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WO2025122865A1 - Composés bifonctionnels de liaison à l'abl1 et leurs utilisations - Google Patents

Composés bifonctionnels de liaison à l'abl1 et leurs utilisations Download PDF

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WO2025122865A1
WO2025122865A1 PCT/US2024/058859 US2024058859W WO2025122865A1 WO 2025122865 A1 WO2025122865 A1 WO 2025122865A1 US 2024058859 W US2024058859 W US 2024058859W WO 2025122865 A1 WO2025122865 A1 WO 2025122865A1
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substituted
unsubstituted
compound
pharmaceutically acceptable
acceptable salt
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Florence Fevrier WAGNER
Dominique Potin
Alexandria P. TAYLOR
Moses Moustakim
Julia N. DOOLEY
Giovanni MUNCIPINTO
Alexander W. HIRD
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Photys Therapeutics Inc
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Photys Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • 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.
  • 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.
  • ABL1 Tyrosine-protein kinase ABL1
  • ABL1 formerly known as ABL
  • ABL1 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.
  • PHICS phosphorylation-inducing chimeric small molecules
  • 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.
  • Phosphorylation of any given target substrate 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.
  • PHICS compounds which 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.
  • 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.
  • a detectable moiety e.g., a chromophore, dye, fluorophore, luminophore or luminescent material, or radioactive material
  • 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.
  • compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R 1 , n, R 2 , R 3 , A, and L are as provided herein and B is a targeting moiety or a detectable moiety.
  • compounds of Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R 1 , n, R 2 , R 3 , 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.
  • compounds of Formula (III) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Y 1 , R 1 , n, R 3 , A, and L are as provided herein and B is a targeting moiety or a detectable moiety.
  • compounds of Formula (IV) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Y 1 , R 1 , n, R 3 , 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.
  • R 1 , n, R 2 , R 3 , A, and L are as provided herein and B is a targeting moiety or a detectable moiety.
  • compounds of Formula (VI) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R 1 , n, R 2 , R 3 , 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.
  • 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.
  • a compound e.g., PHICS
  • a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient e.g., PHICS
  • 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.
  • a target substrate e.g., protein
  • ABL1 a target substrate
  • 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.
  • a protein kinase 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.
  • the protein kinase is ABL1.
  • 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.
  • the kit further comprises instructions for administration and/or use.
  • FIG. 1 depicts Abl phosphorylation for a variety of PHICS: (3)-(9) and (13)-(20).
  • 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.
  • FIG. 2 depicts Abl phosphorylation for a variety of PHICS: (21)-(34, (48), (50), (51), and (54).
  • 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.
  • FIG.3 depicts Abl phosphorylation for a variety of PHICS: (35)-(46).
  • 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.
  • stereocenters labeled with “abs” indicate known absolute stereochemistry
  • stereocenters labeled with “& 1 ” indicate a mixture of the two trans or cis stereoisomers
  • stereocenters labeled with “or 1 ” indicate a single stereoisomer with unknown absolute stereochemistry.
  • In a formula is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, is absent or a single bond, and is a single or double bond.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • C 1-6 alkyl is intended to encompass C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
  • aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C 1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n- butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3- methyl-2-butanyl, tertiary amyl), and hexyl (C 6 ) (e.g., n-hexyl).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C 1-10 alkyl (such as unsubstituted C 1-6 alkyl, e.g., ⁇ CH 3 (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)).
  • unsubstituted C 1-6 alkyl such as unsubstituted C 1-6 alkyl, e.g., ⁇ CH 3 (Me),
  • the alkyl group is a substituted C 1-10 alkyl (such as substituted C 1-6 alkyl, e.g., ⁇ CF 3 , Bn).
  • haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 8 carbon atoms (“C 1-8 haloalkyl”).
  • the haloalkyl moiety has 1 to 6 carbon atoms (“C 1-6 haloalkyl”).
  • the haloalkyl moiety has 1 to 4 carbon atoms (“C 1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C 1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C 1-2 haloalkyl”). Examples of haloalkyl groups include –CHF 2 , ⁇ CH 2 F, ⁇ CF 3 , ⁇ CH 2 CF 3 , ⁇ CF 2 CF 3 , ⁇ CF 2 CF 2 CF 3 , ⁇ CCl 3 , ⁇ CFCl 2 , ⁇ CF 2 Cl, and the like.
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-20 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-18 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-16 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-14 alkyl”). 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 (“heteroC 1-12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-10 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-3 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups.
  • each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
  • the heteroalkyl group is an unsubstituted heteroC 1-2 0 alkyl.
  • the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl.
  • the heteroalkyl group is a substituted heteroC 1-20 alkyl.
  • the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl.
  • 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).
  • an alkenyl group has 2 to 9 carbon atoms (“C 2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C 2-8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C 2-7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms (“C 2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2- propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • the alkenyl group is an unsubstituted C 2-10 alkenyl.
  • the alkenyl group is a substituted C 2-10 alkenyl.
  • heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkenyl”).
  • a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkenyl”). 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 (“heteroC 2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkenyl”).
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkenyl”). 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 (“heteroC 2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-4 alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkenyl”). 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 (“heteroC 2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC 2-10 alkenyl.
  • the heteroalkenyl group is a substituted heteroC 2-10 alkenyl.
  • 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) (“C 2-10 alkynyl”).
  • an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms (“C 2-7 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.
  • the alkynyl group is an unsubstituted C 2-10 alkynyl.
  • the alkynyl group is a substituted C 2-10 alkynyl.
  • heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkynyl”).
  • a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-8 alkynyl”). 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 (“heteroC 2-7 alkynyl”).
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-4 alkynyl”).
  • a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkynyl”). 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 (“heteroC 2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents.
  • the heteroalkynyl group is an unsubstituted heteroC 2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 alkynyl.
  • the term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclyl”).
  • a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”).
  • Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3-10 carbocyclyl groups include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system, such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3 -14 carbocyclyl.
  • the carbocyclyl group is a substituted C 3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3-14 cycloalkyl”).
  • a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”).
  • a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is an unsubstituted C 3 -14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C 3-14 cycloalkyl.
  • 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.
  • each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”).
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • 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
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • aromatic ring system e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is an unsubstituted C 6-14 aryl.
  • the aryl group is a substituted C 6-14 aryl.
  • “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- 14 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • 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”).
  • 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”).
  • 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”).
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • 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.
  • 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.
  • saturated refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • 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 “unsub
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the invention is not intended to be limited in any manner by the exemplary substituents described herein.
  • halo or halogen refers to fluorine (fluoro, ⁇ F), chlorine (chloro, ⁇ Cl), bromine (bromo, ⁇ Br), or iodine (iodo, ⁇ I).
  • hydroxyl or “hydroxy” refers to the group ⁇ OH.
  • amino refers to the group ⁇ NH 2 .
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from ⁇ N(R bb ) 3 and ⁇ N(R bb ) 3 + X ⁇ , wherein R bb and X ⁇ are as defined herein.
  • acyl groups include aldehydes ( ⁇ CHO), carboxylic acids ( ⁇ CO 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyl
  • sil refers to the group –Si(R aa ) 3 , wherein R aa is as defined herein.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Nitrogen protecting groups such as carbamate groups 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- methyle
  • Nitrogen protecting groups such as sulfonamide groups 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), methane
  • Ts p-toluenesulfonamide
  • Mtr 2,
  • 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, pheno
  • 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).
  • Bn benzyl
  • BOC tert-butyloxycarbonyl
  • Cbz carbobenzyloxy
  • Fmoc 9-flurenylmethyloxycarbony
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • 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 (MT), methyl,
  • an oxygen protecting group is silyl.
  • 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), tetra
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”).
  • a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine- sulfenyl, or triphenylmethyl.
  • 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 – ), NO 3 – , ClO 4 – , OH – , H 2 PO 4 – , HCO 3 ⁇ , HSO 4 – , 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.,
  • Exemplary counterions which may be multivalent include CO 3 2 ⁇ , HPO 4 2 ⁇ , PO 4 3 ⁇ , B 4 O 7 2 ⁇ , SO 4 2 ⁇ , S 2 O 3 2 ⁇ , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate,
  • 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.
  • halogen such as F, Cl, Br, or I (iodine
  • the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy.
  • 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.
  • phosphineoxide e.g., formed during a Mitsunobu reaction
  • 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.
  • non-hydrogen group refers to any group that is defined for a particular variable that is not hydrogen.
  • salt refers to any and all salts, and encompasses pharmaceutically acceptable salts.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl) 4 ⁇ salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • “Solvate” encompasses both solution- phase and isolatable solvates.
  • Representative solvates include hydrates, ethanolates, and methanolates.
  • 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 H 2 O, 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 H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H 2 O) and hexahydrates (R ⁇ 6 H 2 O)).
  • monohydrates x is 1
  • lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O)
  • polyhydrates x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H 2 O) and hexahydrates (R ⁇ 6 H 2 O)
  • 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.
  • isomers compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the term “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.
  • 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.
  • a “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • a human i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal.
  • the subject may also be a plant. In certain embodiments, the plant is a land plant.
  • 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.
  • tissue sample refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection) or samples of cells obtained by microdissection
  • samples of whole organisms such as samples of yeasts or bacteria
  • cell fractions, fragments or organelles such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise.
  • biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
  • 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.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into a biological system.
  • an “effective amount” of a compound described herein refers to an amount sufficient to elicit a desired outcome (e.g., induce phosphorylation of a target substrate).
  • An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint (e.g., extent of phosphorylation) and the nature of the biological sample.
  • 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.).
  • 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.
  • 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.
  • the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S.
  • the small molecule may also be complexed with one or more metal atoms and/or metal ions.
  • 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.
  • the small molecule is a drug.
  • 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.
  • targeting moiety refers to any chemical entity that serves to bind or otherwise direct the compound to a particular location or association.
  • 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.
  • 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.
  • the bioactive moiety is a small molecule.
  • the bioactive moiety is a peptide or protein.
  • the bioactive moiety is an FDA-approved drug.
  • 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.
  • 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.
  • 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).
  • a target substrate e.g., protein
  • compounds that act as chemical probes having a detectable moiety e.g., luminescent materials, such as dyes
  • compounds useful in the production and manufacture of the bifunctional compounds and probes described herein are also provided herein.
  • 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.
  • the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, tautomers thereof, and stereoisomers, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, and tautomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.
  • 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.
  • the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, and tautomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.
  • 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.
  • the disclosure provides compounds of Formula (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (III), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (III), and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (III), and pharmaceutically acceptable salts, and tautomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (III), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.
  • 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.
  • the disclosure provides compounds of Formula (IV), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (IV), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (IV), and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (IV), and pharmaceutically acceptable salts, and tautomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (IV), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. [00107] 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.
  • the disclosure provides compounds of Formula (V), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (V), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (V), and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (V), and pharmaceutically acceptable salts, and tautomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (V), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.
  • 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.
  • the disclosure provides compounds of Formula (VI), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (VI), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (VI), and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (VI), and pharmaceutically acceptable salts, and tautomers thereof, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula (VI), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.
  • 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.
  • 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.
  • 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.
  • the disclosure provides additional compounds (i.e., not of Formula (I), (II), (III), (IV), (V), (VI)), and pharmaceutically acceptable salts and tautomers thereof, and pharmaceutical compositions thereof.
  • 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.
  • the compounds of the disclosure 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,
  • R 1 is hydrogen, substituted or unsubstituted alkyl, halogen, hydroxy, or -O-(substituted or unsubstituted alkyl). In some embodiments, R 1 is substituted or unsubstituted alkyl, halogen, hydroxy, or -O-(substituted or unsubstituted alkyl). In certain embodiments, R 1 is chloro, methyl, fluoro, bromo, trifluoromethyl, or trifluoromethoxy. [00115] In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is halogen. In some embodiments, R 1 is substituted or unsubstituted alkyl.
  • R 1 is haloalkyl. In some embodiments, R 1 is hydroxy. In some embodiments, R 1 is or -O-(unsubstituted alkyl). In some embodiments, R 1 is or -O-(haloalkyl). [00116] In certain embodiments, R 1 is hydrogen or halogen. In some embodiments, R 1 is substituted or unsubstituted alkyl or hydrogen. In some embodiments, R 1 is substituted or unsubstituted alkyl or halogen.
  • Y1 is in some embodiments of Formula (III) and (IV), Y 1 is In some embodiments of Formula (III) and (IV), Y 1 is n [00121] 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.
  • R 2 is hydrogen or substituted or unsubstituted alkyl, or R 2 is hydrogen, halogen, substituted or unsubstituted alkyl, -OR A , or -SR A .
  • R 2 is hydrogen.
  • R 2 is halogen.
  • R 2 is chloro, bromo, iodo, or fluoro.
  • R 2 is bromo.
  • R 2 is substituted or unsubstituted alkyl.
  • R 2 is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, or substituted or unsubstituted butyl. In certain embodiments, R 2 is substituted or unsubstituted methyl. In some embodiments, R 2 is substituted or unsubstituted ethyl. In certain embodiments, R 2 is substituted or unsubstituted propyl (e.g., n-propyl, iso- propyl). In some embodiments, R 2 is substituted or unsubstituted butyl (n-butyl, tert-butyl, sec- butyl).
  • R 2 is hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, or substituted or unsubstituted butyl. In certain embodiments, R 2 is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted butyl. In certain embodiments, R 2 is hydrogen, substituted methyl, substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R 2 is hydrogen, methyl, 2-hydroxyethyl, sec-butyl, or isopropyl.
  • R 2 is hydrogen or unsubstituted methyl.
  • R 2 is -OR A .
  • R 2 is -OH.
  • R 2 is -O(substituted or unsubstituted C 1-6 alkyl).
  • R 2 is - O(C 1-6 alkyl).
  • R 2 is -SR A .
  • R 2 is -SH.
  • R 2 is -S(substituted or unsubstituted C 1-6 alkyl).
  • R 2 is -S(C 1- 6 alkyl).
  • the carbon to which R 2 is attached is in an (R) configuration. In certain embodiments, the carbon to which R 2 is attached is in an (S) configuration.
  • R 3 [00130] As described herein, R 3 is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group. In some embodiments, R 3 is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 3 is hydrogen or substituted or unsubstituted methyl. [00131] In certain embodiments, R 3 is hydrogen. [00132] In some embodiments, R 3 is substituted or unsubstituted alkyl. In some embodiments, R 3 is substituted or unsubstituted methyl.
  • R 3 is substituted methyl. In some embodiments, R 3 is unsubstituted methyl. In certain embodiments, R 3 is nitrogen protecting group.
  • A is -X 1 -X 2 -X 3 -X 4 -, wherein X 1 , X 2 , X 3 , and X 4 are as defined herein.
  • 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.
  • A comprises substituted or unsubstituted, saturated or partially unsaturated heterocyclylene.
  • A comprises substituted or unsubstituted, saturated or partially unsaturated carbocyclylene.
  • A comprises substituted or unsubstituted 5-membered heteroarylene.
  • A comprises substituted or unsubstituted bicyclic heteroarylene.
  • A comprises substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene.
  • A comprises substituted or unsubstituted heterocyclylene.
  • A comprises substituted or unsubstituted carbocyclylene.
  • A comprises substituted or unsubstituted 5-membered heteroarylene.
  • A comprises substituted or unsubstituted bicyclic heteroarylene.
  • 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.
  • 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.
  • 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 or unsubstituted piperidinylene; saturated or partially unsaturated, substituted or unsubstituted piperazinylene; saturated or partially unsaturated, substituted or unsubstituted morpholinylene; saturated or partially unsatur
  • 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 tetrahydropyridin
  • A comprises: , , , [00142] In some embodiments of Formulae (I), (II), (III), and (IV), A is , ,
  • A comprises
  • A is , [00144] In some embodiments of Formulae (I), (II), (III), and (IV), A is , , [00145] In some embodiments of Formulae (I), (II), (III), and (IV), A comprises [00146] In some embodiments of Formulae (I), (II), (III), and (IV), A is , [00147] In certain embodiments of Formulae (III) and (IV), A comprises , [00148] 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.
  • A comprises , X 1 [00149]
  • X 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene.
  • X 1 is a bond.
  • X 1 is substituted or unsubstituted alkylene.
  • X 1 is substituted or unsubstituted alkenylene.
  • X 1 is substituted or unsubstituted heteroalkylene.
  • X 1 is substituted or unsubstituted heteroalkenylene.
  • X 1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene comprising -O- or -NR A -.
  • X 1 is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, or substituted or unsubstituted hetero-C 1 alkylene comprising -O- or -NR A -.
  • X 1 is a bond.
  • X 1 is substituted or unsubstituted alkylene. In certain embodiments, X 1 is substituted or unsubstituted C 1-4 alkylene. In certain embodiments, X 1 is substituted or unsubstituted methylene. In certain embodiments, X 1 is unsubstituted methylene. In certain embodiments, X 1 is substituted or unsubstituted ethylene. In certain embodiments, X 1 is substituted or unsubstituted propylene. In certain embodiments, X 1 is substituted or unsubstituted butylene.
  • X 1 is substituted or unsubstituted heteroalkylene comprising - O- or -NR A -. In some embodiments, X 1 is substituted or unsubstituted hetero-C 1 alkylene comprising -O- or -NR A -. In some embodiments, X 1 is substituted or unsubstituted -methylene-O- , -O-methylene-, -NH-methylene-, -methylene-NH-, -N(Me)-methylene-, or -methylene-N(Me)-.
  • X 2 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene.
  • X 2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene.
  • X 2 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene.
  • X 2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene.
  • X 2 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene.
  • X 2 is a substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, or substituted or unsubstituted pyrazinylene.
  • X 2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene.
  • X 2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene.
  • X 2 is a substituted or unsubstituted heterocyclylene. In certain embodiments of Formula (I) and (II), X 2 is a substituted or unsubstituted carbocyclylene. In certain embodiments of Formula (I) and (II), X 2 is a substituted or unsubstituted 5-membered heteroarylene. In certain embodiments of Formula (I) and (II), X 2 is a substituted or unsubstituted bicyclic heteroarylene.
  • X 2 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene.
  • X 2 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene.
  • X 2 is 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.
  • X 2 is 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.
  • X 2 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene.
  • X 2 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted 5-membered heteroarylene, or substituted or unsubstituted bicyclic heteroarylene.
  • X 2 is a bond.
  • X 2 is a substituted or unsubstituted heterocyclylene. In some embodiments of Formula (III) and (IV), X 2 is a substituted or unsubstituted carbocyclylene. In some embodiments of Formula (III) and (IV), X 2 is a substituted or unsubstituted heteroarylene. In some embodiments of Formula (III) and (IV), X 2 is a substituted or unsubstituted 5-membered heteroarylene. In some embodiments of Formula (III) and (IV), X 2 is a substituted or unsubstituted bicyclic heteroarylene.
  • X 2 is a substituted or unsubstituted arylene.
  • X 2 is 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
  • X 2 is saturated or partially unsaturated, substituted or unsubstituted cyclopropylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted cyclobutylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted cyclopentylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted cyclohexylene. In some embodiments, X 2 is substituted or unsubstituted aziridinylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted azetidinylene.
  • X 2 is saturated or partially unsaturated, substituted or unsubstituted pyrrolidinylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted piperidinylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted piperazinylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted morpholinylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted thiomorpholinylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted diazepanylene.
  • X 2 is substituted or unsubstituted pyrazolylene. In some embodiments, X 2 is substituted or unsubstituted imidazolylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted dihydropyrrolopyrimidinylene. In some embodiments, X 2 is substituted or unsubstituted pyrazolopyrimidinylene, substituted or unsubstituted benzisoxazolylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted diazaspiro[3.3]heptanylene.
  • X 2 is saturated or partially unsaturated, substituted or unsubstituted diazaspiro[4.4]nonanylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted diazaspiro[4.5]decanylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted diazaspiro[5.5]undecanylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted oxa- diazaspiro[5.5]undecanylene.
  • X 2 is saturated or partially unsaturated, substituted or unsubstituted triazaspiro[5.5]undecanylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted tetrahydropyridopyrimidinylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted diazabicyclo[2.2.1]heptanylene. In some embodiments, X 2 is saturated or partially unsaturated, substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene.
  • X 2 is saturated or partially unsaturated, substituted or unsubstituted tetrahydropyrazolo[4,3- c]pyridinylene. In some embodiments, X 2 is saturated or partially unsaturated, or substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene.
  • X 2 is 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
  • X 2 is substituted or unsubstituted aziridinylene. In some embodiments, X 2 is substituted or unsubstituted cyclopropylene. In some embodiments, X 2 is substituted or unsubstituted cyclobutylene. In some embodiments, X 2 is substituted or unsubstituted cyclopentylene. In some embodiments, X 2 is substituted or unsubstituted cyclohexylene. In some embodiments, X 2 is substituted or unsubstituted azetidinylene. In some embodiments, X 2 is substituted or unsubstituted pyrrolidinylene.
  • X 2 is substituted or unsubstituted piperidinylene. In some embodiments, X 2 is substituted or unsubstituted piperazinylene. In some embodiments, X 2 is substituted or unsubstituted morpholinylene. In some embodiments, X 2 is substituted or unsubstituted thiomorpholinylene. In some embodiments, X 2 is substituted or unsubstituted diazepanylene. In some embodiments, X 2 is substituted or unsubstituted dihydropyrrolylene. In some embodiments, X 2 is substituted or unsubstituted tetrahydropyridinylene.
  • X 2 is substituted or unsubstituted pyrazolylene. In some embodiments, X 2 is substituted or unsubstituted imidazolylene. In some embodiments, X 2 is substituted or unsubstituted dihydropyrrolopyrimidinylene. In some embodiments, X 2 is substituted or unsubstituted pyrazolopyrimidinylene. In some embodiments, X 2 is substituted or unsubstituted benzisoxazolylene. In some embodiments, X 2 is substituted or unsubstituted diazaspiro[3.3]heptanylene.
  • X 2 is substituted or unsubstituted diazaspiro[4.4]nonanylene. In some embodiments, X 2 is substituted or unsubstituted diazaspiro[4.5]decanylene. In some embodiments, X 2 is substituted or unsubstituted diazaspiro[5.5]undecanylene. In some embodiments, X 2 is substituted or unsubstituted oxa- diazaspiro[5.5]undecanylene. In some embodiments, X 2 is substituted or unsubstituted triazaspiro[5.5]undecanylene.
  • X 2 is substituted or unsubstituted tetrahydropyridopyrimidinylene. In some embodiments, X 2 is substituted or unsubstituted diazabicyclo[2.2.1]heptanylene. In some embodiments, X 2 is substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene. In some embodiments, X 2 is substituted or unsubstituted pyrazolo[4,3-c]pyridinylene. In some embodiments, X 2 is substituted or unsubstituted tetrahydropyrazolo[4,3-c]pyridinylene. In some embodiments, X 2 is substituted or unsubstituted tetrahydropyrazolo[1,5-a]pyrazinylene. [00160] In some embodiments of Formula (I)-(IV), X 2 is substituted or unsubstituted tetrahydropyra
  • X 2 is , , , ,
  • X 2 is a substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, or substituted or unsubstituted pyrazinylene.
  • X 2 is a substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, or substituted or unsubstituted pyrazinylene.
  • X 2 is a substituted or unsubstituted pyridinylene. In some embodiments of Formula (V) and (VI), X 2 is a substituted or unsubstituted pyridazinylene. In some embodiments of Formula (V) and (VI), X 2 is a substituted or unsubstituted pyrimidinylene. In some embodiments of Formula (V) and (VI), X 2 is a substituted or unsubstituted pyrazinylene.
  • X 2 is [00165] In some embodiments of Formula (V) and (VI), X 2 is [00166] In some embodiments of Formula (V) and (VI), X 2 is In some [00167] In some embodiments of Formula (V) and (VI), X 2 is , ,
  • X 3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene. In some embodiments, X 3 is a bond. In certain embodiments, X 3 is substituted or unsubstituted alkylene. In certain some, X 3 is substituted or unsubstituted alkenylene. In certain embodiments, X 3 is substituted or unsubstituted heteroalkylene. In some embodiments, X 3 is substituted or unsubstituted heteroalkenylene.
  • X 3 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene comprising -O- or -NR A -.
  • X 3 is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, or substituted or unsubstituted hetero-C 1 alkylene comprising -O- or -NR A -.
  • X 3 is a bond.
  • X 3 is substituted or unsubstituted alkylene.
  • X 3 is substituted or unsubstituted C 1-4 alkylene. In certain embodiments, X 3 is substituted or unsubstituted methylene. In certain embodiments, X 3 is unsubstituted methylene. In certain embodiments, X 3 is substituted or unsubstituted ethylene. In certain embodiments, X 3 is substituted or unsubstituted propylene. In certain embodiments, X 3 is substituted or unsubstituted butylene. [00173] In certain embodiments, X 3 is substituted or unsubstituted heteroalkylene comprising -O- or -NR A -.
  • X 3 is substituted or unsubstituted hetero-C 1 alkylene comprising -O- or -NR A -. In some embodiments, X 3 is substituted or unsubstituted -methylene-O- , -O-methylene-, -NH-methylene-, -methylene-NH-, -N(Me)-methylene-, or -methylene-N(Me)-.
  • X 4 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene. In some embodiments, X 4 is a bond. In some embodiments, X 4 is substituted or unsubstituted heterocyclylene. In some embodiments, X 4 is substituted or unsubstituted carbocyclylene. In some embodiments, X 4 is substituted or unsubstituted heteroarylene.
  • X 4 is substituted or unsubstituted arylene. In some embodiments, X 4 is a bond, substituted or unsubstituted phenylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted morpholinylene, or substituted or unsubstituted benzisoxazolylene. In some embodiments, X 4 is substituted or unsubstituted phenylene. In some embodiments, X 4 is substituted or unsubstituted piperidinylene. In some embodiments, X 4 is substituted or unsubstituted morpholinylene.
  • 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.
  • L is a chain of at least 5 contiguous atoms. In certain embodiments, L is a chain of at least 6 contiguous atoms. In certain embodiments, L is a chain of at least 7 contiguous atoms. In certain embodiments, L is a chain of at least 8 contiguous atoms. In certain embodiments, L is a chain of at least 9 contiguous atoms. In certain embodiments, L is a chain of at least 10 contiguous atoms. In certain embodiments, L is a chain of at least 11 contiguous atoms. In certain embodiments, L is a chain of at least 12 contiguous atoms. In certain embodiments, L is a chain of at least 13 contiguous atoms.
  • 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. [00176] 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.
  • Z 1 is a bond, -O-, -N(R A )-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In some embodiments, Z 1 is a bond. In some embodiments, Z 1 is -O-. In some embodiments, Z 1 is -N(R A )-. In some embodiments, Z 1 is -N(H)-. In some embodiments, Z 1 is -N(CH 3 )-. In some embodiments, Z 1 is substituted or unsubstituted alkylene. In some embodiments, Z 1 is substituted or unsubstituted methylene.
  • Z 1 is substituted or unsubstituted ethylene. In some embodiments, Z 1 is substituted or unsubstituted heteroalkylene. In some embodiments, Z 1 is substituted or unsubstituted hetero-C 1 -alkylene comprising -O- or -N(R A )-. In some embodiments, Z 1 is substituted or unsubstituted hetero-C 2 -alkylene comprising -O- or -N(R A )-. In some embodiments, Z 1 is substituted or unsubstituted hetero-C 3 -alkylene comprising -O- or -N(R A )-.
  • Z 1 is a repeating substituted or unsubstituted hetero-C 3 -alkylene comprising -O- or -N(R A )-.
  • Z 2 is a bond.
  • Z 2 is -O-.
  • Z 2 is -N(R A )-.
  • Z 2 is -N(H)-.
  • Z 2 is substituted or unsubstituted 6-membered heterocyclylene. In some embodiments, Z 2 is substituted or unsubstituted piperidinylene or substituted or unsubstituted piperazinylene.
  • Q is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene. [00187] 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.
  • Q is substituted or unsubstituted hetero-C 1 -alkylene comprising -O- or -N(R A )-. In some embodiments, Q is substituted or unsubstituted hetero-C 2 - alkylene comprising -O- or -N(R A )-. In some embodiments, Q is substituted or unsubstituted hetero-C 3 -alkylene comprising -O- or -N(R A )-. In some embodiments, Q is a repeating substituted or unsubstituted hetero-C 3 -alkylene comprising -O- or -N(R A )-.
  • Z 2 is a bond
  • t is 0-20
  • u is 0-6; provided that L comprises at least one atom.
  • L is of formula: , , , , In some embodiments, L is of formula: . In some embodiments, L is of formula:
  • L is of formula: .
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula:
  • L is of formula: In some embodiments, L is of [00221] In some embodiments, L is of formula: [00222] In certain embodiments, L is of formula: [00223] 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.
  • 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. [00224] In some embodiments, L is of formula: [00225] In certain embodiments, L is of formula:
  • L is of formula: In some embodiments, L is of
  • L is of formula:
  • L is: . [00229] In certain embodiments, L is: , , [00230] In certain embodiments, L is In certain embodiments, L is , [00231] In some embodiments, L is of formula: , , [00232] In some embodiments, L is . In some embodiments, L is . [00233] In some embodiments, L is selected from any one of L1-L77:
  • L is selected from any one of L78-L251: [00235] 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.
  • each occurrence of R A is, 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 R A groups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
  • each occurrence of R A is, 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 R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
  • each occurrence of R A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.
  • each occurrence of R A is, 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 R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
  • each occurrence of R A is, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
  • each occurrence of R A is, independently, hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 5-6 membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
  • each occurrence of R A is, independently, hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-30 heteroalkyl, substituted or unsubstituted 5-6 membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
  • each occurrence of R A is, independently, hydrogen, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 1-30 heteroalkyl.
  • each occurrence of R A is, independently, hydrogen, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 1-20 heteroalkyl.
  • each occurrence of R A is, independently, hydrogen, or substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R A is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R A is substituted or unsubstituted alkyl. In certain embodiments, R A is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R A is unsubstituted C 1-4 alkyl.
  • R A is t-butyl. In certain embodiments, R A is methyl. In certain embodiments, R A is t-butyl, n-butyl, n-propyl, iso-propyl, ethyl, methyl, or hydrogen. In certain embodiments, R A is methyl. In certain embodiments, R A is t-butyl, methyl, or hydrogen. In certain embodiments, R A is t-butyl or hydrogen. In certain embodiments, R A is hydrogen. In certain embodiments, R A is substituted or unsubstituted hydroxyl. [00246] In certain embodiments, each occurrence of R A is independently hydrogen, unsubstituted alkyl, or haloalkyl.
  • each occurrence of R A is independently hydrogen, unsubstituted C 1-6 alkyl, or C 1-6 haloalkyl. In certain embodiments, each occurrence of R A is independently hydrogen, unsubstituted C 1-4 alkyl, or C 1-4 haloalkyl. In certain embodiments, each occurrence of R A is independently hydrogen, unsubstituted C 1-2 alkyl, or C 1-2 haloalkyl. In certain embodiments, each occurrence of R A is independently hydrogen, -CH 3 , -CF 3 , -CHF 2 , or - CH 2 F.
  • B is a targeting moiety or detectable moiety (e.g., a chromophore, dye, fluorophore, luminophore or luminescent material, or radioactive material).
  • B is a detectable moiety (e.g., a chromophore, dye, fluorophore, luminophore or luminescent material, or radioactive material).
  • B is a dye.
  • B is a targeting moiety.
  • the targeting moiety is a bioactive moiety.
  • the targeting moiety is a protein-binding moiety.
  • the targeting moiety binds an enzyme.
  • the luminescent material is a phosphorescent agent.
  • the targeting moiety provides a means for recruiting, binding, modulating, modifying, inhibiting, and/or associating the compound with a target substrate.
  • the target substrate is a biomolecule.
  • the target substrate is a polypeptide, a polynucleotide, or a polysaccharide.
  • the target substrate is a protein.
  • B is a ligand, binder, modulator, modifier, and/or inhibitor of a protein.
  • B is a protein-binding moiety.
  • B is an inhibitor of a protein.
  • B is an inhibitor of an enzyme.
  • 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.
  • 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.
  • the target substrate e.g., protein
  • the target substrate is not a natural substrate of the kinase to which the compound also binds.
  • 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.
  • the compounds disclosed herein include a moiety that binds to a kinase, such as ABL1, and a targeting moiety that binds to a phosphatase.
  • 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.
  • B is a BTK-binding moiety.
  • B is a bromodomain and extra-terminal domain (BET)-binding moiety.
  • 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.
  • 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.
  • a bromodomain-containing protein e.g., BRD2, BRD3, BRD4,
  • CTSB cerebrospinal bovine serum
  • 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 integrated membrane protein 2B
  • CTSD cathepsin D
  • NOTCH1 Notch homolog 1, translocation- associated
  • TNF tumor necrosis factor (TNF superfamily, member 2
  • INS insulin
  • DYT10 DYT10
  • 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
  • B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with KRAS, BRD4, CAII, TRIM24, BTK, BET, BRD2, BRD3, or BRDT.
  • B is a ligand, recruiter, binder, modulator, modifier, inhibitor, activator, and/or associator of KRAS, BRD4,
  • B is a ligand, recruiter, binder, modulator, modifier, inhibitor, activator, and/or associator of BRD4 or BTK.
  • B is an inhibitor of KRAS, BRD4, CAII, TRIM24, or BTK.
  • B is an inhibitor of
  • BRD4 or BTK 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.
  • 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 of
  • 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.
  • B is a KRAS-binding moiety, a kinase-binding moiety or a phosphatase-binding moiety. [00255] In certain embodiments, B is of formula: or a pharmaceutically acceptable salt thereof. [00256] In certain embodiments, B is of formula: or a pharmaceutically acceptable salt thereof.
  • B is of formula: or a pharmaceutically acceptable salt thereof.
  • B is of formula: or a pharmaceutically acceptable salt thereof.
  • B is of formula: or a pharmaceutically acceptable salt thereof.
  • B is of formula: or a pharmaceutically acceptable salt thereof.
  • B is of formula: or a pharmaceutically acceptable salt thereof.
  • B is of formula: or a pharmaceutically acceptable salt thereof.
  • B is of formula: or a pharmaceutically acceptable salt thereof.
  • B is a detectable moiety.
  • B is a chromophore.
  • B is a dye.
  • B is a fluorophore.
  • B is a luminophore.
  • B is a luminescent material.
  • B is a radioactive material.
  • B is a dye.
  • B is a fluorescent dye.
  • B is of formula: , , , or a pharmaceutically acceptable salt thereof.
  • B is of formula: , or a pharmaceutically acceptable salt thereof.
  • the targeting moiety B 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
  • the targeting moiety B selectively binds a target substrate (e.g., protein) as compared to another substrate (e.g., protein).
  • the selectivity is from about 2-fold to about 5-fold. In certain embodiments, the selectivity is from about 5-fold to about 10-fold. In certain embodiments, the selectivity is from about 10-fold to about 20-fold. In certain embodiments, the selectivity is from about 20-fold to about 50-fold. In certain embodiments, the selectivity is from about 50-fold to about 100-fold. In certain embodiments, the selectivity is from about 100-fold to about 200-fold.
  • 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. [00269] In certain embodiments, B is not of the formula: In certain embodiments of Formula (V), B is not of t he formula: In certain embodiments, B is not of the formula, or s tereoisomer thereof: , In certain embodiments of Formula (V), B is not of the formula, or stereoisomer thereof: .
  • 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.
  • 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 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).
  • 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)
  • 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.
  • click chemistry handles are used that can react to form covalent bonds in the absence of a metal catalyst.
  • 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.
  • the click-chemistry handle comprises an alkenylene group or alkynylene group.
  • the click-chemistry handle comprises an internal alkenylene group or alkynylene group.
  • the click-chemistry handle comprises a terminal alkenylene group or alkynylene group.
  • 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 unsubstituted
  • the click chemistry handle is an azide, tetrazine, tetrazole, dithioester, anthracene, amine, or thiol.
  • T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle.
  • T is hydrogen, a nucleophilic group, a leaving group, a nitrogen protecting group, or an oxygen protecting group.
  • T is hydrogen, a nucleophilic group, a leaving group, or a nitrogen protecting group.
  • T is hydrogen, -ORA, -N3, -COORA, -C ⁇ CH, halogen, or a nitrogen protecting group.
  • 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.
  • T is hydrogen, halogen, -OH, -OMe, -OtBu, -OMs (mesylate), -OTs (tosylate), or -C ⁇ CH.
  • T is -OH or -OMe. In certain embodiments, T is -OH. In certain embodiments, T is hydrogen. [00275] 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) [00276] 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.
  • 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. [00277] 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.
  • the compound is a compound of Formula (I-A), wherein L is any one of LI -LI 49, or a pharmaceutically acceptable salt thereof.
  • 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.
  • the compound is a compound of Formula (I-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53.
  • the compound is a compound of Formula (I-A), wherein L is selected from L54-L59 and L144-L149.
  • 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.
  • the compound is a compound of Formula (I-B), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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. [00279] 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.
  • the compound is a compound of Formula (I-B-1), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • the compound is a compound of Formula (I-B-1), wherein L is selected from L54-L59 and L144- L149.
  • 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.
  • the compound is a compound of Formula (I-B-2), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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. [00281] In certain embodiments, the compound of Formula (I) is a compound of formula:
  • the compound is a compound of Formula (II), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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. [00283] 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.
  • the compound is a compound of Formula (II-A), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149.
  • the compound is a compound of Formula (II-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53.
  • the compound is a compound of Formula (II-A), wherein L is selected from L54-L59 and L144- L149.
  • 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.
  • the compound is a compound of Formula (II-B), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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. [00285] 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.
  • the compound is a compound of Formula (II-B-1), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • the compound is a compound of Formula (II-B-1), wherein L is selected from L54-L59 and L144- L149.
  • 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.
  • the compound is a compound of Formula (II-B-2), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • the compound is a compound of Formula (II-B-2), wherein L is selected from L54-L59 and L144- L149. [00287]
  • the compound of Formula (II) is:
  • the compound is a compound of Formula (III), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • the compound is a compound of Formula (III), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53.
  • the compound is a compound of Formula (III), wherein L is selected from L54-L59 and L144-L149.
  • 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.
  • the compound is a compound of Formula (III-A), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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. [00290] In certain embodiments, the compound of Formula (III) is a compound of formula:
  • the compound is a compound of Formula (IV), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • the compound is a compound of Formula (IV), wherein L is selected from L9, L17, LI 8, L21, L28, L31, L32, and L49-L53.
  • the compound is a compound of Formula (IV), wherein L is selected from L54-L59 and L144-L149.
  • the compound of Formula (IV) is a compound of Formula
  • the compound is a compound of Formula (IV-A), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (IV-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149.
  • 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.
  • the compound of Formula (IV) is:
  • the compound is a compound of Formula (V), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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. [00295] 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.
  • the compound is a compound of Formula (V-A), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • the compound is a compound of Formula (V-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53.
  • the compound is a compound of Formula (V-A), wherein L is selected from L54-L59 and L144- L149.
  • 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.
  • the compound is a compound of Formula (V-B), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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. [00297] 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.
  • the compound is a compound of Formula (V-B-1), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • the compound is a compound of Formula (V-B-1), wherein L is selected from L54-L59 and L144- L149.
  • 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.
  • the compound is a compound of Formula (V-B-2), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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. [00299] 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.
  • the compound is a compound of Formula (VI), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • the compound is a compound of Formula (VI), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53.
  • the compound is a compound of Formula (VI), wherein L is selected from L54-L59 and L144-L149.
  • 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.
  • the compound is a compound of Formula (VI-A), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (VI-A), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, L49-L59, and L144-L149.
  • 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. [00302] 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.
  • the compound is a compound of Formula (VI-B), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • the compound is a compound of Formula (VI-B), wherein L is selected from L9, L17, L18, L21, L28, L31, L32, and L49-L53.
  • the compound is a compound of Formula (VI-B), wherein L is selected from L54-L59 and L144- L149.
  • 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.
  • the compound is a compound of Formula (VI-B-1), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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 certain embodiments, the compound is a compound of Formula (VI-B-1), wherein L is selected from L54-L59 and L144-L149.
  • the compound of Formula (VI) is a compound of Formula
  • the compound is a compound of Formula (VI-B-2), wherein L is any one of L1-L149, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • the compound of Formula (VI) is:
  • B is a targeting moiety or a detectable moiety.
  • B is any targeting moiety or detectable moiety as defined herein.
  • B is a targeting moiety or a detectable moiety.
  • B is any targeting moiety or detectable moiety as defined herein.
  • T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle.
  • T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle.
  • 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.
  • 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.
  • 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.
  • a compound of the disclosure e.g., Formula (I), (II), (III), (IV), (V), (VI), or as provided herein
  • a mixture may include ATP.
  • 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.
  • the amount of phosphorylation is measured at a specified time (e.g., 1, 2, 3, 4, 8, 12, 16, or 24 hours after administration).
  • the phosphorylating is in a cell.
  • the phosphorylating is in a biological sample.
  • 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).
  • the phosphorylation is achieved by ABL1.
  • 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).
  • the protein kinase is ABL1.
  • the phosphorylation or modulation is in a cell.
  • the phosphorylation or modulation is in a biological sample.
  • 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).
  • the protein kinase is ABL1.
  • the target substrate is a protein.
  • the target substrate is a kinase or phosphatase.
  • 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.
  • BRD2, BRD3, BRD4, BRDT histone acetyltransferase
  • methyltransferase e.g., ASH1L, MLL
  • CTSB cerebrospinal bovine serum
  • 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 integrated membrane protein 2B
  • CTSD cathepsin D
  • NOTCH1 Notch homolog 1, translocation-associated
  • TNF tumor necrosis factor (TNF superfamily, member 2
  • INS 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
  • 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 (TEM7
  • 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.
  • 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. [00321]
  • 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.
  • the allosteric site is the PIF-binding pocket.
  • the target substrate is a protein.
  • the protein is a natural substrate of the PIF-binding pocket.
  • the protein is S6K.
  • the target substrate is any of the foregoing target substrates described herein.
  • the method is achieved in a mixture comprising ATP.
  • 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 ⁇ mol) was added to the reaction mixture.
  • the reaction mixture was stirred at 25 °C for 12 h.
  • 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 Na 2 SO 4 , 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 ⁇ mol, 26% yield) as a yellow solid.
  • reaction mixture was concentrated under reduced pressure and purified by prep-HPLC [Column: Waters xbridge 150*25mm 10 ⁇ m, 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 ⁇ mol, 36% yield) as a yellow gum.
  • LCMS calculated, 675.3; observed, 675.0 [M+H] + .
  • reaction mixture was stirred at 60 °C for 12 h.
  • the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (C 18, mobile phase: [water-ACN]; B%: 35%-55%, 25 min) to give tert-butyl (2-(2-(2-((1-(2-((1- (3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)amino)-2-oxoethyl)piperidin-4- yl)oxy)ethoxy)ethoxy)ethyl)carbamate (A-110) (49.2 mg, 80.9 ⁇ mol, 17% yield) as a yellow gum.
  • reaction mixture was purified by reverse phase column (C 18, mobile phase:[water-ACN]; B%: 40%, 25 min) to give (R)-N-(1-(3,4-dichlorophenyl)-4,5-dihydro-1H- pyrazol-3-yl)-4-(2-methoxyacetyl)morpholine-2-carboxamide (A-62) (128 mg, 294 ⁇ mol, 37% yield) as a yellow solid.
  • LCMS calculated, 415.1; observed, 415.1 [M+H] + .
  • reaction mixture was then stirred at 25 °C for 2 h. After concentration, the reaction mixture was purified by preparative HPLC(Column: Waters Xbridge 150*25mm 10 ⁇ m, water-CAN, B%, 0 – 60, 8 min.) to give (2S,4S)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (2.20 g, 6.37 mmol, 30% yield) as a colorless oil.
  • reaction mixture was stirred at 50 °C for 12 h. After concentration, the reaction mixture was purified by preparative HPLC(Column: CD06-Waters Xbridge C18150*40*10 ⁇ m, water( NH 4 HCO 3 )-ACN, B%,70 –100, 10 min.) to give tert-butyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-((1-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3- yl)carbamoyl)pyrrolidine-1-carboxylate (34.0 mg, 54.4 ⁇ mol) as a white solid.
  • N,N-dimethylformamide (0.300 mL, 3.15 mmol) was then added dropwise at 0 °C and the mixture was stirred at 0 °C for 1 h. The completion of the reaction was assessed by quenching an aliquot with methanol and checking LC-MS showed the ester desired mass. The mixture was concentrated under reduced pressure to give the crude product 2-chloropyrimidine-5-carbonyl chloride (1.12 g, 6.31 mmol) as a light yellow solid, which was used directly in the next step.
  • N-(5-bromo-2-(3,4-dichlorophenyl)thiazol-4-yl)pyrimidine-5-carboxamide (A-333) [00467] Synthesis of N-(2-(3,4-dichlorophenyl)thiazol-4-yl)pyrimidine-5-carboxamide (A- 334): to stirred a solution of 2-(3,4-dichlorophenyl)thiazol-4-amine (494 mg, 2.01 mmol) in dimethylformamide (5 mL) were added sequentially, pyrimidine-5-carboxylic acid (250 mg, 2.01 mmol), DIEA (781 mg, 6.04 mmol) and HATU (1.15 g, 3.02 mmol).
  • reaction mixture was warmed to rt and stirred for 20 min, then 2-(3,4-dichlorophenyl)- 1,3-thiazol-4-ylamine (425 mg, 1.73 mmol) was added. The resulting reaction mixture was stirred at rt for 16 h.
  • reaction mixture was the warmed to rt and further refluxed for 1h. After 1h, tert-butyl piperazine-1-carboxylate (912 mg, 4.9 mmol) was added and the reaction mixture was further refluxed for 3h. The reaction mixture was cooled to RT and the reaction mixture was quenched with ice/water and extracted with EtOAc (3 x 50 mL).
  • tert-Butyl (2-(2-bromoethoxy)ethyl)carbamate (627 g, 2.34 mmol) was then added and the reaction mixture was stirred at rt for 2h. The reaction mixture was quenched with ice water and extracted with EtOAc (3 x 70 mL).
  • Biological Assays Measure of binding to ABL1 by HTRF [00511] Compounds were titrated 1:3 in 100% DMSO and 50 nl of compound or DMSO were dispensed to a white Corning Low Volume 384-well plate (Cat #3824). Anti-his-Tb cryptate and a fluorescent probe were diluted in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCl 2 , 0.05 mM TCEP, 0.01% CHAPS) and added to each well for a final concentration of 0.02 nM Anti-His Tb cryptate and 20 nM fluorescent probe.
  • assay buffer 50 mM HEPES pH 7.5, 10 mM MgCl 2 , 0.05 mM TCEP, 0.01% CHAPS
  • ABL1b[46-534, (D382N)] was diluted in assay buffer and added to all wells except positive control wells for a final concentration of 10 nM. Buffer was added to positive control wells at an equal volume. The plate was incubated at room temperature for 30 minutes before reading with excitation 337 nm, emission A 520 nm, and emission B 490 nm (PheraStar, BMG Labtech). HTRF ratio was normalized to wells containing DMSO (0%) and wells containing no ABL (-100%) and IC50s were determined by fitting the data based on a sigmoidal dose-response equation. Results are shown in Table E1.
  • Buffer was added to positive control wells at an equal volume. The plate was incubated at room temperature for 60 minutes before reading fluorescence polarization (excitation 485 nm, parallel and perpendicular emission at 520 nm - PheraStar, BMG Labtech). FP signal (mP) was normalized to wells containing DMSO (0%) and wells containing no ABL (-100%) and IC50s were determined by fitting the data based on a sigmoidal dose- response equation. Results are shown in Table E2. Table E2
  • NanoPro mix by mixing 176 ⁇ l of Premix G23-10 with 2 ⁇ l of each standard 4.8 and 7. Mixed 12 ⁇ l of the premix with 4 ⁇ l of the lysate for each sample. Vortexed then spun down the tubes before transferring to the NanoPro plate. Ran the NanoPro using total CrkII antibody (Abcam, ab45136) for detection.
  • Intact Mass Spectrometry Measurement of compound-mediated phosphorylation of BRD4 by ABL1
  • Compounds of the disclosure were plated in an Eppendorf LoBind 384-well plate (Cat # 951040589) for a final concentration of 1 ⁇ M in 1% DMSO.
  • Recombinant BRD4 (residues 49- 460, BPS Bioscience Cat #31047) and Abl (residues 46-534, produced in-house) were diluted in assay buffer (50 mM HEPES, pH 7.4, 10 mM MgCl 2 , 0.5 mM TCEP) and added to each well for a final concentration of 700 nM BRD4 and 300 nM Abl.
  • the plate was incubated at room temperature for 15 minutes to allow for protein:compound complex formation and then ATP was added to a final concentration of 1 mM to initiate the phosphorylation reaction. Reactions were quenched with formic acid (0.2% final concentration) and analyzed via LC/MS. Intact protein mass is measured on the Waters BioAccord LC-TOF. The quenched reaction plate is stored at 8°C in the sample manager and samples are analyzed by injecting 2 ⁇ l of the reaction onto a Waters ACQUITY UPLC Protein BEH C4 column (300 ⁇ , 1.7 ⁇ m, 2.1 ⁇ 50 mm, Cat #186004495) held at 80°C.
  • Samples were desalted for 1 min before a 2.5 min gradient of 5% to 85% acetonitrile at a flow rate of 0.4 ml/min to elute from the column. Ionization was performed at a cone voltage of 55 V and desolvation temperature of 550 °C. The instrument scans at a rate of 0.2 scans/s over the range 50-2000 m/z. Protein m/z spectra were deconvoluted into intact mass using the MaxEnt1 function and protein identification is performed with Waters UNIFI software. A mass tolerance of 50 ppm is set for protein identification due to complexity of the sample.
  • Recombinant TRIM24 (residues 896-1014, BPS Bioscience Cat #31116) and Abl (residues 46-534, produced in-house) were diluted in assay buffer (50 mM HEPES, pH 7.4, 10 mM MgCl2, 0.5 mM TCEP) and added to each well for a final concentration of 1 ⁇ M TRIM24 and 300 nM Abl.
  • the plate was incubated at room temperature for 15 minutes to allow for protein:compound complex formation and then ATP is added to a final concentration of 1 mM to initiate the phosphorylation reaction. Reactions were quenched with formic acid (0.2% final concentration) and analyzed via LC/MS.
  • Intact protein mass was measured on the Waters BioAccord LC-TOF.
  • the quenched reaction plate was stored at 8°C in the sample manager and samples were analyzed by injecting 2 ⁇ l of the reaction onto a Waters ACQUITY UPLC Protein BEH C4 column (300 ⁇ , 1.7 ⁇ m, 2.1 ⁇ 50 mm, Cat #186004495) held at 80°C. Samples were desalted for 1 min before a 2.5 min gradient of 5% to 85% acetonitrile at a flow rate of 0.4 ml/min to elute from the column. Ionization was performed at a cone voltage of 55 V and desolvation temperature of 550 °C.
  • the instrument scans at a rate of 0.2 scans/s over the range 50-2000 m/z. Protein m/z spectra were deconvoluted into intact mass using the MaxEnt1 function and protein identification was performed with Waters UNIFI software. A mass tolerance of 50 ppm was set for protein identification due to complexity of the sample. 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. See FIG 3.
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

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Abstract

L'invention concerne des composés qui se lient à la protéine kinase-1 dépendante de la 3-phosphoinositide (ABL1) et/ou favorisent la phosphorylation ciblée d'un substrat. La phosphorylation induite du substrat cible peut modifier la structure et la fonction du substrat, ce qui permet de fournir des composés qui permettent la phosphorylation de substrats cibles, y compris ceux qui sinon ne peuvent pas constituer des substrats pour l'ABL1, et de fournir de nouveaux modes destinés à induire une phosphorylation stratégique. L'invention concerne également des composés qui constituent des intermédiaires des composés bifonctionnels. L'invention concerne également des composés qui se lient à un site allostérique d'ABL1I et inhibent la phosphorylation d'un substrat cible. L'invention concerne également des compositions pharmaceutiques comprenant les composés divulgués et des procédés de promotion de la phosphorylation de substrats cibles dans un échantillon biologique par l'administration d'un composé ou d'une composition de l'invention.
PCT/US2024/058859 2023-12-08 2024-12-06 Composés bifonctionnels de liaison à l'abl1 et leurs utilisations Pending WO2025122865A1 (fr)

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WO2022225728A2 (fr) * 2021-04-09 2022-10-27 The Broad Institute, Inc. Molécules bifonctionnelles pour la modification sélective de substrats cibles

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WO2022225728A2 (fr) * 2021-04-09 2022-10-27 The Broad Institute, Inc. Molécules bifonctionnelles pour la modification sélective de substrats cibles

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