl)(iodo)phenyl, (methyl)(bromo)phenyl, (methyl)(fluoro)phenyl,(chloro)(fluoro)phenyl, (bromo)(chloro)phenyl, (chloro)(iodo)phenyl, (bromo)(fluoro)phenyl, (iodo)(fluoro)phenyl, or (bromo)(iodo)phenyl.

[0118] In some embodiments,is 3,4-dichlorophenyl, 3-methyl-4-chlorophenyl, 3- chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 3-bromophenyl, 2-fluoro-5-chlorophenyl, 3,5- dichlorophenyl, 2,4-dichlorophenyl,3-fluoro-4-chlorophenyl, 3-chloro-5-fluorophenyl, 2,5- dichlorophenyl, 2-fluoro-3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4- trifluoromethoxyphenyl, or 2,3-dichlorophenyl.

[0119] In some embodiments,is 3,4-dichlorophenyl. Y1

[0120] In some embodiments of Formula (III) and (IV), Y1isIn some embodiments of Formula (III) and (IV), Y1isn

[0121] As provided herein, n is an integer selected from 0, 1, 2, 3, 4, and 5. In certain embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In certain embodiments, n is 3. In some embodiments, n is 4. In certain embodiments, n is 5. In some embodiments, n is 0, 1, or 2. R2

[0122] As described herein, R2is hydrogen or substituted or unsubstituted alkyl, or R2is hydrogen, halogen, substituted or unsubstituted alkyl, -ORA, or -SRA.

[0123] In some embodiments, R2is hydrogen.

[0124] In some embodiments, R2is halogen. In certain embodiments, R2is chloro, bromo, iodo, or fluoro. In some embodiments, R2is bromo.

[0125] In some embodiments, R2is substituted or unsubstituted alkyl. In certain embodiments, R2is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted orunsubstituted propyl, or substituted or unsubstituted butyl. In certain embodiments, R2is substituted or unsubstituted methyl. In some embodiments, R2is substituted or unsubstituted ethyl. In certain embodiments, R2is substituted or unsubstituted propyl (e.g., n-propyl, iso- propyl). In some embodiments, R2is substituted or unsubstituted butyl (n-butyl, tert-butyl, sec- butyl).

[0126] In certain embodiments, R2is hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, or substituted or unsubstituted butyl. In certain embodiments, R2is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted butyl. In certain embodiments, R2is hydrogen, substituted methyl, substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R2is hydrogen, methyl, 2-hydroxyethyl, sec-butyl, or isopropyl. In certain embodiments, R2is hydrogen or unsubstituted methyl.

[0127] In some embodiments, R2is -ORA. In some embodiments, R2is -OH. In some embodiments, R2is -O(substituted or unsubstituted C1-6alkyl). In some embodiments, R2is - O(C1-6alkyl).

[0128] In some embodiments, R2is -SRA. In some embodiments, R2is -SH. In some embodiments, R2is -S(substituted or unsubstituted C1-6alkyl). In some embodiments, R2is -S(C1-6alkyl).

[0129] In certain embodiments, the carbon to which R2is attached is in an (R) configuration. In certain embodiments, the carbon to which R2is attached is in an (S) configuration. R3

[0130] As described herein, R3is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group. In some embodiments, R3is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R3is hydrogen or substituted or unsubstituted methyl.

[0131] In certain embodiments, R3is hydrogen.

[0132] In some embodiments, R3is substituted or unsubstituted alkyl. In some embodiments, R3is substituted or unsubstituted methyl. In some embodiments, R3is substituted methyl. In some embodiments, R3is unsubstituted methyl.

[0133] In certain embodiments, R3is nitrogen protecting group. A

[0134] As described herein, A is -X1-X2-X3-X4-, wherein X1, X2, X3, and X4are as defined herein.

[0135] In some embodiments of Formulae (I), (II), (III), and (IV), A comprises substituted or unsubstituted, saturated or partially unsaturated heterocyclylene; substituted or unsubstituted, saturated or partially unsaturated carbocyclylene; substituted or unsubstituted 5-membered heteroarylene; or substituted or unsubstituted bicyclic heteroarylene. In some embodiments, A comprises substituted or unsubstituted, saturated or partially unsaturated heterocyclylene. In some embodiments, A comprises substituted or unsubstituted, saturated or partially unsaturated carbocyclylene. In some embodiments, A comprises substituted or unsubstituted 5-membered heteroarylene. In some embodiments, A comprises substituted or unsubstituted bicyclic heteroarylene.

[0136] In some embodiments of Formulae (I), (II), (III), and (IV), A comprises substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene. In some embodiments, A comprises substituted or unsubstituted heterocyclylene. In some embodiments, A comprises substituted or unsubstituted carbocyclylene. In some embodiments, A comprises substituted or unsubstituted 5-membered heteroarylene. In some embodiments, A comprises substituted or unsubstituted bicyclic heteroarylene.

[0137] In some embodiments of Formulae (III) and (IV), A comprises substituted or unsubstituted, saturated or partially unsaturated heterocyclylene; substituted or unsubstituted, saturated or partially unsaturated carbocyclylene; or substituted or unsubstituted heteroarylene. In some embodiments, A comprises substituted or unsubstituted, saturated or partially unsaturated heterocyclylene. In some embodiments, A comprises substituted or unsubstituted, saturated or partially unsaturated carbocyclylene. In some embodiments, A comprises substituted or unsubstituted heteroarylene.

[0138] In some embodiments of Formulae (III) and (IV), A comprises substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted heteroarylene. In some embodiments, A comprises substituted or unsubstituted heterocyclylene. In some embodiments, A comprises substituted or unsubstituted carbocyclylene. In some embodiments, A comprises substituted or unsubstituted heteroarylene.

[0139] In some embodiments of Formulae (I), (II), (III), and (IV), A comprises saturated or partially unsaturated, substituted or unsubstituted cyclopropylene; saturated or partially unsaturated, substituted or unsubstituted cyclobutylene; saturated or partially unsaturated, substituted or unsubstituted cyclopentylene; saturated or partially unsaturated, substituted or unsubstituted cyclohexylene; substituted or unsubstituted aziridinylene; saturated or partially unsaturated, substituted or unsubstituted azetidinylene; saturated or partially unsaturated, substituted or unsubstituted pyrrolidinylene; saturated or partially unsaturated, substituted orunsubstituted piperidinylene; saturated or partially unsaturated, substituted or unsubstituted piperazinylene; saturated or partially unsaturated, substituted or unsubstituted morpholinylene; saturated or partially unsaturated, substituted or unsubstituted thiomorpholinylene; saturated or partially unsaturated, substituted or unsubstituted diazepanylene; substituted or unsubstituted pyrazolylene; substituted or unsubstituted imidazolylene; saturated or partially unsaturated, substituted or unsubstituted dihydropyrrolopyrimidinylene; substituted or unsubstituted pyrazolopyrimidinylene, substituted or unsubstituted benzisoxazolylene; saturated or partially unsaturated, substituted or unsubstituted diazaspiro[3.3]heptanylene; saturated or partially unsaturated, substituted or unsubstituted diazaspiro[4.4]nonanylene; saturated or partially unsaturated, substituted or unsubstituted diazaspiro[4.5]decanylene; saturated or partially unsaturated, substituted or unsubstituted diazaspiro[5.5]undecanylene; saturated or partially unsaturated, substituted or unsubstituted oxa-diazaspiro[5.5]undecanylene; saturated or partially unsaturated, substituted or unsubstituted triazaspiro[5.5]undecanylene; saturated or partially unsaturated, substituted or unsubstituted tetrahydropyridopyrimidinylene; saturated or partially unsaturated, substituted or unsubstituted diazabicyclo[2.2.1]heptanylene; saturated or partially unsaturated, substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene; saturated or partially unsaturated, substituted or unsubstituted tetrahydropyrazolo[4,3-c]pyridinylene; or saturated or partially unsaturated, or substituted or unsubstituted tetrahydropyrazolo[1,5- a]pyrazinylene.

[0140] In some embodiments of Formulae (I), (II), (III), and (IV), A comprises substituted or unsubstituted cyclopropylene, substituted or unsubstituted cyclobutylene, substituted or unsubstituted cyclopentylene, substituted or unsubstituted cyclohexylene, substituted or unsubstituted aziridinylene, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted morpholinylene, substituted or unsubstituted thiomorpholinylene, substituted or unsubstituted diazepanylene, substituted or unsubstituted dihydropyrrolylene, substituted or unsubstituted tetrahydropyridinylene, substituted or unsubstituted pyrazolylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted dihydropyrrolopyrimidinylene, substituted or unsubstituted pyrazolopyrimidinylene, substituted or unsubstituted benzisoxazolylene, substituted or unsubstituted diazaspiro[3.3]heptanylene, substituted or unsubstituted diazaspiro[4.4]nonanylene; substituted or unsubstituted diazaspiro[4.5]decanylene; substituted or unsubstituted diazaspiro[5.5]undecanylene, substituted or unsubstituted oxa-diazaspiro[5.5]undecanylene, substituted or unsubstituted triazaspiro[5.5]undecanylene, substituted or unsubstituted tetrahydropyridopyrimidinylene, substituted or unsubstituted diazabicyclo[2.2.1]heptanylene,substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene, substituted or unsubstituted pyrazolo[4,3-c]pyridinylene, substituted or unsubstituted tetrahydropyrazolo[4,3-c]pyridinylene, or substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene.

[0141] In some embodiments of Formulae (I), (II), (III), and (IV), A comprises:,, ,

[0142] In some embodiments of Formulae (I), (II), (III), and (IV), A is, ,

[0143] In some embodiments of Formulae (I), (II), (III), and (IV), A comprises

[0144] In some embodiments of Formulae (I), (II), (III), and (IV), A is, ,

[0145] In some embodiments of Formulae (I), (II), (III), and (IV), A comprises

[0146] In some embodiments of Formulae (I), (II), (III), and (IV), A is,

[0147] In certain embodiments of Formulae (III) and (IV), A comprises,

[0148] In some embodiments of Formulae (V) and (VI), A comprises substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, or substituted or unsubstituted pyrazinylene. In some embodiments of Formulae (V) and (VI), A comprises,X1

[0149] As provided herein, X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene. In some embodiments, X1is a bond. In certain embodiments, X1is substituted or unsubstituted alkylene. In certain some, X1is substituted or unsubstituted alkenylene. In certain embodiments, X1is substituted or unsubstituted heteroalkylene. In some embodiments, X1is substituted or unsubstituted heteroalkenylene.

[0150] In some embodiments, X1is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene comprising -O- or -NRA-.

[0151] In certain embodiments, X1is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, or substituted or unsubstituted hetero-C1alkylene comprising -O- or -NRA-.

[0152] In certain embodiments, X1is a bond.

[0153] In some embodiments, X1is substituted or unsubstituted alkylene. In certain embodiments, X1is substituted or unsubstituted C1-4alkylene. In certain embodiments, X1is substituted or unsubstituted methylene. In certain embodiments, X1is unsubstituted methylene. In certain embodiments, X1is substituted or unsubstituted ethylene. In certain embodiments, X1is substituted or unsubstituted propylene. In certain embodiments, X1is substituted or unsubstituted butylene.

[0154] In certain embodiments, X1is substituted or unsubstituted heteroalkylene comprising - O- or -NRA-. In some embodiments, X1is substituted or unsubstituted hetero-C1alkylene comprising -O- or -NRA-. In some embodiments, X1is substituted or unsubstituted -methylene-O- , -O-methylene-, -NH-methylene-, -methylene-NH-, -N(Me)-methylene-, or -methylene-N(Me)-. X2

[0155] Provided herein, X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene. In some embodiments of Formula (I)-(IV), X2is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene. In some embodiments of Formula (III) and (IV), X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene. In some embodiments of Formula (III) and (IV), X2is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene. In some embodiments of Formula (III) and (IV), X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene. In certain embodiments of Formula (I)-(VI), X2is a substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, or substituted or unsubstituted pyrazinylene.

[0156] In some embodiment, X2is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene. In certain embodiments of Formula (I) and (II), X2is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene. In certain embodiments of Formula (I) and (II), X2is asubstituted or unsubstituted heterocyclylene. In certain embodiments of Formula (I) and (II), X2is a substituted or unsubstituted carbocyclylene. In certain embodiments of Formula (I) and (II), X2is a substituted or unsubstituted 5-membered heteroarylene. In certain embodiments of Formula (I) and (II), X2is a substituted or unsubstituted bicyclic heteroarylene.

[0157] In certain embodiments, X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene. In some embodiments of Formula (III) and (IV), X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene. In certain embodiments, X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted 5- membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene. In some embodiments of Formula (III) and (IV), X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene. In certain embodiments, X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene. In some embodiments of Formula (III) and (IV), X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene. In some embodiments of Formula (III) and (IV), X2is a bond. In some embodiments of Formula (III) and (IV), X2is a substituted or unsubstituted heterocyclylene. In some embodiments of Formula (III) and (IV), X2is a substituted or unsubstituted carbocyclylene. In some embodiments of Formula (III) and (IV), X2is a substituted or unsubstituted heteroarylene. In some embodiments of Formula (III) and (IV), X2is a substituted or unsubstituted 5-membered heteroarylene. In some embodiments of Formula (III) and (IV), X2is a substituted or unsubstituted bicyclic heteroarylene. In some embodiments of Formula (III) and (IV), X2is a substituted or unsubstituted arylene.

[0158] In some embodiments of Formula (I)-(IV), X2is saturated or partially unsaturated, substituted or unsubstituted cyclopropylene; saturated or partially unsaturated, substituted or unsubstituted cyclobutylene; saturated or partially unsaturated, substituted or unsubstituted cyclopentylene; saturated or partially unsaturated, substituted or unsubstituted cyclohexylene; substituted or unsubstituted aziridinylene; saturated or partially unsaturated, substituted or unsubstituted azetidinylene; saturated or partially unsaturated, substituted or unsubstituted pyrrolidinylene; saturated or partially unsaturated, substituted or unsubstituted piperidinylene;saturated or partially unsaturated, substituted or unsubstituted piperazinylene; saturated or partially unsaturated, substituted or unsubstituted morpholinylene; saturated or partially unsaturated, substituted or unsubstituted thiomorpholinylene; saturated or partially unsaturated, substituted or unsubstituted diazepanylene; substituted or unsubstituted pyrazolylene; substituted or unsubstituted imidazolylene; saturated or partially unsaturated, substituted or unsubstituted dihydropyrrolopyrimidinylene; substituted or unsubstituted pyrazolopyrimidinylene, substituted or unsubstituted benzisoxazolylene; saturated or partially unsaturated, substituted or unsubstituted diazaspiro[3.3]heptanylene; saturated or partially unsaturated, substituted or unsubstituted diazaspiro[4.4]nonanylene; saturated or partially unsaturated, substituted or unsubstituted diazaspiro[4.5]decanylene; saturated or partially unsaturated, substituted or unsubstituted diazaspiro[5.5]undecanylene; saturated or partially unsaturated, substituted or unsubstituted oxa- diazaspiro[5.5]undecanylene; saturated or partially unsaturated, substituted or unsubstituted triazaspiro[5.5]undecanylene; saturated or partially unsaturated, substituted or unsubstituted tetrahydropyridopyrimidinylene; saturated or partially unsaturated, substituted or unsubstituted diazabicyclo[2.2.1]heptanylene; saturated or partially unsaturated, substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene; saturated or partially unsaturated, substituted or unsubstituted tetrahydropyrazolo[4,3-c]pyridinylene; or saturated or partially unsaturated, or substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted cyclopropylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted cyclobutylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted cyclopentylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted cyclohexylene. In some embodiments, X2is substituted or unsubstituted aziridinylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted azetidinylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted pyrrolidinylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted piperidinylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted piperazinylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted morpholinylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted thiomorpholinylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted diazepanylene. In some embodiments, X2is substituted or unsubstituted pyrazolylene. In some embodiments, X2is substituted or unsubstituted imidazolylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted dihydropyrrolopyrimidinylene. In some embodiments, X2is substituted or unsubstitutedpyrazolopyrimidinylene, substituted or unsubstituted benzisoxazolylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted diazaspiro[3.3]heptanylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted diazaspiro[4.4]nonanylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted diazaspiro[4.5]decanylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted diazaspiro[5.5]undecanylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted oxa- diazaspiro[5.5]undecanylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted triazaspiro[5.5]undecanylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted tetrahydropyridopyrimidinylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted diazabicyclo[2.2.1]heptanylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene. In some embodiments, X2is saturated or partially unsaturated, substituted or unsubstituted tetrahydropyrazolo[4,3- c]pyridinylene. In some embodiments, X2is saturated or partially unsaturated, or substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene.

[0159] In some embodiments of Formula (I)-(IV), X2is substituted or unsubstituted cyclopropylene, substituted or unsubstituted cyclobutylene, substituted or unsubstituted cyclopentylene, substituted or unsubstituted cyclohexylene, substituted or unsubstituted aziridinylene, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted morpholinylene, substituted or unsubstituted thiomorpholinylene, substituted or unsubstituted diazepanylene, substituted or unsubstituted dihydropyrrolylene, substituted or unsubstituted tetrahydropyridinylene, substituted or unsubstituted pyrazolylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted dihydropyrrolopyrimidinylene, substituted or unsubstituted pyrazolopyrimidinylene, substituted or unsubstituted benzisoxazolylene, substituted or unsubstituted diazaspiro[3.3]heptanylene, substituted or unsubstituted diazaspiro[4.4]nonanylene, substituted or unsubstituted diazaspiro[4.5]decanylene, substituted or unsubstituted diazaspiro[5.5]undecanylene, substituted or unsubstituted oxa-diazaspiro[5.5]undecanylene, substituted or unsubstituted triazaspiro[5.5]undecanylene, substituted or unsubstituted tetrahydropyridopyrimidinylene, substituted or unsubstituted diazabicyclo[2.2.1]heptanylene, substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene, substituted or unsubstituted pyrazolo[4,3-c]pyridinylene, substituted or unsubstituted tetrahydropyrazolo[4,3-c]pyridinylene, or substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene. In some embodiments, X2is substituted or unsubstituted aziridinylene. In some embodiments, X2is substituted or unsubstituted cyclopropylene. In some embodiments, X2is substituted or unsubstituted cyclobutylene. In some embodiments, X2is substituted or unsubstituted cyclopentylene. In some embodiments, X2is substituted or unsubstituted cyclohexylene. In some embodiments, X2is substituted or unsubstituted azetidinylene. In some embodiments, X2is substituted or unsubstituted pyrrolidinylene. In some embodiments, X2is substituted or unsubstituted piperidinylene. In some embodiments, X2is substituted or unsubstituted piperazinylene. In some embodiments, X2is substituted or unsubstituted morpholinylene. In some embodiments, X2is substituted or unsubstituted thiomorpholinylene. In some embodiments, X2is substituted or unsubstituted diazepanylene. In some embodiments, X2is substituted or unsubstituted dihydropyrrolylene. In some embodiments, X2is substituted or unsubstituted tetrahydropyridinylene. In some embodiments, X2is substituted or unsubstituted pyrazolylene. In some embodiments, X2is substituted or unsubstituted imidazolylene. In some embodiments, X2is substituted or unsubstituted dihydropyrrolopyrimidinylene. In some embodiments, X2is substituted or unsubstituted pyrazolopyrimidinylene. In some embodiments, X2is substituted or unsubstituted benzisoxazolylene. In some embodiments, X2is substituted or unsubstituted diazaspiro[3.3]heptanylene. In some embodiments, X2is substituted or unsubstituted diazaspiro[4.4]nonanylene. In some embodiments, X2is substituted or unsubstituted diazaspiro[4.5]decanylene. In some embodiments, X2is substituted or unsubstituted diazaspiro[5.5]undecanylene. In some embodiments, X2is substituted or unsubstituted oxa- diazaspiro[5.5]undecanylene. In some embodiments, X2is substituted or unsubstituted triazaspiro[5.5]undecanylene. In some embodiments, X2is substituted or unsubstituted tetrahydropyridopyrimidinylene. In some embodiments, X2is substituted or unsubstituted diazabicyclo[2.2.1]heptanylene. In some embodiments, X2is substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene. In some embodiments, X2is substituted or unsubstituted pyrazolo[4,3-c]pyridinylene. In some embodiments, X2is substituted or unsubstituted tetrahydropyrazolo[4,3-c]pyridinylene. In some embodiments, X2is substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene.

[0160] In some embodiments of Formula (I)-(IV), X2is

[0161] In some embodiments of Formula (I)-(IV), X2is, , ,

[0162] In some embodiments of Formula (I)-(IV), X2is

[0163] In some embodiments, X2is a substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, or substituted orunsubstituted pyrazinylene. In some embodiments of Formula (V) and (VI), X2is a substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, or substituted or unsubstituted pyrazinylene. In some embodiments of Formula (V) and (VI), X2is a substituted or unsubstituted pyridinylene. In some embodiments of Formula (V) and (VI), X2is a substituted or unsubstituted pyridazinylene. In some embodiments of Formula (V) and (VI), X2is a substituted or unsubstituted pyrimidinylene. In some embodiments of Formula (V) and (VI), X2is a substituted or unsubstituted pyrazinylene.

[0164] In some embodiments of Formula (V) and (VI), X2is

[0165] In some embodiments of Formula (V) and (VI), X2is

[0166] In some embodiments of Formula (V) and (VI), X2isIn some

[0167] In some embodiments of Formula (V) and (VI), X2is, ,X3

[0168] As provided herein, X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene. In some embodiments, X3is a bond. In certain embodiments, X3is substituted or unsubstituted alkylene. In certain some, X3is substituted or unsubstituted alkenylene. In certain embodiments, X3is substituted or unsubstituted heteroalkylene. In some embodiments, X3is substituted or unsubstituted heteroalkenylene.

[0169] In some embodiments, X3is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene comprising -O- or -NRA-.

[0170] In certain embodiments, X3is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, or substituted or unsubstituted hetero-C1alkylene comprising -O- or -NRA-.

[0171] In certain embodiments, X3is a bond.

[0172] In some embodiments, X3is substituted or unsubstituted alkylene. In certain embodiments, X3is substituted or unsubstituted C1-4alkylene. In certain embodiments, X3issubstituted or unsubstituted methylene. In certain embodiments, X3is unsubstituted methylene. In certain embodiments, X3is substituted or unsubstituted ethylene. In certain embodiments, X3is substituted or unsubstituted propylene. In certain embodiments, X3is substituted or unsubstituted butylene.

[0173] In certain embodiments, X3is substituted or unsubstituted heteroalkylene comprising -O- or -NRA-. In some embodiments, X3is substituted or unsubstituted hetero-C1alkylene comprising -O- or -NRA-. In some embodiments, X3is substituted or unsubstituted -methylene-O- , -O-methylene-, -NH-methylene-, -methylene-NH-, -N(Me)-methylene-, or -methylene-N(Me)-. X4

[0174] As described herein in Formulae (I), (II), (V), and (VI), X4is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene. In some embodiments, X4is a bond. In some embodiments, X4is substituted or unsubstituted heterocyclylene. In some embodiments, X4is substituted or unsubstituted carbocyclylene. In some embodiments, X4is substituted or unsubstituted heteroarylene. In some embodiments, X4is substituted or unsubstituted arylene. In some embodiments, X4is a bond, substituted or unsubstituted phenylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted morpholinylene, or substituted or unsubstituted benzisoxazolylene. In some embodiments, X4is substituted or unsubstituted phenylene. In some embodiments, X4is substituted or unsubstituted piperidinylene. In some embodiments, X4is substituted or unsubstituted morpholinylene. In some embodiments, X4is substituted or unsubstituted benzisoxazolylene. L

[0175] 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 contiguousatoms. 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.

[0176] 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.

[0177] In certain embodiments, L is substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -N(RA)-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)NRA-, -NRAC(=O)-, -C(=O)-, -NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2N(RA)-, or -NRAS(O)2-, or a combination thereof.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] In certain embodiments, L is substituted or unsubstituted alkylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene, -N(AR )-, -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 unsubstitutedtriazolylene, -N(RA)-, -O-,A-N(R )C(=O)-, and -C(=O)-.

[0182] In certain embodiments, L is 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)-, 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)-.

[0183] In some embodiments, L is of formula:wherein: Z1is a bond, -O-, -N(RA)-, 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; Z3is 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.

[0184] In some embodiments, Z1is a bond, -O-, -N(RA)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In some embodiments, Z1is a bond. In some embodiments, Z1is -O-. In some embodiments, Z1is -N(RA)-. In some embodiments, Z1is -N(H)-. In some embodiments, Z1is -N(CH3)-. In some embodiments, Z1is substituted or unsubstituted alkylene. In some embodiments, Z1is substituted or unsubstituted methylene. In some embodiments, Z1is substituted or unsubstituted ethylene. In some embodiments, Z1is substituted or unsubstituted heteroalkylene. In some embodiments, Z1is substituted or unsubstituted hetero-C1-alkylene comprising -O- or -N(RA)-. In some embodiments, Z1issubstituted or unsubstituted hetero-C2-alkylene comprising -O- or -N(RA)-. In some embodiments, Z1is substituted or unsubstituted hetero-C3-alkylene comprising -O- or -N(RA)-. In some embodiments, Z1is a repeating substituted or unsubstituted hetero-C3-alkylene comprising -O- or -N(RA)-.

[0185] In some embodiments, Z2is a bond, -N(RA)-, -NRAC(=O)-, -C(=O)-, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted alkylene. In some embodiments, Z2is a bond. In some embodiments, Z2is -O-. In some embodiments, Z2is -N(RA)-. In some embodiments, Z2is -N(H)-. In some embodiments, Z2is -N(CH3)-. In some embodiments Z2is -C(=O)-. In some embodiments, Z2is -NRAC(=O)-. In some embodiments, Z2is -N(H)C(=O)-. In some embodiments, Z2is -N(CH3)C(=O)-. In some embodiments, Z2is substituted or unsubstituted alkylene. In some embodiments, Z2is substituted or unsubstituted methylene. In some embodiments, Z2is substituted or unsubstituted ethylene. In some embodiments, Z2is substituted or unsubstituted heterocyclylene. In some embodiments, Z2is substituted or unsubstituted 6-membered heterocyclylene. In some embodiments, Z2is substituted or unsubstituted piperidinylene or substituted or unsubstituted piperazinylene.

[0186] In some embodiments, Q is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene.

[0187] In some embodiments, Q is a bond. In some embodiments, Q is substituted or unsubstituted heteroalkylene. In some embodiments, Q is substituted or unsubstituted heteroalkylene. In some embodiments, Q is substituted or unsubstituted hetero-C1-alkylene comprising -O- or -N(RA)-. In some embodiments, Q is substituted or unsubstituted hetero-C2- alkylene comprising -O- or -N(RA)-. In some embodiments, Q is substituted or unsubstituted hetero-C3-alkylene comprising -O- or -N(RA)-. In some embodiments, Q is a repeating substituted or unsubstituted hetero-C3-alkylene comprising -O- or -N(RA)-. In some embodiments, Q is substituted or unsubstituted heterocyclylene. In some embodiments, Q is substituted or unsubstituted 6-membered heterocyclylene. In some embodiments, Q is substituted or unsubstituted piperidinylene or substituted or unsubstituted piperazinylene. In some embodiments, Q is substituted or unsubstituted heteroarylene. In some embodiments, Q is substituted or unsubstituted is substituted or unsubstituted 5-membered heteroarylene. In some embodiments, Q is triazolylene.

[0188] In some embodiments, Z3is a bond, -C(=O)-, -O-, or -N(RA)-. In some embodiments, Z3is a bond. In some embodiments, Z3is -C(=O)-. In some embodiments, Z3is -O-. In some embodiments, Z3is -N(RA)-. In some embodiments, Z3is -N(H)-. In some embodiments, Z3is - N(CH3)-.

[0189] In certain embodiments, L is of formula:, wherein: Z1is a bond, -O-, -N(RA)-, substituted or unsubstituted alkylene, 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.

[0190] 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.

[0191] In some embodiments, L is of formula:, wherein: Z1is a bond, -O-, -N(RA)-, unsubstituted C1-6alkylene,Z2is a bond, -N(RA)-, -NRAC(=O)-, -C(=O)-, -CH2-,Q is a bond,Z3is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[0192] In certain embodiments, L is of formula:wherein: Z1is a bond, -N(RA)-, unsubstituted C1-6alkylene,, ,Z2is a bond, -NRAC(=O)-, -C(=O)-, -CH2-,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.

[0193] In certain embodiments, L is of formula:, wherein: Z1is a bond, -N(RA)-, unsubstituted C1-6alkylene,, ; 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.

[0194] In some embodiments, L is of formula:wherein: Z1is a bond, -O-, or -C(=O)-; Z2is a bond; Qis a bond,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.

[0195] In some embodiments,, wherein: Z1is a bond, -O-, or -C(=O)-; Z2is a bond; QisZ3is a bond, -C(=O)-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[0196] In some embodiments, L is of formula: L is of formula:, wherein: Z1is a bond, -O-, or -C(=O)-; Z2is a bond; Q isZ3is a bond, -C(=O)-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.

[00197] In some embodiments, L is of formula:, ,, , In some embodiments, L is of formula:. In some embodiments, L is of formula:

[0198] In some embodiments, L is of formula:.

[0199] In certain embodiments, L is of formula:

[0200] In certain embodiments, L is of formula:

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

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

[0203] In certain embodiments, L is of formula:

[0204] In certain embodiments, L is of formula:

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

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

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

[0208] In certain embodiments, L is of formula:

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

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

[0211] In some embodiments, L is of formula:

[0212] In some embodiments, L is of formula:

[0213] In some embodiments, L is of formula:

[0214] In some embodiments, L is of formula:

[0215] In some embodiments, L is of formula:

[0216] In some embodiments, L is of formula:

[0217] In some embodiments, L is of formula:

[0218] In some embodiments, L is of formula:

[0219] In certain embodiments, L is of formula:, ,

[0220] In some embodiments, L is of formula:In some embodiments, L is of

[0221] In some embodiments, L is of formula:

[0222] In certain embodiments, L is of formula:

[0223] In certain embodiments, t is 0-30. In certain embodiments, t is 0-20. In certain embodiments, t is 0-6. 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 0-30. In certain embodiments, u is 0-20. In certain embodiments, u is 0- 6. 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.

[0224] In some embodiments, L is of formula:

[0225] In certain embodiments, L is of formula:

[0226] In some embodiments, L is of formula:In some embodiments, L is of

[0227] In certain embodiments, L is of formula:

[0228] In certain embodiments, L is:.

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

[0230] In certain embodiments, L isIn certain embodiments, L is,

[0231] In some embodiments, L is of formula:, ,

[0232] In some embodiments, L is. In some embodiments, L is.

[0233] In some embodiments, L is selected from any one of L1-L77:

[0234] In some embodiments, L is selected from any one of L78-L251:

[0235] In some embodiments, L is selected from any one of L1-L251. In certain embodiments, L is selected from L11, L16, L17, L20, L28, L13, L34, L35, L49-L51, L82-L84, L86-L89, L193- 195, L205, L206, and L208. In certain embodiments, L is selected from L11, L16, L17, L20, L28, L13, L34, L35, and L49-L51. In some embodiments, L is selected from L82-L84, L86-L88, L193-195, L205, L206, and L208. RA

[0236] As described herein, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a sulfur protecting group when attached to a sulfur atom, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or two RAgroups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

[0237] 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.

[0238] 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 unsubstitutedaryl, substituted or unsubstituted heteroaryl, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

[0239] 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 a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or two RAgroups are joined to form a substituted or unsubstituted heterocyclic ring.

[0240] 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.

[0241] 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.

[0242] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C1-30heteroalkyl, 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.

[0243] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C1-30heteroalkyl.

[0244] In certain embodiments, each occurrence of RAis, independently, hydrogen, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C1-20heteroalkyl.

[0245] 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. In certain embodiments, RAis substituted or unsubstituted hydroxyl.

[0246] In certain embodiments, each occurrence of RAis independently hydrogen, unsubstituted alkyl, or haloalkyl. In certain embodiments, each occurrence of RAis independently hydrogen, unsubstituted C1-6alkyl, or C1-6haloalkyl. In certain embodiments, each occurrence of RAis independently hydrogen, unsubstituted C1-4alkyl, or C1-4haloalkyl. In certain embodiments, each occurrence of RAis independently hydrogen, unsubstituted C1-2alkyl, or C1-2haloalkyl. In certain embodiments, each occurrence of RAis independently hydrogen, -CH3, -CF3, -CHF2, or - CH2F. B

[0247] 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 certain embodiments, 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.

[0248] 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.

[0249] The compounds disclosed herein may bind to a kinase, such as ABL1, 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 ABL1, 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.

[0250] In certain embodiments, the compounds disclosed herein include a moiety that binds to a kinase, such as ABL1, 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 ABL1, and a targeting moiety that binds to a phosphatase.

[0251] 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.

[0252] In certain embodiments, B is a moiety that recruits, binds, modulates, modifies, inhibits, activates, and / or associates with a bromodomain-containing protein (e.g., BRD2, BRD3, BRD4, BRDT); histone acetyltransferase (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 receptor alpha); 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-b2 erythroblastic 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; anALB 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); Receptor tyrosine 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-CoAcarboxylase; 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, P and / 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); Tumor necrosis 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.

[0253] In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with KRAS, 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 BRD4 or BTK. In certain embodiments, B is a ligand, recruiter, binder, modulator, modifier, inhibitor, activator, and / or associator of KRAS, 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, BRD4, CAII, TRIM24, or BTK. In certain embodiments, B is an inhibitor ofBRD4 or BTK. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and / or associates with KRAS. 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 CAIL 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. 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 ofTRIM24. 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.

[0254] In certain embodiments, B is a KRAS-binding moiety, a kinase-binding moiety or a phosphatase-binding moiety.

[0255] In certain embodiments, B is of formula:or a pharmaceutically acceptable salt thereof.

[0256] In certain embodiments, B is of formula:or a pharmaceutically acceptable salt thereof.

[0257] In certain embodiments, B is of formula:or a pharmaceutically acceptable salt thereof.

[0258] In certain embodiments, B is of formula:or a pharmaceutically acceptable salt thereof.

[0259] In certain embodiments, B is of formula:or a pharmaceutically acceptable salt thereof.

[0260] In certain embodiments, B is of formula:or a pharmaceutically acceptable salt thereof.

[0261] In certain embodiments, B is of formula:or a pharmaceutically acceptable salt thereof.

[0262] In certain embodiments, B is of formula:or a pharmaceutically acceptable salt thereof.

[0263] In certain embodiments, B is of formula:or a pharmaceutically acceptable salt thereof.

[0264] 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.

[0265] In certain embodiments, B is a dye. In certain embodiments, B is a fluorescent dye. In certain embodiments, B is of formula:, , ,or a pharmaceutically acceptable salt thereof.

[0266] In certain embodiments, B is of formula:, or a pharmaceutically acceptable salt thereof.

[0267] 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.

[0268] 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 toabout 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.

[0269] In certain embodiments, B is not of the formula:In certain embodiments of Formula (V), B is not of the formula:In certain embodiments, B is not of the formula, or stereoisomer thereof:,In certain embodiments of Formula (V), B is not of the formula, or stereoisomer thereof:. T

[0270] As described herein, 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.

[0271] 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.

[0272] 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.

[0273] 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 –C≡CH, 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 unsubstitutedIn certain embodiments, the click chemistry handle is an azide, tetrazine, tetrazole, dithioester, anthracene, amine, or thiol.

[0274] 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 certain embodiments, 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 nitrogenprotecting 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.

[0275] In some embodiments, the compound is not of the formula:In certain embodiments of Formula (VI), the compound is not of the formula:Further Embodiments of Formula (I)

[0276] In certain embodiments, the compound is a compound of Formula (I), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (I), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (I), wherein L is selected from L54-L59 and L144-L149.

[0277] In certain embodiments, the compound of Formula (I) is a compound of Formula (I- A):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (I-A), wherein L is any one of LI -LI 49, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (I-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (I-A), wherein L is selected from L54-L59 and L144-L149.

[0278] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-B):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (I-B), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (I-B), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (I-B), wherein L is selected from L54-L59 and L144-L149.

[0279] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-B- 1):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (I-B-1), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B-1), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (I-B-1), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (I-B-1), wherein L is selected from L54-L59 and L144- L149.

[0280] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-B- 2):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (I-B-2), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B-2), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (I-B-2), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (I-B-2), wherein L is selected from L54-L59 and L144- L149.

[0281] In certain embodiments, the compound of Formula (I) is a compound of formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. Further Embodiments of Formula (II)

[0282] In certain embodiments, the compound is a compound of Formula (II), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (II), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (II), wherein L is selected from L54-L59 and L144-L149.

[0283] In certain embodiments, the compound of Formula (II) is a compound of Formula (II- A):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (II-A), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, andL144-L149. In certain embodiments, the compound is a compound of Formula (II-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (II-A), wherein L is selected from L54-L59 and L144- L149.

[0284] In certain embodiments, the compound of Formula (II) is a compound of Formula (II- B):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (II-B), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (II-B), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (II-B), wherein L is selected from L54-L59 and L144- L149.

[0285] In certain embodiments, the compound of Formula (II) is a compound of Formula (II- B-1):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (II-B-1), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B-1), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (II-B-1), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (II-B-1), wherein L is selected from L54-L59 and L144- L149.

[0286] In certain embodiments, the compound of Formula (II) is a compound of Formula (II- B-2):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (II-B-2), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B-2), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (II-B-2), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (II-B-2), wherein L is selected from L54-L59 and L144- L149.

[0287] In some embodiments, the compound of Formula (II) is:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.Further Embodiments of Formula (III)

[0288] In certain embodiments, the compound is a compound of Formula (III), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (III), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (III), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (III), wherein L is selected from L54-L59 and L144-L149.

[0289] In certain embodiments, the compound of Formula (III) is a compound of Formula (III-A):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (III-A), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (III-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (III-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (III-A), wherein L is selected from L54-L59 and L144- L149.

[0290] In certain embodiments, the compound of Formula (III) is a compound of formula:or a pharmaceutically acceptable salt thereof.Further Embodiments of Formula (IV)

[0291] In certain embodiments, the compound is a compound of Formula (IV), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (IV), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (IV), wherein L is selected from L9, L17, LI 8, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (IV), wherein L is selected from L54-L59 and L144-L149.

[0292] In certain embodiments, the compound of Formula (IV) is a compound of Formula(IV-A):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (IV-A), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (IV-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, andL144-L149. In certain embodiments, the compound is a compound of Formula (IV-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (IV-A), wherein L is selected from L54-L59 and L144- L149.

[0293] In certain embodiments, the compound of Formula (IV) is:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. Further Embodiments of Formula (V)

[0294] In certain embodiments, the compound is a compound of Formula (V), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (V), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (V), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (V), wherein L is selected from L54-L59 and L144-L149.

[0295] In certain embodiments, the compound of Formula (V) is a compound of Formula (V- A):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (V-A), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (V-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (V-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (V-A), wherein L is selected from L54-L59 and L144- L149.

[0296] In certain embodiments, the compound of Formula (V) is a compound of Formula (V- B):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (V-B), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (V-B), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (V-B), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (V-B), wherein L is selected from L54-L59 and L144- L149.

[0297] In certain embodiments, the compound of Formula (V) is a compound of Formula (V- B-1):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (V-B-1), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (V-B-1), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (V-B-1), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (V-B-1), wherein L is selected from L54-L59 and L144- L149.

[0298] In certain embodiments, the compound of Formula (V) is a compound of Formula (V- B-2):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (V-B-2), wherein L is any one of L1-L149, or apharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (V-B-2), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (V-B-2), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (V-B-2), wherein L is selected from L54-L59 and L144- L149.

[0299] In certain embodiments, the compound of Formula (V) is a compound of formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. Further Embodiments of Formula (VI)

[0300] In certain embodiments, the compound is a compound of Formula (VI), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (VI), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (VI), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (VI), wherein L is selected from L54-L59 and L144-L149.

[0301] In certain embodiments, the compound of Formula (VI) is a compound of Formula (VI-A):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (VI-A), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compoundof Formula (VI-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (VI-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (VI-A), wherein L is selected from L54-L59 and L144- L149.

[0302] In certain embodiments, the compound of Formula (VI) is a compound of Formula (VI-B):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (VI-B), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (VI-B), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (VI-B), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (VI-B), wherein L is selected from L54-L59 and L144- L149.

[0303] In certain embodiments, the compound of Formula (VI) is a compound of Formula (VI-B-1):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (VI-B-1), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (VI-B-1), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (VI-B-1), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certainembodiments, the compound is a compound of Formula (VI-B-1), wherein L is selected from L54-L59 and L144-L149.

[0304] In certain embodiments, the compound of Formula (VI) is a compound of Formula(VI-B-2):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (VI-B-2), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (VI-B-2), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149. In certain embodiments, the compound is a compound of Formula (VI-B-2), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53. In certain embodiments, the compound is a compound of Formula (VI-B-2), wherein L is selected from L54-L59 and L144-L149.

[0305] In some embodiments, the compound of Formula (VI) is:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.Additional Compounds

[0306] Also provided herein is a compound of formula:or a pharmaceutically acceptable salt or stereoisomer thereof, wherein B is a targeting moiety or a detectable moiety. In certain embodiments, B is any targeting moiety or detectable moiety as defined herein.

[0307] Also provided herein is a compound of formula:or a pharmaceutically acceptable salt thereof, wherein B is a targeting moiety or a detectable moiety. In certain embodiments, B is any targeting moiety or detectable moiety as defined herein.

[0308] Also provided herein is a compound of formula:or a pharmaceutically acceptable salt or stereoisomer thereof, wherein T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle.

[0309] Also provided herein is a compound of formula:or a pharmaceutically acceptable salt thereof, wherein T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle.

[0310] Also provided herein is a compound of formula:or a pharmaceutically acceptable salt thereof.

[0311] Also provided herein is a compound of formula:or a pharmaceutically acceptable salt thereof.

[0312] Also provided herein is a compound of formula:or a pharmaceutically acceptable salt thereof.

[0313] Also provided herein is a compound of formula:or a pharmaceutically acceptable salt thereof.

[0314] Also provided herein is a compound of formula:or a pharmaceutically acceptable salt thereof.Pharmaceutical Compositions

[0315] The present disclosure provides pharmaceutical compositions comprising a compound of the disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), or as provided herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of the disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), or as provided herein), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.Methods of Use

[0316] The present disclosure provides methods for phosphorylating a target substrate (e.g., protein) with a compound of the disclosure (e.g., Formula (I), (II), (III), (IV), (V), (VI), or as provided herein), in a mixture that comprises ABL1 and the target substrate. One of ordinary skill would understand that such a mixture may include ATP. In certain embodiments, 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 ABL1 and the target substrate but without the compound. In certain embodiments, the amount of phosphorylation is measured at a specified time (e.g., 1, 2, 3, 4, 8, 12, 16, or 24 hours after administration). In certain embodiments, the phosphorylating is in a cell. In certain embodiments, the phosphorylating is in a biological sample.

[0317] The present disclosure also provides methods for promoting the phosphorylation of a target substrate with a compound of the disclosure (e.g., Formula (I), (II), (III), (IV), (V), (VI), or as provided herein). In certain embodiments, the phosphorylation is achieved by ABL1. One of ordinary skill would understand that phosphorylation may include the use of ATP. The present disclosure also provides methods for modulating a protein kinase with a compound of the disclosure (e.g., Formula (I), (II), (III), (IV), (V), (VI), or as provided herein). In certain embodiments, the protein kinase is ABL1. In certain embodiments, the phosphorylation ormodulation is in a cell. In certain embodiments, the phosphorylation or modulation is in a biological sample.

[0318] The present disclosure also provides methods for detecting a protein kinase with a compound of the disclosure (e.g., Formula (I), (II), (III), (IV), (V), (VI), or as provided herein). In certain embodiments, the protein kinase is ABL1.

[0319] In certain embodiments, the target substrate is a protein. In certain embodiments, the target substrate is a kinase or phosphatase. In certain embodiments, the target substrate is a bromodomain-containing protein (e.g., BRD2, BRD3, BRD4, BRDT); histone acetyltransferase (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 receptor alpha); 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-b2 erythroblastic 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 / orCEACAM-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; LILRB1; 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); Receptor tyrosine 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- HRa); 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);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, P and / 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); Tumor necrosis 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.

[0320] In certain embodiments, the target substrate is a kinase. In certain embodiments, the target substrate is a phosphatase. In certain embodiments, the target substrate is KRAS or KRAS mutant, BRD4, CAII, TRIM24, or BTK. In certain embodiments, the target substrate is KRAS or KRAS mutant, BRD4, CAII, TRIM24, BET, BRD2, BRD3, BRDT, or BTK. In certain embodiments, the target substrate is BRD4 or BTK. In certain embodiments, the target substrate is KRAS or KRAS mutant. In certain embodiments, the target substrate is BRD4. In certain embodiments, the target substrate is BTK. In certain embodiments, the target substrate is CAII. In certain embodiments, the target substrate is TRIM24. In certain embodiments, the target substrate is BET. In certain embodiments, the target substrate is BRD2. In certain embodiments, the target substrate is BRD3. In certain embodiments, the target substrate is BRDT.

[0321] The present disclosure also provides methods for inhibiting phosphorylation of a target substrate with a compound of the disclosure (e.g., Formula ((I), (II), (III), (IV), (V), (VI), or as provided herein), the methods comprising contacting ABL1 with the compound. In certain embodiments, the compound is a compound of Formula (II). In certain embodiments, the methods further comprise the compound binding an allosteric site of ABL1. In certain embodiments, the allosteric site is the PIF-binding pocket. In certain embodiments, the target substrate is a protein. In certain embodiments, the protein is a natural substrate of the PIF-binding pocket. In certain embodiments, the protein is S6K. In certain embodiments, the target substrate is any of the foregoing target substrates described herein. In certain embodiments, the method is achieved in a mixture comprising ATP. EXAMPLES

[0322] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[0323] Compounds are prepared in order to interrogate their ability of the ABL1 -binding portion of the compound to bind and / or activate ABL1.

[0324] Abbreviations used:

[0325] ACN acetonitrile

[0326] CDI 1,1′-Carbonyldiimidazole

[0327] DCC N,N′-Dicyclohexylcarbodiimide

[0328] DCM dichloromethane

[0329] DIEA N,N-Diisopropylethylamine

[0330] DMA N,N-Dimethylacetamide

[0331] DMAP N,N-dimethylpyridin-4-amine

[0332] DMF dimethylformamide

[0333] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0334] FA formic acid

[0335] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate

[0336] HOBt Hydroxybenzotriazole

[0337] NBS N-bromosuccinimide

[0338] PyBOP benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate

[0339] T3P Propanephosphonic acid anhydride

[0340] TBAI tetrabutylammonium iodide

[0341] TBS tert-butyldimethylsilyl

[0342] TBSCl tert-butyldimethylsilyl chloride

[0343] TEA triethylamine

[0344] THF tetrahydrofurane

[0345] TFA trifluoroacetic acid

[0346] TMSOK potassium trimethylsilanolate Preparation of Exemplary Compounds

[0347] Compounds of the disclosure are prepared following means known in the art of organic synthesis. For example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof are representative and instructive. Methods for optimizing reaction conditions, and if necessary, minimizing competing by-products, are known in the art. Synthetic Procedures 3-(3-((1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)amino)-3-oxopropoxy)propanoic acid (A-325)

[0348] Synthesis of 1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-amine: sodium methanolate (122g, 2.26 mol) was added to a solution of (3,4-dichlorophenyl)hydrazine (80g, 452 mmol) in methanol (708ml). The reaction mixture was heated at 70°C for 12 h. After cooling down to room temperature, the precipitate was filtered, washed twice with water (2 x 500ml) and dried under vacuum to give 1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-amine 975g, 326 mmol) as a yellow solid. LCMS: 321.2 (M+H)+, 95 %.1H NMR (400 MHz, DMSO-d6) δ = 7.27 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.66 (dd, J = 2.0, 8.8 Hz, 1H), 5.92 (br s, 2H), 3.52 (t, J = 9.4 Hz, 2H), 2.80 (t, J = 9.2 Hz, 2H).

[0349] Using a similar procedure, starting from the appropriate phenylhydrazines, the following derivatives were prepared:

[0350] Synthesis of 3-(3-((1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)amino)-3- oxopropoxy)propanoic acid (A-325): To a solution of 1-(3,4-dichlorophenyl)-4,5-dihydro-1H- pyrazol-3-amine (1.70 g, 7.40 mmol) and 3-(2-carboxyethoxy)propanoic acid (6.00 g, 37.0 mmol) in dimethylacetamide (25.0 mL) was added HATU (1.74 g, 7.40 mmol) and DIEA (2.87 g, 22.2 mmol). The mixture was stirred at 25 °C for 1 h. LCMS showed desired mass was detected. The residue was purified by reversed phase column (C 18, mobile phase: [water(0.1% FA)-ACN]; B%: 35%-40%, 25 min) to give 3-(3-((1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3- yl)amino)-3-oxopropoxy)propanoic acid (A-325) (220 mg, 512 µmol, 7% yield) as a yellow solid. LCMS: 373.7 (M+H)+, Rt 1.40 min, 87.01 %. Column: Kinetex® EVO C182.1x30mm 5µm Mobile Phase A: 0.0375% TFA in water (v / v) B: 0.01875% TFA in Acetonitrile (v / v) Gradient B (%):0 / 5,0.6 / 95,0.78 / 95,0.79 / 5.0.80 / 5 Flow rate: 2ml / min.1H NMR (400 MHz, DMSO-d6) δ = 10.73 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 2.4, 8.8 Hz, 1H), 3.70 (t, J = 9.6 Hz, 2H), 3.64-3.55 (m, 4H), 3.36 (s, 2H), 2.57-2.51 (m, 2H), 2.42 (t, J = 6.4 Hz, 2H).

[0351] Using the same conditions, the following acids were prepared:N-(1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)-5-oxo-5-(piperidin-1- yl)pentanamide (A-336)

[0352] Synthesis of methyl 5-((1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3- yl)amino)-5-oxopentanoate: A mixture of HATU (12.4 g, 32.6 mmol) and 5-methoxy-5- oxopentanoic acid (3.18 g, 1.0 eq, 21.7 mmol) in dimethylacetamide (50 mL) was stirred at 0 °C for 0.5 h. Then 1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-amine (5 g, 21.7 mmol) and DIEA(8.4 g, 65.2 mmol) was added and the mixture was stirred at 25 °C for 12 h. LCMS showed desired m / z. The reaction was diluted with H2O (200 mL) and filtered, the filtrate was extracted with ethyl acetate (100 mL×3), washed with brine (50 mL× 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash silica gel chomatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~80% Ethyl acetate / Petroleum ether gradient @ 80mL / min) to give a yellow solid. The product was triturated with acetonitrile (10 mL) to give methyl 5-((1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)amino)-5-oxopentanoate (1.71 g, 4.77 mmol, 32% yield) as a white solid. LCMS: [M+H]+: calculated, 358.1; observed, 358.2.1H NMR (400 MHz, DMSO-d6) δ = 10.70 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 2.4, 8.8 Hz, 1H), 3.78-3.64 (m, 2H), 3.59 (s, 3H), 2.69 (s, 4H), 2.33 (t, J = 7.6 Hz, 4H).

[0353] Synthesis of 5-((1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)amino)-5- oxopentanoic acid: A mixture of methyl 5-((1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3- yl)amino)-5-oxopentanoate (1.7 g, 5 mmol) in tetrahydrofuran (17.9 mL) was added TMSOK (7.02 g, 9.99 mmol) at 25 °C, the resulting mixture was stirred for 2 h. LCMS showed desired m / z. The mixture pH was adjusted to 4~5 with 1 M hydrogen chloride and extracted with EtOAc (3 × 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 5-((1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)amino)-5-oxopentanoic acid (1.59 g, 4.38 mmol, 88% yield) as a yellow solid. LCMS: [M+H]+: calculated, 344.1; observed, 344.0.

[0354] Using the same conditions, the following acids were prepared:

[0355] Synthesis of N-(1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)-5-oxo-5- (piperidin-1-yl)pentanamide (A-336): A mixture of 5-((1-(3,4-dichlorophenyl)-4,5-dihydro-1H- pyrazol-3-yl)amino)-5-oxopentanoic acid (0.1 g, 291 µmol) and piperidine (32.2 mg, 378 µmol) in dimethylacetamide (2.01 mL) at 0 °C was added HATU (166 mg, 436 µmol) and DIEA (112 mg, 872 µmol). The resulting mixture was stirred at 25 °C for 2 h. LCMS showed desired m / z. The reaction was diluted with H2O (5 mL) and filtered. The filtrate was extracted with ethyl acetate (4 mL×3), washed with brine (4 mL×5). The combined organic layers dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Column: Waters xbridge 150*25mm 10µm, water( NH4HCO3)-ACN, B%, 15 – 45,15 min to give N-[1-(3,4-dichlorophenyl)-4,5-dihydro-1H- pyrazol-3-yl]-5-oxo-5-(piperidin-1-yl)pentanamide (A-336) (51.9 mg, 125 µmol, 43% yield) as an off-white solid. LCMS: 411.0 (M+H)+, Rt 1.83 min, 98.91 %. Method Details: Column: X- Bridge C18, (50mm*3.0mm, 5µm) Mobile Phase A: 10mM Ammonium Bicarbonate in Water+5% ACN Mobile Phase B: 100%ACN Flow rate: 1.2mL / min. Column temperature: 40°C. Gradient Program (B %):0.0 / 5, 2.2 / 95, 2.7 / 95, 2.71 / 5, 3.0 / 5.1H NMR (400 MHz, DMSO-d6) δ = 10.67 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 2.4, 8.8 Hz, 1H),3.74-3.63 (m, 2H), 3.44-3.35 (m, 6H), 2.39-2.25 (m, 4H), 1.79-1.68 (m, 2H), 1.61-1.52 (m, 2H), 1.52-1.36 (m, 4H).

[0356] Using the same procedure, starting from the appropriate carboxylic acids and amines, the following compounds were prepared:4-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-N- (4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)-4- oxobutanamide ((57))

[0357] Synthesis of methyl (R)-4-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)piperidin-1-yl)-4-oxobutanoate: HATU (985 mg, 2.59 mmol) was added to a solution of 4-methoxy-4-oxobutanoic acid (342 mg, 2.59 mmol) in tetrahydrofuran (10 mL) at 0 °C and the mixture was stirred at 0 °C for 0.5 h. DIEA (1.67 g, 12.9 mmol) and (R)-3-(4- phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1 g, 2.59 mmol) were then added to the reaction mixture. After 2 h at 25 °C, the reaction mixture was extracted with EtOAc (50 mL × 3), and the combined organic layers were washed with brine (50 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give methyl (R)-4- (3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4- oxobutanoate (1.7 g) as a yellow gum which was used in the next step without any further purification. LCMS: calculated, 501.2; observed, 501.5 [M+H]+.

[0358] Synthesis of (R)-4-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)piperidin-1-yl)-4-oxobutanoic acid: potassium trimethylsilanolate (659 mg, 5.09 mmol) was added to a solution of methyl (R)-4-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)piperidin-1-yl)-4-oxobutanoate (1.7 g, 3.4 mmol) in tetrahydrofuran (17 mL). After 2 h at 25 °C, the reaction mixture was acidified with diluted hydrochloride acid. The reaction mixture was then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (R)-4-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)piperidin-1-yl)-4-oxobutanoic acid (1.56 g, 2.9 mmol) as a yellow gum which was used inthe following step without further purification. LCMS: calculated, 487.2; observed, 487.2 [M+H]+.

[0359] Synthesis of 4-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)piperidin-1-yl)-N-(4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3- yl)amino)-4-oxobutyl)-4-oxobutanamide ((57)): HATU (48.2 mg, 127 µmol) was added to a solution of (R)-4-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin- 1-yl)-4-oxobutanoic acid (66.5 mg, 137 µmol) in dimethylacetamide (1 mL) at 0 °C and the mixture was stirred at 0 °C for 0.5 h. The mixture was adjusted to pH 10 with DIEA, then 4- amino-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)butanamide (45 mg, 137 µmol) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep- HPLC (Column: Phenomenex luna C18150*25mm* 10µm, water(FA)-ACN, B%, 0-49, 10 min.) to give 4-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- yl)-N-(4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)-4- oxobutanamide (11.6 mg, 14.1 µmol) as an off-white solid. LCMS: calculated, 797.3; observed, 797.6 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 10.47 (br s, 1H), 8.29-8.21 (m, 1H), 7.87- 7.76 (m, 1H), 7.69-7.60 (m, 2H), 7.47-7.35 (m, 3H), 7.21-7.09 (m, 5H), 7.03 (br s, 1H), 6.84-6.77 (m, 1H), 4.85-4.70 (m, 1H), 4.65-4.48 (m, 1H), 4.32-4.17 (m, 1H), 4.11-4.01 (m, 1H), 3.98-3.77 (m, 2H), 3.67-3.55 (m, 2H), 3.17-3.01 (m, 3H), 2.87-2.75 (m, 1H), 2.69-2.56 (m, 1H), 2.35-2.18 (m, 5H), 2.13-2.06 (m, 1H), 1.93-1.81 (m, 1H), 1.71-1.47 (m, 3H), 1.15 (br d, J = 6.8 Hz, 3H).

[0360] Using a similar procedure, the following derivative was prepared:2-oxo-2-(piperidin-1-yl)ethyl (4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol- 3-yl)amino)-4-oxobutyl)carbamate (A-326)

[0361] Synthesis of tert-butyl 2-(((4-nitrophenoxy)carbonyl)oxy)acetate: 4-nitrophenyl carbonochloridate (1.53 g, 7.57 mmol) was added slowly to a solution of tert-butyl glycolate (1.00 g, 7.57 mmol) and DIEA (92.4 mg, 757 µmol) in dichloromethane (20.0 mL) at 0 °C.The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition H2O (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue which was used directly for next step.

[0362] Synthesis of tert-butyl 2-(((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)amino)-4-oxobutyl)carbamoyl)oxy)acetate: DIEA (196 mg, 1.52 mmol) and tert- butyl 2-(((4-nitrophenoxy)carbonyl)oxy)acetate (135 mg, 456 µmol) were added to a solution of 4-amino-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)butanamide (0.1 g, 304 µmol) in tetrahydrofuran (2.00 mL) 25 °C. After 2 h, the reaction mixture was quenched by H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers wereconcentrated under reduced pressure to give a residue which was purified by Prep-TLC (PE / EtOAc=3 / 1) to give tert-butyl 2-(((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)amino)-4-oxobutyl)carbamoyl)oxy)acetate (0.1 g, 205 µmol, 68% yield) as a yellow oil. LCMS: calculated, 487.2; observed, 487.4 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.17 (s, 1H), 6.96-6.92 (m, 1H), 6.70-6.60 (m, 1H), 5.11-4.88 (m, 1H), 4.48 (s, 2H), 4.00-3.87 (m, 1H), 3.72-3.61 (m, 1H), 3.48 (dd, J = 4.0, 9.4 Hz, 1H), 3.25 (t, J = 6.4 Hz, 2H), 2.38 (s, 2H), 1.91-1.75 (m, 2H), 1.42 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H).

[0363] Synthesis of 2-(((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3- yl)amino)-4-oxobutyl)carbamoyl)oxy)acetic acid: HCl / dioxane (4 M) (1.00 mL) was added to a solution of of tert-butyl 2-(((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3- yl)amino)-4-oxobutyl)carbamoyl)oxy)acetate (100 mg, 349 µmol) in dichloromethane (1.00 mL) and the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 2-(((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3- yl)amino)-4-oxobutyl)carbamoyl)oxy)acetic acid (117 mg, 314 µmol, 90% yield) as a yellow solid. LCMS: calculated, 431.1; observed, 431.0 [M+H]+.

[0364] Synthesis of 2-oxo-2-(piperidin-1-yl)ethyl (4-((1-(3,4-dichlorophenyl)-4-methyl- 4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)carbamate (A-326): A mixture of 2-(((4-((1- (3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4- oxobutyl)carbamoyl)oxy)acetic acid (100 mg, 232 µmol) and HATU (106 mg, 278 µmol) in THF (1.25 mL) was stirred at 0 °C for 0.5 h. A solution of piperidine (23.7 mg, 278 µmol) and DIEA (89.9 mg, 696 µmol, 3 eq) in THF (1.25 mL) was then added to the mixture and stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP flash (Phenomenex luna C1840 g , water(FA)-ACN, B%, 35– 50, 10 min), to give after lyophilization 2-oxo-2-(piperidin-1-yl)ethyl (4-((1-(3,4-dichlorophenyl)-4-methyl-4,5- dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)carbamate (A-326) (33.0 mg, 64.2 µmol, 28% yield) as a yellow solid. LCMS: calculated, 498.2; observed, 498.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 10.56-10.42 (m, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.37-7.27 (m, 1H), 7.05 (d, J = 2.8 Hz, 1H), 6.82 (dd, J = 2.8, 8.8 Hz, 1H), 4.63 (s, 2H), 3.92-3.77 (m, 1H), 3.72-3.63 (m, 1H), 3.63- 3.58 (m, 1H), 3.37 (d, J = 4.4 Hz, 2H), 3.28 (s, 2H), 3.05-2.96 (m, 2H), 2.36-2.29 (m, 2H), 1.67 (d, J = 7.2 Hz, 2H), 1.60-1.53 (m, 2H), 1.49 (d, J = 4.4 Hz, 2H), 1.44-1.38 (m, 2H), 1.16 (d, J = 7.2 Hz, 3H).4-((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4- oxobutyl)amino)-4-oxobutanoic acid（A-327)

[0365] Synthesis of tert-butyl (4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)amino)-4-oxobutyl)carbamate (A-337): A mixture of 1-(3,4-dichlorophenyl)-4- methyl-4,5-dihydro-1H-pyrazol-3-amine (25 g, 102 mmol, prepared according to J. Med. Chem. 2019, 62, 2154–2171), 4-(tert-butoxycarbonylamino)butyric acid (25 g, 123 mmol), DCC (25.4 g, 123 mmol) and DMAP (15 g, 123 mmol) in dichloromethane (250 mL) was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition of DCM (50 mL × 3) and filtered, then concentrated under reduced pressure to give a residue which was purified by Prep-HPLC (Phenomenex luna C18250*50 mm*15 µm, 60-65% water(FA)-ACN, 60 ml / min, 15 min) to give tert-butyl (4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4- oxobutyl)carbamate (23.9 g, 53.4 mmol) as a yellow solid. LCMS: 429.2 (M+H)+, Rt 1.40 min, 99.8 %, 3min Method: column: Kinetex® EVO C18 (3.0x50mm 2.6µm);.Mobile phase A: 0.0375% TFA in water (v / v) Mobile phase B: 0.01875% TFA in ACN (v / v) Gradient B%:0 / 5,2.4 / 95,2.7 / 95,2.71 / 5,3.0 / 5 Flow rate: 1.2 mL / min.1H NMR (400 MHz, CDCl3) δ = 8.62 (s, 1H), 7.24 (s, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.74 (dd, J = 2.4, 8.8 Hz, 1H), 4.78 (d, J = 5.6 Hz, 1H), 3.99 (s, 1H), 3.72 (t, J = 9.6 Hz, 1H), 3.59-3.53 (m, 1H), 3.22 (d, J = 6.4 Hz, 2H), 2.40 (s, 2H), 1.87 (quin, J = 6.4 Hz, 2H), 1.46 (s, 9H), 1.31 (d, J = 7.2 Hz, 3H).

[0366] Using a similar procedure, the following acid was prepared:

[0367] Synthesis of 4-amino-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol- 3-yl)butanamide hydrochloride (A-328): To a solution of tert-butyl (4-((1-(3,4- dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)carbamate (1.80 g, 4.19 mmol) in dichloromethane (18.0 mL) was added hydrogen chloride (18.0 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The organic solvent was removed under reduced pressure to give 4-amino-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3- yl)butanamide hydrochloride (1.20 g, 3.28 mmol, 78% yield) as white solid. LCMS: 329.2 (M+H)+, Rt 1.40 min, 99.6 %, 3min Method: column: Kinetex® EVO C18 (3.0x50mm 2.6µm);.Mobile phase A: 0.0375% TFA in water (v / v) Mobile phase B: 0.01875% TFA in ACN (v / v) Gradient B%:0 / 5,2.4 / 95,2.7 / 95,2.71 / 5,3.0 / 5 Flow rate: 1.2 mL / min.1H NMR (400 MHz, CD3OD) δ = 7.29 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 1.6 Hz, 1H), 6.89-6.80 (m, 1H), 3.85 (s, 1H), 3.75-3.60 (m, 2H), 3.31 (s, 1H), 3.02 (t, J = 7.6 Hz, 2H), 2.57 (t, J = 6.4 Hz, 2H), 2.03-1.96 (m, 2H), 1.28 (d, J = 6.4 Hz, 3H).

[0368] Using a similar procedure, the following compound was prepared:

[0369] Synthesis of methyl 4-((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)amino)-4-oxobutyl)amino)-4-oxobutanoate: A mixture of 4-methoxy-4- oxobutanoic acid (482 mg, 3.64 mmol) and HATU (1.73 g, 4.56 mmol) in DMAc (5 mL) was stirred at 0 °C for 30 min. Then 4-amino-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)butanamide (1.00 g, 3.04 mmol) and DIEA (propan-2-yl)amine (1.18 g, 9.11 mmol)was added and the resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered and dried to give a residue which was purified by flash silica gel chomatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 20~30% Ethylacetate / Petroleum ether gradient @ 60 mL / min) to give methyl 4-((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4- oxobutyl)amino)-4-oxobutanoate (420 mg, 947 µmol, 31% yield) as a purple oil. LCMS: (ESI): [M+H]+: calculated, 443.1; observed, 443.1.

[0370] Synthesis of 4-((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3- yl)amino)-4-oxobutyl)amino)-4-oxobutanoic acid (A-327): To a solution of methyl 4-((4-((1- (3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)amino)-4- oxobutanoate (0.400 g, 902 µmol) in tetrahydrofuran (4 mL) was added potassium trimethylsilanolate (233 mg, 1.80 mmol) at 0 °C over a period of 30 min. Then reaction mixture was stirred at 25 ° for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated to give 4-((4-((1-(3,4-dichlorophenyl)-4- methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)amino)-4-oxobutanoic acid (0.1 g, 233 µmol, 26% yield) as a yellow solid. LCMS: 429.0 (M+H), Rt 1.40 min, 95.7 %, 3min Method: column: Kinetex® EVO C18 (3.0x50mm 2.6µm);.mobile phase A: 0.0375% TFA in water (v / v) mobile phase B: 0.01875% TFA in ACN (v / v) Gradient B%:0 / 5,2.4 / 95,2.7 / 95,2.71 / 5,3.0 / 5 Flow rate: 1.2 mL / min.1H NMR (400 MHz, CD3OD) δ = 7.27 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 2.4, 8.8 Hz, 1H), 3.92-3.84 (m, 1H), 3.69 (t, J = 9.6 Hz, 1H), 3.62-3.56 (m, 1H), 3.24 (t, J = 6.4 Hz, 2H), 2.64-2.57 (m, 2H), 2.49-2.44 (m, 2H), 2.44-2.33 (m, 2H), 1.84 (t, J = 7.2 Hz, 2H), 1.26 (d, J = 7.2 Hz, 3H).

[0371] Using a similar procedure, the following acid was prepared:4-acetamido-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)butanamide (A-329)

[0372] A mixture of 4-amino-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3- yl)butanamide (50 mg, 152 µmol) and acetic anhydride (46.5 mg, 456 µmol) in dichloromethane (1 mL) was stirred at 25 °C for 2 h. The organic volatiles were removed under reduced pressure to give a residue which was purified by reverse phase flash chromatography (40 g, 50-60% water- ACN, 30 ml / min, 12 min) to give 4-acetamido-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro- 1H-pyrazol-3-yl)butanamide (21.5 mg, 56.7 µmol) as a white solid. LCMS: MS (ESI): [M+H]+: calculated, 371.1; observed, 371.1.1H NMR (400 MHz, DMSO-d6) δ = 10.52 (s, 1H), 7.83 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 6.83 (dd, J = 2.8, 8.8 Hz, 1H), 3.85 (s, 1H), 3.72-3.64 (m, 1H), 3.63-3.58 (m, 1H), 3.03 (q, J = 6.8 Hz, 2H), 2.31 (t, J = 6.8 Hz, 2H), 1.79 (s, 3H), 1.65 (t, J = 7.2 Hz, 2H), 1.16 (d, J = 7.2 Hz, 3H).

[0373] Using a similar procedure, the following acid was prepared:6-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetamido)-N-(4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)amino)-4-oxobutyl)hexanamide ((20))

[0374] Synthesis of tert-butyl (6-((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)amino)-4-oxobutyl)amino)-6-oxohexyl)carbamate (A-217): A solution of 6- ((tert-butoxycarbonyl)amino)hexanoic acid (843 mg, 3.64 mmol), HATU (1.66 g, 4.37 mmol) in tetrahydrofuran (12 mL) was stirred at 0 °C for 30 min, then DIEA (1.41 g, 10.9 mmol) and 4- amino-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)butanamide (1.2 g, 3.64 mmol) was added to the reaction mixture and stirred at 25 °C for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL × 3), the combined organic layers were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by RP flash (80.0 g, 55-65% water-ACN, 60 ml / min, 15 min) to give tert-butyl (6-((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)amino)-4-oxobutyl)amino)-6-oxohexyl)carbamate (249 mg, 450 µmol, 12% yield) as a white solid. LCMS: calculated 542.2, observed 542.3 (M+H)+, Rt 1.93 min, 98.5 %, 3minMethod: column: Kinetex® EVO C18 (3.0x50mm 2.6µm);.Mobile phase A: 0.0375% TFA in water (v / v) Mobile phase B: 0.01875% TFA in ACN (v / v) Gradient B%:0 / 5,2.4 / 95,2.7 / 95,2.71 / 5,3.0 / 5 Flow rate: 1.2 mL / min.1H NMR (400 MHz, DMSO-d6) δ = 10.52 (s, 1H), 7.77 (t, J = 5.6 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 2.4, 8.8 Hz, 1H), 6.75 (t, J = 5.2 Hz, 1H), 3.91-3.79 (m, 1H), 3.72-3.64 (m, 1H), 3.63- 3.58 (m, 1H), 3.03 (q, J = 6.8 Hz, 2H), 2.87 (q, J = 6.8 Hz, 2H), 2.30 (t, J = 6.8 Hz, 2H), 2.08- 1.99 (m, 2H), 1.65 (t, J = 7.2 Hz, 2H), 1.47 (quin, J = 7.6 Hz, 2H), 1.36 (s, 11H), 1.25-1.13 (m, 5H).

[0375] Using a similar procedure, the following compounds were prepared:

[0376] Synthesis of 6-amino-N-(4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)amino)-4-oxobutyl)hexanamide hydrochloride (A-218): A solution of tert-butyl (6-((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4- oxobutyl)amino)-6-oxohexyl)carbamate (40.0 mg, 73.7 µmol) and 1,4-dioxane / hydrogen chloride (1 / 1) (0.400 mL) in dichloromethane (0.4 mL) was stirred at 0 °C, then for 2 h at 25 °C. The organic solvent was removed under reduced pressure to give 6-amino-N-(4-((1-(3,4- dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)hexanamide hydrochloride (28.4 mg, 59.3 µmol, 81% yield) as a brown solid. LCMS: calculated 442.2, observed 442.1(M+H), Rt 1.18 min, 95.8 %.3min Method: column: Kinetex® EVO C18 (3.0x50mm 2.6µm);.Mobile phase A: 0.0375% TFA in water (v / v) Mobile phase B: 0.01875% TFA in ACN (v / v) Gradient B%:0 / 5,2.4 / 95,2.7 / 95,2.71 / 5,3.0 / 5 Flow rate: 1.2 mL / min.1H NMR (400 MHz, DMSO-d6) δ = 10.56 (s, 1H), 8.03-7.73 (m, 4H), 7.40 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 6.82 (dd, J = 2.8, 8.8 Hz, 1H), 3.90-3.77 (m, 1H), 3.70-3.63 (m, 1H), 3.63-3.55 (m, 1H), 3.04 (q, J = 6.4 Hz, 2H), 2.80-2.68 (m, 2H), 2.32 (t, J = 6.8 Hz, 2H), 2.09-2.04 (m, 2H), 1.71-1.61 (m, 2H), 1.56-1.44 (m, 4H), 1.26 (dd, J = 7.2, 15.2 Hz, 2H), 1.16 (d, J = 7.2 Hz, 3H).

[0377] Using a similar procedure, the following compounds were prepared:

[0378] Synthesis of 6-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(4-((1-(3,4-dichlorophenyl)-4-methyl- 4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)hexanamide ((20)): A mixture of 6-amino-N- (4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4- oxobutyl)hexanamide (50.0 mg, 113 µmol), 2,5-dioxopyrrolidin-1-yl (S)-2-(4-(4-chlorophenyl)- 2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (56.3 mg, 113 µmol), DIEA (43.8 mg, 339 µmol) in dimethylacetamide (0.5 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by Prep-HPLC (Waters xbridge 150*25mm 10µm, 48-78% water( NH4HCO3)-ACN, 30 ml / min, 12 min) to give 6-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)hexanamide (26.8 mg, 31.8 µmol, yield: 28%) as a white solid. LCMS: calculated, 824.2; observed, 824.3 [M+H]+, Rt 2.02 min, 98.5 %, 3min Method: column: Kinetex® EVO C18 (3.0x50mm 2.6µm);.Mobile phase A: 0.0375% TFA in water (v / v) Mobile phase B: 0.01875% TFA in ACN (v / v) Gradient B%:0 / 5,2.4 / 95,2.7 / 95,2.71 / 5,3.0 / 5 Flow rate: 1.2 mL / min.1H NMR: (400 MHz, DMSO-d6) δ = 10.62-10.43 (m, 1H), 8.17 (t, J = 5.6 Hz, 1H), 7.77 (t, J = 5.6 Hz, 1H), 7.51-7.45 (m, 2H), 7.44- 7.35 (m, 3H), 7.03 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 2.4, 8.8 Hz, 1H), 4.52 (t, J = 7.2 Hz, 1H), 3.91-3.79 (m, 1H), 3.71-3.62 (m, 1H), 3.62-3.57 (m, 1H), 3.26-3.18 (m, 2H), 3.13-2.99 (m, 4H), 2.59 (s, 3H), 2.40 (s, 3H), 2.34-2.26 (m, 2H), 2.09-2.03 (m, 2H), 1.66 (t, J = 7.2 Hz, 2H), 1.60 (s, 3H), 1.54-1.47 (m, 2H), 1.44 (t, J = 7.2 Hz, 2H), 1.32-1.23 (m, 2H), 1.15 (d, J = 7.2 Hz, 3H).

[0379] Using a similar procedure, the following compounds were prepared:14-amino-N-(4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4- oxobutyl)-6-methyl-3,9,12-trioxa-6-azatetradecanamide (A-230)

[0380] Synthesis of ethyl 2-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)acetate: ethyl 2-diazoacetate (12.8 g, 112 mmol) was added dropwise to a solution of tert-butyl (2- hydroxyethyl)(methyl)carbamate (10.0 g, 57.1 mmol) and Rh2(OAc)4(497 mg, 1.12 mmol) in dichloromethane (120 mL). The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by H2O (100 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue which was purified byflash chromatography (PE / EtOAc=5 / 1 to 1 / 1) to give ethyl 2-(2-((tert- butoxycarbonyl)(methyl)amino) ethoxy)acetate (13.5 g, 51.7 mmol, 91% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ = 4.18-4.13 (m, 2H), 4.01 (s, 2H), 3.59 (s, 2H), 3.36 (s, 2H), 2.86 (s, 3H), 1.38 (s, 9H), 1.23 (dd, J = 2.4, 7.2 Hz, 3H).

[0381] Synthesis of ethyl 2-(2-(methylamino)ethoxy)acetate hydrogen chloride: HCl / dioxane (50 mL) was added slowly to a solution of ethyl 2-(2-((tert-butoxycarbonyl) (methyl)amino)ethoxy)acetate (10.0 g, 38.3 mmol) in dichloromethane (50 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give ethyl 2-(2-(methylamino)ethoxy)acetate hydrogen chloride (7.90 g, 48.6 mmol, crude) as brown oil, which was used directly in the next step. LCMS: calculated, 162.1; observed, 162.1 [M+H]+.

[0382] Synthesis of ethyl 2,2,14-trimethyl-4-oxo-3,8,11,17-tetraoxa-5,14-diazanonadecan- 19-oate: tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (6.03 g, 19.3 mmol) was added to a solution of ethyl 2-(2-(methylamino)ethoxy)acetate hydrogen chloride (5.25 g, 21.2 mmol) and DIEA (9.98 g, 77.3 mmol) in acetonitrile (52.0 mL). The mixture was stirred at 80 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 µm); mobile phase: [water(FA)-ACN]; B%: 20%-45%, 15 min) and lyophilizated to give ethyl 2,2,14-trimethyl-4- oxo-3,8,11,17-tetraoxa-5,14-diazanonadecan-19-oate (1.53 g, 3.65 mmol, 17% yield) as yellow oil. LCMS: calculated, 393.3; observed, 393.5 [M+H]+.1H NMR: (400 MHz, CDCl3) δ = 5.15 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.09 (s, 2H), 3.82 (t, J = 5.2 Hz, 2H), 3.77 (t, J = 5.2 Hz, 2H), 3.59 (s, 4H), 3.52 (t, J = 5.2 Hz, 2H), 3.29 (d, J = 5.2 Hz, 2H), 3.10-2.98 (m, 4H), 2.64 (s, 3H), 1.43 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H).

[0383] Synthesis of 2,2,14-trimethyl-4-oxo-3,8,11,17-tetraoxa-5,14-diazanonadecan-19-oic acid: lithium hydroxide monohydrate (489 mg, 11.7 mmol) in water (8 mL) was added to a solution of ethyl 2,2,14-trimethyl-4-oxo-3,8,11,17-tetraoxa-5,14-diazanonadecan-19-oate (1.53 g, 3.89 mmol) in tetrahydrofuran (8 mL) at 25 °C. After 0.5 h, the pH of the reaction mixture was adjusted to 4 with citric acid at 0°C. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL×3). The water layer was lyophilized to give 2,2,14-trimethyl-4-oxo- 3,8,11,17-tetraoxa-5,14-diazanonadecan-19-oic acid (851 mg, 2.17 mmol, 56% yield) as yellow oil. LCMS: calculated, 365.4; observed, 365.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ = 6.80 (t, J = 5.2 Hz, 1H), 3.69 (s, 2H), 3.56 (q, J = 5.6 Hz, 4H), 3.50 (s, 4H), 3.38 (t, J = 6.4 Hz, 2H), 3.06 (q, J = 6.0 Hz, 2H), 2.75-2.61 (m, 4H), 2.35 (s, 3H), 1.37 (s, 9H).

[0384] Synthesis of tert-butyl (19-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)amino)-9-methyl-14,19-dioxo-3,6,12-trioxa-9,15-diazanonadecyl)carbamate (A-229): HATU (1.78 g, 4.67 mmol) was added to a solution of 2,2,14-trimethyl-4-oxo-3,8,11,17- tetraoxa-5,14-diazanonadecan-19-oic acid (851 mg, 2.34 mmol) in tetrahydrofuran (9 mL) at 0 °C. After 0.5 h, 4-amino-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3- yl)butanamide (769 mg, 2.34 mmol) and DIEA (1.21 g, 9.34 mmol) were added and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with H2O (30 mL), extracted with ethyl acetate (30 mL× 3), washed with brine (30 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (neutral condition). The collected fraction was lyophilized to give tert-butyl (19-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3- yl)amino)-9-methyl-14,19-dioxo-3,6,12-trioxa-9,15-diazanonadecyl)carbamate (A-229) (129 mg, 182 µmol, 8% yield) as a white solid. LCMS: calculated, 675.3; observed, 675.4 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ = 10.54 (s, 1H), 8.06 (t, J = 5.6 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 6.82 (dd, J = 2.8, 8.8 Hz, 1H), 6.73 (t, J = 4.8 Hz, 1H), 3.84 (s, 2H), 3.70-3.59 (m, 2H), 3.55-3.49 (m, 2H), 3.53-3.45 (m, 1H), 3.49-3.44 (m, 5H), 3.38-3.34 (m, 3H), 3.17-3.09 (m, 2H), 3.05 (q, J = 5.6 Hz, 2H), 2.54 (t, J = 5.6 Hz, 4H), 2.36-2.27 (m, 2H), 2.22 (s, 3H), 1.76-1.63 (m, 2H), 1.36 (s, 9H), 1.16 (d, J = 7.2 Hz, 3H).

[0385] Synthesis of 14-amino-N-(4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)amino)-4-oxobutyl)-6-methyl-3,9,12-trioxa-6-azatetradecanamide (A-230): HCl / dioxane (0.5 mL, 4M) was added to a solution of tert-butyl (19-((1-(3,4-dichlorophenyl)-4- methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-9-methyl-14,19-dioxo-3,6,12-trioxa-9,15- diazanonadecyl)carbamate (40 mg, 59.2 µmol) in dichloromethane (0.5 mL) at 0 °C. After 1 h the reaction was concentrated under reduced pressure to give a residue which was purified by reverse-phase HPLC (0.1% HCl condition). The collected fraction was lyophilized to give 14- amino-N-(4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)- 6-methyl-3,9,12-trioxa-6-azatetradecanamide dihydrochloride (A-230) (12 mg, 18.5 µmol, 31% yield) as a pink oil. LCMS: calculated, 575.3; observed, 575.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ = 10.57 (s, 1H), 10.12 (s, 1H), 8.36-8.17 (m, 1H), 8.05-7.80 (m, 3H), 7.41 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 6.83 (dd, J = 2.8, 8.8 Hz, 1H), 3.96 (s, 2H), 3.91-3.74 (m, 6H), 3.71-3.57 (m, 9H), 3.27 (s, 2H), 3.16-3.10 (m, 2H), 3.01-2.93 (m, 2H), 2.84 (d, J = 4.6 Hz, 3H), 2.36-2.30 (m, 2H), 1.72 (m, 2H), 1.17 (d, J = 7.2 Hz, 3H).1-amino-N-(4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4- oxobutyl)-6-methyl-3,9,12-trioxa-6-azatetradecan-14-amide (A-232)

[0386] Synthesis of ethyl 2-(2-(2-(benzyloxy)ethoxy)ethoxy)acetate: sodium hydride (4.89 g, 122 mmol) was added to a solution of 2-(2-(benzyloxy)ethoxy)ethan-1-ol (20 g, 102 mmol) in tetrahydrofuran (160 mL) at 0 °C and the mixture was stirred for 0.5 h. Ethyl bromoacetate (18.7 g, 112 mmol) was then added at 0 °C and the mixture was warmed to 25 °C and stirred for 12 hours. The mixture was quenched by NH4Cl (100 mL, aq.), extracted with EtOAc (50 mL × 5). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered and concentrated to give a residue which was purified by flash chromatography to give ethyl 2- (2-(2-(benzyloxy)ethoxy)ethoxy)acetate (16.0 g, 56.7 mmol, 56% yield) as a yellow oil. LCMS: calculated, 283.2; observed, 283.2 [M+H]+.1H NMR: (400 MHz, CDCl3) δ = 7.29-7.19 (m, 5H), 4.50 (s, 2H), 4.14 (q, J = 7.2Hz, 2H), 4.09 (s, 2H), 3.70-3.56 (m, 8H), 1.21 (t, J = 7.2 Hz, 3H).

[0387] Synthesis of ethyl 2-(2-(2-hydroxyethoxy)ethoxy)acetate: a mixture of ethyl 2-(2-(2- (benzyloxy)ethoxy)ethoxy)acetate (15.0 g, 53.1 mmol) and Pd / C (1.5 g, 10% w / w) in ethanol (0.4 L) was stirred at 45 °C for 24 hours under H2. The catalyst was filtered-off and the filtrate was concentrated under reduced pressure to give ethyl 2-(2-(2-hydroxyethoxy)ethoxy)acetate (10 g, 49.4 mmol, 93% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ = 4.23 (q, J = 7.1 Hz, 2H), 4.14 (s, 2H), 3.76-3.70 (m, 6H), 3.66-3.60 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H).

[0388] Synthesis of ethyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate: p-tosylchloride (3.57 g, 18.7 mmol) was added to a solution of ethyl 2-(2-(2-hydroxyethoxy)ethoxy)acetate (2.40 g, 12.5 mmol), pyridine (3.46 g, 43.7 mmol) and DMAP (153 mg, 1.25 mmol) in dichloromethane (30 mL) at 0°C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was washed with brine and the organice layer was concentrated under reduced pressure. The residue was purified by flash chromatography to give ethyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate (1.10 g, 3.18 mmol, 25% yield) as a yellow solid. LCMS: calculated, 347.1; observed, 347.0 [M+H]+.1H NMR: (400 MHz, CDCl3) δ = 7.81 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.25-4.10 (m, 6H), 3.73-3.61 (m, 6H), 2.45 (s, 3H), 1.31-1.24 (m, 3H).

[0389] Synthesis of ethyl 2,2,11-trimethyl-4-oxo-3,8,14,17-tetraoxa-5,11-diazanonadecan- 19-oate: A mixture of ethyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate (5.00 g, 14.4 mmol), tert- butyl (2-(2-(methylamino)ethoxy)ethyl)carbamate (3.15 g, 14.4 mmol), DIEA (7.16 mL, 43.3 mmol) and tetrabutylammonium iodide (533 mg, 1.44 mmol) in acetonitrile (50 mL) was stirred at 80 °C for 16 hours. The reaction mixture was concentrated under reduced pressure and chromatographed [Column: Waters xbridge 150*25mm 10µm, water (FA)-ACN, B%, 0-30, 15 min] to give ethyl 2,2,11-trimethyl-4-oxo-3,8,14,17-tetraoxa-5,11-diazanonadecan-19-oate (7.8 g, 18.5 mmol, 78% yield) as a brown oil. LCMS: calculated, 393.3; observed, 393.2 [M+H]+.

[0390] Synthesis of 2,2,11-trimethyl-4-oxo-3,8,14,17-tetraoxa-5,11-diazanonadecan-19-oic acid: a mixture of ethyl 2,2,11-trimethyl-4-oxo-3,8,14,17-tetraoxa-5,11-diazanonadecan-19-oate (0.500 g, 1.27 mmol), potassium trimethylsilanolate (180 mg, 1.40 mmol) and tetrahydrofuran (5 mL) was stirred at 25 °C for 4 hours. The pH of the solution was adjusted with HCl (1 M, aq) around pH=4 and concentrated under reduced pressure to give 2,2,11-trimethyl-4-oxo-3,8,14,17- tetraoxa-5,11-diazanonadecan-19-oic acid (1.20 g, 1.98 mmol) as a yellow oil, which was used directly in the next step. LCMS: calculated, 365.2; observed, 365.1 [M+H]+.

[0391] Synthesis of tert-butyl (19-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)amino)-6-methyl-14,19-dioxo-3,9,12-trioxa-6,15-diazanonadecyl)carbamate (A- 231): A mixture of 2,2,11-trimethyl-4-oxo-3,8,14,17-tetraoxa-5,11-diazanonadecan-19-oic acid (1.1 g, 1.81 mmol) and HATU (689 mg, 1.81 mmol) in dimethyl acetamide (2 mL) was stirred at 0 °C for 0.5 h. DIEA (877 µL, 4.94 mmol) and 4-amino-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5- dihydro-1H-pyrazol-3-yl)butanamide (542 mg, 1.65 mmol) were then added and the mixture was stirred at 25 °C for 6 hours. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC [Column: Waters xbridge 150*25mm 10µm, water-ACN, B%, 40-50, 8 min] to give tert-butyl (19-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3- yl)amino)-6-methyl-14,19-dioxo-3,9,12-trioxa-6,15-diazanonadecyl)carbamate (A-231) (412 mg, 599 µmol, 36% yield) as a yellow gum. LCMS: calculated, 675.3; observed, 675.0 [M+H]+.1HNMR: (400 MHz, CDCl3) δ = 9.42 (s, 1H), 7.33 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 2.8, 8.8 Hz, 1H), 5.27 (s, 1H), 4.09-3.91 (m, 3H), 3.75-3.61 (m, 7H), 3.60-3.48 (m, 5H), 3.40 (td, J = 6.0, 12.0 Hz, 2H), 3.30 (d, J = 5.2 Hz, 2H), 2.76-2.58 (m, 4H), 2.40 (s, 2H), 2.34 (s, 3H), 1.99-1.85 (m, 2H), 1.44 (s, 9H), 1.29 (d, J = 7.2 Hz, 3H).

[0392] Synthesis of 1-amino-N-(4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)amino)-4-oxobutyl)-6-methyl-3,9,12-trioxa-6-azatetradecan-14-amide (A-232): hydrogen chloride (146 mg, 4 mmol, 4M in dioxane) was added to a solution of tert-butyl (19- ((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-6-methyl-14,19-dioxo- 3,9,12-trioxa-6,15-diazanonadecyl)carbamate (30.0 mg, 44.4 µmol) in dichloromethane (1 mL), and the reaction mixture was stirred at 25 °C for 3 hours. The mixture was concentrated under reduced pressure and purified by chromatography [Column: Waters Xbridge 150*25mm 10µm, water(NH4HCO3)-MeOH, B%, 41-61, 11 min] to give 1-amino-N-(4-((1-(3,4-dichlorophenyl)-4- methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)-6-methyl-3,9,12-trioxa-6-azatetradecan- 14-amide (A-232) (9.50 mg, 16.5 µmol, 37% yield) as a yellow gum. LCMS: calculated, 575.2; observed, 575.1 [M+H]+.1H NMR: (400 MHz, CD3OD): δ = 7.28 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 2.8 Hz, 1H), 6.83 (dd, J = 2.4, 8.8 Hz, 1H), 4.01 (s, 2H), 3.89 (m, 1H), 3.73-3.53 (m, 12H), 3.37-3.32 (m, 2H), 2.98-2.85 (m, 2H), 2.67 (td, J = 5.6, 11.6 Hz, 4H), 2.50-2.37 (m, 2H), 2.33 (s, 3H), 1.95-1.81 (m, 2H), 1.27 (d, J = 6.8 Hz, 3H).4-(2-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)acetamido)-N-(1-(3,4- dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)butanamide（(33))

[0393] Synthesis 4-(2-chloroacetamido)-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro- 1H-pyrazol-3-yl)butanamide: chloroacetyl chloride (2.06 g, 18.2 mmol) was added to a solution of 4-amino-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)butanamide (6 g, 18.2 mmol) and DIEA (7.07 g, 54.7 mmol) in dichloromethane (60 mL) at 0 °C. After 0.5 hours, the reaction mixture was partitioned between DCM (100 ml) and H2O (100 ml). The organic phase was separated, washed with brine (100 ml ×3) dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(2-chloroacetamido)-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5- dihydro-1H-pyrazol-3-yl)butanamide (5.9 g, 13.1 mmol) as a brown solid. LCMS: calculated, 405.1; observed, 405.9 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ = 10.54 (s, 1H), 8.25 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.86-6.79 (m, 1H), 4.04 (s, 2H), 3.85 (s, 1H), 3.70-3.59 (m, 2H), 3.14-3.07 (m, 2H), 2.33 (s, 2H), 1.74-1.65 (m, 2H), 1.16 (d, J = 6.8 Hz, 3H).

[0394] Synthesis of tert-butyl 4-((4-(2-((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro- 1H-pyrazol-3-yl)amino)-4-oxobutyl)amino)-2-oxoethyl)piperazin-1-yl)methyl)piperidine-1- carboxylate (A-237): A mixture of 4-(2-chloroacetamido)-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)butanamide (1.5 g, 3.7 mmol), tert-butyl 4-(piperazin-1- ylmethyl)piperidine-1-carboxylate (1.26 g, 4.44 mmol) and DIEA (1.93 mL, 11.1 mmol) in acetonitrile (15 mL) was stirred at 60 °C for 2 h. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography [Column: Waters xbridge 150*25mm 10µm, water -ACN, B%, 30-40, 15 min.] to give tert-butyl 4-((4-(2-((4-((1-(3,4- dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)amino)-2- oxoethyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (897 mg, 1.35 mmol) as an off-white solid. LCMS: calculated, 652.3; observed, 652.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ = 10.53 (br s, 1H), 7.69 (t, J = 6.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 9.0, 2.6 Hz, 1H), 3.89 (m, 3H), 3.70-3.63 (m, 1H), 3.63-3.58 (m, 1H), 3.17-3.04 (m, 2H), 2.87 (s, 2H), 2.65 (d, J = 4.8 Hz, 2H), 2.49-2.16 (m, 10H), 2.07 (d, J = 6.4 Hz, 2H), 1.75-1.66 (m, 2H), 1.61 (m, 3H), 1.38 (s, 9H), 1.16 (d, J = 7.2 Hz, 3H), 0.96-0.82 (m, 2H).

[0395] Using a similar procedure, the following compounds were prepared:

[0396] Synthesis of N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)-4- (2-(4-(piperidin-4-ylmethyl)piperazin-1-yl)acetamido)butanamide trihydrochloride (A-238): 1,4-dioxane / hydrogen chloride (1 / 1) (0.5 mL) was added to a solution of tert-butyl 4-((4-(2-((4- ((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)amino)-2- oxoethyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (60 mg, 91.9 µmol) in dichloromethane (0.5 mL) at 25 °C. After 1 h the reaction mixture was concentrated under vacuum to give N-(1- (3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)-4-(2-(4-(piperidin-4- ylmethyl)piperazin-1-yl)acetamido)butanamide trihydrochloride (49 mg, 74 µmol) as a brown solid. LCMS: calculated, 552.3; observed, 552.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ = 12.06-10.96 (m, 1H), 10.60 (s, 1H), 9.12-8.87 (m, 2H), 8.61 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.04 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 3.84 (s, 4H), 3.66 (d, J = 10.4 Hz, 4H), 3.25 (d, J = 11.6Hz, 4H), 3.18-3.00 (m, 6H), 2.81 (d, J = 10.4 Hz, 3H), 2.37 (s, 2H), 2.13-1.88 (m, 4H), 1.72 (d, J = 6.0 Hz, 2H), 1.43 (d, J = 11.2 Hz, 2H), 1.16 (d, J = 6.4 Hz, 3H).

[0397] Using a similar procedure, the following compounds were prepared:

[0398] Synthesis of 4-(2-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperazin-1- yl)acetamido)-N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)butanamide （(33)): 2,5-dioxopyrrolidin-1-yl (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (54.1 mg, 109 µmol) was added to a mixture of N-(1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)-4-(2-(4-(piperidin-4- ylmethyl)piperazin-1-yl)acetamido)butanamide trihydrochloride (60 mg, 91 µmol) and DIEA (42.1 mg, 326 µmol) in dimethylacetamide (1 mL) at 25 °C. After 12 hour, the reaction mixture was concentrated under reduced pressure. The crude product was purified by prep HPLC [Column: Waters xbridge 150*25mm 10µm, water(FA) -ACN, B%, 36– 56, 12 min.] to give 4- (2-(4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)acetamido)-N-(1-(3,4- dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)butanamide (10.5 mg, 10.9 µmol) as a white solid. LCMS: calculated, 934.3 ; observed, 934.4 [M+H]+.1H NMR: (400 MHz, CD3OD) δ = 7.50-7.36 (m, 4H), 7.28 (d, J = 9.2 Hz, 1H), 7.13 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.70 (d, J = 6.8 Hz, 1H), 4.65-4.45 (m, 2H), 4.33-4.17 (m, 1H), 3.96-3.80 (m, 1H), 3.70 (t, J = 10.0 Hz, 1H), 3.67-3.52 (m, 3H), 3.27-3.17 (m, 2H), 3.10 (s, 2H), 2.95-2.57 (m, 12H), 2.56-2.36 (m, 7H), 1.99-1.74 (m, 5H), 1.70 (s, 3H), 1.47-1.31 (m, 1H), 1.27 (d, J = 7.2 Hz, 3H), 1.19-1.07 (m, 1H).

[0399] Using a similar procedure, the following compounds were prepared:4-((1-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)-N-(4-((1-(3,4-dichlorophenyl)-4-methyl- 4,5-dihydro-1H-pyrazol-3-yl)amino)-4-oxobutyl)piperazine-1-carboxamide ((56))

[0400] Synthesis of methyl 4-isocyanatobutanoate : DIEA (5.05 g, 39.1 mmol) was added to a solution of methyl 4-aminobutanoate hydrochloride (2.00 g, 13.0 mmol) and triphosgene (1.55g., 5.21 mmol) in dichloromethane (20.0 mL) at 25 °C. After 2 h at 25 °C, the starting material was consumed and the solution of methyl 4-isocyanatobutanoate was used for next step without further purification.

[0401] Synthesis of tert-butyl 4-((4-((4-methoxy-4-oxobutyl)carbamoyl)piperazin-1- yl)methyl)piperidine-1-carboxylate: tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1- carboxylate (4.05 g, 14.3 mmol) and DIEA (3.36 g, 26.0 mmol) were added to the previously prepared solution of methyl 4-isocyanatobutanoate (1.86 g, 13.0 mmol) in dichloromethane (20.0 mL) at 25 °C. The mixture was stirred for 12 h at 25 °C. The solvent was removed under reduced pressure and the residue was purified by HPLC [Column: Waters xbridge 150*25mm 10µm, water (FA)-ACN, B%, 35–40, 10 min.] to give tert-butyl 4-((4-((4-methoxy-4- oxobutyl)carbamoyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (5.31 g, 12.3 mmol, 95% yield) as an orange solid. LCMS: calculated, 427.3; observed, 427.2 [M+H]+.

[0402] Synthesis of 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazine-1- carboxamido)butanoic acid: lithium hydroxide monohydrate (216 mg, 5.16 mmol) was added to a solution of tert-butyl 4-((4-((4-methoxy-4-oxobutyl)carbamoyl)piperazin-1- yl)methyl)piperidine-1-carboxylate (2.00 g, 4.69 mmol) in a mixture of tetrahydrofuran (20.0 mL) and water (20.0 mL) at 0 °C. After 2 h at 0 °C, aqueous HCl (1 mol / L) was added to adjust the pH = 4 and the reaction mixture was concentrated under vacuum to give the crude 4-(4-((1- (tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazine-1-carboxamido)butanoic acid (2.45 g, 5.52 mmol, crude) as a white solid. LCMS: calculated, 413.3; observed, 413.1 [M+H]+.

[0403] Synthesis of tert-butyl 4-((4-((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H- pyrazol-3-yl)amino)-4-oxobutyl)carbamoyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (A-330): HATU (899 mg, 2.36 mmol) was added to a solution of 4-(4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methyl)piperazine-1-carboxamido)butanoic acid (1.95 g, 4.73 mmol) in dimethylacetamide (7.96 mL) at 0°C. After 1h at 0°C, 1-(3,4-dichlorophenyl)-4-methyl- 4,5-dihydro-1H-pyrazol-3-amine (577 mg, 2.36 mmol) and DIEA (1.83 g, 14.2 mmol) were added and the reaction mixture was stirred at 25 °C for 3 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 6), dried with anhydrous sodium sulfate and concentrated under vacuum to give a residue which was purified by prep-HPLC (FA condition) to give tert-butyl 4-((4-((4-((1- (3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4- oxobutyl)carbamoyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (200 mg, 7% yield) (A-330) as a yellow solid. LCMS: calculated, 638.3; observed, 638.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ = 10.51 (s, 1H), 8.18 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 2.8, 8.8 Hz, 1H), 6.44 (t, J = 5.2 Hz, 1H), 4.00-3.76 (m, 4H), 3.71-3.58 (m, 3H), 3.25 (d,J = 4.4 Hz, 4H), 3.06-2.99 (m, 2H), 2.33-2.28 (m, 2H), 2.28-2.20 (m, 4H), 2.09 (d, J = 6.8 Hz, 2H), 1.71-1.59 (m, 5H), 1.39 (s, 9H), 1.17 (d, J = 7.2 Hz, 3H), 0.97-0.85 (m, 2H).

[0404] Using a similar procedure, the following compounds were prepared:

[0405] Synthesis of N-(4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3- yl)amino)-4-oxobutyl)-4-(piperidin-4-ylmethyl)piperazine-1-carboxamide: A solution of tert- butyl 4-((4-((4-((1-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)amino)-4- oxobutyl)carbamoyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (0.100 g, 157 µmol) and TFA (0.3 mL) in dichloromethane (0.9 mL) was stirred at 25 °C for 1 h. The mixture was concentrated to give the crude N-(4-...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 0, 1, 2, 3, 4, and 5; R2is hydrogen, or substituted or unsubstituted alkyl; R3is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; A is -X1-X2-X3-X4-; X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X2is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene; X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X4is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; L is a bond or a linker; B is a targeting moiety or a detectable moiety; andeach 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.

2. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 0, 1, 2, 3, 4, and 5; R2is hydrogen, or substituted or unsubstituted alkyl; R3is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; A is -X1-X2-X3-X4-; X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X2is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene; X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene;X4is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; L is a bond or a linker; T is hydrogen, 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.

3. A compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 0, 1, 2, 3, 4, and 5; Y1isR2is hydrogen, halogen, substituted or unsubstituted alkyl, -ORA, or -SRA; R3is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; A is -X1-X2-X3-X4-;X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X4is a bond, -N(RA)-, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; 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.

4. A compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2;n is an integer selected from 0, 1, 2, 3, 4, and 5; Y1isR2is hydrogen, halogen, substituted or unsubstituted alkyl, -ORA, or -SRA; R3is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; A is -X1-X2-X3-X4-; X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X2is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X4is a bond, -N(RA)-, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; L is a bond or a linker; T is hydrogen, 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.

5. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A comprises substituted or unsubstituted cyclopropylene, substituted or unsubstituted cyclobutylene, substituted or unsubstituted cyclopentylene, substituted or unsubstitutedcyclohexylene, substituted or unsubstituted aziridinylene, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted morpholinylene, substituted or unsubstituted thiomorpholinylene, substituted or unsubstituted diazepanylene, substituted or unsubstituted dihydropyrrolylene, substituted or unsubstituted tetrahydropyridinylene, substituted or unsubstituted pyrazolylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted dihydropyrrolopyrimidinylene, substituted or unsubstituted pyrazolopyrimidinylene, substituted or unsubstituted benzisoxazolylene, substituted or unsubstituted diazaspiro[3.3]heptanylene, substituted or unsubstituted diazaspiro[4.4]nonanylene, substituted or unsubstituted diazaspiro[4.5]decanylene, substituted or unsubstituted diazaspiro[5.5]undecanylene, substituted or unsubstituted oxa- diazaspiro[5.5]undecanylene, substituted or unsubstituted triazaspiro[5.5]undecanylene, substituted or unsubstituted tetrahydropyridopyrimidinylene, substituted or unsubstituted diazabicyclo[2.2.1]heptanylene, substituted or unsubstituted tetrahydropyrazolo[1,5- a]pyrazinylene, substituted or unsubstituted pyrazolo[4,3-c]pyridinylene, substituted or unsubstituted tetrahydropyrazolo[4,3-c]pyridinylene, or substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene.

6. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X2is substituted or unsubstituted cyclopropylene, substituted or unsubstituted cyclobutylene, substituted or unsubstituted cyclopentylene, substituted or unsubstituted cyclohexylene, substituted or unsubstituted aziridinylene, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted morpholinylene, substituted or unsubstituted thiomorpholinylene, substituted or unsubstituted diazepanylene, substituted or unsubstituted dihydropyrrolylene, substituted or unsubstituted tetrahydropyridinylene, substituted or unsubstituted pyrazolylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted dihydropyrrolopyrimidinylene, substituted or unsubstituted pyrazolopyrimidinylene, substituted or unsubstituted benzisoxazolylene, substituted or unsubstituted diazaspiro[3.3]heptanylene, substituted or unsubstituted diazaspiro[4.4]nonanylene, substituted or unsubstituted diazaspiro[4.5]decanylene, substituted or unsubstituted diazaspiro[5.5]undecanylene, substituted or unsubstituted oxa- diazaspiro[5.5]undecanylene, substituted or unsubstituted triazaspiro[5.5]undecanylene, substituted or unsubstituted tetrahydropyridopyrimidinylene, substituted or unsubstituteddiazabicyclo[2.2.1]heptanylene, substituted or unsubstituted tetrahydropyrazolo[l,5- a]pyrazinylene, substituted or unsubstituted pyrazolo[4,3-c]pyridinylene, substituted or unsubstituted tetrahydropyrazolo[4,3-c]pyridinylene, or substituted or unsubstituted tetrahydropyrazolo[ 1 ,5-a]pyrazinylene.

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

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

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

10. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein: A is, , ,11. A compound of Formula (V):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 0, 1, 2, 3, 4, and 5; R2is hydrogen, or substituted or unsubstituted alkyl; R3is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; A is -X1-X2-X3-X4-; X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X2is a substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, or substituted or unsubstituted pyrazinylene; X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X4is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; 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; provided that the compound is not of the following formula, or stereoisomer thereof:

12. A compound of Formula (VI):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 0, 1, 2, 3, 4, and 5; R2is hydrogen, or substituted or unsubstituted alkyl; R3is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group; A is -X1-X2-X3-X4-;X1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X2is a substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, or substituted or unsubstituted pyrazinylene; X3is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; X4is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; L is a bond or a linker; T is hydrogen, 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; provided that the compound is not of the following formula:,.

13. The compound of claim 11 or 12, or a pharmaceutically acceptable salt thereof, wherein:

14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X1is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene comprising -O- or -NRA-.

15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X1is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, or substituted or unsubstituted hetero-C1alkylene comprising -O- or -NRA-.

16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X3is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene comprising -O- or -NRA-.

17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X3is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, or substituted or unsubstituted hetero C1alkylene comprising -O- or -NRA-.

18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X4is a bond, substituted or unsubstituted phenylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted morpholinylene, or substituted or unsubstituted benzisoxazolylene.

19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R1is substituted or unsubstituted alkyl, halogen, hydroxy, or -O-(substituted or unsubstituted alkyl).

20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R1is chloro, methyl, fluoro, bromo, trifluoromethyl, or trifluoromethoxy.

21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:is 3,4-dichlorophenyl, 3-methyl-4-chlorophenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 3-bromophenyl, 2-fluoro-5-chlorophenyl, 3,5-dichlorophenyl, 2,4- dichlorophenyl,3-fluoro-4-chlorophenyl, 3-chloro-5-fluorophenyl, 2,5-dichlorophenyl, 2-fluoro- 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, or 2,3- dichlorophenyl.

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

23. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R2is hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, or substituted or unsubstituted butyl.

24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:R2is hydrogen, methyl, 2-hydroxyethyl, sec-butyl, or isopropyl.

25. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R3is hydrogen or substituted or unsubstituted methyl.

26. 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.

27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: L is substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -N(RA)-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)NRA-, -NRAC(=O)-, -C(=O)-, -NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2N(RA)-, or -NRAS(O)2-, or a combination thereof.

28. 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.

29. 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(H)-, -N(CH3)-, -O-, -N(H)C(=O)-, -N(CH3)C(=O)-, -C(=O)-, or a combination thereof.

30. 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)-, 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; Z3is 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.

31. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: L is of formula:, wherein: Z1is a bond, -O-, -N(RA)-, unsubstituted C1-6alkylene,, ,Z2is a bond, -N(RA)-, -NRAC(=O)-, -C(=O)-, -CH2-,Q is a bond,, , , ,Z3is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.

32. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: L is of formula:, wherein: Z1is a bond, -N(RA)-, unsubstituted C1-6alkylene,, ; 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.

33. 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-, or -C(=O)-; Z2is a bond; Qis a bond,, , , ,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.

34. 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-, or -C(=O)-; Z2is a bond; QisZ3is a bond, -C(=O)-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.

35. 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-, or -C(=O)-; Z2is 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.

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

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

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

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

40. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:L is of formula:,41. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:L is of formula:

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

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

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

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

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

47. The compound of claim 3, wherein the compound of Formula (III) is of Formula (III-A):or a pharmaceutically acceptable salt thereof.

48. The compound of claim 11, wherein the compound of Formula (V) is of Formula (V-A):or a pharmaceutically acceptable salt thereof.

49. The compound of claim 11, wherein the compound of Formula (V) is of Formula (V-B):or a pharmaceutically acceptable salt thereof.

50. The compound of claim 11, wherein the compound of Formula (V) is of Formula (V-B-1):or a pharmaceutically acceptable salt thereof.

51. The compound of claim 11, wherein the compound of Formula (V) is of Formula (V-B-2):or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

59. The compound of claim 11, wherein B is not of the formula, or stereoisomer thereof:

60. The compound of claim 12, wherein the compound is not of the formula:

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

62. The compound of claim 3, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.

63. The compound of claim 11, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.

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

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

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

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

68. The compound of claim 4, wherein the compound of Formula (IV) is of Formula (IV-A):or a pharmaceutically acceptable salt thereof.

69. The compound of claim 12, wherein the compound of Formula (VI) is of Formula (VI- A):or a pharmaceutically acceptable salt thereof.

70. The compound of claim 12, wherein the compound of Formula (VI) is of Formula (VI- B):or a pharmaceutically acceptable salt thereof.

71. The compound of claim 12, wherein the compound of Formula (VI) is of Formula (VI-B-1):or a pharmaceutically acceptable salt thereof.

72. The compound of claim 12, wherein the compound of Formula (VI) is of Formula (VI-B- 2):or a pharmaceutically acceptable salt thereof.

73. 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.

74. 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.

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

76. The compound of claim 4, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.

77. The compound of claim 12, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.

78. A compound selected from:or a pharmaceutically acceptable salt thereof, wherein:B is a targeting moiety or a detectable moiety.

79. A compound selected from:or a pharmaceutically acceptable salt thereof, wherein:B is a targeting moiety or a detectable moiety.

80. A compound selected from:or a pharmaceutically acceptable salt thereof, wherein:T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle.

81. A compound selected from:or a pharmaceutically acceptable salt thereof, wherein:T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle.

82. The compound of claim 78, selected from:or a pharmaceutically acceptable salt thereof.

83. The compound of claim 79, selected from:or a pharmaceutically acceptable salt thereof.

84. The compound of claim 80, selected from:or a pharmaceutically acceptable salt thereof.

85. A compound selected from:or a pharmaceutically acceptable salt thereof.

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

87. 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 86, to a mixture that comprises ABL1 and the target substrate.

88. The method of claim 87, 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 ABL1 and the target substrate but without the compound.

89. The method of claim 87 or 88, wherein the amount of phosphorylation is measured at a specified time.

90. 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 86.

91. The method of claim 90, wherein the target substrate is a protein.

92. 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 86.

93. The method of claim 92, wherein the protein kinase is ABL1.

94. The method of any of claims 87-93, wherein the phosphorylation or modulation is in a cell.

95. The method of any of claims 87-92, wherein the phosphorylation or modulation is in a biological sample.

96. The method of any of claims 87-93, wherein the target substrate is a kinase or a phosphatase.

97. The method of any of claims 87-96, wherein the target substrate is KRAS or mutant thereof, BRD4, BRD2, BRD3, BET, BRDT, CAII, TRIM24, or BTK.

98. A kit comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 84; and instructions for use.

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