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WO2025166015A2 - Bifunctional abl1-binding compounds and uses thereof - Google Patents

Bifunctional abl1-binding compounds and uses thereof

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Publication number
WO2025166015A2
WO2025166015A2 PCT/US2025/013801 US2025013801W WO2025166015A2 WO 2025166015 A2 WO2025166015 A2 WO 2025166015A2 US 2025013801 W US2025013801 W US 2025013801W WO 2025166015 A2 WO2025166015 A2 WO 2025166015A2
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WIPO (PCT)
Prior art keywords
substituted
unsubstituted
compound
pharmaceutically acceptable
acceptable salt
Prior art date
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PCT/US2025/013801
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French (fr)
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WO2025166015A3 (en
Inventor
Florence Fevrier WAGNER
Dominique Potin
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Photys Therapeutics Inc
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Photys Therapeutics Inc
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Publication of WO2025166015A2 publication Critical patent/WO2025166015A2/en
Publication of WO2025166015A3 publication Critical patent/WO2025166015A3/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

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.
  • R 1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A , -SR A , -N(R A )2, -NO 2 , -CN, - n is an integer selected from 0, 1, 2, 3, 4, and 5;
  • R 2 is hydrogen, or substituted or unsubstituted alkyl
  • R 3 is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group
  • A is -X’-X ⁇ -X 4 -;
  • X 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
  • X 2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • X 3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
  • X 4 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene;
  • L is a bond or a linker
  • 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 attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
  • R 2 is hydrogen, or substituted or unsubstituted alkyl
  • R 3 is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group
  • A is -X’-X ⁇ -X 4 -;
  • X 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
  • X 2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • X 3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
  • X 4 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene;
  • L is a bond or a linker
  • T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle; and each occurrence of 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 attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
  • 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: compounds 16-19.
  • 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.
  • 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 “&i” indicate a mixture of the two trans or cis stereoisomers
  • stereocenters labeled with “ori” indicate a single stereoisomer with unknown absolute stereochemistry.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of 12 C with 13 C or 14 C are within the scope of the disclosure.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • Ci-6 alkyl is intended to encompass Ci, C2, C3, C4, C5, Ce, C 1-6 , C1-5, CM, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 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 (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-s alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“Ci-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms (“CM alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”).
  • C 1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n- butyl, tert-butyl, sec -butyl, zso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3- methyl-2-butanyl, tertiary amyl), and hexyl (Ce) (e.g., n-hexyl).
  • alkyl groups include n-heptyl (C7), n-octyl (Cs), 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 C1-10 alkyl (such as unsubstituted C 1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec -butyl (sec-Bu), unsubstituted isobutyl (i-Bu)).
  • the alkyl group is a substituted C1-10 alkyl (such as substituted C 1-6 alkyl, e.g.
  • 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 (“Ci-s haloalkyl”).
  • the haloalkyl moiety has 1 to 6 carbon atoms (“C 1-6 haloalkyl”).
  • the haloalkyl moiety has 1 to 4 carbon atoms (“CM haloalkyl”).
  • the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCI2, -CF2CI, 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 (“heteroCi-20 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-is alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-i6 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 (“heteroCi-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 (“heteroCi-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 (“heteroCi-10 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-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 (“heteroCi-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 (“heteroCi-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 (“heteroCi-3 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi 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 heteroCi-20 alkyl.
  • the heteroalkyl group is an unsubstituted heteroCi-10 alkyl.
  • the heteroalkyl group is a substituted heteroCi-20 alkyl.
  • the heteroalkyl group is an unsubstituted heteroCi-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 (“C2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), 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 C2-10 alkenyl.
  • the alkenyl group is a substituted C2-10 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 (“heteroC2 io alkenyl”).
  • a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 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 (“heteroC2-s alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkenyl”).
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3 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 (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroCz io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroCz-io 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) (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.
  • Examples of C2-6 alkynyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like.
  • Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), 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 C2-10 alkynyl.
  • the alkynyl group is a substituted C2-10 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 (“heteroC2 io alkynyl”).
  • a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 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 (“heteroC2-7 alkynyl”).
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-s alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkynyl”).
  • a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2 io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2 io alkynyl.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”).
  • Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like.
  • Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like.
  • Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), 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 C3-14 carbocyclyl.
  • the carbocyclyl group is a substituted C3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”).
  • a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”).
  • a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (Ce). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).
  • C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs).
  • 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 C3-14 cycloalkyl.
  • the cycloalkyl group is a substituted C3-14 cycloalkyl.
  • heterocyclyl 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”).
  • 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. In certain embodiments, 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.
  • 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-Z?]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, I A/-benzo[e][
  • 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 147t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”).
  • an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • 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 Ce-i4 aryl.
  • the aryl group is a substituted Ce-i4 aryl.
  • Alkyl 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 147t 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.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is an unsubstituted 5-14 membered heteroaryl.
  • 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.
  • unsaturated or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
  • 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 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.
  • each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R 33 , R bb , R cc , and R dd are as defined herein.
  • 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), l-(l-adamantyl)-!-
  • 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-(lO)- 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 l,3-dibenzyl-l,3,5-triazacyclohexan
  • 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), t
  • 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 (z.e., including one formal negative charge).
  • An anionic counterion may also be multivalent (z.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 “, CIOT, OH-, H 2 PO4-, HCO 3 ”, HSO4-, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p- toluenesulf onate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4-, PF4-, PFe”, AsFe”, SbFe”, B[
  • Exemplary counterions which may be multivalent include CO 3 2- , HPO4 2- , PO4 3- , B4O? 2- , SO4 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
  • carboranes e.g., tartrate, citrate, fumarate, maleate, malate, malonate,
  • leaving group is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March’ s Advanced Organic Chemistry 6th ed. (501-502).
  • Suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl- carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, A,(9-dimethylhydroxylamino, pixyl, and haloformates.
  • halogen such as F, Cl, Br, or I (iodine)
  • alkoxycarbonyloxy such as F, Cl, Br, or I (iodine)
  • alkanesulfonyloxy alkanesulfonyloxy
  • arenesulfonyloxy alkyl- carbonyloxy (e.g., acetoxy)
  • alkyl- carbonyloxy e.g., acetoxy
  • 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 nonlimiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
  • At least one instance refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
  • 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 + (CI-4 alkyl)4- salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • 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 solutionphase and isolatable solvates.
  • Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is associated with water.
  • the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H2O, wherein R is the compound, and x is a number greater than 0.
  • a given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).
  • monohydrates x is 1
  • lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H2O)
  • polyhydrates x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)
  • 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.
  • 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”.
  • 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. Ci-s alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, C7-12 substituted aryl, and C7-12 arylalkyl esters of the compounds described herein may be preferred.
  • composition and “formulation” are used interchangeably.
  • 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.
  • 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)).
  • primate e.g., cynomolgus monkey or rhesus monkey
  • commercially relevant mammal e.g., cattle, pig, horse, sheep, goat, cat, or dog
  • bird e.g., commercially relevant bird, such as
  • 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.
  • the plant is a land plant.
  • the plant is a non-vascular land plant.
  • the plant is a vascular land plant.
  • the plant is a seed plant.
  • the plant is a cultivated plant.
  • the plant is a dicot.
  • the plant is a monocot.
  • the plant is a flowering plant.
  • the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet.
  • the plant is a legume, e.g., a bean plant, e.g., soybean plant.
  • 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.
  • small molecule refers to molecules, whether naturally occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight.
  • 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
  • a kinase e.g., ABL1
  • 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.
  • compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof.
  • R 1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A , -SR A , -N(R A )2, -NO 2 , -CN, - n is an integer selected from 0, 1, 2, 3, 4, and 5;
  • R 2 is hydrogen, or substituted or unsubstituted alkyl
  • R 3 is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group
  • A is -X’-X ⁇ -X 4 -;
  • X 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
  • X 2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • X 3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
  • X 4 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene;
  • L is a bond or a linker;
  • 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 attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
  • 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 thereof, 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.
  • compounds of Formula (II) provided herein are compounds of Formula (II):
  • R 1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A , -SR A , -N(R A )2, -NO 2 , -CN, n is an integer selected from 0, 1, 2, 3, 4, and 5;
  • R 2 is hydrogen, or substituted or unsubstituted alkyl
  • R 3 is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group
  • A is -X'-X 2 -X 3 -X 4 -;
  • X 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
  • X 2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • X 3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
  • X 4 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene;
  • L is a bond or a linker
  • T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle; and each occurrence of 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 attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
  • 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 thereof, 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 additional compounds (i.e., not of Formula (I) or (II)), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, and stereoisomers 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, or less than 1 nM.
  • R 1 is hydrogen, substituted or unsubstituted alkyl, halogen, hydroxy, or - ⁇ -(substituted or unsubstituted alkyl). In some embodiments, R 1 is substituted or unsubstituted alkyl, halogen, hydroxy, or - ⁇ -(substituted or unsubstituted alkyl). In certain embodiments, R 1 is chloro, methyl, fluoro, bromo, trifluoromethyl, or trifluoromethoxy.
  • R 1 is hydrogen. In certain embodiments, R 1 is halogen. In some embodiments, R 1 is substituted or unsubstituted alkyl. In some embodiments, 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).
  • 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.
  • 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. In some embodiments, n is 1 or 2.
  • R 2 is hydrogen or substituted or unsubstituted alkyl.
  • R 2 is hydrogen
  • R 2 is substituted or unsubstituted alkyl. In certain embodiments, 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, isopropyl). In some embodiments, R 2 is substituted or unsubstituted butyl (n-butyl, tert-butyl, secbutyl).
  • 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, 2-methoxy ethyl, sec-butyl, or isopropyl. In certain embodiments, R 2 is hydrogen or unsubstituted methyl.
  • 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 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.
  • R 3 is hydrogen
  • R 3 is substituted or unsubstituted alkyl. In some embodiments, R 3 is substituted or unsubstituted methyl. In some embodiments, R 3 is substituted methyl. In some embodiments, R 3 is unsubstituted methyl.
  • 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 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 substituted or unsubstituted phenylene, substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, substituted or unsubstituted pyrazinylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, or substituted or unsubstituted triazolylene.
  • A comprises substituted or unsubstituted phenylene, substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, substituted or unsubstituted pyrazinylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, or substituted or unsubstituted triazolylene.
  • A comprises substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, or substituted or unsubstituted triazolylene.
  • A comprises substituted or unsubstituted pyrazolylene, or substituted or unsubstituted pyrimidinylene.
  • X 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene. In some embodiments, X 1 is a bond. In certain embodiments, X 1 is substituted or unsubstituted alkylene. In certain some, X 1 is substituted or unsubstituted alkenylene. In certain embodiments, X 1 is substituted or unsubstituted heteroalkylene. In some embodiments, X 1 is substituted or unsubstituted heteroalkenylene.
  • X 1 is 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-Ci alkylene comprising -O- or -NR A .
  • X 1 is a bond. [00131] In some embodiments, X 1 is substituted or unsubstituted alkylene. In certain embodiments, X 1 is substituted or unsubstituted CM 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-Ci 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 substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • X 2 is substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • X 2 is substituted or unsubstituted heterocyclylene.
  • X 2 is substituted or unsubstituted carbocyclylene.
  • X 2 is substituted or unsubstituted heteroarylene.
  • X 2 is substituted or unsubstituted phenylene, substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, substituted or unsubstituted pyrazinylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, or substituted or unsubstituted triazolylene.
  • X 2 is substituted or unsubstituted phenylene.
  • X 2 is substituted or unsubstituted pyridinylene.
  • X 2 is substituted or unsubstituted pyridazinylene. In some embodiments, X 2 is substituted or unsubstituted pyrimidinylene. In some embodiments, X 2 is substituted or unsubstituted pyrazinylene. In some embodiments, X 2 is substituted or unsubstituted imidazolylene. In some embodiments, X 2 is substituted or unsubstituted pyrazolylene. In some embodiments, X 2 is substituted or unsubstituted triazolylene.
  • X 2 is substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, or substituted or unsubstituted triazolylene.
  • X 2 is substituted or unsubstituted pyridinylene.
  • X 2 is substituted or unsubstituted pyridazinylene.
  • X 2 is substituted or unsubstituted pyrimidinylene.
  • X 2 is substituted or unsubstituted imidazolylene. In some embodiments, X 2 is substituted or unsubstituted pyrazolylene. In some embodiments, X 2 is substituted or unsubstituted triazolylene.
  • X 2 is substituted or unsubstituted pyrazolylene, or substituted or unsubstituted pyrimidinylene. In some embodiments, X 2 is substituted or unsubstituted pyrazolylene. In some embodiments, X 2 is substituted or unsubstituted pyrimidinylene. Some embodiments, X 2 is some embodiments, X 2 is . In some embodiments, X 2 is some embodiments, X 2 is some embodiments, X 2 is some embodiments, X 2 is In some embodiments, X 2 is . some embodiments, X 2 is . In some embodiments, X 2 is . In some embodiments, X 2 is . In some embodiments, X 2 is . In some embodiments, X is , X is , In some embodiments, X is , In some embodiments, X 2 is , In some embodiments, X 2 is , In some embodiments, X 2 is , In some embodiments,
  • 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, substituted or unsubstituted alkenylene, or substituted or unsubstituted heteroalkylene comprising -O- or - NR A -.
  • X 3 is substituted or unsubstituted alkylene, or substituted or unsubstituted alkenylene. In certain embodiments, X 3 is substituted or unsubstituted alkylene. In certain embodiments, X 3 is substituted or unsubstituted alkenylene.
  • X 3 is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted ethenylene, or substituted or unsubstituted hetero-Ci alkylene comprising -O- or -NR A -.
  • X 3 is a bond
  • X 3 is unsubstituted ethenylene. In certain embodiments, X 3 is substituted or unsubstituted propylene. In certain embodiments, X 3 is substituted or unsubstituted butylene.
  • X 3 is substituted or unsubstituted heteroalkylene comprising - O- or -NR A -. In some embodiments, X 3 is substituted or unsubstituted hetero-Ci 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 or substituted or unsubstituted heterocyclylene. 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, or substituted or unsubstituted heterocyclylene. In some embodiments, X 4 is a bond, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperdinylene, or substituted or unsubstituted piperazinylene. In some embodiments, X 4 is substituted or unsubstituted pyrrolidinylene. In some embodiments, X 4 is substituted or unsubstituted piperdinylene. In some embodiments, X 4 is substituted or unsubstituted piperazinylene.
  • L is a bond or a linker. In certain embodiments, L is a bond. In certain embodiments, L is a linker. In certain embodiments, L is a chain of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous atoms. In certain embodiments, L is a chain of at least 1 atom. In certain embodiments, L is a chain of at least 2 contiguous atoms. In certain embodiments, L is a chain of at least 3 contiguous atoms. In certain embodiments, L is a chain of at least 4 contiguous atoms. In certain embodiments, L is a chain of at least 5 contiguous atoms.
  • L is a chain of at least 6 contiguous atoms. In certain embodiments, L is a chain of at least 7 contiguous atoms. In certain embodiments, L is a chain of at least 8 contiguous atoms. In certain embodiments, L is a chain of at least 9 contiguous atoms. In certain embodiments, L is a chain of at least 10 contiguous atoms. In certain embodiments, L is a chain of at least 11 contiguous atoms. In certain embodiments, L is a chain of at least 12 contiguous atoms. In certain embodiments, L is a chain of at least 13 contiguous atoms. In certain embodiments, L is a chain of at least 14 contiguous atoms. In certain embodiments, L is a chain of at least 15 contiguous atoms. In certain embodiments, L is a chain of any range of from 1 to 15 contiguous atoms.
  • 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.
  • the lefthand attachment point is to B and the righthand attachment point is to A when B is present; or the lefthand attachment point is to T and the righthand attachment point is to A when T is present.
  • L is substituted or unsubstituted alkylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene, -
  • L is a combination of two or more of substituted or unsubstituted alkylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene, , ,
  • L is of formula: wherein:
  • Q is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene;
  • Q 1 is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene;
  • Z 1 is a bond.
  • Z 1 is -O-.
  • Z 1 is - N(R A )-.
  • Z 1 is -N(H)-.
  • Z 1 is -N(CH 3 )-.
  • Z 1 is substituted or unsubstituted alkylene.
  • Z 1 is substituted or unsubstituted methylene. In some embodiments, 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-Ci -alkylene comprising -O- or -N(R A )-. In some embodiments, Z 1 is substituted or unsubstituted hetero-Cz-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 )-. In some embodiments, Z 1 is a repeating substituted or unsubstituted hetero-Cs-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 -N(CH3)-.
  • Q is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene.
  • Q is a bond.
  • Q is substituted or unsubstituted heteroalkylene.
  • Q is substituted or unsubstituted heteroalkylene.
  • Q is substituted or unsubstituted hetero-Ci -alkylene comprising -O- or -N(R A )-.
  • Q is substituted or unsubstituted hetero-C?- alkylene comprising -O- or -N(R A )-. In some embodiments, Q is substituted or unsubstituted hetero-C3-alkylene comprising -O- or -N(R A )-. In some embodiments, Q is a repeating substituted or unsubstituted hetero-C3-alkylene comprising -O- or -N(R A )-. In some embodiments, Q is substituted or unsubstituted heterocyclylene. In some embodiments, Q is substituted or unsubstituted 6-membered heterocyclylene.
  • Q is substituted or unsubstituted piperidinylene or substituted or unsubstituted piperazinylene. In some embodiments, Q is substituted or unsubstituted heteroarylene. In some embodiments, Q is substituted or unsubstituted is substituted or unsubstituted 5-membered heteroarylene. In some embodiments, Q is triazolylene.
  • Q 1 is a bond. In some embodiments, Q 1 is substituted or unsubstituted heteroalkylene. In some embodiments, Q 1 is substituted or unsubstituted heteroalkylene. In some embodiments, Q 1 is substituted or unsubstituted hetero-Ci -alkylene comprising -O- or -N(R A )-. In some embodiments, Q 1 is substituted or unsubstituted hetero-C?- alkylene comprising -O- or -N(R A )-. In some embodiments, Q 1 is substituted or unsubstituted hetero-C3-alkylene comprising -O- or -N(R A )-.
  • Q 1 is a repeating substituted or unsubstituted hetero-C3-alkylene comprising -O- or -N(R A )-.
  • Q 1 is substituted or unsubstituted heterocyclylene.
  • Q 1 is substituted or unsubstituted 6-membered heterocyclylene.
  • Q 1 is substituted or unsubstituted piperidinylene or substituted or unsubstituted piperazinylene.
  • Q 1 is substituted or unsubstituted heteroarylene.
  • Q 1 is substituted or unsubstituted is substituted or unsubstituted 5-membered heteroarylene.
  • Q 1 is triazolylene.
  • Z 3 is a bond.
  • Z 4 is -O-.
  • Z 4 is -N(R A )-.
  • Z 4 is -N(H)-.
  • Z 4 is - N(CH 3 )-.
  • L is of formula: wherein:
  • L is of formula:
  • L is of formula:
  • L is of formula: wherein:
  • Q is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene;
  • L is of formula: wherein:
  • L is of formula: [00168] In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: In some embodiments, L is of formula: . In some embodiments, L is of formula:
  • L is of formula: . In some embodiments, L is of formula: In some embodiments, L is of formula:
  • L is of formula: . In some embodiments, L is of , some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula:
  • L is of formula:
  • L is of formula:
  • L is selected from any one of L1-L60 or L161-L177:
  • L is selected from any one of L1-L60 or L161-L177. In some embodiments, L is selected from any one of L1-L60. In some embodiments, L is Li77.
  • L is of formula: . In some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of . In some embodiments, L is of . , of formula: some embodiments, L is of formula: . In some embodiments, L mula: . In some embodiments, L is of formula: formula: In some embodiments, L is of formula:
  • L is of formula: In some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: In some embodiments, L is of some embodiments, L is of formula: In some embodiments, L is of embodiments, L is of formula: In some embodiments, L is of embodiments, L is of formula: In some embodiments, L is of embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: .
  • L is of formula: In some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of 0 0 formula: some embodiments, L is of formula:
  • L is of formula: some embodiments, L is of , . In some embodiments, L is of formula:
  • t is 0-30. In certain embodiments, t is 0-20. In certain embodiments, t is 0-6. In certain embodiments, t is 1-20, 1-10, 1-8, 1-6, 1-5, 1-4, 1-3, or 1-2. In certain embodiments, t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, u is 0-30. In certain embodiments, u is 0-20. In certain embodiments, u is 0- 6. In certain embodiments, u is 1-6, 1-5, 1-4, 1-3, or 1-2. In certain embodiments, u is 1, 2, 3, 4, 5, or 6.
  • L is selected from any one of L61-L241:
  • L is selected from any one of L1-L179 (not including L16I- Li77). In certain embodiments, L is selected from any one of L1-L241 (including L161-L177). In certain embodiments, L is selected from any one of L61-L179 or L61-L241. In certain embodiments, L is selected from any one of L61-L179 or L180-L241. In certain embodiments, L is selected from any one of L61-L179. In certain embodiments, L is selected from any one of L61-L241.
  • L is of formula:
  • L is of formula: embodiments, L is of formula: . In some embodiments, L is of formula:
  • L is of formula: formula: . In some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: embodiments, L is of formula: ' ' . In some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In
  • L is of formula: embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula:
  • L is of formula: .
  • T In some embodiments, L is of formula: . In some embodiments, ,
  • L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of . , . some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some f N embodiments, L is of formula: H . In some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: .In some embodiments, L is of formula: H H . In some embodiments, L is of formula: . n some em
  • L is of formula: . In some embodiments, L is of . , . T In some embodiments, L is of formula: . In some embodiments, L is of . , : .In some embodiments, L is of formula: . In some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: In some embodiments, L is of formula some embodiments, L is of formula: In some embodiments, L is of formula: In some embodiments, L is of formula:
  • L is of formula: In some embodiments, L is of formula: mbodiments, L is of formula: . In some embodiments, L is o f formula: . In some embodiments, L is of formula: . In some embodiments,
  • L is of formula: . In some embodiments, L is of formula:
  • L is of formula: . In some embodiments, L is of formula: In some embodiments, L is of formula:
  • L is of formula: . In some embodiments, L is of , some embodiments, L is of formula . In some embodiments, L is of
  • L is of formula: . In some embodiments, L is of In some embodiments, L is of formula: . In some embodiments, L is of formula: In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: embodiments, L is of formula: . In some embodiments, L is of formula:
  • L is of formula: . , a: . , la: some embodiments, L is of formula: some embodiments, L is of
  • 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 attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
  • each 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 a nitrogen protecting group.
  • 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
  • MAPK14 mitogen-activated protein kinase 14, also called p38-a
  • PRG2 proteoglycan
  • PRKC A protein kinase C, alpha
  • LI CAM LI cell adhesion molecule
  • CD40 CD40 molecule
  • NR1I2 nuclear receptor subfamily 1, group I, member 2
  • JAG2 jagged 2
  • CTNND1 catenin (cadherin-associated protein), delta 1
  • CDH2 cadherin 2, type 1, N- cadherin
  • CMA1 chymase 1
  • SORT1 sortilin 1
  • DLK1 delta-like 1 homolog
  • THEM4 thioesterase superfamily member 4
  • JUP junction plakoglobin
  • CD46 CD46 molecule, complement regulatory protein
  • CCL11 chemokine (C-C motif) ligand 11
  • CAV3 caveolin 3
  • RNASE3 ribonuclease, RNase A family, 3
  • HSPA8 heat shock 70kDa protein 8
  • CASP9 caspase 9
  • CYP3A4 cytochrome P450
  • TGFA transforming growth factor, alpha
  • RXRA retinoid X receptor, alpha
  • STX1A serotonin 1A
  • PSMC4 proteasome (prosome, macropain) 26S subunit, ATPase, 4
  • P2RY2 purinergic receptor P2Y, G-protein coupled, 2
  • TNFRSF21 tumor necrosis factor receptor superfamily, member 21
  • DLG1 discs, large homolog 1
  • NUMBL noumb homolog
  • SPN salophorin
  • PLSCR1 phospholipid scramblase 1
  • UBQLN2 ubiquilin 2
  • UBQLN1 ubiquilin 1
  • PCSK7 proprotein convertase subtilisin/kexin type 7
  • SPON1 pondin 1, extracellular matrix protein
  • SILV salver homolog
  • QPCT glutaminyl-peptide cyclotransferase
  • HESS hairy and enhancer of split 5
  • GCC transforming
  • B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with KRAS or KRAS mutant, BRD4, CAII, TRIM24, BTK, BET, BRD2, BRD3, or BRDT.
  • B is a ligand, recruiter, binder, modulator, modifier, inhibitor, activator, and/or associator of KRAS or KRAS mutant, BRD4, CAII, TRIM24, or BTK.
  • B is a ligand, recruiter, binder, modulator, modifier, inhibitor, activator, and/or associator of BRD4 or BTK.
  • B is an inhibitor of KRAS or KRAS mutant, BRD4, CAII, TRIM24, or BTK.
  • B is an inhibitor of BRD4 or 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 or KRAS mutant. In certain embodiments, B is an inhibitor of BRD4.
  • B is an inhibitor of CAIL In certain embodiments, B is an inhibitor of TRIM24. In certain embodiments, B is an inhibitor of BTK. In certain embodiments, B is an inhibitor of BET. In certain embodiments, B is an inhibitor of BRD2. In certain embodiments, B is an inhibitor of BRD3. In certain embodiments, B is an inhibitor of BRDT.
  • B is a KRAS-binding moiety, a kinase-binding moiety, or a phosphatase-binding moiety.
  • B is of formula:
  • B is of formula:
  • B is of formula: [00193] In certain embodiments, B is of formula:
  • B is a detectable moiety. In certain embodiments, B is a chromophore. In certain embodiments, B is a dye. In certain embodiments, B is a fluorophore. In certain embodiments, B is a luminophore. In certain embodiments, B is a luminescent material. In certain embodiments, B is a radioactive material.
  • B is a dye. In certain embodiments, B is a fluorescent dye. In certain embodiments, B is of formula:
  • 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 than 3 nM, less than 2 nM, or less than 1 nM.
  • a target substrate e.g., protein
  • 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. In certain embodiments, the selectivity is from about 200-fold to about 500-fold. In certain embodiments, the selectivity is from about 500-fold to about 1000-fold. In certain embodiments, the selectivity is at least about 1000-fold.
  • T 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 2001 40, 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).
  • Examples of click chemistry reactions and click-chemistry handles can be found in, e.g., Kolb, H. C.; Finn, M. G. and Sharpless, K. B., Angew. Chem. Int.
  • 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. In certain embodiments, the click-chemistry handle comprises an internal alkenylene group or alkynylene group. In certain embodiments, the click-chemistry handle comprises a terminal alkenylene group or alkynylene group.
  • 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, an amine, a carboxylic acid, an aldehyde, an alkyne, an alkene, an azide, an alcohol, a halogen, or a nitrogen protecting group.
  • T is -OH or -OMe. In certain embodiments, T is -OH. In certain embodiments, T is hydrogen. In certain embodiments, T is -NHR A . In certain embodiments, T is -NH2. In certain embodiments, T is -Cl.
  • the compound is a compound of Formula (I), wherein L is selected from any one of L1-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (I- A):
  • the compound is a compound of Formula (I-A), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-A), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-A), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-A), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • 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-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-B), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-B), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-B), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (I-B- 1):
  • the compound is a compound of Formula (I-B-l), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-B-l), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-B-)
  • the compound is a compound of Formula (I-B-l), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-B-l), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (I-B-
  • the compound is a compound of Formula (I-B-2), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-B-2), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-B- 2), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-B-2), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (I-B-2), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • 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-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is a compound of Formula (II-
  • the compound is a compound of Formula (II-A), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-A), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-A), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-A), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174- L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-A), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is a compound of Formula (II-
  • the compound is a compound of Formula (II-B), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-B), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-B), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-B), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-B), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is a compound of Formula (II-
  • the compound is a compound of Formula (II-B-1), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-B-1), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-B- 1), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-B-1), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-B-1), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is a compound of Formula (II- B-2):
  • the compound is a compound of Formula (II-B-2), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-B-2), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-B- 2), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-B-2), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (II-B-2), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is a compound of formula: or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • compositions comprising a compound of the disclosure (e.g., a compound of Formula (I), (II), 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), 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), or as provided herein), in a mixture that comprises ABL1 and the target substrate.
  • a target substrate e.g., protein
  • a compound of the disclosure e.g., Formula (I), (II), or as provided herein
  • 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), 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), 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), or as provided herein).
  • a compound of the disclosure e.g., Formula (I), (II), 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.
  • 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
  • NOTCH2 (Notch homolog 2); M6PR (mannose-6-phosphate receptor (cation dependent)); CYP46A1 (cytochrome P450, family 46, subfamily A, polypeptide 1); CSNK1 D (casein kinase
  • MAPK14 mitogen-activated protein kinase 14, also called p38-a
  • PRG2 proteoglycan
  • PRKC A protein kinase C, alpha
  • LI CAM LI cell adhesion molecule
  • CD40 CD40 molecule
  • NR1I2 nuclear receptor subfamily 1, group I, member 2
  • JAG2 jagged 2
  • CTNND1 catenin (cadherin-associated protein), delta 1
  • CDH2 cadherin 2, type 1, N- cadherin
  • CMA1 chymase 1
  • SORT1 sortilin 1
  • DLK1 delta-like 1 homolog
  • THEM4 thioesterase superfamily member 4
  • JUP junction plakoglobin
  • CD46 CD46 molecule, complement regulatory protein
  • CCL11 chemokine (C-C motif) ligand 11
  • CAV3 caveolin 3
  • RNASE3 ribonuclease, RNase A family, 3
  • HSPA8 heat shock 70kDa protein 8
  • CASP9 caspase 9
  • CYP3A4 cytochrome P450
  • SCN10A Sodium Channel, Voltage Gated, Type X Alpha Subunit
  • ATXN2 Spinocerebellar Ataxia Type 2 Protein
  • DMPK Dystrophia Myotonica-Protein Kinase
  • ACADM acyl-coenzyme A dehydrogenase for medium chain fatty acids
  • HADHA long- chain 3-hydroxyl-coenzyme A dehydrogenase for long chain fatty acids
  • ACADVL acylcoenzyme A dehydrogenase for very long-chain fatty acids
  • TTR Transthyretin
  • TTR Angiopoietin-like 4
  • ANGPTL4 Sodium Voltage-Gated Channel Alpha Subunit 9
  • SCN9A Interleukin-7 receptor
  • IL7R Interleukin-7 receptor
  • G6PC catalytic
  • HFE haemochromatosis
  • SERPINA1 C90RF72; P-globin; dystrophin
  • Cancer/testis antigen 1 (NY-ESO-1); Cancer/testis antigen 2 (LAGE-la); Melanoma- associated antigen 1 (MAGE-A1); ETS translocation- variant gene 6, located on chromosome 12p (ETV6- AML); sperm protein 17 (SPA 17); X Antigen Family, Member 1A (XAGE1); angiopoietin- binding cell surface receptor 2 (Tie 2); melanoma cancer testis antigen-1 (MAD-CT-1); melanoma cancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; wild-type p53-induced phosphatase 1 (Wipl); prostein; surviving; telomerase; prostate carcinoma tumor antigen-1 (PCTA-1 or Galectin 8); melanoma antigen recognized by T cells 1 (MelanA or MARTI); Rat sarcoma (Ras) mutant; human Telomerase
  • the target substrate is a kinase. In certain embodiments, the target substrate is a phosphatase. In certain embodiments, the target substrate is KRAS or KRAS mutant, BRD4, CAII, TRIM24, or BTK. In certain embodiments, the target substrate is KRAS or KRAS mutant, BRD4, CAII, TRIM24, BET, BRD2, BRD3, BRDT, or BTK. In certain embodiments, the target substrate is BRD4 or BTK. In certain embodiments, the target substrate is KRAS or KRAS mutant. In certain embodiments, the target substrate is BRD4. In certain embodiments, the target substrate is BTK. In certain embodiments, the target substrate is CAII. In certain embodiments, the target substrate is TRIM24. In certain embodiments, the target substrate is BET. In certain embodiments, the target substrate is BRD2. In certain embodiments, the target substrate is BRD3. In certain embodiments, the target substrate is BRDT.
  • the present disclosure also provides methods for inhibiting phosphorylation of a target substrate with a compound of the disclosure (e.g., Formula ((I), (II), or as provided herein), the methods comprising contacting ABL1 with the compound.
  • the compound is a compound of Formula (II).
  • the methods further comprise the compound binding an allosteric site of ABLE
  • Compounds are prepared in order to interrogate their ability of the ABL1 -binding portion of the compound to bind and/or activate ABLE
  • reaction mixture was concentrated under reduced pressure to give a residue which was purified by Prep-HPLC (Phenomenex luna C18 150*25mm* 10pm water(NH4HCO3)-ACN, B%, 16-46, 10 min) and lyophilized to give A-(l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)-2-methyl-6-((4- methylpiperazin-l-yl)methyl)pyrimidin-4-amine (A- 12) (22.7 mg, 47 pmol) as a white solid.
  • Prep-HPLC Phenomenex luna C18 150*25mm* 10pm water(NH4HCO3)-ACN, B%, 16-46, 10 min
  • reaction mixture was purified by prep-HPLC (Column: Waters Xbridge BEH Cl 8 150*25mm*5pm, water( NH 4 HCO 3 )-ACN, B%, 50-70, 10 min.) to give (S,E)-A-(2-(2-(2-(2-(4- (4-chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)ethoxy)ethoxy)ethyl)-3-(6-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3- yl)amino)pyrimidin-4-yl)acrylamide (16) (21.1 mg, 31.1 pmol, 22% yield) as an orange solid.
  • tert-butyl piperazine- 1 -carboxylate 91.5 mg, 492 pmol
  • DIEA 212 mg, 4 eq., 1.64 mmol
  • tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (3.39 g, 10.8 mmol) was added and the resulting mixture was stirred at 25 °C for 2 h.
  • reaction mixture was purified by reverse phase chromatography (CD02-Waters Xbidge BEH C18 150*25*10pm, water(FA)-ACN, B%, 30-52, 10 min) and lyophilized to give 2-((S)-4-(4-chlorophenyl)-2,3,9- tri methyl -6H-thieno
  • HATU 29.1 mg, 76.6 pmol
  • (S)-2-(2-(2-(2-(2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)ethoxy)ethoxy)acetic acid (41.8 mg, 76.6 pmol) in dimethylacetamide (2.14 mL) at 0 °C.
  • ABLlb[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 ICsos were determined by fitting the data based on a sigmoidal dose -response equation. Results are shown in Table 2.
  • Compounds are assessed for BRD4 binding in the BRD4 AlphaScreen Assay at Reaction Biology (Malvern, PA). Compounds are titrated 1:3 in 100% DMSO and dispensed to the reaction plate using acoustic technology (Echo550, Labcyte) containing His-BRD4[2-1362] in reaction buffer containing 50 mM HEPES pH 7.5, 100 mM NaCl, 0.05% CHAPS, 0.1% BSA. Histone H4 peptide (1-21) K5/8/12/16Ac-Biotin is prepared in reaction buffer and dispensed to the plate following the addition of compound, and the plate is incubated for 30 minutes at room temperature.
  • acoustic technology Echo550, Labcyte
  • Histone H4 peptide (1-21) K5/8/12/16Ac-Biotin is prepared in reaction buffer and dispensed to the plate following the addition of compound, and the plate is incubated for 30 minutes at room temperature.
  • 5X donor beads Streptavidin- coated
  • 5X acceptor beads AlphaScreen Ni beads
  • the plate is incubated with gentle shaking in the dark for 60 minutes.
  • NanoBret NanoGio substrate and Extracellular NanoLuc inhibitor (Promega) reagent are added to the wells and incubated for 2 min at room temperature. Donor and acceptor emission are read out at 480 nm and 610 nm, respectively. The mBret ratio was calculated using the formula [(Acceptorsample / Donorsample) - (AcceptorDMSO/DonorDMSO)] x 1000. Results are shown in Table 4.
  • Intact Mass Spectrometry Measurement of compound-mediated phosphorylation ofBRD4 by ABL
  • Compounds of the disclosure are plated in an Eppendorf LoBind 384-well plate (Cat # 951040589) for a final concentration of 1 pM in 1% DMSO.
  • Recombinant BRD4 (residues 49- 460, BPS Bioscience Cat #31047) and Abl (residues 46-534, produced in-house) are diluted in assay buffer (50 mM HEPES, pH 7.4, 10 mM MgC12, 0.5 mM TCEP) and added to each well for a final concentration of 700 nM BRD4 and 300 nM Abl.
  • the plate is 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 are 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 2pl of the reaction onto a Waters ACQUITY UPLC Protein BEH C4 column (300 A, 1.7 pm, 2.1 x 50 mm, Cat #186004495) held at 80°C.
  • Samples are 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 is 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 are deconvoluted into intact mass using the MaxEntl 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.
  • PI score (4.8 x W%) + (4.95 x X%) + (5.1 x Y%) + (5.4 x Z%). PI score can then be plotted as bar graph in graphpad.
  • 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

Provided herein are compounds that bind 3-phosphoinositide-dependent protein kinase- 1 (ABL1) and/or promote targeted phosphorylation of a substrate. The induced phosphorylation of the target substrate can alter the substrate's structure and function, thus providing compounds which enable phosphorylation of target substrates, including those that may not otherwise be substrates for ABL1, and providing new modes for inducing strategic phosphorylation. Also provided are compounds that are intermediates of the bifunctional compounds. Also provided are compounds that bind an allosteric site of ABL1 and inhibit the phosphorylation of a target substrate. Also provided are pharmaceutical compositions comprising the disclosed compounds and methods of promoting the phosphorylation of target substrates in a biological sample by administering a compound or composition described herein.

Description

BIFUNCTIONAL ABL1-BINDING COMPOUNDS AND USES THEREOF
RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N. 63/549,396, filed February 2, 2024, which is incorporated herein by reference in its entirety.
BACKGROUND
[0002] Protein kinases regulate critical substrates (e.g., protein) and cellular functions like substrate half-life, substrate engagement with various biomolecules, metabolism, differentiation, proliferation, and apoptosis. Kinase dysfunction is also associated with a variety of human diseases, including, but not limited to, cancer, inflammatory conditions, autoimmune disorders, and cardiovascular diseases. Agents that block protein phosphorylation via kinase inhibition have had a transformative impact in basic science and medicine. However, agents that can both engage a kinase and one or more other target substrates of interest (e.g., proteins) to be phosphorylated may also be useful as a means of evoking desired attributes or responses from those target substrates.
[0003] Tyrosine-protein kinase ABL1 (referred herein as ABL1, formerly known as ABL) is a protein that has been implicated in cell differentiation, cell division, cell adhesion, and stress response. The activity of ABL1 protein is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABL1 into an oncogene. The ubiquitously expressed protein has DNA- binding activity that is regulated by CDC2-mediated phosphorylation, suggesting a cell cycle function.
[0004] Recently, a new strategy for promoting the phosphorylation of target proteins of interest, PHICS (phosphorylation-inducing chimeric small molecules), was introduced. PHICS are bifunctional molecules containing two small molecule binding moieties, joined together by a linker. One of the small molecule moieties is designed to bind to a target protein while the other small molecule moiety binds to a protein kinase. The PHICS selectively binds to the target substrate of interest and simultaneously binds to and recruits a specific kinase to phosphorylate the target substrate. The PHICS then dissociate from the target substrate and initiate another catalytic cycle.
SUMMARY
[0005] Phosphorylation of any given target substrate (e.g., a protein) can alter its structure, activity, localization, and/or function. Such modifications may be accomplished by compounds that bring a kinase in proximity to a target substrate. Provided herein are PHICS 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. Also provided are bifunctional compounds that comprise a first functional moiety that engages/binds ABL1 and a second functional moiety that comprises a detectable moiety (e.g., a chromophore, dye, fluorophore, luminophore or luminescent material, or radioactive material) joined together by a linker. Also provided are compounds that are useful as synthetic intermediates in methods of preparing the aforementioned bifunctional compounds. Accordingly, the present disclosure provides new compounds, compositions, kits, uses, and methods for modulating (e.g., phosphorylating) a target substrate (e.g., protein) via proximity-induced engagement between ABL1 and a target substrate.
[0006] In one aspect, provided herein are compounds of Formula (I):
(I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:
R1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, - n is an integer selected from 0, 1, 2, 3, 4, and 5;
R2 is hydrogen, or substituted or unsubstituted alkyl;
R3 is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group;
A is -X’-X^-X4-;
X1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
X2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; X3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
X4 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene;
L is a bond or a linker;
B is a targeting moiety or a detectable moiety; and each occurrence of RA 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 RA groups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
[0007] In another aspect, provided herein are compounds of Formula (II):
(II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:
R1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 0, 1, 2, 3, 4, and 5;
R2 is hydrogen, or substituted or unsubstituted alkyl;
R3 is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group;
A is -X’-X^-X4-; X1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
X2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
X3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
X4 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene;
L is a bond or a linker;
T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle; and each occurrence of RA 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 RA groups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring. [0008] In another aspect, provided are pharmaceutical compositions comprising a compound (e.g., PHICS) of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.
[0009] In another aspect, provided are methods of phosphorylating a target substrate (e.g., protein), the method comprising administering a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a compound of the disclosure, to a mixture that comprises ABL1 and the target substrate.
[0010] In another aspect, provided are methods of promoting the phosphorylation of a target substrate (e.g., protein) with ABL1, the method comprising contacting the target substrate with a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a compound of the disclosure.
[0011] In another aspect, provided are methods of modulating a protein kinase, the method comprising contacting the protein kinase with a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a compound of the disclosure. In certain embodiments, the protein kinase is ABL1.
[0012] In another aspect, provided are kits comprising a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a compound of the disclosure. In certain embodiments, the kit further comprises instructions for administration and/or use.
[0013] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 depicts ABL phosphorylation for a variety of PHICS: compounds 16-19. To assess phosphorylation, the measured mass of BRD4 after incubation with ABL+/- PHICS was compared to the mass of BRD4 alone. Quantification of the modification was performed using deconvoluted peak height. Each phosphorylation state is expressed as a percentage of the total BRD4 protein detected in the LCMS run.
DEFINITIONS
Chemical definitions
[0015] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’ s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. [0016] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [0017] Where compound structures are depicted, stereocenters labeled with “abs” indicate known absolute stereochemistry, stereocenters labeled with “&i” indicate a mixture of the two trans or cis stereoisomers, and stereocenters labeled with “ori” indicate a single stereoisomer with unknown absolute stereochemistry.
[0018] In a formula, is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, - is absent or a single bond, and = or is a single or double bond.
[0019] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19F with 18F, or the replacement of 12C with 13C or 14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
[0020] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-6 alkyl” is intended to encompass Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, CM, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
[0021] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
[0022] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-s alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“Ci-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“CM alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n- butyl, tert-butyl, sec -butyl, zso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3- methyl-2-butanyl, tertiary amyl), and hexyl (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec -butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10 alkyl (such as substituted C1-6 alkyl, e.g., -CF3, Bn).
[0023] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“Ci-s haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“CM haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCI2, -CF2CI, and the like.
[0024] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-is alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-i6 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 (“heteroCi-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 (“heteroCi-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 (“heteroCi-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-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 (“heteroCi-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 (“heteroCi-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 (“heteroCi-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl.
[0025] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified may be an (E)- or (Z)-double bond.
[0026] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2 io alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 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 (“heteroC2-s alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 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 (“heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3 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 (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroCz io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroCz-io alkenyl.
[0027] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkynyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.
[0028] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2 io alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 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 (“heteroC2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-s alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 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 (“heteroC2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2 io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2 io alkynyl.
[0029] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system, such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl. [0030] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (Ce). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.
[0031] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
[0032] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
[0033] 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-Z?]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, I A/-benzo[e][ l ,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-Z?]pyrrolyl, 5,6- dihydro-4Z/-furo[3,2-Z?]pyrrolyl, 6,7-dihydro-5Z/-furo[3,2-Z?]pyranyl, 5,7-dihydro-4A/-thieno[2,3- c]pyranyl, 2,3-dihydro-l A/-pyrrolo|2,3-/?]pyridinyl, 2,3-dihydrofuro[2,3-&]pyridinyl, 4, 5,6,7- tetrahydro-l A/-pyrro]o[2,3-/?]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydro- thieno[3,2-Z?]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.
[0034] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 147t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted Ce-i4 aryl. In certain embodiments, the aryl group is a substituted Ce-i4 aryl.
[0035] “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.
[0036] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 147t electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- 14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). [0037] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
[0038] 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.
[0039] “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.
[0040] The term “unsaturated bond” refers to a double or triple bond.
[0041] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
[0042] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
[0043] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.
[0044] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” acyl, “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents described herein.
[0045] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR33, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3 +X“, -N(ORcc)Rbb, -SH, -SR33, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)3, -CO2Raa, -OC(=O)R33, -OCO2R33, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)R33, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)R33, -C(=NRbb)0R33, -OC(=NRbb)R33, -OC(=NRbb)0R33, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2R33, -NRbbSO2R33, -SO2N(Rbb)2, -SO2R33, -SO2OR33, -OSO2R33, -S(=O)R33, -0S(=O)R33, -Si(Raa)3, -OSi(Raa)3 -C(=S)N(Rbb)2, -C(=O)SR33, -C(=S)SR33, -SC(=S)SR33, -SC(=O)SR33, -OC(=O)SR33, -SC(=O)0R33, -SC(=O)R33, -P(=O)(R33)2, -P(=O)(ORCC)2, -OP(=O)(R33)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(R33)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3 +X“, -P(ORCC)3 +X“, -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3 +X“, -OP(ORCC)2, -OP(ORCC)3 +X“, -OP(RCC)4, -OP(ORCC)4, -B(R33)2, -B(ORCC)2, -BR33(0RCC), Ci-io alkyl, Ci-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; wherein X“ is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)R33, =NNRbbC(=O)0R33, =NNRbbS(=O)2R33, =NRbb, or =NORCC; each instance of R33 is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2.10 alkenyl, heteroC2-io alkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce i4 aryl, and 5-14 membered heteroaryl, or two R33 groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rbb is, independently, selected from hydrogen, -OH, -OR33, -N(RCC)2, -CN, -C(=O)R33, -C(=O)N(RCC)2, -CO2R33, -SO2R33, -C(=NRcc)0R33, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, CI-10 alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2. 10 alkynyl, heteroCi-io alkyl, heteroC2-io alkenyl, heteroC2-i oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; wherein X“ is a counterion; each instance of Rcc is, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rdd is, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -0N(Rff)2, -N(Rff)2, -N(Rff)3 +X“, -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC 1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form =O or =S; wherein X“ is a counterion; each instance of Ree is, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, he teroC2-6 alkenyl, heteroC 2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of Rff is, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC 1-6 alkyl, heteroC2-6 alkenyl, heteroC 2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl and 5-10 membered heteroaryl, or two Rff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and each instance of Rgg is, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(C1-6 alkyl)2, -N(C1-6 alkyl)2, -N(C1-6 alkyl^X", -NH(C1-6 alkyVX", -NH2(C1-6 alkyl)+X“, -NH3 +X-, -N(OC1-6 alkyl)(C1-6 alkyl), -N(OH)(C1-6 alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SS(C1-6 alkyl), -C(=O)(C1-6 alkyl), -CO2H, -CO2(C1-6 alkyl), -OC(=O)(C1-6 alkyl), -OCO2(C1-6 alkyl), -C(=O)NH2, -C(=O)N(C1-6 alkyl)2, -OC(=O)NH(C1-6 alkyl), -NHC(=O)(C1-6 alkyl), -N(C1-6 alkyl)C(=O)( C1-6 alkyl), -NHCO2(C1-6 alkyl), -NHC(=O)N(C1-6 alkyl)2, -NHC(=O)NH(C1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C1-6 alkyl), -OC(=NH)(C1-6 alkyl), -OC(=NH)OC1-6 alkyl, -C(=NH)N(C1-6 alkyl)2, -C(=NH)NH(C1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6 alkyl)2, -OC(=NH)NH(C1-6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(C1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6 alkyl), -SO2N(C1-6 alkyl)2, -SO2NH(C1-6 alkyl), -SO2NH2, -SO2(C1-6 alkyl), -SO2O(C1-6 alkyl), -OSO2(C1-6 alkyl), -SO(C1-6 alkyl), -Si(C1-6 alkyl)3, -OSi(C1-6 alkyl)3 -C(=S)N(C1-6 alkyl)2, C(=S)NH(C1-6 alkyl), C(=S)NH2, -C(=O)S(C1-6 alkyl), -C(=S)SC1-6 alkyl, -SC(=S)SC1-6 alkyl, -P(=O)(OC1-6 alkyl)2, -P(=O)(C1-6 alkyl)2, -OP(=O)(Ci-6 alkyl)2, -OP(=O)(OC1-6 alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2.6 alkenyl, C2.6 alkynyl, heteroC 1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgg substituents can be joined to form =O or =S; wherein X“ is a counterion.
[0046] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).
[0047] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -OR33, -ON(Rbb)2, -OC(=O)SR33, -OC(=O)R33, -OCO2R33, -OC(=O)N(Rbb)2, -OC(=NRbb)R33, -OC(=NRbb)0R33, -OC(=NRbb)N(Rbb)2, -0S(=O)R33, -OSO2R33, -OSi(Raa)3, -OP(RCC)2, -OP(RCC)3 +X-, -OP(ORCC)2, -OP(ORCC)3 +X-, -OP(=O)(R33)2, -OP(=O)(ORCC)2, and -OP(=O)(N(Rbb)2)2, wherein X", R33, Rbb, and Rcc are as defined herein. [0048] The term “amino” refers to the group -NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group. [0049] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=O)Raa, -NHCO2RA -NHC(=O)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, -NHSO2Raa, -NHP(=O)(ORCC)2, and -NHP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rcc are as defined herein, and wherein Rbb of the group -NH(Rbb) is not hydrogen.
[0050] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from -N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -NRbbSO2Raa, -NRbbP(=O)(ORcc)2, and -NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rcc are as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.
[0051] The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(Rbb)3 and -N(Rbb)3+X“, wherein Rbb and X“ are as defined herein.
[0052] The term “acyl” refers to a group having the general formula -C(=O)RX1, -C(=O)ORX1, -C(=O)-O-C(=O)RX1, -C(=O)SRX1, -C(=O)N(RX1)2, -C(=S)RX1, -C(=S)N(RX1)2, -C(=S)O(RX1), -C(=S)S(RX1), -C(=NRX1)RX1, -C(=NRX1)ORX1, -C(=NRX1)SRX1, and -C(=NRX1)N(RX1)2, wherein RX1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1 groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
[0053] The term “carbonyl” refers a group wherein the carbon directly attached to the parent molecule is sp2 hybridized, and is substituted with an oxygen (i.e., -C(=O)-).
[0054] The term “silyl” refers to the group -Si(Raa)3, wherein Raa is as defined herein.
[0055] The term “oxo” refers to the group =O, and the term “thiooxo” refers to the group =S. [0056] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2R33, -SO2Raa, -C(=NRbb)R33, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -S0R33, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(ORCC)2, -P(=O)(R33)2, -P(=O)(N(RCC)2)2, CI-IO alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2. io alkynyl, heteroCi- walkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rcc groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein R33, Rbb, Rcc, and Rdd are as defined herein.
[0057] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, -OH, -OR33, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2R33, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOR33, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, CI-IO alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein R33, Rbb, Rcc and Rdd are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
[0058] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)R33) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o- nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, and o- (benzoyloxymethyl)benzamide.
[0059] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-!- methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1- methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N- hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9 -anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2- phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1- dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3, 5 -dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1 , 1 -dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1 -methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, l-methyl-l-(3,5- dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1- phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.
[0060] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy- 4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.
[0061] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)- 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 l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5- dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fem), N-2-picolylamino N’- oxide, N- 1,1 -dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N’ ,N’ -dimethylaminomethylene)amine, N,N’ -isopropylidenediamine, N-p- nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l- cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N- [phenyl(pentaacylchromium- or tungsten)acyl] amine, N-copper chelate, N-zinc chelate, N- nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o- nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3- nitropyridinesulfenamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds). [0062] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO^, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3 +X-, -P(ORCC)2, -P(ORCC)3 +X-, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb) 2)2, wherein X“, Raa, Rbb, and Rcc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
[0063] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, l-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin- 4-yl (CTMP), 1 ,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2, 3, 3a, 4, 5, 6, 7,7a- octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1 -methyl- 1 -benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o- nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cy anobenzyl, p-phenylbenzyl, 2- picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p'-dinitrobenzhydryl, 5- dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'- bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-l- yl)bis(4',4"-dimethoxyphenyl)methyl, l,l-bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9- (9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S,S- dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dime thy Ithexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxy acetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p- methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p- nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4- (methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-( 1 , 1 ,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis( 1,1- dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2- methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1 -ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2- trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).
[0064] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, -R”, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3 +X“, -P(ORCC)2, -P(ORCC)3 +X“, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb) 2)2, wherein Raa, Rbb, and Rcc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine- sulfenyl, or triphenylmethyl.
[0065] 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 (z.e., including one formal negative charge). An anionic counterion may also be multivalent (z.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F“, Cl", Br“, I-), NO3“, CIOT, OH-, H2PO4-, HCO3”, HSO4-, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p- toluenesulf onate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4-, PF4-, PFe”, AsFe”, SbFe”, B[3,5-(CF3)2C6H3]4]“, B(C6Fs)4-, BPtu”, A1(OC(CF3)3)4-, and carborane anions (e.g., CBnHi2“ or (HCBnMesBre)-). Exemplary counterions which may be multivalent include CO3 2-, HPO42-, PO43-, B4O?2-, SO42-, S2O3 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.
[0066] The term “leaving group” is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March’ s Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl- carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, A,(9-dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p- bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2- nitrobenzenesulfonyloxy. The leaving group may also be a phosphineoxide (e.g. , formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other nonlimiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Further exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SRaa, -OC(=O)Raa, -OC02Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OP(RCC)2, -OP(RCC)3, -OP(=O)2Raa, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -OP(=O)2N(Rbb)2, and -0P(=O)(NRbb)2, wherein R”, Rbb, and Rcc are as defined herein).
[0067] As used herein, use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
[0068] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.
[0069] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, Figures, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.
Other definitions
[0070] The following definitions are more general terms used throughout the present application.
[0071] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.
[0072] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alkyl)4- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
[0073] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solutionphase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
[0074] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).
[0075] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to- imine, and enamine-to-(a different enamine) tautomerizations.
[0076] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.
[0077] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
[0078] 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.
[0079] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Ci-s alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, C7-12 substituted aryl, and C7-12 arylalkyl esters of the compounds described herein may be preferred.
[0080] The terms “composition” and “formulation” are used interchangeably.
[0081] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The subject may also be a plant. In certain embodiments, the plant is a land plant. In certain embodiments, the plant is a non-vascular land plant. In certain embodiments, the plant is a vascular land plant. In certain embodiments, the plant is a seed plant. In certain embodiments, the plant is a cultivated plant. In certain embodiments, the plant is a dicot. In certain embodiments, the plant is a monocot. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, the plant is a legume, e.g., a bean plant, e.g., soybean plant. In some embodiments, the plant is a tree or shrub.
[0082] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
[0083] The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is the object to which a compound and/or composition of the disclosure is delivered. A tissue may be an abnormal or unhealthy tissue. A tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy.
[0084] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into a biological system.
[0085] 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.
[0086] The term “small molecule” refers to molecules, whether naturally occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than about 1,000 g/mol, not more than about 900 g/mol, not more than about 800 g/mol, not more than about 700 g/mol, not more than about 600 g/mol, not more than about 500 g/mol, not more than about 400 g/mol, not more than about 300 g/mol, not more than about 200 g/mol, or not more than about 100 g/mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, or at least about 900 g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g., at least about 200 g/mol and not more than about 500 g/mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms and/or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R.
§§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present invention.
[0087] The term “targeting moiety” refers to any chemical entity that serves to bind or otherwise direct the compound to a particular location or association.
[0088] The term “detectable moiety” refers to a chemical entity that can be used to produce a detectable signal that indicates the presence or concentration of the compound having the detectable moiety in a sample.
[0089] The term “bioactive moiety” refers to an agent or moiety that can influence (i.e., effect a change in) a biological system, such as in an organism, tissue, or cell. In some embodiments, the bioactive moiety is a small molecule. In some embodiments, the bioactive moiety is a peptide or protein. In some embodiments, the bioactive moiety is an FDA-approved drug.
[0090] The term “nucleophilic group” refers to a chemical entity having a nucleophile, a moiety that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Nucleophiles may take part in nucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge, and nucleophilic addition.
[0091] The term “electrophilic group” refers to a chemical entity having an electrophile, a moiety that forms bonds with nucleophiles by accepting an electron pair. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons. Electrophiles mainly interact with nucleophiles through addition and substitution reactions.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0092] Provided herein are bifunctional compounds that bind a target substrate (e.g., protein) and recruit a kinase (e.g., ABL1) to promote the phosphorylation of the target substrate (e.g., protein). Also provided are compounds that act as chemical probes having a detectable moiety (e.g., luminescent materials, such as dyes) that bind ABLE Also provided are compounds useful in the production and manufacture of the bifunctional compounds and probes described herein. [0093] In one aspect, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. In some embodiments, provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. In some embodiments, provided herein are compounds of Formula (I):
(I), or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, - n is an integer selected from 0, 1, 2, 3, 4, and 5;
R2 is hydrogen, or substituted or unsubstituted alkyl;
R3 is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group;
A is -X’-X^-X4-;
X1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
X2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
X3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
X4 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene; L is a bond or a linker;
B is a targeting moiety or a detectable moiety; and each occurrence of RA 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 RA groups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring. [0094] In some embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, tautomers thereof, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts and tautomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.
[0095] In one aspect, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. In some embodiments, provided herein are compounds of Formula (II):
(II), or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, n is an integer selected from 0, 1, 2, 3, 4, and 5;
R2 is hydrogen, or substituted or unsubstituted alkyl;
R3 is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group;
A is -X'-X2-X3-X4-;
X1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
X2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
X3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
X4 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene;
L is a bond or a linker;
T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle; and each occurrence of RA 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 RA groups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring. [0096] In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts, tautomers thereof, and stereoisomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts and tautomers thereof, and pharmaceutical compositions thereof. In some embodiments, the disclosure provides compounds of Formula (II), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.
[0097] In certain embodiments, the disclosure provides additional compounds (i.e., not of Formula (I) or (II)), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, and stereoisomers thereof, and pharmaceutical compositions thereof.
[0098] In certain embodiments, the compounds of the disclosure (e.g., a compound of Formula (I), (II), or otherwise as provided herein) bind ABL1 with a Kd of less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.
R1
[0099] As described herein, R1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, - SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, - N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2.
[00100] In some embodiments, R1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, - SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, - N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2.
[00101] In some embodiments, R1 is hydrogen, substituted or unsubstituted alkyl, halogen, hydroxy, or -©-(substituted or unsubstituted alkyl). In some embodiments, R1 is substituted or unsubstituted alkyl, halogen, hydroxy, or -©-(substituted or unsubstituted alkyl). In certain embodiments, R1 is chloro, methyl, fluoro, bromo, trifluoromethyl, or trifluoromethoxy.
[00102] In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is halogen. In some embodiments, R1 is substituted or unsubstituted alkyl. In some embodiments, R1 is haloalkyl. In some embodiments, R1 is hydroxy. In some embodiments, R1 is or -O-(unsubstituted alkyl). In some embodiments, R1 is or -O-(haloalkyl).
[00103] In certain embodiments, R1 is hydrogen or halogen. In some embodiments, R1 is substituted or unsubstituted alkyl or hydrogen. In some embodiments, R1 is substituted or unsubstituted alkyl or halogen.
[00104] In some embodiments, is bromophenyl, chlorophenyl, iodophenyl, fluorophenyl, methylphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, hydroxyphenyl, methoxyphenyl, dibromophenyl, dichlorophenyl, diiodophenyl, difluorophenyl, dimethylphenyl, (methyl)(chloro)phenyl, (methyl)(iodo)phenyl, (methyl)(bromo)phenyl, (methyl)(fluoro)phenyl, (chloro)(fluoro)phenyl, (bromo)(chloro)phenyl, (chloro)(iodo)phenyl, (bromo)(fluoro)phenyl, (iodo)(fluoro)phenyl, or (bromo)(iodo)phenyl.
[00105] In some embodiments, is 3,4-dichlorophenyl, 3-methyl-4-chlorophenyl, 3- chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 3-bromophenyl, 2-fluoro-5-chlorophenyl, 3,5- dichlorophenyl, 2,4-dichlorophenyl,3-fluoro-4-chlorophenyl, 3-chloro-5-fluorophenyl, 2,5- dichlorophenyl, 2-fluoro-3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4- trifluoromethoxyphenyl, or 2,3-dichlorophenyl.
[00106] In some embodiments, is 3,4-dichlorophenyl. n
[00107] 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. In some embodiments, n is 1 or 2.
R2
[00108] As described herein, R2 is hydrogen or substituted or unsubstituted alkyl.
[00109] In some embodiments, R2 is hydrogen.
[00110] In some embodiments, R2 is substituted or unsubstituted alkyl. In certain embodiments, R2 is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, or substituted or unsubstituted butyl. In certain embodiments, R2 is substituted or unsubstituted methyl. In some embodiments, R2 is substituted or unsubstituted ethyl. In certain embodiments, R2 is substituted or unsubstituted propyl (e.g., n-propyl, isopropyl). In some embodiments, R2 is substituted or unsubstituted butyl (n-butyl, tert-butyl, secbutyl).
[00111] In certain embodiments, R2 is hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, or substituted or unsubstituted butyl. In certain embodiments, R2 is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted butyl. In certain embodiments, R2 is hydrogen, substituted methyl, substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R2 is hydrogen, methyl, 2-hydroxyethyl, 2-methoxy ethyl, sec-butyl, or isopropyl. In certain embodiments, R2 is hydrogen or unsubstituted methyl.
[00112] In certain embodiments, the carbon to which R2 is attached is in an (R) configuration. In certain embodiments, the carbon to which R2 is attached is in an (S) configuration.
R3
[00113] As described herein, R3 is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group. In some embodiments, R3 is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R3 is hydrogen or substituted or unsubstituted methyl.
[00114] In certain embodiments, R3 is hydrogen.
[00115] In some embodiments, R3 is substituted or unsubstituted alkyl. In some embodiments, R3 is substituted or unsubstituted methyl. In some embodiments, R3 is substituted methyl. In some embodiments, R3 is unsubstituted methyl.
[00116] In certain embodiments, R3 is nitrogen protecting group.
A
[00117] As described herein, A is -X1-X2-X3-X4-, wherein X1, X2, X3, and X4 are as defined herein.
[00118] In some embodiments, 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.
[00119] In some embodiments, A comprises substituted or unsubstituted phenylene, substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, substituted or unsubstituted pyrazinylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, or substituted or unsubstituted triazolylene.
[00120] In some embodiments, A comprises substituted or unsubstituted phenylene, substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, substituted or unsubstituted pyrazinylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, or substituted or unsubstituted triazolylene.
[00121] In some embodiments, A comprises substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, or substituted or unsubstituted triazolylene.
[00122] In some embodiments, A comprises substituted or unsubstituted pyrazolylene, or substituted or unsubstituted pyrimidinylene.
X1
[00127] As provided herein, X1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene. In some embodiments, X1 is a bond. In certain embodiments, X1 is substituted or unsubstituted alkylene. In certain some, X1 is substituted or unsubstituted alkenylene. In certain embodiments, X1 is substituted or unsubstituted heteroalkylene. In some embodiments, X1 is substituted or unsubstituted heteroalkenylene.
[00128] In certain embodiments, X1 is bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene comprising -O- or -NRA-.
[00129] In certain embodiments, X1 is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, or substituted or unsubstituted hetero-Ci alkylene comprising -O- or -NRA.
[00130] In certain embodiments, X1 is a bond. [00131] In some embodiments, X1 is substituted or unsubstituted alkylene. In certain embodiments, X1 is substituted or unsubstituted CM alkylene. In certain embodiments, X1 is substituted or unsubstituted methylene. In certain embodiments, X1 is unsubstituted methylene. In certain embodiments, X1 is substituted or unsubstituted ethylene. In certain embodiments, X1 is substituted or unsubstituted propylene. In certain embodiments, X1 is substituted or unsubstituted butylene.
[00132] In certain embodiments, X1 is substituted or unsubstituted heteroalkylene comprising - O- or -NRA-. In some embodiments, X1 is substituted or unsubstituted hetero-Ci alkylene comprising -O- or -NRA-. In some embodiments, X1 is substituted or unsubstituted -methylene-O- , -O-methylene-, -NH-methylene-, -methylene-NH-, -N(Me)-methylene-, or -methylene-N(Me)-.
X2
[00133] Provided herein, X2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, X2 is substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, X2 is substituted or unsubstituted heterocyclylene. In some embodiments, X2 is substituted or unsubstituted carbocyclylene. In some embodiments, X2 is substituted or unsubstituted heteroarylene.
[00134] In some embodiments, X2 is substituted or unsubstituted phenylene, substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, substituted or unsubstituted pyrazinylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, or substituted or unsubstituted triazolylene. In some embodiments, X2 is substituted or unsubstituted phenylene. In some embodiments, X2 is substituted or unsubstituted pyridinylene. In some embodiments, X2 is substituted or unsubstituted pyridazinylene. In some embodiments, X2 is substituted or unsubstituted pyrimidinylene. In some embodiments, X2 is substituted or unsubstituted pyrazinylene. In some embodiments, X2 is substituted or unsubstituted imidazolylene. In some embodiments, X2 is substituted or unsubstituted pyrazolylene. In some embodiments, X2 is substituted or unsubstituted triazolylene.
[00135] In some embodiments, X2 is substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, or substituted or unsubstituted triazolylene. In some embodiments, X2 is substituted or unsubstituted pyridinylene. In some embodiments, X2 is substituted or unsubstituted pyridazinylene. In some embodiments, X2 is substituted or unsubstituted pyrimidinylene. In some embodiments, X2 is substituted or unsubstituted imidazolylene. In some embodiments, X2 is substituted or unsubstituted pyrazolylene. In some embodiments, X2 is substituted or unsubstituted triazolylene.
[00136] In some embodiments, X2 is substituted or unsubstituted pyrazolylene, or substituted or unsubstituted pyrimidinylene. In some embodiments, X2 is substituted or unsubstituted pyrazolylene. In some embodiments, X2 is substituted or unsubstituted pyrimidinylene. some embodiments, X2 is some embodiments, X2 is . In some embodiments, X2 is some embodiments, X2 is . In some embodiments, X2 is some embodiments, X2 is In some embodiments, X2 is . some embodiments, X2 is . In some embodiments, X is , In some embodiments, X2 is
X3
[00141] As provided herein, X3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene. In some embodiments, X3 is a bond. In certain embodiments, X3 is substituted or unsubstituted alkylene. In certain some, X3 is substituted or unsubstituted alkenylene. In certain embodiments, X3 is substituted or unsubstituted heteroalkylene. In some embodiments, X3 is substituted or unsubstituted heteroalkenylene.
[00142] In some embodiments, X3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted heteroalkylene comprising -O- or - NRA-.
[00143] In certain embodiments, X3 is substituted or unsubstituted alkylene, or substituted or unsubstituted alkenylene. In certain embodiments, X3 is substituted or unsubstituted alkylene. In certain embodiments, X3 is substituted or unsubstituted alkenylene.
[00144] In certain embodiments, X3 is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted ethenylene, or substituted or unsubstituted hetero-Ci alkylene comprising -O- or -NRA-.
[00145] In certain embodiments, X3 is a bond.
[00146] In some embodiments, X3 is substituted or unsubstituted alkylene. In certain embodiments, X3 is substituted or unsubstituted CM alkylene. In certain embodiments, X3 is substituted or unsubstituted methylene. In certain embodiments, X3 is methylene substituted with =O. In certain embodiments, X3 is unsubstituted methylene. In certain embodiments, X3 is substituted or unsubstituted ethylene. In certain embodiments, X3 is unsubstituted ethylene. In certain embodiments, X3 is substituted or unsubstituted ethenylene. In certain embodiments, X3 is unsubstituted ethenylene. In certain embodiments, X3 is substituted or unsubstituted propylene. In certain embodiments, X3 is substituted or unsubstituted butylene.
[00147] In certain embodiments, X3 is substituted or unsubstituted heteroalkylene comprising - O- or -NRA-. In some embodiments, X3 is substituted or unsubstituted hetero-Ci alkylene comprising -O- or -NRA-. In some embodiments, X3 is substituted or unsubstituted -methylene-O- , -O-methylene-, -NH-methylene-, -methylene-NH-, -N(Me)-methylene-, or -methylene-N(Me)-.
X4
[00148] As provided herein, X4 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene. In some embodiments, X4 is a bond or substituted or unsubstituted heterocyclylene. In some embodiments, X4 is a bond. In some embodiments, X4 is substituted or unsubstituted heterocyclylene. In some embodiments, X4 is substituted or unsubstituted carbocyclylene. In some embodiments, X4 is substituted or unsubstituted heteroarylene. In some embodiments, X4 is substituted or unsubstituted arylene. In some embodiments, X4 is a bond, or substituted or unsubstituted heterocyclylene. In some embodiments, X4 is a bond, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperdinylene, or substituted or unsubstituted piperazinylene. In some embodiments, X4 is substituted or unsubstituted pyrrolidinylene. In some embodiments, X4 is substituted or unsubstituted piperdinylene. In some embodiments, X4 is substituted or unsubstituted piperazinylene.
L
[00149] As described herein, L is a bond or a linker. In certain embodiments, L is a bond. In certain embodiments, L is a linker. In certain embodiments, L is a chain of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous atoms. In certain embodiments, L is a chain of at least 1 atom. In certain embodiments, L is a chain of at least 2 contiguous atoms. In certain embodiments, L is a chain of at least 3 contiguous atoms. In certain embodiments, L is a chain of at least 4 contiguous atoms. In certain embodiments, L is a chain of at least 5 contiguous atoms. In certain embodiments, L is a chain of at least 6 contiguous atoms. In certain embodiments, L is a chain of at least 7 contiguous atoms. In certain embodiments, L is a chain of at least 8 contiguous atoms. In certain embodiments, L is a chain of at least 9 contiguous atoms. In certain embodiments, L is a chain of at least 10 contiguous atoms. In certain embodiments, L is a chain of at least 11 contiguous atoms. In certain embodiments, L is a chain of at least 12 contiguous atoms. In certain embodiments, L is a chain of at least 13 contiguous atoms. In certain embodiments, L is a chain of at least 14 contiguous atoms. In certain embodiments, L is a chain of at least 15 contiguous atoms. In certain embodiments, L is a chain of any range of from 1 to 15 contiguous atoms.
[00150] 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.
[00151] In certain embodiments of L disclosed herein where L is depicted as a chemical structure, the lefthand attachment point is to B and the righthand attachment point is to A when B is present; or the lefthand attachment point is to T and the righthand attachment point is to A when T is present.
[00152] In certain embodiments, L is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted heteroarylene, -N(RA)-, -O-, -C(=O)NRA-, -NRAC(=O)-, or -C(=O)-, or a combination thereof.
[00153] In certain embodiments, L is substituted or unsubstituted alkylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene, -
N(CH3)-, -O-, -N(H)C(=O)-, -N(CH3)C(=O)-, -C(=O)-, or a combination thereof. In certain embodiments, L is a combination of two or more of substituted or unsubstituted alkylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene, , ,
N(H)-, -N(CH3)-, -O-, -N(H)C(=O)-, -N(CH3)C(=O)-, -C(=O)-.
[00154] In some embodiments, L is of formula: wherein:
Z1 is a bond, -O-, -N(RA)-, -C(=O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
Z2 is a bond, -N(RA)-, -NRAC(=O)-, -C(=O)-, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted alkylene;
Q is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene;
Q1 is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene;
Z3 is a bond, -C(=O)-, -O-, or -N(RA)-;
Z4 is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-30; and u is 0-30; provided that L comprises at least one atom.
[00155] In some embodiments, Zi is a bond, -O-, -N(RA)-, -C(=O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In some embodiments, Z1 is a bond. In some embodiments, Z1 is -O-. In some embodiments, Zi is -C(=O). In some embodiments, Z1 is - N(RA)-. In some embodiments, Z1 is -N(H)-. In some embodiments, Z1 is -N(CH3)-. In some embodiments, Z1 is substituted or unsubstituted alkylene. In some embodiments, Z1 is substituted or unsubstituted methylene. In some embodiments, Z1 is substituted or unsubstituted ethylene. In some embodiments, Z1 is substituted or unsubstituted heteroalkylene. In some embodiments, Z1 is substituted or unsubstituted hetero-Ci -alkylene comprising -O- or -N(RA)-. In some embodiments, Z1 is substituted or unsubstituted hetero-Cz-alkylene comprising -O- or -N(RA)-. In some embodiments, Z1 is substituted or unsubstituted hetero-C3-alkylene comprising -O- or - N(RA)-. In some embodiments, Z1 is a repeating substituted or unsubstituted hetero-Cs-alkylene comprising -O- or -N(RA)-.
[00156] In some embodiments, Z2 is a bond, -N(RA)-, -NRAC(=O)-, -C(=O)-, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted alkylene. In some embodiments, Z2 is a bond. In some embodiments, Z2 is -O-. In some embodiments, Z2 is -N(RA)-. In some embodiments, Z2 is -N(H)-. In some embodiments, Z2 is -N(CH3)-. In some embodiments Z2 is - C(=O)-. In some embodiments, Z2 is -NRAC(=O)-. In some embodiments, Z2 is -N(H)C(=O)-. In some embodiments, Z2 is -N(CH3)C(=O)-. In some embodiments, Z2 is substituted or unsubstituted alkylene. In some embodiments, Z2 is substituted or unsubstituted methylene. In some embodiments, Z2 is substituted or unsubstituted ethylene. In some embodiments, Z2 is substituted or unsubstituted heterocyclylene. In some embodiments, Z2 is substituted or unsubstituted 6-membered heterocyclylene. In some embodiments, Z2 is substituted or unsubstituted piperidinylene or substituted or unsubstituted piperazinylene.
[00157] In some embodiments, Q is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene. [00158] In some embodiments, Q is a bond. In some embodiments, Q is substituted or unsubstituted heteroalkylene. In some embodiments, Q is substituted or unsubstituted heteroalkylene. In some embodiments, Q is substituted or unsubstituted hetero-Ci -alkylene comprising -O- or -N(RA)-. In some embodiments, Q is substituted or unsubstituted hetero-C?- alkylene comprising -O- or -N(RA)-. In some embodiments, Q is substituted or unsubstituted hetero-C3-alkylene comprising -O- or -N(RA)-. In some embodiments, Q is a repeating substituted or unsubstituted hetero-C3-alkylene comprising -O- or -N(RA)-. In some embodiments, Q is substituted or unsubstituted heterocyclylene. In some embodiments, Q is substituted or unsubstituted 6-membered heterocyclylene. In some embodiments, Q is substituted or unsubstituted piperidinylene or substituted or unsubstituted piperazinylene. In some embodiments, Q is substituted or unsubstituted heteroarylene. In some embodiments, Q is substituted or unsubstituted is substituted or unsubstituted 5-membered heteroarylene. In some embodiments, Q is triazolylene.
[00159] In some embodiments, Q1 is a bond. In some embodiments, Q1 is substituted or unsubstituted heteroalkylene. In some embodiments, Q1 is substituted or unsubstituted heteroalkylene. In some embodiments, Q1 is substituted or unsubstituted hetero-Ci -alkylene comprising -O- or -N(RA)-. In some embodiments, Q1 is substituted or unsubstituted hetero-C?- alkylene comprising -O- or -N(RA)-. In some embodiments, Q1 is substituted or unsubstituted hetero-C3-alkylene comprising -O- or -N(RA)-. In some embodiments, Q1 is a repeating substituted or unsubstituted hetero-C3-alkylene comprising -O- or -N(RA)-. In some embodiments, Q1 is substituted or unsubstituted heterocyclylene. In some embodiments, Q1 is substituted or unsubstituted 6-membered heterocyclylene. In some embodiments, Q1 is substituted or unsubstituted piperidinylene or substituted or unsubstituted piperazinylene. In some embodiments, Q1 is substituted or unsubstituted heteroarylene. In some embodiments, Q1 is substituted or unsubstituted is substituted or unsubstituted 5-membered heteroarylene. In some embodiments, Q1 is triazolylene.
[00160] In some embodiments, Z3 is a bond, -C(=O)-, -O-, or -N(RA)-. In some embodiments, Z3 is a bond. In some embodiments, Z3 is -C(=O)-. In some embodiments, Z3 is -O-. In some embodiments, Z3 is -N(RA)-. In some embodiments, Z3 is -N(H)-. In some embodiments, Z3 is - N(CH3)-.
[00161] In some embodiments, Z4 is a bond, -C(=O)-, -O-, or -N(RA)-. In some embodiments, Z3 is a bond. In some embodiments, Z4 is -C(=O)-. In some embodiments, Z4 is -O-. In some embodiments, Z4 is -N(RA)-. In some embodiments, Z4 is -N(H)-. In some embodiments, Z4 is - N(CH3)-.
[00162] In certain embodiments, L is of formula: wherein:
Z1 is a bond, -O-, -N(RA)-, -C(=O)-, unsubstituted Ci-6 alkylene, RA
Z3 is a bond, -C(=O)-, -O-, or -N(RA)-;
Z4 is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.
[00163] In certain embodiments, L is of formula:
Z3 is a bond, -C(=O)-, -O-, or -N(RA)-;
Z4 is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.
[00164] In certain embodiments, L is of formula:
Z3 is a bond, -C(=O)-, -O-, or -N(RA)-;
Z4 is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.
[00165] In certain embodiments, L is of formula: wherein:
Z1 is a bond, -O-, -N(RA)-, -C(=O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
Z2 is a bond, -N(RA)-, -NRAC(=O)-, -C(=O)-, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted alkylene;
Q is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene;
Z3 is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-30; and u is 0-30; provided that L comprises at least one atom.
[00166] In some embodiments, L is of formula: wherein:
Z3 is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.
[00167] In certain embodiments, L is of formula: [00168] In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: In some embodiments, L is of formula: . In some embodiments, L is of formula:
O O . In some embodiments, L is of formula: . In some embodiments, L is of formula: In some embodiments, L is of formula:
In some embodiments, L is of formula: . In some embodiments, L is of , some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula:
In some embodiments, L is of formula:
[00169] In certain embodiments, L is of formula:
[00170] In some embodiments, L is selected from any one of L1-L60 or L161-L177:
[00171] In some embodiments, L is selected from any one of L1-L60 or L161-L177. In some embodiments, L is selected from any one of L1-L60. In some embodiments, L is Li77.
[00172] In some embodiments, L is of formula: . In some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of . , of formula: some embodiments, L is of formula: . In some embodiments, L mula: . In some embodiments, L is of formula: formula: In some embodiments, L is of formula:
In some embodiments, L is of formula: In some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: In some embodiments, L is of some embodiments, L is of formula: In some embodiments, L is of embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of formula: In some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of 0 0 formula: some embodiments, L is of formula:
. In some embodiments, L is of formula: some embodiments, L is of , . In some embodiments, L is of formula:
[00173] In certain embodiments, t is 0-30. In certain embodiments, t is 0-20. In certain embodiments, t is 0-6. In certain embodiments, t is 1-20, 1-10, 1-8, 1-6, 1-5, 1-4, 1-3, or 1-2. In certain embodiments, t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, u is 0-30. In certain embodiments, u is 0-20. In certain embodiments, u is 0- 6. In certain embodiments, u is 1-6, 1-5, 1-4, 1-3, or 1-2. In certain embodiments, u is 1, 2, 3, 4, 5, or 6.
[00174] In certain embodiments, L is -C(=O)- or -O-. In certain embodiments, L is -C(=O)-. In certain embodiments, L is -O-.
[00175] In some embodiments, L is selected from any one of L61-L241:
[00176] In certain embodiments, L is selected from any one of L1-L179 (not including L16I- Li77). In certain embodiments, L is selected from any one of L1-L241 (including L161-L177). In certain embodiments, L is selected from any one of L61-L179 or L61-L241. In certain embodiments, L is selected from any one of L61-L179 or L180-L241. In certain embodiments, L is selected from any one of L61-L179. In certain embodiments, L is selected from any one of L61-L241.
[00177] In certain embodiments, L is of formula:
[00178] In some embodiments, L is of formula: embodiments, L is of formula: . In some embodiments, L is of formula:
. In some embodiments, L is of formula: formula: . In some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . , In some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of formula: embodiments, L is of formula: ' ' . In some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula:
O O o . In some embodiments, L is of formula: . T In some embodiments, L is of formula: . In some embodiments, ,
0 O . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of , some embodiments, L is of formula: . In some embodiments, L is of . , . some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some f N embodiments, L is of formula: H . In some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of formula: some embodiments, L is of formula: . In some embodiments, L is of formula: .In some embodiments, L is of formula: H H . In some embodiments, L is of formula: . n some em o mens, s o ormua:
. In some embodiments, L is of formula: . In some embodiments, L is of . , . T In some embodiments, L is of formula: . In some embodiments, L is of . , : .In some embodiments, L is of formula: . In some embodiments, L is of formula: some embodiments, L is of formula: some embodiments, L is of formula: In some embodiments, L is of formula some embodiments, L is of formula: In some embodiments, L is of formula:
. In some embodiments, L is of formula: In some embodiments, L is of formula: mbodiments, L is of formula: . In some embodiments, L is o f formula: . In some embodiments, L is of formula: . In some
O embodiments, L is of formula: . In some embodiments, L is of formula:
O
In some embodiments, L is of formula: . In some embodiments, L is of formula: In some embodiments, L is of formula:
O some embodiments, L is of formula: . In some embodiments, L is of , some embodiments, L is of formula . In some embodiments, L is of
. In some embodiments, L is of formula: . In some embodiments, L is of In some embodiments, L is of formula: . In some embodiments, L is of formula: In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: . In some embodiments, L is of formula: embodiments, L is of formula: . In some embodiments, L is of formula:
In some embodiments, L is of formula: . , a: . , la: some embodiments, L is of formula: some embodiments, L is of
RA
[00179] As described herein, each occurrence of RA 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 RA groups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
[00180] In some embodiments, each RA 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 a nitrogen protecting group.
B
[00181] As described herein, B is a targeting moiety or detectable moiety (e.g., a chromophore, dye, fluorophore, luminophore or luminescent material, or radioactive material). In certain embodiments, B is a detectable moiety (e.g., a chromophore, dye, fluorophore, luminophore or luminescent material, or radioactive material). In certain embodiments, B is a dye. In certain embodiments, B is a targeting moiety. In certain embodiments, the targeting moiety is a bioactive moiety. In certain embodiments, the targeting moiety is a protein-binding moiety. In certain embodiments, the targeting moiety binds an enzyme. In some embodiments, the luminescent material is a phosphorescent agent.
[00182] The targeting moiety provides a means for recruiting, binding, modulating, modifying, inhibiting, and/or associating the compound with a target substrate. In certain embodiments, the target substrate is a biomolecule. In certain embodiments, the target substrate is a polypeptide, a polynucleotide, or a polysaccharide. In certain embodiments, the target substrate is a protein. In certain embodiments, B is a ligand, binder, modulator, modifier, and/or inhibitor of a protein. In certain embodiments, B is a protein-binding moiety. In certain embodiments, B is an inhibitor of a protein. In certain embodiments, B is an inhibitor of an enzyme.
[00183] The compounds disclosed herein may bind to a kinase, such as ABL1, and to a target substrate associated with the targeting moiety in order to alter the function of the kinase or the target substrate. In certain embodiments, a compound recruits, binds, modulates, modifies, inhibits, activates, and/or associates with a kinase, such as ABL1, to phosphorylate the target substrate associated with the targeting moiety. In an embodiment, the target substrate (e.g., protein) is not a natural substrate of the kinase to which the compound also binds.
[00184] In certain embodiments, the compounds disclosed herein include a moiety that binds to a kinase, such as ABL1, and a targeting moiety that binds to a second kinase. In certain embodiments, the compounds disclosed herein include a moiety that binds to a kinase, such as ABL1, and a targeting moiety that binds to a phosphatase.
[00185] In some embodiments, B is a BTK-binding moiety, bromodomain and extra-terminal domain (BET)-binding moiety, BRD2-binding moiety, BRD3-binding moiety, BRD4-binding moiety, BRDT-binding moiety, a kinase-binding moiety, KRAS-binding moiety, TRIM24- binding moiety, CAII-binding moiety, or a phosphatase -binding moiety. In some embodiments, B is a BTK-binding moiety. In some embodiments, B is a bromodomain and extra-terminal domain (BET)-binding moiety. In some embodiments, B is a BRD2-binding moiety. In some embodiments, B is a BRD3-binding moiety. In some embodiments, B is a BRD4-binding moiety. In some embodiments, B is a BRDT-binding moiety. In some embodiments, B is a kinase-binding moiety. In some embodiments, B is a KRAS-binding moiety. In some embodiments, B is a phosphatase-binding moiety. In some embodiments, B is a TRIM24-binding moiety. In some embodiments, B is a CAII-binding moiety.
[00186] In certain embodiments, B is a moiety that recruits, binds, modulates, modifies, inhibits, activates, and/or associates with a bromodomain-containing protein (e.g., BRD2, BRD3, BRD4, BRDT); histone acetyltransferase (e.g., CREBBP, GCN5, PCAF, TAFII250); methyltransferase (e.g., ASH1L, MLL); Swi2/Snf2; estrogen receptor; p53; Max; beta-catenin; BTK; BCR-ABL; KRAS (K-Ras protein or Kirsten rat sarcoma virus protein) or KRAS mutant; TRIM24 (Tripartite motif-containing 24); MDM2; EGFR; CDK4; CDK6; C-MET; PSENEN (presenilin enhancer 2 homolog (C. elegans)); CTSB (cathepsin B); PSEN1 (presenilin 1); APP (amyloid beta (A4) precursor protein); APH1B (anterior pharynx defective 1 homolog B (C. elegans)); PSEN2 (presenilin 2); BACE1 (beta-site APP-cleaving enzyme 1); ITM2B (integral membrane protein 2B); CTSD (cathepsin D); NOTCH1 (Notch homolog 1, translocation- associated); TNF (tumor necrosis factor (TNF superfamily, member 2)); INS (insulin); DYT10 (dystonia 10); ADAM17 (ADAM metallopeptidase domain 17); APOE (apolipoprotein E); ACE (angiotensin I converting enzyme (peptidyl-dipeptidase A) 1); STN (statin); TP53 (tumor protein p53); IL6 (interleukin 6 (interferon, beta 2)); NGFR (nerve growth factor receptor (TNFR superfamily, member 16)); IL1B (interleukin 1, beta); ACHE (acetylcholinesterase (Yt blood group)); CTNNB1 (catenin (cadherin-associated protein); beta 1, 88kDa); IGF1 (insulin-like growth factor 1 (somatomedin C)); IFNG (interferon, gamma); NRG1 (neuregulin 1); CASP3 (caspase 3, apoptosis-related cysteine peptidase); MAPK1 (mitogen-activated protein kinase 1); CDH1 (cadherin 1, type 1, E-cadherin (epithelial)); APBB1 (amyloid beta (A4) precursor proteinbinding, family B, member 1 (Fe65)); HMGCR (3- hydroxy-3-methylglutaryl-Coenzyme A reductase); CREB1 (cAMP responsive element binding protein 1); PTGS2 (prostaglandinendoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)); HES1 (hairy and enhancer of split 1); CAT (catalase); TGFB1 (transforming growth factor, beta 1); EN02 (enolase 2 (gamma, neuronal)); ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4); TRAPPC10 (trafficking protein particle complex 10); MAOB (monoamine oxidase B); NGF (nerve growth factor (beta polypeptide)); MMP12 (matrix metallopeptidase 12 (macrophage elastase)); JAG1 (jagged 1 (Alagille syndrome)); CD40LG (CD40 ligand); PPARG (peroxisome proliferator-activated receptor gamma); FGF2 (fibroblast growth factor 2 (basic)); IL3 (interleukin 3 (colony-stimulating factor, multiple)); LRP1 (low density lipoprotein receptor- related protein 1); NOTCH4 (Notch homolog 4); MAPK8 (mitogen-activated protein kinase 8); PREP (prolyl endopeptidase); NOTCH3 (Notch homolog 3); PRNP (prion protein); CTSG (cathepsin G); EGF (epidermal growth factor (beta-urogastrone)); REN (renin); CD44 (CD44 molecule); SELP (selectin P (granule membrane protein 140 kDa, antigen CD62)); GHR (growth hormone receptor); ADCYAP1 (adenylate cyclase activating polypeptide 1); INSR (insulin receptor); GFAP (glial fibrillary acidic protein); MMP3 (matrix metallopeptidase 3); MAPK10 (mitogen-activated protein kinase 10); SP1 (Spl transcription factor); MYC (v-myc myelocytomatosis viral oncogene homolog); CTSE (cathepsin E); PPARA (peroxisome proliferator-activated receptor alpha); JUN (jun oncogene); TIMP1 (TIMP metallopeptidase inhibitor 1); IL5 (interleukin 5 (colony-stimulating factor, eosinophil)); ILIA (interleukin 1, alpha); MMP9 (matrix metallopeptidase 9); HTR4 (5- hydroxytryptamine (serotonin) receptor 4); HSPG2 (heparan sulfate proteoglycan 2); CYCS (cytochrome c, somatic); SMG1 (SMG1 homolog, phosphatidylinositol 3 -kinase-related kinase); IL1R1 (interleukin 1 receptor, type I); PROK1 (prokineticin 1); MAPK3 (mitogen-activated protein kinase 3); NTRK1 (neurotrophic tyrosine kinase, receptor, type 1); IL13 (interleukin 13); MME (membrane metallo- endopeptidase); TKT (transketolase); CXCR2 (chemokine (C-X-C motif) receptor 2); IGF1R (insulin-like growth factor 1 receptor); RARA (retinoic acid receptor, alpha); CREBBP (CREB binding protein); PTGS1 (prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)); GALT (galactose- 1 -phosphate uridylyltransf erase); CHRM1 (cholinergic receptor, muscarinic 1); ATXN1 (ataxin 1); PAWR (PRKC, apoptosis, WT1, regulator); NOTCH2 (Notch homolog 2); M6PR (mannose-6-phosphate receptor (cation dependent)); CYP46A1 (cytochrome P450, family 46, subfamily A, polypeptide 1); CSNK1 D (casein kinase
1, delta); MAPK14 (mitogen-activated protein kinase 14, also called p38-a); PRG2 (proteoglycan
2, bone marrow); PRKC A (protein kinase C, alpha); LI CAM (LI cell adhesion molecule); CD40 (CD40 molecule); NR1I2 (nuclear receptor subfamily 1, group I, member 2); JAG2 (jagged 2); CTNND1 (catenin (cadherin-associated protein), delta 1); CDH2 (cadherin 2, type 1, N- cadherin); CMA1 (chymase 1); SORT1 (sortilin 1); DLK1 (delta-like 1 homolog); THEM4 (thioesterase superfamily member 4); JUP (junction plakoglobin); CD46 (CD46 molecule, complement regulatory protein); CCL11 (chemokine (C-C motif) ligand 11); CAV3 (caveolin 3); RNASE3 (ribonuclease, RNase A family, 3); HSPA8 (heat shock 70kDa protein 8); CASP9 (caspase 9); CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4); CCR3 (chemokine (C-C motif) receptor 3); TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)); SCP2 (sterol carrier protein 2); CDK4 (cyclin-dependent kinase 4); HIF1A (hypoxia inducible factor 1, alpha subunit); TCF7L2 (transcription factor 7- like 2); IL1R2 (interleukin 1 receptor, type II); B3GALTL (beta 1,3-galactosyltransferase-like); MDM2 (Mdm2 p53 binding protein homolog); RELA (v-rel reticuloendotheliosis viral oncogene homolog A); CASP7 (caspase 7); IDE (insulin-degrading enzyme); FABP4 (fatty acid binding protein 4, adipocyte); CASK (calcium/calmodulin-dependent serine protein kinase (MAGUK family)); ADCYAPIRI (adenylate cyclase activating polypeptide 1 (pituitary) receptor type I); ATF4 (activating transcription factor 4 (tax-responsive enhancer element B 67)); PDGFA (platelet-derived growth factor alpha polypeptide); C21 or f33 (chromosome 21 open reading frame 33); SCG5 (secretogranin V (7B2 protein)); RNF123 (ring finger protein 123); NFKB1 (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1); ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog); CAV1 (caveolin 1, caveolae protein, 22 kDa); MMP7 (matrix metallopeptidase 7);
TGFA (transforming growth factor, alpha); RXRA (retinoid X receptor, alpha); STX1A (syntaxin 1A); PSMC4 (proteasome (prosome, macropain) 26S subunit, ATPase, 4); P2RY2 (purinergic receptor P2Y, G-protein coupled, 2); TNFRSF21 (tumor necrosis factor receptor superfamily, member 21); DLG1 (discs, large homolog 1); NUMBL (numb homolog); SPN (sialophorin); PLSCR1 (phospholipid scramblase 1); UBQLN2 (ubiquilin 2); UBQLN1 (ubiquilin 1); PCSK7 (proprotein convertase subtilisin/kexin type 7); SPON1 (spondin 1, extracellular matrix protein); SILV (silver homolog); QPCT (glutaminyl-peptide cyclotransferase); HESS (hairy and enhancer of split 5); GCC1 (GRIP and coiled-coil domain containing 1); Angiopoietin-like 4 (ANGPTL4); Apolipoprotein C3 (APOCIII); Recombination Activating Gene 1 (RAG1); BCL11 A; PCSK9; laminin; alpha 2 (lama2); ATXN3; alanine-glyoxylate aminotransferase (AGXT); collagen type vii alpha 1 chain (COL7al); spinocerebellar ataxia type 1 protein (ATXN1); Angiopoietin-like 3 (ANGPTL3); Frataxin (FXN); Superoxidase Dismutase 1 (SOD1); Synuclein Alpha (SNCA); Sodium Channel, Voltage Gated, Type X Alpha Subunit (SCN10A); Spinocerebellar Ataxia Type 2 Protein (ATXN2); Dystrophia Myotonica-Protein Kinase (DMPK); beta globin locus on chromosome 11; acyl-coenzyme A dehydrogenase for medium chain fatty acids (ACADM); long- chain 3-hydroxyl-coenzyme A dehydrogenase for long chain fatty acids (HADHA); acylcoenzyme A dehydrogenase for very long-chain fatty acids (ACADVL); Transthyretin (TTR); Angiopoietin-like 4 (ANGPTL4); Sodium Voltage-Gated Channel Alpha Subunit 9 (SCN9A); Interleukin-7 receptor (IL7R); glucose-6-phosphatase; catalytic (G6PC); haemochromatosis (HFE); SERPINA1; C90RF72; P-globin; dystrophin; g-globin; an AAVS1 (PPPIR12C) gene; an ALB gene; an Angptl3 gene; an ApoC3 gene; an ASGR2 gene; a CCR5 gene; a FIX (F9) gene; a G6PC gene; a Gys2 gene; an HGD gene; a Lp(a) gene; a Pcsk9 gene; a Serpinal gene; a TF gene; a TTR gene; B2M; CD247; CD3D; CD3E; CD3G; TRAC; TRBC1; TRBC2; HLA-A; HLA-B; HLA-C; DCK; CD52; FKBP1A; CIITA; NLRC5; RFXANK; RFX5; RFXAP; or NR3C1; HAVCR2; LAG3; PDCD1; PD-L2; CTLA4; CEACAM (CEACAM-1, CEACAM-3 and/or CEACAM-5); VISTA; BTLA; TIGIT; LAIR1; CD 160; 2B4; CD80; CD86; B7-H3 (CD113); B7-H4 (VTCN1); HVEM (TNFRSF14 or CD 107); KIR; A2aR; MHC class I; MHC class II; GAL9; adenosine; TGF beta; PTPN11; DCK; CD52; NR3C1; LILRB1; CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRvIII); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2- 3)bDGalp(l-4)bDGlcp(l-l)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAca-Ser/Thr)); prostate-specific membrane antigen (PSMA); Receptor tyrosine kinase-like orphan receptor 1 (ROR1); Fms-Like Tyrosine Kinase 3 (FLT3); Tumor- associated glycoprotein 72 (TAG72); CD38; CD44v6; Carcinoembryonic antigen (CEA); Epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); Interleukin- 13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); Mesothelin; Interleukin 11 receptor alpha (IL- HRa); prostate stem cell antigen (PSCA); Protease Serine 21 (Testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis(Y) antigen; CD24; Platelet-derived growth factor receptor beta (PDGFR-beta); Stage-specific embryonic antigen-4 (S SEA-4); CD20; Folate receptor alpha; Receptor tyrosine-protein kinase ERBB2 (Her2/neu); n kinase ERBB2 (Her2/neu); Mucin 1; cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); Prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); Ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor); carbonic anhydrase IX (CAIX); carbonic anhydrase II (CAII); Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2); glycoprotein 100 (gplOO); oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr- abl); tyrosinase; ephrin type- A receptor 2 (EphA2); Fucosyl GM1; sialyl Eewis adhesion molecule (sEe); ganglioside GM3 (aNeu5Ac(2-3)bDGalp(l-4)bDGlcp(l-l)Cer); transglutaminase 5 (TGS5); high molecular weight- melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); Folate receptor beta; tumor endothelial marker 1 (TEM1/CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CEDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (AEK); Polysialic acid; placentaspecific 1 (PEACI); hexasaccharide portion of globoH glycoceramide (GloboH); mammary gland differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); Hepatitis A virus cellular receptor 1 (HAVCR1); adrenoceptor beta 3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K 9 (EY6K); Olfactory receptor 51E2 (OR51E2); TCR Gamma Alternate Reading Frame Protein (TARP); Wilms tumor protein (WT1); Cancer/testis antigen 1 (NY-ESO-1); Cancer/testis antigen 2 (EAGE-la); Melanoma- associated antigen 1 (MAGE-A1); ETS translocation- variant gene 6, located on chromosome 12p (ETV6- AME); sperm protein 17 (SPA 17); X Antigen Family, Member 1A (XAGE1); angiopoietin- binding cell surface receptor 2 (Tie 2); melanoma cancer testis antigen-1 (MAD-CT-1); melanoma cancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; wild-type p53-induced phosphatase 1 (Wipl); prostein; surviving; telomerase; prostate carcinoma tumor antigen-1 (PCTA-1 or Galectin 8); melanoma antigen recognized by T cells 1 (MelanA or MARTI); Rat sarcoma (Ras) mutant; human Telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-Acetyl glucosaminyl- transferase V (NA17); paired box protein Pax-3 (PAX3); Androgen receptor; Cyclin Bl; v- myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN); Ras Homolog Family Member C (RhoC); Tyrosinase -related protein 2 (TRP-2); Cytochrome P450 1B1 (CYP1B1); CCCTC-Binding Factor (Zinc Finger Protein)-Eike (BORIS or Brother of the Regulator of Imprinted Sites); Squamous Cell Carcinoma Antigen Recognized By T Cells 3 (SART3); Paired box protein Pax-5 (PAX5); proacrosin binding protein sp32 (OY- TES1); lymphocyte-specific protein tyrosine kinase (ECK); Janus kinase 2 (JAK2); large tumor suppressor kinase 1 (EATS1); large tumor suppressor kinase 2 (EATS2); A kinase anchor protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 (SSX2); Receptor for Advanced Glycation Endproducts (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papilloma virus E6 (HPV E6); human papilloma virus E7 (HPV E7); intestinal carboxyl esterase; heat shock protein 70-2 mutated (mut hsp70-2); CD79a; CD79b; CD72; Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89); Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 moleculelike family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module- containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); Glypican-3 (GPC3); Fc receptor-like 5 (FCRLS); and immunoglobulin lambda-like polypeptide 1 (IGLL1); CD 19; BCMA; CD70; G6PC; Dystrophin, including modification of exon 51 by deletion or excision; DMPK; CFTR (cystic fibrosis transmembrane conductance regulator); the SCNN1A gene; acetyl-CoA carboxylase; fatty acid synthase; 3-ketoacyl acyl- carrier protein synthase III; glycerol-3-phospate dehydrogenase (G3PDH); Enoyl-acyl carrier protein reductase (Enoyl- ACP-reductase); glycerol- 3-phosphate acyltransferase; lysophosphatidic acyl transferase; diacylglycerol acyltransferase; phoshatidate phosphatase; fatty acid thioesterase such as palmitoyi protein thioesterase or malic enzyme; acyl-CoA synthetase; 3-ketoacyl-CoA thiolase; acyl-CoA oxidase activity; phosphoglucomutase; Arylsulfatase A; Wiskott-Aldrich Syndrome protein; ATP- binding cassette DI; receptor type 5- C-C chemokine or CXCR4 gene; Hemoglobin beta subunit; interelukin-2 receptor subunit gamma; cystinosin; Ribosomal protein S19; Fanconi anemia complementation groups (e.g., FNACA, FNACB, FANCC, FANCD1, FANCD2, FANCE, FANCF, RAD51C); Shwachman syndrome gene; Glucocerebrosidase; Anti-hemophiliac factor OR Factor VIII; Christmas factor; Serine protease; Factor Hemophilia B IX; Adenosine deaminase; betagalactosidase; alpha-glucosidase; sphingomyelinase; galactercerebrosidease; Human leukocyte antigens DR-15; DQ-6; DRB1; RSI, RL2 and/or LAT genes; PreC, C, X, PreSl, PreS2, S, P and/or SP gene(s); Chromosomal Sequence Encoded Protein, Delta-aminolevulinate synthase 2 (ALAS2); ATP-binding cassette transporter (ABCA1); Angiotensin I converting enzyme (ACE); Apolipoprotein E precursor (APOE); amyloid precursor protein (APP); aquaporin 1 protein (AQP1); Myc box-dependent- interacting protein 1 or bridging integrator 1 protein (BINI); brain- derived neurotrophic factor (BDNF); Butyrophilin-like protein 8 (BTNL8); chromosome 1 open reading frame 49 (C10RF49); CDH4 (Cadherin-4 CHRNB2 Neuronal acetylcholine receptor subunit beta-2); CKLF-like MARVEL transmembrane domain- containing protein 2 (CKLFSF2); C-type lectin domain family 4, member e (CLEC4E); CLU clusterin protein (also known as apoplipoprotein J); Erythrocyte complement receptor 1 (CR1, also known as CD35, C3b/C4b receptor and immune adherence receptor); Erythrocyte complement receptor 1 (CR1L); granulocyte colony-stimulating factor 3 receptor (CSF3R); CST3 (Cystatin C or cystatin 3); CYP2C (Cytochrome P4502C); Death-associated protein kinase 1 (DAPK1); Estrogen receptor 1 (ESRI); fragment of IgA receptor (FCAR, also known as CD89); Fc fragment of IgG, low affinity Illb, receptor (FCGR3B or CD16b); Free fatty acid receptor 2 (FFA2); FGA Fibrinogen (Factor I); GRB2-associated-binding protein 2 (GAB2); Galanin-like peptide (GAEP);
Glyceraldehyde-3- phosphate dehydrogenase, spermatogenic (GAPDHS); Haptoglobin (HP); serotonin receptor 7; Insulin degrading enzyme (IDE); IF 127; IFI6 Interferon, alpha-inducible protein 6 (IFI6); Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2); interleukin- 1 receptor antagonist (IE- IRA); Interleukin 8 receptor, alpha (IE8RA or CD181); Interleukin 8 receptor, beta (IE8RB); Jagged 1 (JAG1); Potassium inwardly-rectifying channel, subfamily J, member 15 (KCNJ15); Eow-density lipoprotein receptor-related protein 6 (ERP6); microtubule- associated protein tau (MAPT); MAP/microtubule affinity-regulating kinase 4 (MARK4); M- phase phosphoprotein 1 (MPH0SPH1); 5, 10-methylenetetrahydrofolate reductase (MTHFR); Interferon- induced GTP-binding protein Mx2 (MX2); Nibrin (NBN); Nicastrin (NCSTN); Niacin receptor 2 (NIACR2, also known as GPR109B); nicotinamide nucleotide adenylyltransferase 3 (NMNAT3); Neurotrimin (NTM or HNT); Orosmucoid 1 (0RM1); Alpha- 1-acid glycoprotein 1; P2Y purinoceptor 13 (P2RY13); Nicotinamide phosphoribosyltransferase (NAmPRTase or Nampt) also known as pre-B-cell colony-enhancing factor 1 (PBEF1); visfatin; Phosphoenolpyruvate carboxy kinase (PCK1); phosphatidylinositol binding clathrin assembly protein (PICAEM); Urokinase-type plasminogen activator (PEAU); Plexin Cl (PEXNC1); Prion protein (PRNP); PSEN1 presenilin 1 protein (PSEN1); presenilin 2 protein (PSEN2); protein tyrosine phosphatase receptor type A protein (PTPRA); Rai GEF with PH domain and SH3 binding motif 2 (RALGPS2); regulator of G-protein signaling like 2 (RGSL2); Selenium binding protein 1 (SELNBP1); SLC25A37 Mitoferrin-1, sortilin-related receptor L(DLR class) A repeats- containing protein (SORL1); Transferrin; Mitochondrial transcription factor A (TEAM); Tumor necrosis factor (TNF); Tumor necrosis factor receptor superfamily member IOC (TNFRSF10C); Tumor necrosis factor receptor superfamily, (TRAIL) member 10a (TNFSF10); ubiquitin-like modifier activating enzyme 1 (UBA1); NEDD8-activating enzyme El catalytic subunit protein (UBE1C); ubiquitin B protein (UBB); Ubiquilin-1 (UBQLN1); ubiquitin carboxyl-terminal esterase LI protein (UCHL1); ubiquitin carboxyl-terminal hydrolase isozyme L3 protein (UCHL3); very low density lipoprotein receptor protein (VLDLR); low density lipoprotein receptor protein (VLDLR) encoded by the VLDLR gene; the ubiquitin-like modifier activating enzyme 1 (UBA1) encoded by the UBA1 gene; the NEDD8-activating enzyme El catalytic subunit protein (UBE1C) encoded by the UBA3 gene; the aquaporin 1 protein (AQP1) encoded by the AQP1 gene; the ubiquitin carboxyl-terminal esterase LI protein (UCHL1) encoded by the UCHL1 gene; the ubiquitin carboxyl-terminal hydrolase isozyme L3 protein (UCHL3) encoded by the UCHL3 gene; the ubiquitin B protein (UBB) encoded by the UBB gene; the microtubule- associated protein tau (MAPT) encoded by the MAPT gene; the protein tyrosine phosphatase receptor type A protein (PTPRA) encoded by the PTPRA gene; the phosphatidylinositol binding clathrin assembly protein (PICALM) encoded by the PICALM gene; the clusterin protein (also known as apoplipoprotein J) encoded by the CLU gene; the presenilin 1 protein encoded by the PSEN1 gene; the presenilin 2 protein encoded by the PSEN2 gene; the sortilin-related receptor L(DLR class) A repeats-containing protein (SORL1) protein encoded by the SORL1 gene; the amyloid precursor protein (APP) encoded by the APP gene; the Apolipoprotein E precursor (APOE) encoded by the APOE gene; the brain-derived neurotrophic factor (BDNF) encoded by the BDNF gene; cell surface receptors; cell surface receptors on cancer cells; TfRs; folate receptors (FRs); VCAM (vascular endothelium); E- and P-selectins; VCAM-1; ICAMs; TIMP1- 4; MT1-MMP; MMP-2; an RGD peptide; phospholipase A2; alkaline phosphatase; transglutaminase; phosphatidylinositol-specific phospholipase C; cell -penetrating peptides (CPPs); amphipathic helical peptides; transportan; MAP; TATp; Antennapedia; penetratin; or VP22; or any combination thereof.
[00187] In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with KRAS or KRAS mutant, BRD4, CAII, TRIM24, BTK, BET, BRD2, BRD3, or BRDT. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with a kinase or phosphatase. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with BRD4 or BTK. In certain embodiments, B is a ligand, recruiter, binder, modulator, modifier, inhibitor, activator, and/or associator of KRAS or KRAS mutant, BRD4, CAII, TRIM24, or BTK. In certain embodiments, B is a ligand, recruiter, binder, modulator, modifier, inhibitor, activator, and/or associator of BRD4 or BTK. In certain embodiments, B is an inhibitor of KRAS or KRAS mutant, BRD4, CAII, TRIM24, or BTK. In certain embodiments, B is an inhibitor of BRD4 or BTK. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with KRAS or KRAS mutant. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with BRD4. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with CAII. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with TRIM24. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with BTK. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with BET. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with BRD2. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with BRD3. In certain embodiments, B recruits, binds, modulates, modifies, inhibits, activates, and/or associates with BRDT. In certain embodiments, B is an inhibitor of KRAS or KRAS mutant. In certain embodiments, B is an inhibitor of BRD4. In certain embodiments, B is an inhibitor of CAIL In certain embodiments, B is an inhibitor of TRIM24. In certain embodiments, B is an inhibitor of BTK. In certain embodiments, B is an inhibitor of BET. In certain embodiments, B is an inhibitor of BRD2. In certain embodiments, B is an inhibitor of BRD3. In certain embodiments, B is an inhibitor of BRDT.
[00188] In certain embodiments, B is a KRAS-binding moiety, a kinase-binding moiety, or a phosphatase-binding moiety.
[00189] In certain embodiments, B is of formula:
[00191] In certain embodiments, B is of formula:
[00192] In certain embodiments, B is of formula: [00193] In certain embodiments, B is of formula:
[00194]
[00195]
[00196] In certain embodiments, B is a detectable moiety. In certain embodiments, B is a chromophore. In certain embodiments, B is a dye. In certain embodiments, B is a fluorophore. In certain embodiments, B is a luminophore. In certain embodiments, B is a luminescent material. In certain embodiments, B is a radioactive material.
[00197] In certain embodiments, B is a dye. In certain embodiments, B is a fluorescent dye. In certain embodiments, B is of formula:
[00198] In certain embodiments, the targeting moiety B (e.g., protein-binding moiety) binds a target substrate (e.g., protein) with a Kd of less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.
[00199] In certain embodiments, the targeting moiety B (e.g., protein-binding moiety) selectively binds a target substrate (e.g., protein) as compared to another substrate (e.g., protein). In certain embodiments, the selectivity is from about 2-fold to about 5-fold. In certain embodiments, the selectivity is from about 5-fold to about 10-fold. In certain embodiments, the selectivity is from about 10-fold to about 20-fold. In certain embodiments, the selectivity is from about 20-fold to about 50-fold. In certain embodiments, the selectivity is from about 50-fold to about 100-fold. In certain embodiments, the selectivity is from about 100-fold to about 200-fold. In certain embodiments, the selectivity is from about 200-fold to about 500-fold. In certain embodiments, the selectivity is from about 500-fold to about 1000-fold. In certain embodiments, the selectivity is at least about 1000-fold.
T
[00200] As described herein, T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, a nitrogen protecting group, an oxygen protecting group, or a click chemistry handle.
[00201] In certain embodiments, T is a click chemistry handle. “Click chemistry” refers to a chemical approach to conjugation introduced by Sharpless in 2001 and describes chemistry tailored to generate substances quickly and reliably by joining units together. See, e.g., Kolb, Finn and Sharpless Angewandte Chemie International Edition 2001 40, 2004-2021; Evans, Australian Journal of Chemistry 200760, 384-395. Exemplary coupling reactions (some of which may be classified as “click chemistry”) include, but are not limited to, formation of esters, thioesters, amides (e.g., such as peptide coupling) from activated acids or acyl halides; nucleophilic displacement reactions (e.g., such as nucleophilic displacement of a halide or ring opening of strained ring systems); azide-alkyne Huisgen cycloaddition; thiol-yne addition; imine formation; Michael additions (e.g., maleimide addition reactions); and Diels-Alder reactions (e.g., tetrazine [4 + 2] cycloaddition). Examples of click chemistry reactions and click-chemistry handles can be found in, e.g., Kolb, H. C.; Finn, M. G. and Sharpless, K. B., Angew. Chem. Int.
Ed. 2001, 40, 2004-2021. Kolb, H. C. and Sharless, K. B. Drug Disc. Today, 2003, 8, 1128-1137; Rostovtsev, V. V.; Green L. G.; Fokin, V. V. and Shrapless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596-2599; Tomoe, C. W.; Christensen, C. and Meldal, M. J. Org. Chem. 2002, 67, 3057- 3064. Wang, Q. et al. J. Am. Chem. Soc. 2003, 725, 3192-3193; Lee, L. V. et al., J. Am. Chem. Soc. 2003 725, 9588-9589; Lewis, W. G. et al., Angew. Chem. Int. Ed. 2002, 41, 1053-1057; Manetsch, R. et al., J. Am. Chem. Soc. 2004, 126, 12809- 12818; Mocharla, V. P. et al., Angew. Chem., Int. Ed. 2005, 44, 116-120.
[00202] In some embodiments, click chemistry handles are used that can react to form covalent bonds in the absence of a metal catalyst. Such click chemistry handles are known to those of skill in the art and include the click chemistry handles described in Becer, Hoogenboom, and Schubert, Click Chemistry beyond Metal-Catalyzed Cycloaddition, Angewandte Chemie International Edition 2009, 48, 4900-4908.
[00203] In certain embodiments, the click-chemistry handle comprises an alkenylene group or alkynylene group. In certain embodiments, the click-chemistry handle comprises an internal alkenylene group or alkynylene group. In certain embodiments, the click-chemistry handle comprises a terminal alkenylene group or alkynylene group. In certain embodiments, the clickchemistry 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 0 substituted or unsubstituted phenyl, or substituted or unsubstituted [n certain embodiments, the click chemistry handle is an azide, tetrazine, tetrazole, dithioester, anthracene, amine, or thiol. [00204] In some embodiments, T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle. In certain embodiments, T is hydrogen, a nucleophilic group, a leaving group, a nitrogen protecting group, or an oxygen protecting group. In certain embodiments, T is hydrogen, a nucleophilic group, a leaving group, or a nitrogen protecting group. In some embodiments, T is hydrogen, -ORA, -N3, -COORA, -C=CH, halogen, or a nitrogen protecting group. In some embodiments, T is hydrogen, an amine, a carboxylic acid, an aldehyde, an alkyne, an alkene, an azide, an alcohol, a halogen, or a nitrogen protecting group. In some embodiments, T is -ORA, -Br, -Cl, -F, -COORA, -NHRA, -C(=O)H, -C=CH, -N3, or a nitrogen protecting group. In certain embodiments, T is hydrogen, halogen, -OH, -OMe, -OtBu, -OMs (mesylate), -OTs (tosylate), or -C=CH. In certain embodiments, T is -C=CH. In certain embodiments, T is hydrogen or a halogen (e.g., -Br). In certain embodiment, T is halogen. In certain embodiments, T is -Cl or -Br. In certain embodiments, T is -Br. In certain embodiments, T is hydrogen, -OH, -OMe, -OtBu, -OMs (mesylate), -OTs (tosylate), -C=CH, -Br, or a nitrogen protecting group (e.g., Boc). In certain embodiments, T is a nitrogen protecting group (e.g., Boc). In certain embodiments, T is hydrogen, -OH, -OMe, or -OtBu. In certain embodiments, T is -OH or -OMe. In certain embodiments, T is -OH. In certain embodiments, T is hydrogen. In certain embodiments, T is -NHRA. In certain embodiments, T is -NH2. In certain embodiments, T is -Cl.
[00205]
Further Embodiments of Formula (1)
[00206] In certain embodiments, the compound is a compound of Formula (I), wherein L is selected from any one of L1-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
[00207] In certain embodiments, the compound of Formula (I) is a compound of Formula (I- A):
(I-A), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (I-A), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-A), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-A), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-A), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
[00208] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-B): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (I-B), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
[00209] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-B- 1):
(I-B-l),
[00210] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (I-B-l), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B-l), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B-
1), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B-l), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B-l), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
[00211] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-B-
2):
(I-B-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (I-B-2), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B-2), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B- 2), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B-2), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I-B-2), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof. [00212] In certain embodiments, the compound of Formula (I) is a compound of formula:
or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
Further Embodiments of Formula (II)
[00213] In certain embodiments, the compound is a compound of Formula (II), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
[00214] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-
A):
(II-A) or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (II-A), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-A), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-A), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-A), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174- L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-A), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
[00215] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-
B):
(II-B) or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (II-B), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof.
[00216] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-
B-1):
(II-B-1) or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (II-B-1), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B-1), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B- 1), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B-1), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B-1), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof. [00217] In certain embodiments, the compound of Formula (II) is a compound of Formula (II- B-2):
(II-B-2) or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound is a compound of Formula (II-B-2), wherein L is any one of L1-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B-2), wherein L is selected from any one of L1-L60, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B- 2), wherein L is selected from any one of L61-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B-2), wherein L is selected from any one of L8, L14, L15, L18, L52, L58-L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II-B-2), wherein L is selected from any one of L61, L63, L66, L73, L107, L167, L168, and L174-L179, or a pharmaceutically acceptable salt thereof. [00218] In certain embodiments, the compound of Formula (II) is a compound of formula: or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
Pharmaceutical Compositions
[00219] The present disclosure provides pharmaceutical compositions comprising a compound of the disclosure (e.g., a compound of Formula (I), (II), or as provided herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of the disclosure (e.g., a compound of Formula (I), (II), or as provided herein), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
Methods of Use
[00220] The present disclosure provides methods for phosphorylating a target substrate (e.g., protein) with a compound of the disclosure (e.g., Formula (I), (II), or as provided herein), in a mixture that comprises ABL1 and the target substrate. One of ordinary skill would understand that such a mixture may include ATP. In certain embodiments, the compound causes phosphorylation of the target substrate at a rate or amount that is increased over the rate or amount of phosphorylation in the same mixture comprising the ABL1 and the target substrate but without the compound. In certain embodiments, the amount of phosphorylation is measured at a specified time (e.g., 1, 2, 3, 4, 8, 12, 16, or 24 hours after administration). In certain embodiments, the phosphorylating is in a cell. In certain embodiments, the phosphorylating is in a biological sample.
[00221] 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), or as provided herein). In certain embodiments, the phosphorylation is achieved by ABL1. One of ordinary skill would understand that phosphorylation may include the use of ATP. The present disclosure also provides methods for modulating a protein kinase with a compound of the disclosure (e.g., Formula (I), (II), or as provided herein). In certain embodiments, the protein kinase is ABL1. In certain embodiments, the phosphorylation or modulation is in a cell. In certain embodiments, the phosphorylation or modulation is in a biological sample. [00222] The present disclosure also provides methods for detecting a protein kinase with a compound of the disclosure (e.g., Formula (I), (II), or as provided herein). In certain embodiments, the protein kinase is ABL1.
[00223] In certain embodiments, the target substrate is a protein. In certain embodiments, the target substrate is a kinase or phosphatase. In certain embodiments, the target substrate is a bromodomain-containing protein (e.g., BRD2, BRD3, BRD4, BRDT); histone acetyltransferase (e.g., CREBBP, GCN5, PCAF, TAFII250); methyltransferase (e.g., ASH1L, MLL); Swi2/Snf2; estrogen receptor; p53; Max; beta-catenin; BTK; BCR-ABL; KRAS (K-Ras protein or Kirsten rat sarcoma virus protein) or KRAS mutant; TRIM24 (Tripartite motif-containing 24); MDM2; EGFR; CDK4; CDK6; C-MET; PSENEN (presenilin enhancer 2 homolog (C. elegans)); CTSB (cathepsin B); PSEN1 (presenilin 1); APP (amyloid beta (A4) precursor protein); APH1B (anterior pharynx defective 1 homolog B (C. elegans)); PSEN2 (presenilin 2); BACE1 (beta-site APP-cleaving enzyme 1); ITM2B (integral membrane protein 2B); CTSD (cathepsin D); NOTCH1 (Notch homolog 1, translocation-associated); TNF (tumor necrosis factor (TNF superfamily, member 2)); INS (insulin); DYT10 (dystonia 10); ADAM17 (ADAM metallopeptidase domain 17); APOE (apolipoprotein E); ACE (angiotensin I converting enzyme (peptidyl-dipeptidase A) 1); STN (statin); TP53 (tumor protein p53); IL6 (interleukin 6 (interferon, beta 2)); NGFR (nerve growth factor receptor (TNFR superfamily, member 16)); IL1B (interleukin 1, beta); ACHE (acetylcholinesterase (Yt blood group)); CTNNB1 (catenin (cadherin-associated protein); beta 1, 88kDa); IGF1 (insulin-like growth factor 1 (somatomedin C)); IFNG (interferon, gamma); NRG1 (neuregulin 1); CASP3 (caspase 3, apoptosis-related cysteine peptidase); MAPK1 (mitogen-activated protein kinase 1); CDH1 (cadherin 1, type 1, E- cadherin (epithelial)); APBB1 (amyloid beta (A4) precursor protein-binding, family B, member 1 (Fe65)); HMGCR (3- hydroxy-3-methylglutaryl-Coenzyme A reductase); CREB1 (cAMP responsive element binding protein 1); PTGS2 (prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)); HES1 (hairy and enhancer of split 1); CAT (catalase); TGFB1 (transforming growth factor, beta 1); EN02 (enolase 2 (gamma, neuronal)); ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4); TRAPPC10 (trafficking protein particle complex 10); MAOB (monoamine oxidase B); NGF (nerve growth factor (beta polypeptide)); MMP12 (matrix metallopeptidase 12 (macrophage elastase)); JAG1 (jagged 1 (Alagille syndrome)); CD40LG (CD40 ligand); PPARG (peroxisome proliferator-activated receptor gamma); FGF2 (fibroblast growth factor 2 (basic)); IL3 (interleukin 3 (colonystimulating factor, multiple)); LRP1 (low density lipoprotein receptor-related protein 1); NOTCH4 (Notch homolog 4); MAPK8 (mitogen-activated protein kinase 8); PREP (prolyl endopeptidase); NOTCH3 (Notch homolog 3); PRNP (prion protein); CTSG (cathepsin G); EGF (epidermal growth factor (beta-urogastrone)); REN (renin); CD44 (CD44 molecule); SELP (selectin P (granule membrane protein 140 kDa, antigen CD62)); GHR (growth hormone receptor); ADC YAP 1 (adenylate cyclase activating polypeptide 1); INSR (insulin receptor); GFAP (glial fibrillary acidic protein); MMP3 (matrix metallopeptidase 3); MAPK10 (mitogen- activated protein kinase 10); SP1 (Spl transcription factor); MYC (v-myc myelocytomatosis viral oncogene homolog); CTSE (cathepsin E); PPARA (peroxisome proliferator-activated receptor alpha); JUN (jun oncogene); TIMP1 (TIMP metallopeptidase inhibitor 1); IL5 (interleukin 5 (colony-stimulating factor, eosinophil)); ILIA (interleukin 1, alpha); MMP9 (matrix metallopeptidase 9); HTR4 (5- hydroxytryptamine (serotonin) receptor 4); HSPG2 (heparan sulfate proteoglycan 2); CYCS (cytochrome c, somatic); SMG1 (SMG1 homolog, phosphatidylinositol 3-kinase -related kinase); IL1R1 (interleukin 1 receptor, type I); PROK1 (prokineticin 1); MAPK3 (mitogen-activated protein kinase 3); NTRK1 (neurotrophic tyrosine kinase, receptor, type 1); IL13 (interleukin 13); MME (membrane metallo-endopeptidase); TKT (transketolase); CXCR2 (chemokine (C-X-C motif) receptor 2); IGF1R (insulin-like growth factor 1 receptor); RARA (retinoic acid receptor, alpha); CREBBP (CREB binding protein); PTGS 1 (prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)); GALT (galactose- 1 -phosphate uridylyltransf erase); CHRM1 (cholinergic receptor, muscarinic 1); ATXN1 (ataxin 1); PAWR (PRKC, apoptosis, WT1, regulator);
NOTCH2 (Notch homolog 2); M6PR (mannose-6-phosphate receptor (cation dependent)); CYP46A1 (cytochrome P450, family 46, subfamily A, polypeptide 1); CSNK1 D (casein kinase
1, delta); MAPK14 (mitogen-activated protein kinase 14, also called p38-a); PRG2 (proteoglycan
2, bone marrow); PRKC A (protein kinase C, alpha); LI CAM (LI cell adhesion molecule); CD40 (CD40 molecule); NR1I2 (nuclear receptor subfamily 1, group I, member 2); JAG2 (jagged 2); CTNND1 (catenin (cadherin-associated protein), delta 1); CDH2 (cadherin 2, type 1, N- cadherin); CMA1 (chymase 1); SORT1 (sortilin 1); DLK1 (delta-like 1 homolog); THEM4 (thioesterase superfamily member 4); JUP (junction plakoglobin); CD46 (CD46 molecule, complement regulatory protein); CCL11 (chemokine (C-C motif) ligand 11); CAV3 (caveolin 3); RNASE3 (ribonuclease, RNase A family, 3); HSPA8 (heat shock 70kDa protein 8); CASP9 (caspase 9); CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4); CCR3 (chemokine (C-C motif) receptor 3); TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)); SCP2 (sterol carrier protein 2); CDK4 (cyclin-dependent kinase 4); HIF1A (hypoxia inducible factor 1, alpha subunit); TCF7L2 (transcription factor 7- like 2); IL1R2 (interleukin 1 receptor, type II); B3GALTL (beta 1,3-galactosyltransferase-like); MDM2 (Mdm2 p53 binding protein homolog); RELA (v-rel reticuloendotheliosis viral oncogene homolog A); CASP7 (caspase 7); IDE (insulin-degrading enzyme); FABP4 (fatty acid binding protein 4, adipocyte); CASK (calcium/calmodulin-dependent serine protein kinase (MAGUK family)); ADCYAPIRI (adenylate cyclase activating polypeptide 1 (pituitary) receptor type I); ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)); PDGFA (platelet-derived growth factor alpha polypeptide); C21 or f33 (chromosome 21 open reading frame 33); SCG5 (secretogranin V (7B2 protein)); RNF123 (ring finger protein 123); NFKB1 (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1); ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog); CAV1 (caveolin 1, caveolae protein, 22 kDa); MMP7 (matrix metallopeptidase 7); TGFA (transforming growth factor, alpha); RXRA (retinoid X receptor, alpha); STX1A (syntaxin 1A); PSMC4 (proteasome (prosome, macropain) 26S subunit, ATPase, 4); P2RY2 (purinergic receptor P2Y, G-protein coupled, 2); TNFRSF21 (tumor necrosis factor receptor superfamily, member 21); DLG1 (discs, large homolog 1); NUMBL (numb homolog); SPN (sialophorin); PLSCR1 (phospholipid scramblase 1); UBQLN2 (ubiquilin 2); UBQLN1 (ubiquilin 1); PCSK7 (proprotein convertase subtilisin/kexin type 7); SPON1 (spondin 1, extracellular matrix protein); SILV (silver homolog); QPCT (glutaminyl-peptide cyclotransferase); HESS (hairy and enhancer of split 5); GCC1 (GRIP and coiled-coil domain containing 1); Angiopoietin-like 4 (ANGPTL4); Apolipoprotein C3 (APOCIII); Recombination Activating Gene 1 (RAG1); BCL11 A; PCSK9; laminin; alpha 2 (lama2); ATXN3; alanine-glyoxylate aminotransferase (AGXT); collagen type vii alpha 1 chain (COL7al); spinocerebellar ataxia type 1 protein (ATXN1); Angiopoietin-like 3 (ANGPTL3); Frataxin (FXN); Superoxidase Dismutase 1 (SOD1); Synuclein Alpha (SNCA);
Sodium Channel, Voltage Gated, Type X Alpha Subunit (SCN10A); Spinocerebellar Ataxia Type 2 Protein (ATXN2); Dystrophia Myotonica-Protein Kinase (DMPK); beta globin locus on chromosome 11; acyl-coenzyme A dehydrogenase for medium chain fatty acids (ACADM); long- chain 3-hydroxyl-coenzyme A dehydrogenase for long chain fatty acids (HADHA); acylcoenzyme A dehydrogenase for very long-chain fatty acids (ACADVL); Transthyretin (TTR); Angiopoietin-like 4 (ANGPTL4); Sodium Voltage-Gated Channel Alpha Subunit 9 (SCN9A); Interleukin-7 receptor (IL7R); glucose-6-phosphatase; catalytic (G6PC); haemochromatosis (HFE); SERPINA1; C90RF72; P-globin; dystrophin; g-globin; an AAVS1 (PPPIR12C) gene; an ALB gene; an Angptl3 gene; an ApoC3 gene; an ASGR2 gene; a CCR5 gene; a FIX (F9) gene; a G6PC gene; a Gys2 gene; an HGD gene; a Lp(a) gene; a Pcsk9 gene; a Serpinal gene; a TF gene; a TTR gene; B2M; CD247; CD3D; CD3E; CD3G; TRAC; TRBC1; TRBC2; HLA-A; HLA-B; HLA-C; DCK; CD52; FKBP1A; CIITA; NLRC5; RFXANK; RFX5; RFXAP; or NR3C1; HAVCR2; LAG3; PDCD1; PD-L2; CTLA4; CEACAM (CEACAM-1, CEACAM-3 and/or CEACAM-5); VISTA; BTLA; TIGIT; LAIR1; CD 160; 2B4; CD80; CD86; B7-H3 (CD113); B7-H4 (VTCN1); HVEM (TNFRSF14 or CD 107); KIR; A2aR; MHC class I; MHC class II; GAL9; adenosine; TGF beta; PTPN11; DCK; CD52; NR3C1; LILRB1; CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRvIII); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2- 3)bDGalp(l-4)bDGlcp(l-l)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAca-Ser/Thr)); prostate-specific membrane antigen (PSMA); Receptor tyrosine kinase-like orphan receptor 1 (ROR1); Fms-Like Tyrosine Kinase 3 (FLT3); Tumor- associated glycoprotein 72 (TAG72); CD38; CD44v6; Carcinoembryonic antigen (CEA); Epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); Interleukin- 13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); Mesothelin; Interleukin 11 receptor alpha (IL- HRa); prostate stem cell antigen (PSCA); Protease Serine 21 (Testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis(Y) antigen; CD24; Platelet-derived growth factor receptor beta (PDGFR-beta); Stage-specific embryonic antigen-4 (S SEA-4); CD20; Folate receptor alpha; Receptor tyrosine-protein kinase ERBB2 (Her2/neu); n kinase ERBB2 (Her2/neu); Mucin 1; cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); Prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); Ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor); carbonic anhydrase IX (CAIX); Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2); glycoprotein 100 (gplOO); oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr- abl); tyrosinase; ephrin type-A receptor 2 (EphA2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2- 3)bDGalp(l-4)bDGlcp(l-l)Cer); transglutaminase 5 (TGS5); high molecular weight-melanoma- associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); Folate receptor beta; tumor endothelial marker 1 (TEM1/CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); Polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide portion of globoH glycoceramide (GloboH); mammary gland differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); Hepatitis A virus cellular receptor 1 (HAVCR1); adrenoceptor beta 3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K 9 (LY6K); Olfactory receptor 51E2 (OR51E2); TCR Gamma Alternate Reading Frame Protein (TARP); Wilms tumor protein (WT1);
Cancer/testis antigen 1 (NY-ESO-1); Cancer/testis antigen 2 (LAGE-la); Melanoma- associated antigen 1 (MAGE-A1); ETS translocation- variant gene 6, located on chromosome 12p (ETV6- AML); sperm protein 17 (SPA 17); X Antigen Family, Member 1A (XAGE1); angiopoietin- binding cell surface receptor 2 (Tie 2); melanoma cancer testis antigen-1 (MAD-CT-1); melanoma cancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; wild-type p53-induced phosphatase 1 (Wipl); prostein; surviving; telomerase; prostate carcinoma tumor antigen-1 (PCTA-1 or Galectin 8); melanoma antigen recognized by T cells 1 (MelanA or MARTI); Rat sarcoma (Ras) mutant; human Telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-Acetyl glucosaminyl- transferase V (NA17); paired box protein Pax-3 (PAX3); Androgen receptor; Cyclin Bl; v- myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN); Ras Homolog Family Member C (RhoC); Tyrosinase -related protein 2 (TRP-2); Cytochrome P450 1B1 (CYP1B1); CCCTC-Binding Factor (Zinc Finger Protein)-Like (BORIS or Brother of the Regulator of Imprinted Sites); Squamous Cell Carcinoma Antigen Recognized By T Cells 3 (SART3); Paired box protein Pax-5 (PAX5); proacrosin binding protein sp32 (OY- TES1); lymphocyte-specific protein tyrosine kinase (LCK); Janus kinase 2 (JAK2); large tumor suppressor kinase 1 (LATS1); large tumor suppressor kinase 2 (LATS2); A kinase anchor protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 (SSX2); Receptor for Advanced Glycation Endproducts (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papilloma virus E6 (HPV E6); human papilloma virus E7 (HPV E7); intestinal carboxyl esterase; heat shock protein 70-2 mutated (mut hsp70-2); CD79a; CD79b; CD72; Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89); Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 moleculelike family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module- containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); Glypican-3 (GPC3); Fc receptor-like 5 (FCRLS); and immunoglobulin lambda-like polypeptide 1 (IGLL1); CD 19; BCMA; CD70; G6PC; Dystrophin, including modification of exon 51 by deletion or excision; DMPK; CFTR (cystic fibrosis transmembrane conductance regulator); the SCNN1A gene; acetyl-CoA carboxylase; fatty acid synthase; 3-ketoacyl acyl- carrier protein synthase III; glycerol-3-phospate dehydrogenase (G3PDH); Enoyl-acyl carrier protein reductase (Enoyl- ACP-reductase); glycerol- 3-phosphate acyltransferase; lysophosphatidic acyl transferase; diacylglycerol acyltransferase; phoshatidate phosphatase; fatty acid thioesterase such as palmitoyi protein thioesterase or malic enzyme; acyl-CoA synthetase; 3-ketoacyl-CoA thiolase; acyl-CoA oxidase activity; phosphoglucomutase; Arylsulfatase A; Wiskott-Aldrich Syndrome protein; ATP- binding cassette DI; receptor type 5- C-C chemokine or CXCR4 gene; Hemoglobin beta subunit; interelukin-2 receptor subunit gamma; cystinosin; Ribosomal protein S19; Fanconi anemia complementation groups (e.g., FNACA, FNACB, FANCC, FANCD1, FANCD2, FANCE, FANCF, RAD51C); Shwachman syndrome gene; Glucocerebrosidase; Anti-hemophiliac factor OR Factor VIII; Christmas factor; Serine protease; Factor Hemophilia B IX; Adenosine deaminase; betagalactosidase; alpha-glucosidase; sphingomyelinase; galactercerebrosidease; Human leukocyte antigens DR-15; DQ-6; DRB1; RSI, RL2 and/or LAT genes; PreC, C, X, PreSl, PreS2, S, P and/or SP gene(s); Chromosomal Sequence Encoded Protein, Delta-aminolevulinate synthase 2 (ALAS2); ATP-binding cassette transporter (ABCA1); Angiotensin I converting enzyme (ACE); Apolipoprotein E precursor (APOE); amyloid precursor protein (APP); aquaporin 1 protein (AQP1); Myc box-dependent- interacting protein 1 or bridging integrator 1 protein (BINI); brain- derived neurotrophic factor (BDNF); Butyrophilin-like protein 8 (BTNL8); chromosome 1 open reading frame 49 (C10RF49); CDH4 (Cadherin-4 CHRNB2 Neuronal acetylcholine receptor subunit beta-2); CKLF-like MARVEL transmembrane domain- containing protein 2 (CKLFSF2); C-type lectin domain family 4, member e (CLEC4E); CLU clusterin protein (also known as apoplipoprotein J); Erythrocyte complement receptor 1 (CR1, also known as CD35, C3b/C4b receptor and immune adherence receptor); Erythrocyte complement receptor 1 (CR1L); granulocyte colony-stimulating factor 3 receptor (CSF3R); CST3 (Cystatin C or cystatin 3); CYP2C (Cytochrome P4502C); Death-associated protein kinase 1 (DAPK1); Estrogen receptor 1 (ESRI); fragment of IgA receptor (FCAR, also known as CD89); Fc fragment of IgG, low affinity Illb, receptor (FCGR3B or CD16b); Free fatty acid receptor 2 (FFA2); FGA Fibrinogen (Factor I); GRB2-associated-binding protein 2 (GAB2); Galanin-like peptide (GALP); Glyceraldehyde-3- phosphate dehydrogenase, spermatogenic (GAPDHS); Haptoglobin (HP); serotonin receptor 7; Insulin degrading enzyme (IDE); IF 127; IFI6 Interferon, alpha-inducible protein 6 (IFI6); Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2); interleukin- 1 receptor antagonist (IL- IRA); Interleukin 8 receptor, alpha (IL8RA or CD181); Interleukin 8 receptor, beta (IL8RB); Jagged 1 (JAG1); Potassium inwardly-rectifying channel, subfamily J, member 15 (KCNJ15); Low-density lipoprotein receptor-related protein 6 (LRP6); microtubule- associated protein tau (MAPT); MAP/microtubule affinity-regulating kinase 4 (MARK4); M- phase phosphoprotein 1 (MPHOSPH1); 5, 10-methylenetetrahydrofolate reductase (MTHFR); Interferon- induced GTP-binding protein Mx2 (MX2); Nibrin (NBN); Nicastrin (NCSTN); Niacin receptor 2 (NIACR2, also known as GPR109B); nicotinamide nucleotide adenylyltransferase 3 (NMNAT3); Neurotrimin (NTM or HNT); Orosmucoid 1 (0RM1); Alpha- 1-acid glycoprotein 1; P2Y purinoceptor 13 (P2RY13); Nicotinamide phosphoribosyltransferase (NAmPRTase or Nampt) also known as pre-B-cell colony-enhancing factor 1 (PBEF1); visfatin; Phosphoenolpyruvate carboxy kinase (PCK1); phosphatidylinositol binding clathrin assembly protein (PIC ALM); Urokinase-type plasminogen activator (PLAU); Plexin Cl (PLXNC1); Prion protein (PRNP); PSEN1 presenilin 1 protein (PSEN1); presenilin 2 protein (PSEN2); protein tyrosine phosphatase receptor type A protein (PTPRA); Rai GEF with PH domain and SH3 binding motif 2 (RALGPS2); regulator of G-protein signaling like 2 (RGSL2); Selenium binding protein 1 (SELNBP1); SLC25A37 Mitoferrin-1, sortilin-related receptor L(DLR class) A repeats- containing protein (SORL1); Transferrin; Mitochondrial transcription factor A (TEAM); Tumor necrosis factor (TNF); Tumor necrosis factor receptor superfamily member 10C (TNFRSF10C); Tumor necrosis factor receptor superfamily, (TRAIL) member 10a (TNFSF10); ubiquitin-like modifier activating enzyme 1 (UBA1); NEDD8-activating enzyme El catalytic subunit protein (UBE1C); ubiquitin B protein (UBB); Ubiquilin-1 (UBQLN1); ubiquitin carboxyl-terminal esterase LI protein (UCHL1); ubiquitin carboxyl-terminal hydrolase isozyme L3 protein (UCHL3); very low density lipoprotein receptor protein (VLDLR); low density lipoprotein receptor protein (VLDLR) encoded by the VLDLR gene; the ubiquitin-like modifier activating enzyme 1 (UBA1) encoded by the UBA1 gene; the NEDD8-activating enzyme El catalytic subunit protein (UBE1C) encoded by the UBA3 gene; the aquaporin 1 protein (AQP1) encoded by the AQP1 gene; the ubiquitin carboxyl-terminal esterase LI protein (UCHL1) encoded by the UCHL1 gene; the ubiquitin carboxyl-terminal hydrolase isozyme L3 protein (UCHL3) encoded by the UCHL3 gene; the ubiquitin B protein (UBB) encoded by the UBB gene; the microtubule- associated protein tau (MAPT) encoded by the MAPT gene; the protein tyrosine phosphatase receptor type A protein (PTPRA) encoded by the PTPRA gene; the phosphatidylinositol binding clathrin assembly protein (PICALM) encoded by the PICALM gene; the clusterin protein (also known as apoplipoprotein J) encoded by the CLU gene; the presenilin 1 protein encoded by the PSEN1 gene; the presenilin 2 protein encoded by the PSEN2 gene; the sortilin-related receptor L(DLR class) A repeats-containing protein (SORL1) protein encoded by the SORL1 gene; the amyloid precursor protein (APP) encoded by the APP gene; the Apolipoprotein E precursor (APOE) encoded by the APOE gene; the brain-derived neurotrophic factor (BDNF) encoded by the BDNF gene; cell surface receptors; cell surface receptors on cancer cells; TfRs; folate receptors (FRs); VCAM (vascular endothelium); E- and P-selectins; VCAM-1; ICAMs; TIMP1- 4; MT1-MMP; MMP-2; an RGD peptide; phospholipase A2; alkaline phosphatase; transglutaminase; phosphatidylinositol-specific phospholipase C; cell -penetrating peptides (CPPs); amphipathic helical peptides; transportan; MAP; TATp; Antennapedia; penetratin; or VP22; or any combination thereof.
[00224] In certain embodiments, the target substrate is a kinase. In certain embodiments, the target substrate is a phosphatase. In certain embodiments, the target substrate is KRAS or KRAS mutant, BRD4, CAII, TRIM24, or BTK. In certain embodiments, the target substrate is KRAS or KRAS mutant, BRD4, CAII, TRIM24, BET, BRD2, BRD3, BRDT, or BTK. In certain embodiments, the target substrate is BRD4 or BTK. In certain embodiments, the target substrate is KRAS or KRAS mutant. In certain embodiments, the target substrate is BRD4. In certain embodiments, the target substrate is BTK. In certain embodiments, the target substrate is CAII. In certain embodiments, the target substrate is TRIM24. In certain embodiments, the target substrate is BET. In certain embodiments, the target substrate is BRD2. In certain embodiments, the target substrate is BRD3. In certain embodiments, the target substrate is BRDT.
[00225] The present disclosure also provides methods for inhibiting phosphorylation of a target substrate with a compound of the disclosure (e.g., Formula ((I), (II), 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 ABLE
EXAMPLES
[00226] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.
[00227] Compounds are prepared in order to interrogate their ability of the ABL1 -binding portion of the compound to bind and/or activate ABLE
[00228] Abbreviations used:
[00229] ACN acetonitrile
[00230] Ad2BuP Di( 1 -adamantyl)-n-butylphosphine
[00231] DBU 1 , 8-Diazabicyclo(5.4.0)undec-7 -ene
[00232] DCM dichloromethane
[00233] DIBAL Diisobutylaluminium hydride
[00234] DIEA M/V-Diisopropylethylamine
[00235] DMA A,A-Dimethylacetamide
[00236] FA formic acid
[00237] HATU l-[Bis(dimethylamino)methylene]-17/-l,2,3-triazolo[4,5-&]pyridinium 3- oxide hexafluorophosphate
[00238] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
[00239] PE petroleum ether
[00240] THF tetrahydrofurane [00241] TFA trifluoroacetic acid
[00242] TMSOK potassium trimethylsilanolate
[00243] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
[00244] XantPhos Pd G3 [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino- 1 , 1 '-biphenyl)]palladium(II) methanesulfonate
Preparation of Exemplary Compounds
[00245] Compounds of the disclosure are prepared following means known in the art of organic synthesis. For example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof are representative and instructive. Methods for optimizing reaction conditions, and if necessary, minimizing competing by-products, are known in the art.
Synthetic Procedures
N-{ l-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro- lH-pyrazol-3-yl)pyrimidin-4-amine (A- 18)
1 A-18
[00246] Synthesis of A-(l-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-l//-pyrazol-3- yl)pyrimidin-4-amine (A-18): a mixture of l-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-177- pyrazol-3-amine (150 mg, 614 pmol), 4-chloropyrimidine (42.2 mg, 369 pmol), cesium carbonate (601 mg, 1.84 mmol) and XantPho Pd G3 (0.03 eq., 18.4 pmol) in 1,4-dioxane (5 mL) was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure and purified by HPLC [Column: Waters xbridge 150*25mm 10pm, water(FA)-ACN, B%, 53-55, lOmin] to give A-(l-(3,4-dichlorophenyl)-4-methyl-4,5-dihydro-lf/-pyrazol-3-yl)pyrimidin-4-amine (A-18) (30.6 mg, 90.6 pmol, 15% yield) as a yellow solid. LCMS: [M+H]+: calculated, 322.1; observed, 322.0. 'H NMR (400 MHz, CD3OD) δ = 8.68 (s, 1H), 8.52 (d, J = 6.0 Hz, 1H), 8.00 (dd, J = 1.0, 6.0 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 2.8 Hz, 1H), 6.90 (dd, J = 2.8, 8.8 Hz, 1H), 3.78-3.70 (m, 1H), 3.57-3.46 (m, 2H), 1.36 (d, J = 6.8 Hz, 3H). [00247] Using analogous Buchwald reaction conditions, the following compounds were prepared:
6-((l-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)amino)-2V-(2-methoxyethyl)-2- methylpyrimidine-4-carboxamide (A-14)
A-2 A-14
[00248] Synthesis of methyl 6-((l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3- yl)amino)-2-methylpyrimidine-4-carboxylate: To a solution of l-(3,4-dichlorophenyl)-2- pyrazolin-3-ylamine (617 mg, 2.68 mmol) and methyl 6-chloro-2-methyl-4- pyrimidinecarboxylate (0.500 g, 2.68 mmol) in 1,4-dioxane (6.00 mL) was added 2-biphenylid- 2'-amine-4,5-bis(diphenylphosphino)-9,9-dimethyl-9Z/-xanthene -methanesulfonic acid-palladium (l/l/l/l) (254 mg, 268 pmol) and cesium carbonate (2.62 g, 8.04 mmol). The resulting mixture was degassed and purged three times with N23 times and stirred at 100 °C for 12 h. The reaction mixture was quenched by H2O (10 mL) and extracted with EtOAc (40 mL x 2). The organic layers were concentrated under reduced pressure to give a residue which was triturated with ACN (5 mL) at 25 °C for 30 min to give methyl 6-[l-(3,4-dichlorophenyl)-2-pyrazolin-3-ylamino]-2- methyl-4-pyrimidinecarboxylate (0.400 g, 863 pmol, 32% yield) as a yellow oil. LCMS: [M+H]+: calculated, 380.1, observed, 380.0.
[00249] Synthesis of 6-((l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3-yl)amino)-2- methylpyrimidine-4-carboxylic acid (A-2): lithium hydroxide monohydrate (36.2 mg, 863 pmol) was added to a mixture of methyl 6-[l-(3,4-dichlorophenyl)-2-pyrazolin-3-ylamino]-2- methyl-4-pyrimidinecarboxylate (0.200 g, 431 pmol) in tetrahydrofuran (1.00 mL) and water (1.00 mL). The resulting mixture was stirred at 25 °C for 2 h. The pH of the reaction was adjusted to 3~4. The mixture was filtered and concentrated to give a crude product which was triturated with ACN (5 mL) at 25 °C for 10 min to give 6-((l-(3,4-dichlorophenyl)-4,5-dihydro-177- pyrazol-3-yl)amino)-2-methylpyrimidine-4-carboxylic acid (A-2) (29.7 mg, 69.7 pmol, 16% yield) as an orange solid. LCMS: [M+H]+: calculated, 366.1, observed, 366.1. 1H NMR (400 MHz, DMSO-ds) δ = 8.14 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.87-6.81 (m, 1H), 3.73-3.68 (m, 2H), 3.23 (t, J = 9.2 Hz, 2H), 2.53 (s, 3H). [00250] Synthesis of 6-((l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3-yl)amino)-2V-(2- methoxyethyl)-2-methylpyrimidine-4-carboxamide (A-14): a mixture of 6-((l-(3,4- dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-2-methylpyrimidine-4-carboxylic acid (A- 2) (155 mg, 254 pmol) and HATU (116 mg, 305 pmol) in dimethylacetamide (4 mL) was stirred 0 °C for 1 h. 2-Methoxyethylamine (22.9 mg, 305 pmol) and DIEA (98.5 mg, 762 pmol) were then added, and the resulting mixture was stirred at 25 °C for 12 h. After concentration under reduced pressure, the crude product was purified by reversed-phase HPLC (48%-78% ACN in water (0.225% FA), 10 min) and lyophilized to give 6-((l-(3,4-dichlorophenyl)-4,5-dihydro-177- pyrazol-3-yl)amino)-A-(2-methoxyethyl)-2-methylpyrimidine-4-carboxamide (A-14) (7.05 mg, 15.3 pmol) as a yellow solid. LCMS: [M+H]+: calculated, 423.1, observed, 423.1. 1H NMR (400 MHz, DMSO-rfs) δ = 10.56 (s, 1H), 8.62 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.91-6.84 (m, 1H), 3.73 (t, J = 9.6 Hz, 2H), 3.48 (s, 4H), 3.28-3.22 (m, 5H), 2.56 (s, 3H).
(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6//-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-
6-yl)-2V-(2-(2-(2-(4-(6-(( l-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)amino)-2- methylpyrimidine-4-carbonyl)piperazin-l-yl)-2-oxoethoxy)ethoxy)ethyl)acetamide (1)
[00251] Synthesis of tert-butyl 4-(6-(( l-(3,4-dichlorophenyl)-4,5-dihydro- l.H-pyrazol-3- yl)amino)-2-methylpyrimidine-4-carbonyl)piperazine-l-carboxylate: HATU (3.74 g, 9.83 mmol) was added to a solution of 6-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3- yl)amino)-2-methylpyrimidine-4-carboxylic acid (A-2) (3 g, 8.19 mmol) in dimethylacetamide (30 mL) at 0 °C. After Ih at 0 °C, tert-butyl piperazine- 1 -carboxylate (1.53 g, 8.19 mmol) and DIEA (3.18 g, 24.6 mmol) were added. The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water (200 ml) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over Na2SO4, filtered and concentrated in vacuum to give a residue which was triturated with MeCN (20 mL) at 25 °C for 30 min to give tert-butyl 4-(6-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-2- methylpyrimidine-4-carbonyl)piperazine-l -carboxylate (2.8 g, 5.24 mmol, 64% yield) as a yellow solid. LCMS: [M+H]+: calculated, 534.2, observed, 534.1. 'H NMR (400 MHz, DMSO-rftf) 5 = 10.54 (s, 1H), 7.65 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 2.4, 8.8 Hz, 1H), 3.71 (t, J = 9.6 Hz, 2H), 3.65-3.59 (m, 2H), 3.45-3.5 (m, 2H), 3.3-3.44 (m, 4H), 3.22 (t, J = 9.2 Hz, 2H), 2.50 (s, 3H), 1.40 (s, 9H).
[00252] Synthesis of (6-((l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3-yl)amino)-2- methylpyrimidin-4-yl)(piperazin-l-yl)methanone hydrochloride (A-20) : Hydrogen chloride (2M in diethyl ether, 2 mL, 4 mmol) was added to a solution of tert-butyl 4-(6-((l-(3,4- dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-2-methylpyrimidine-4-carbonyl)piperazine- 1-carboxylate (0.3 g, 561 pmol) in dichloromethane (2 mL). After Ih at 25 °C, the reaction mixture was concentrated under reduced pressure to give compound (6-((l-(3,4-dichlorophenyl)- 4,5-dihydro-17/-pyrazol-3-yl)amino)-2-methylpyrimidin-4-yl)(piperazin-l-yl)methanone hydrochloride (A-20) (0.2 g, 425 pmol, 76% yield) as a yellow solid. LCMS: [M+H]+: calculated, 434.1, observed, 434.1.
[00253] Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- J[l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-iV-(2-(2-(2-(4-(6-((l-(3,4-dichlorophenyl)-4,5- dihydro-lH-pyrazol-3-yl)amino)-2-methylpyrimidine-4-carbonyl)piperazin-l-yl)-2- oxoethoxy)ethoxy)ethyl)acetamide (1): HATU (105 mg, 276 pmol) was added to a solution of (S)-2-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2-/][l,2,4]triazolo[4,3- cz][l,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)acetic acid (126 mg, 230 pmol) in dimethylacetamide (1 mL) at 0 °C. After Ih at 0 °C, (6-((l-(3,4-dichlorophenyl)-4,5-dihydro-177- pyrazol-3-yl)amino)-2-methylpyrimidin-4-yl)(piperazin-l-yl)methanone hydrochloride (0.1 g, 212 pmol) and DIEA (89.3 mg, 691 pmol) were added. The mixture was stirred at 25 °C for 1 h. The residue was purified by reversed phase chromatography (column C 18, mobile phase: [water(0.1% EA)-ACN]; B%: 44%-74%, 12 min)) to give (S)-2-(4-(4-chlorophenyl)-2,3,9- tri methyl -6A/-thieno| 3, 2;/] [ 1 ,2,4]triazolo[4,3-cz] [ 1 ,4]diazepin-6-yl)-A-(2-(2-(2-(4-(6-(( 1 -(3,4- dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-2-methylpyrimidine-4-carbonyl)piperazin- l-yl)-2-oxoethoxy)ethoxy)ethyl)acetamide (1) (52.6 mg, 51.1 pmol, 22% yield) as a yellow solid. LCMS: [M+H]+: calculated, 961.3, observed, 961.2. 'H NMR (400 MHz, DMSO-rftf) δ =10.52 (s, IH), 8.27 (s, IH), 7.65 (s, IH), 7.50-7.45 (m, 2H), 7.44-7.36 (m, 3H), 7.04 (s, IH), 6.86-6.80 (m, 1H), 4.50 (s, 1H), 4.26-4.13 (m, 2H), 3.77-3.68 (m, 2H), 3.68-3.52 (m, 9H), 3.51-3.35 (m, 8H), 3.29-3.13 (m, 6H), 2.58 (s, 3H), 2.40 (s, 3H), 1.61 (s, 3H).
[00254] Using an analogous procedure, the following compounds were prepared:
(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6//-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-
6-yl)-N-(2-(2-(2-(4-(6-((l-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)amino)-2- methylpyrimidine-4-carbonyl)piperazin-l-yl)ethoxy)ethoxy)ethyl)acetamide (4).
[00255] Synthesis of tert-butyl (2-(2-(2-(4-(6-((l-(3,4-dichlorophenyl)-4,5-dihydro-l//- pyrazol-3-yl)amino)-2-methylpyrimidine-4-carbonyl)piperazin-l- yl)ethoxy)ethoxy)ethyl)carbamate: tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (144 mg, 460 pmol) and DIEA (119 mg, 921 pmol) were added to a solution of (6-((l-(3,4- dichlorophenyl)-4,5-dihydro-lf/-pyrazol-3-yl)amino)-2-methylpyrimidin-4-yl)(piperazin-l- yl)methanone hydrochloride (A-20) (0.2 g, 425 pmol) in dimethylformamide (2 mL). The mixture was stirred at 25 °C for 24 h. The residue was purified by reversed phase chromatography (C 18 column, mobile phase: [water(0.1% FA)-ACN]; B%: 35%, 10 min) to give tert-butyl (2-(2-(2-(4-(6-((l-(3,4-dichlorophenyl)-4,5-dihydro-lf/-pyrazol-3-yl)amino)-2- methylpyrimidine-4-carbonyl)piperazin-l-yl)ethoxy)ethoxy)ethyl)carbamate (110 mg, 165 pmol) as a yellow solid. LCMS: [M+H]+: calculated, 665.3, observed, 665.3
[00256] Synthesis of (4-(2-(2-(2-aminoethoxy)ethoxy)ethyl)piperazin-l-yl)(6-((l-(3,4- dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)amino)-2-methylpyrimidin-4-yl)methanone hydrochloride (A-21): Hydrogen chloride (4M in dioxane, ImL, 4 mmol) was added to a solution of tert-butyl (2-(2-(2-(4-(6-((l-(3,4-dichlorophenyl)-4,5-dihydro-lf/-pyrazol-3- yl)amino)-2-methylpyrimidine-4-carbonyl)piperazin- 1 -yl)ethoxy)ethoxy)ethyl)carbamate (0.1 g, 150 pmol) in dichloromethane (1 mL). After Ih at 25 °C, the reaction mixture was concentrated in vacuo to give (4-(2-(2-(2-aminoethoxy)ethoxy)ethyl)piperazin-l-yl)(6-((l-(3,4- dichlorophenyl)-4,5-dihydro-lf/-pyrazol-3-yl)amino)-2-methylpyrimidin-4-yl)methanone hydrochloride (A-21) (80 mg, 133 pmol) as a yellow solid which was used in the following step without any further purification. LCMS: [M+H]+: calculated, 565.2, observed, 565.2.
[00257] Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-A-(2-(2-(2-(4-(6-((l-(3,4-dichlorophenyl)-4,5- dihydro-lH-pyrazol-3-yl)amino)-2-methylpyrimidine-4-carbonyl)piperazin-l- yl)ethoxy)ethoxy)ethyl)acetamide (4): 2,5-dioxopyrrolidin-l-yl (S)-2-(4-(4-chlorophenyl)-2,3,9- trimethyl-6Z/-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetate (70.4 mg, 141 pmol) and DIEA (54.9 mg, 424 pmol) were added to a solution of (4-(2-(2-(2- aminoethoxy)ethoxy)ethyl)piperazin-l-yl)(6-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3- yl)amino)-2-methylpyrimidin-4-yl)methanone hydrochloride (80 mg, 133 pmol) in dimethylformamide (1 mL). The mixture was stirred at 25 °C for 1 h. After concentration under reduced pressure, the residue was purified by reversed phase column chromatography (Cl 8 column, mobile phase: [water(0.1% FA)-ACN]; B%: 45%, 10 min) to give (S)-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-A-(2-(2- (2-(4-(6-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-2-methylpyrimidine-4- carbonyl)piperazin-l-yl)ethoxy)ethoxy)ethyl)acetamide (4) (112 mg, 106 pmol) as a yellow solid. LCMS: [M+H]+: calculated, 947.3, observed, 947.2. 'H NMR (400 MHz, DMSO-rftf) 5 = 10.51 (s, 1H), 8.26 (t, J = 5.2 Hz, 1H), 8.21 (s, 1H), 7.60 (s, 1H), 7.50-7.45 (m, 2H), 7.45-7.39 (m, 3H), 7.04 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 2.4, 8.8 Hz, 1H), 4.53-4.47 (m, 1H), 3.71 (t, J = 9.6 Hz, 2H), 3.60 (d, J = 4.4 Hz, 2H), 3.55-3.49 (m, 7H), 3.44 (d, J = 6.0 Hz, 2H), 3.30-3.25 (m, 4H), 3.25-3.16 (m, 6H), 2.58 (s, 3H), 2.49-2.47 (m, 4H), 2.42-2.37 (m, 5H), 1.61 (s, 3H).
2V-( l-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)-2-methyl-6-((4-methylpiperazin-l- yl)methyl)pyrimidin-4-amine (A-12)
[00258] Synthesis of (6-chloro-2-methylpyrimidin-4-yl)methanol: lithium borohydride (0.3 g, 13.8 mmol) was added portionwise to a solution of methyl 6-chloro-2-methylpyrimidine-4- carboxylate (1 g, 5.36 mmol) in ethanol (15 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 3 h. The reaction mixture was quenched with NH4CI (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous NazSCL, filtered and dried to give (6-chloro-2-methylpyrimidin-4- yl)methanol (709 mg, 4.47 mmol, 83% yield) as a yellow oil, which was used directly without purification. 'H NMR (400 MHz, DMSO-rftf) 8 = 7.42 (s, 1H), 5.72 (t, J = 5.6 Hz, 1H), 4.53 (d, J = 5.6 Hz, 2H), 2.60-2.54 (m, 3H).
[00259] Synthesis of (6-((l-(3,4-dichlorophenyl)-4,5-dihydro-LH-pyrazol-3-yl)amino)-2- methylpyrimidin-4-yl)methanol: A mixture of 1 -(3,4-dichlorophenyl)-4,5-dihydro-l H-pyrazol- 3-amine (484 mg, 2.1 mmol), cesium carbonate (1.37 g, 4.2 mmol), Xantphos-Pd-Gs (0.2 g, 210 pmol) in 1,4-dioxane (3.33 mL) was stirred at 100 °C for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous NazSCL, filtered and concentrated under reduced pressure. The residue was purified by RP-flash (Phenomenex luna C18 150*25mm* 10pm; 46%-56% water (NH4HCO3)-ACN, 25 ml/min, 25 min) to give (6-((l-(3,4- dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-2-methylpyrimidin-4-yl)methanol (418 mg, 1.19 mmol, 57% yield) as a white solid. LCMS: [M+H]+: calculated, 352.1, observed, 352.1. 'H NMR (400 MHz, DMSO-d6) 8 = 8.01 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 6.91 (dd, J = 2.4, 8.8 Hz, 1H), 4.61 (s, 2H), 3.77-3.69 (m, 2H), 3.26 (t, J = 9.6 Hz, 2H), 2.51 (s, 3H).
[00260] Synthesis of (6-(( l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3-yl)amino)-2- methylpyrimidin-4-yl)methyl methanesulfonate: methanesulfonic anhydride (148 mg, 852 pmol) was added to a mixture of (6-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3- yl)amino)-2-methylpyrimidin-4-yl)methanol (250 mg, 710 pmol) and 2,6-dimethylpyridine (304 mg, 2.84 mmol) in tetrahydrofuran (3 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction was diluted with H2O (10 mL) and extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give (6-((l-(3,4- dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-2-methylpyrimidin-4-yl)methyl methanesulfonate (243 mg, 0.565 mmol, crude) as a yellow oil. The crude product was used for next step directly without purification. LCMS: [M+H]+: calculated, 430.1, observed, 430.1.
[00261] Synthesis of 2V-(l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3-yl)-2-methyl-6- ((4-methylpiperazin-l-yl)methyl)pyrimidin-4-amine (A-12): a mixture of (6-((l-(3,4- dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-2-methylpyrimidin-4-yl)methyl methanesulfonate (170 mg, 395 pmol), DIEA (153 mg, 1.19 mmol) and 1 -methylpiperazine (79.1 mg, 790 pmol) in acetonitrile (2 mL) was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by Prep-HPLC (Phenomenex luna C18 150*25mm* 10pm water(NH4HCO3)-ACN, B%, 16-46, 10 min) and lyophilized to give A-(l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)-2-methyl-6-((4- methylpiperazin-l-yl)methyl)pyrimidin-4-amine (A- 12) (22.7 mg, 47 pmol) as a white solid.
LCMS: [M+H]+: calculated, 434.2, observed, 434.2. 'H NMR (400 MHz, CD3OD) δ =8.01-7.86 (m, 1H), 7.34-7.21 (m, 1H), 7.15-7.04 (m, 1H), 6.93 (dd, J = 2.4, 8.8 Hz, 1H), 3.77-3.64 (m, 2H), 3.62-3.52 (m, 2H), 3.22 (t, J = 9.6 Hz, 2H), 2.83-2.38 (m, 11H), 2.33-2.23 (m, 3H).
[00262] Using an analogous procedure, the following compound was prepared:
2V-((6-(( l-(3,4-dichlorophenyl)-4,5-dihydro- lH-pyrazol-3-yl)amino)-2-methylpyrimidin-
HCI/dioxane, DCM
[00263] Synthesis of tert-butyl ((6-chloro-2-methylpyrimidin-4-yl)methyl)carbamate: A mixture of 4,6-dichloro-2-methylpyrimidine (1 g, 6.13 mmol), potassium [[(tert- butoxycarbonyl)amino]methyl]trifluoroborate (1.45 g, 6.13 mmol), potassium carbonate (1.7 g, 12.3 mmol), [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (224 mg, 307 pmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 100 °C for 12 h. The reaction was diluted with water (15 mL) and filtered, the filtrate was extracted with ethyl acetate (10 mLx3), washed with brine (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give tert-butyl ((6-chloro-2- methylpyrimidin-4-yl)methyl)carbamate (590 mg, 1.99 mmol, crude) as a yellow oil. LCMS: [M- 56+H]+: calculated, 202.1, observed, 202.2.
[00264] Synthesis of tert-butyl ((6-((l-(3,4-dichlorophenyl)-4,5-dihydro-LH-pyrazol-3- yl)amino)-2-methylpyrimidin-4-yl)methyl)carbamate: A mixture of give tert-butyl ((6-chloro-
2-methylpyrimidin-4-yl)methyl)carbamate (520 mg, 2.02 mmol), l-(3,4-dichlorophenyl)-4,5- dihydro-l A/-pyrazo]-3-amine (464 mg, 2.02 mmol), cesium carbonate (1.31 g, 4.04 mmol), Xantphos-Pd-G3 (192 mg, 202 pmol) in 1,4-dioxane (6.58 mL) was stirred at 115 °C for 12 h. The reaction was diluted with water (15 mL) and filtered. The filtrate was extracted with ethyl acetate (10 mLx3). The combined organic layers were washed with brine (8 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ethyl acetate = 0/1) to give tert-butyl ((6-((l- (3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)amino)-2-methylpyrimidin-4- yl)methyl)carbamate (650 mg, 1.17 mmol, 58% yield) as a yellow solid. LCMS: [M+H]+: calculated, 451.1 , observed, 451.1.
[00265] Synthesis of 6-(amiiwmethyl)-V-( l-(3,4-dichlorophenyl)-4,5-dihydro- l//-pyrazol-
3-yl)-2-methylpyrimidin-4-amine hydrochloride (A-l): HC1 in dioxane (4.5 mL, IM) was added to a solution of tert-butyl ((6-((l-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3- yl)amino)-2-methylpyrimidin-4-yl)methyl)carbamate (640 mg, 1.42 mmol) in dichloromethane (4.5 mL) at 25 °C, and the reaction mixture was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure and the residue was triturated with MeOH (2 mL) to give 6- (aminomethyl)-A-(l-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)-2-methylpyrimidin-4- amine hydrochloride (A-l) (531 mg, 1.25 mmol, 88% yield) as a brown solid. LCMS: [M+H]+: calculated, 351.1, observed, 351.1. *H NMR (400 MHz, DMSO-d6) δ = 10.97 (s, 1H), 8.72 (s, 3H), 7.67 (s, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.12 (d, 7= 2.6 Hz, 1H), 7.02 (dd, 7= 2.5, 8.9 Hz, 1H), 4.22 (d, 7 = 4.8 Hz, 2H), 3.75 (t, 7 = 9.8 Hz, 2H), 3.27 (t, 7= 9.7 Hz, 2H), 2.57 (s, 3H).
[00266] Synthesis of /V-((6-((l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3-yl)amino)-2- methylpyrimidin-4-yl)methyl)-2-methoxyacetamide (A-13): a mixture of 2-methoxyacetic acid (34.9 mg, 387 pmol) and HATU (162 mg, 1.1 eq., 426 pmol) in dimethylformamide (4.91 mL) was stirred at 0 °C for 0.5 h. 6-(aminomethyl)-A-( 1 -(3,4-dichlorophenyl)-4,5-dihydro-l H- pyrazol-3-yl)-2-methylpyrimidin-4-amine hydrochloride (A-l) (150 mg, 387 pmol) and DIEA (250 mg, 1.93 mmol) were then added. The reaction mixture was stirred at 25 °C for 12 h. The reaction was filtered and concentrated under reduced pressure. The residue was triturated with ACN (2 mL) to give A-((6-((l-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)amino)-2- methylpyrimidin-4-yl)methyl)-2-methoxyacetamide (A-13) (37.1 mg, 82.2 pmol, 21% yield) as a yellow solid. LCMS: [M+H]+: calculated, 423.1, observed, 423.1. 'H NMR (400 MHz, DMSO- d6) 8 = 10.20 (s, 1H), 8.53 (t, J = 5.6 Hz, 1H), 7.53 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.03-6.91
(m, 2H), 4.29 (d, J = 6.0 Hz, 2H), 3.94 (s, 2H), 3.68 (t, J = 9.6 Hz, 2H), 3.34 (s, 3H), 3.17 (t, J =
9.6 Hz, 2H), 2.45 (s, 3H).
[00267] Using an analogous procedure, the following comopund was prepared:
3-(4-((l-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)propanoic acid (A-3) [00268] Synthesis of 2-chloro- V-( l-(3,4-dichlorophenyl)-4,5-dihydro- lH-pyrazol-3- yl)pyrimidin-4-amine: A mixture of 1 -(3,4-dichlorophenyl)-4,5-dihydro-l H-pyrazol-3-amine (6 g, 26.1 mmol) and 2,4-dichloropyrimidine (2.72 g, 18.3 mmol) and Xantphos (1.51 g, 2.61 mmol) and tris(dibenzylideneacetone)dipalladium (2.39 g, 2.61 mmol) and cesium carbonate (25.5 g, 78.2 mmol) in 1,4-dioxane (60 mL) was stirred at 60 °C for 12 h. The reaction mixture was quenched by addition of water (400 mL) and extracted with EtOAc (500 mL x 3), the combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with PE/EtOAc = 2/1 (20 mL) at 25 °C for 60 min to give 2-chloro-A-(l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3- yl)pyrimidin-4-amine (4.3 g, 11.7 mmol, 45% yield) as a yellow solid. LCMS: [M+H]+: calculated, 342.0, observed, 342.1.
[00269] Using an analogous procedure, the following compound was prepared:
[00270] Synthesis of ethyl (£')-3-(4-((l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3- yl)amino)pyrimidin-2-yl)acrylate: to a solution of 2-chloro-/V-( 1 -(3,4-dichlorophenyl)-4,5- dihydro-17/-pyrazol-3-yl)pyrimidin-4-amine (3.35 g, 9.76 mmol), ethyl (E)-3-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)acrylate (4.41 g, 19.5 mmol) and dipotassium carbonate (2.7 g, 19.5 mmol) in 1,4-dioxane (33.5 mL) and water (3.35 mL) at 25 °C was added palladium (II) acetate (221 mg, 976 pmol) and Ad2BuP (266 mg, 742 pmol) under a nitrogen atmosphere. The mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature.
EtOAc (80 mL) and water (80 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (60 mL x 2). The combined extracts were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO?, Petroleum ether/Ethyl acetate = 5/1 to 3/1) to give ethyl (£')-3-(4-((l-(3,4- dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)pyrimidin-2-yl)acrylate (3.1 g, 7.02 mmol, 72% yield) as a yellow solid. LCMS: [M+H]+: calculated,406.1, observed, 406.0.
[00271] Synthesis of ethyl 3-(4-(( l-(3,4-dichlorophenyl)-4,5-dihydro- LH-pyrazol-3- yl)amino)pyrimidin-2-yl)propanoate: To a solution of ethyl (£)-3-(4-((l-(3,4-dichlorophenyl)- 4,5-dihydro-l H-pyrazo]-3-yl)amino)pyrimidin-2-yl)acrylate (1.9 g, 4.68 mmol) and DBU (712 mg, 4.68 mmol) in ethanol (380 mL) at 25 °C, was added PtV/C (0.5 mL, 468 pmol). The reaction mixture was degassed and purged 3 times with H2. The mixture was then stirred at 50 °C for 12 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase column (C 18, mobile phase: [water(0.1% FA)- ACN]; B%: 25%-40%, 25 min) to give ethyl 3-(4-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/- pyrazol-3-yl)amino)pyrimidin-2-yl)propanoate (0.5 g, 1.1 mmol, 24% yield) as a yellow solid. LCMS: [M+H]+: calculated,408.1, observed, 408.2.
[00272] Synthesis of 3-(4-(( l-(3,4-dichlorophenyl)-4,5-dihydro- lH-pyrazol-3- yl)amino)pyrimidin-2-yl)propanoic acid (A-3): potassium trimethylsilanolate (283 mg, 2 eq., 2.2 mmol) was added to a solution of ethyl 3-(4-((l-(3,4-dichlorophenyl)-4,5-dihydro-lf/- pyrazol-3-yl)amino)pyrimidin-2-yl)propanoate (450 mg, 1.1 mmol) in tetrahydrofuran (5 mL) at 25 °C under a nitrogen atmosphere. The mixture was then stirred at 25 °C for 12 h. After concentration under reduced pressure, the residue was purified by reversed phase column (C 18, mobile phase: [water(0.1% FA)-ACN]; B%: 19%-49%, 25 min) to give 3-(4-((l-(3,4- dichlorophenyl)-4,5-dihydro-lf/-pyrazol-3-yl)amino)pyrimidin-2-yl)propanoic acid (A-3) (139 mg, 357 pmol, 32% yield) as a yellow solid. LCMS: [M+H]+: calculated, 380.1, observed, 380.0. 'H NMR (400 MHz, DMSO-dU 5 = 12.21 (s, 1H), 10.25 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 7.58 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.04 (s, 1H), 6.89 (d, J = 7.2 Hz, 1H), 3.69 (t, J = 9.6 Hz, 2H), 3.26- 3.19 (m, 2H), 2.97 (t, J = 6.8 Hz, 2H), 2.76-2.69 (m, 2H).
[00273] Using an analogous procedure, the following carboxylic acids were prepared:
(SyE')-A-(2-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6//-thieno[3,2-/][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl)-3-(6-((l-(3,4-dichlorophenyl)-4,5- dihydro-l//-pyrazol-3-yl)amino)pyrimidin-4-yl)acrylamide (16)
[00274] Synthesis of tert-butyl (S)-(2-(2-(2-(2-(4-(4-chlorophenyl )-2,3,9-trimethvl-6//- thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)ethoxy)ethoxy)ethyl)carbamate: DIEA (234 mg, 3 eq., 1.81 mmol) was added to a solution of 2,5-dioxopyrrolidin-l-yl (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2- /][l,2,4]triazolo[4,3-cz][l,4]diazepin-6-yl)acetate (0.3 g, 602 pmol) and tert-butyl (2-(2-(2- aminoethoxy)ethoxy)ethyl)carbamate (180 mg, 723 pmol) in dimethylacetamide (3 mL). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was extracted with EtOAc (50 mL x 3), the combined organic layers were washed with brine (50 mL x 3), dried over anhydrous NazSCX filtered and concentrated under reduced pressure to give tert-butyl (S)-(2-(2-(2-(2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)ethoxy)ethoxy)ethyl)carbamate (470 mg, crude). The crude product was used for next step directly without purification. LCMS: [M+H]+: calculated, 631.2, observed, 631.2. [00275] Using an analogous procedure, the following compounds were prepared:
[00276] Synthesis of (S)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-(4-(4-chlorophenyl)-2,3,9- trimethyl-6//-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetamide hydrochloride: hydrogen chloride (4M in dioxane, 2 mL) was added to a solution of tert-butyl (S)-(2-(2-(2-(2-(4- (4-chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)ethoxy)ethoxy)ethyl)carbamate (470 mg, 745 pmol) in dichloromethane (5 mL). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC(Column: Waters xbridge 150*25mm 10pm, water-ACN, B%, 0-60, 8 min.) to give (S)-2V-(2-(2-(2- aminoethoxy)ethoxy)ethyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2- /][l,2,4]triazolo[4,3-cz][l,4]diazepin-6-yl)acetamide hydrochloride (0.3 g, 488 pmol, 66% yield) as a yellow gum. LCMS: [M+H]+: calculated, 531.2, observed, 531.1. 1H NMR (400 MHz, DMSO-ds) 8 = 8.37-8.23 (m, 1H), 8.04-7.85 (m, 2H), 7.53-7.46 (m, 2H), 7.45-7.39 (m, 2H), 4.53 (t, J = 7.2 Hz, 1H), 3.64-3.60 (m, 4H), 3.49-3.44 (m, 2H), 3.31-3.23 (m, 4H), 3.01-2.93 (m, 2H), 2.61 (s, 3H), 2.44 (s, 2H), 2.42 (s, 3H), 1.62 (s, 3H). [00277] Synthesis of (S^')-W(2-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6//-thieno[3,2- /][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl)-3-(6-((l-(3,4- dichlorophenyl)-4,5-dihydro-l//-pyrazol-3-yl)amino)pyrimidin-4-yl)acrylamide (16): HATU (68.7 mg, 181 pmol) and DIEA (58.4 mg, 452 pmol) were added to a solution of (E)-3-(6-((l- (3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)pyrimidin-4-yl)acrylic acid (85.5 mg, 226 pmol) in dimethylacetamide (1 mL). The reaction mixture was stirred at 0 °C for 0.5 h, then (S)-A-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2- /][l,2,4]triazolo[4,3-cz][l,4]diazepin-6-yl)acetamide hydrochloride (80 mg, 141 pmol) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 12 h. After concentration, the reaction mixture was purified by prep-HPLC (Column: Waters Xbridge BEH Cl 8 150*25mm*5pm, water( NH4HCO3)-ACN, B%, 50-70, 10 min.) to give (S,E)-A-(2-(2-(2-(2-(4- (4-chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)ethoxy)ethoxy)ethyl)-3-(6-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3- yl)amino)pyrimidin-4-yl)acrylamide (16) (21.1 mg, 31.1 pmol, 22% yield) as an orange solid. LCMS: [M+H]+: calculated, 890.2, observed, 890.1. 'H NMR (400 MHz, DMSO-dU 5 =8.63- 8.54 (m, 1H), 7.82-7.70 (m, 1H), 7.41-7.37 (m, 2H), 7.36-7.30 (m, 3H), 7.28-7.22 (m, 1H), 7.18- 7.11 (m, 1H), 7.02 (d, 7 = 2.4 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 4.47 (dd, 7= 6.4, 7.6 Hz, 1H), 3.68-3.65 (m, 2H), 3.52 (s, 4H), 3.48-3.44 (m, 4H), 3.37-3.27 (m, 4H), 3.23-3.16 (m, 4H), 2.53 (s, 3H), 2.32 (s, 3H), 1.57 (s, 3H).
[00278] Using an analogous procedure, the following compounds were prepared:
(S)-2-(4-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6//-thieno[3,2-/][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)acetyl)piperazin-l-yl)piperidin-l-yl)-A^-((6-((l-(3,4-dichlorophenyl)-4,5- dihydro-l//-pyrazol-3-yl)amino)-2-methylpyrimidin-4-yl)methyl)acetamide (6).
Synthesis of tert-butyl (S)-4-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- /][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetyl)piperazin-l-yl)piperidine-l-carboxylate:
DIEA (156 mg, 1.2 mmol) was added to a solution of 2,5-dioxopyrrolidin-l-yl (S)-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetate (0.2 g, 402 pmol) and tert-butyl 4-(piperazin-l-yl)piperidine-l -carboxylate (130 mg, 482 pmol) in THF (2 mL) at 0 °C, the reaction mixture was then stirred at 25 °C for 1 h. The reaction mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with brine (10 ml x3), dried over NazSCX filtered and concentrated under reduced pressure to give tert-butyl (S)-4-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6A/- thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetyl)piperazin-l-yl)piperidine-l- carboxylate (383 mg, 581 pmol) as a yellow solid. LCMS: [M+H]+: calculated, 652.3, observed, 652.4. 'H NMR (400 MHz, DMSO-d6) δ = 7.52-7.39 (m, 4H), 4.57 (t, J = 6.8 Hz, 1H), 3.96 (br d, J - 11.6 Hz, 2H), 3.66-3.54 (m, 3H), 3.49-3.34 (m, 3H), 3.33-3.29 (m, 2H), 2.73-2.67 (m, 1H), 2.62-2.53 (m, 5H), 2.46-2.41 (m, 5H), 1.73 (br d, J - 11.2 Hz, 2H), 1.63 (s, 3H), 1.39 (s, 9H), 1.17 (t, 7 = 7.1 Hz, 2H). [00279] Using an analogous procedure, the following compounds were prepared:
[00280] Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- /][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-l-(4-(piperidin-4-yl)piperazin-l-yl)ethan-l-one hydrochloride: HCl/dioxane (1/1) (4M, 1.5 mL) was added to a solution of tert-butyl (S)-4-(4- (2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetyl)piperazin-l-yl)piperidine-l -carboxylate (262 mg, 402 pmol) in dichloromethane (4.5 mL) at room temperature. After Ih, the mixture was concentrated to give (S)-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-l-(4- (piperidin-4-yl)piperazin-l-yl)ethan-l-one hydrochloride (319 mg, 542 pmol) as a white solid. LCMS: [M+H]+: calculated, 552.2, observed, 552.3.
[00281] Using similar acidic deprotection conditions, the following compound was prepared:
[00282] Synthesis of tert-butyl (S)-2-(4-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6//- thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetyl)piperazin-l-yl)piperidin-l- yl)acetate: a mixture of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f\ [ 1 ,2,4]triazolo[4,3-cz] [ 1 ,4]diazepin-6-yl)- 1 -(4-(piperidin-4-yl)piperazin- 1 -yl)ethan- 1 -one hydrochloride (0.3 g, 510 pmol), tert-butyl 2-bromoacetate (106 mg, 543 pmol) and potassium carbonate (225 mg, 1.63 mmol) in acetonitrile (7.5 mL) was stirred at 40 °C for 12 h. The reaction was filtered, the filtrate was concentrated under reduced pressure to give tert-butyl (S)-2- (4-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin- 6-yl)acetyl)piperazin-l-yl)piperidin-l-yl)acetate (210 mg, 315 pmol) as a white solid, which was used in the following step without further purification. LCMS: [M+H]+: calculated, 666.3, observed, 666.5.
[00283] Using similar acidic deprotection conditions, the following compound were prepared:
[00284] Synthesis of (S)-2-(4-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- /][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetyl)piperazin-l-yl)piperidin-l-yl)acetic acid:
HCl/dioxane (1/1) (4M, 3 mL) was added to a solution of tert-butyl (S)-2-(4-(4-(2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetyl)piperazin-l-yl)piperidin-l-yl)acetate (210 mg, 315 pmol) in dichloromethane (2mL) at 0 °C, the resulting mixture was stirred at 25 °C for 12 h. The reaction was concentrated under reduced pressure to give a residue which was purified by preparative-HPLC (column:
Phenomenex luna C18 150*25mm* 10pm; mobile phase: [water(HCl)-ACN] ; B%: 10%-40%,14 min) and lyophilized to give (S)-2-(4-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2- /][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetyl)piperazin-l-yl)piperidin-l-yl)acetic acid (79.6 mg, 129 pmol) as a yellow gum. LCMS: [M+H]+: calculated, 610.2, observed, 610.2. 1H NMR (400 MHz, CD3OD) δ = 7.70-7.44 (m, 4H), 5.09 (br t, J = 6.4 Hz, 1H), 4.84-4.65 (m, 1H), 4.58- 4.36 (m, 1H), 4.18 (br s, 2H), 4.01-3.63 (m, 8H), 3.39-3.32 (m, 2H), 3.31-3.25 (m, 3H), 2.94 (s, 3H), 2.64-2.46 (m, 5H), 2.40-2.18 (m, 2H), 1.73 (s, 3H).
[00285] Using similar acidic deprotection conditions, the following compound was prepared:
[00286] Synthesis of (S)-2-(4-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetyl)piperazin-l-yl)piperidin-l-yl)-N-((6-((l-(3,4- dichlorophenyl)-4,5-dihydro-l//-pyrazol-3-yl)amino)-2-methylpyrimidin-4- yl)methyl)acetamide (6): HATU (10.6 mg, 27.9 pmol) was added to a solution of (S)-2-(4-(4-(2- (4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetyl)piperazin-l-yl)piperidin-l-yl)acetic acid (17 mg, 27.9 pmol) in dimethylformamide (167 pL) at 0 °C. After 0.5 h, 6-(aminomethyl)-A-(l-(3,4-dichlorophenyl)-4,5-dihydro-lH- pyrazol-3-yl)-2-methylpyrimidin-4-amine hydrochloride (A-l) (11.9 mg, 1.1 eq., 30.6 pmol) DIE A (18 mg, 139 pmol) were added, then the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was purified by preparative- HPLC (column: YMC Triart C18 250*50mm*7pm; mobile phase: [water(FA)-ACN];B%: 18%- 48%,8min) and lyophilized to give (S)-2-(4-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetyl)piperazin-l-yl)piperidin-l-yl)-A-((6- ((l-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)amino)-2-methylpyrimidin-4- yl)methyl)acetamide (6) (6.42 mg, 6.74 pmol) as yellow solid. LCMS: [M+H]+: calculated, 942.3, observed, 942.3. 'H NMR (400 MHz, CD3OD) δ = 7.68 (s, 1H), 7.49-7.38 (m, 4H), 7.35 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 2.4, 8.8 Hz, 1H), 4.69 (t, J= 6.8 Hz, 1H), 4.45 (s, 2H), 3.80-3.68 (m, 4H), 3.68-3.52 (m, 4H), 3.21 (t, J = 9.6 Hz, 2H), 3.18-3.13 (m, 2H), 2.98 (d, 7 = 11.6 Hz, 2H), 2.74-2.64 (m, 5H), 2.63-2.54 (m, 2H), 2.52 (s, 3H), 2.45 (s, 3H), 2.31-2.23 (m, 1H), 2.17 (t, 7 = 10.8 Hz, 2H), 1.78 (d, 7 = 11.2 Hz, 2H), 1.70 (s, 3H), 1.67-1.56 (m, 2H).
[00287] Using an analogous procedure, the following compound was prepared:
(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6//-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-
6-yl)-2V-(2-(2-(2-(4-(4-(( l-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)amino)-6- methylpyrimidine-2-carbonyl)piperazin-l-yl)-2-oxoethoxy)ethoxy)ethyl)acetamide (8).
[00288] Synthesis of methyl 4-((l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3- yl)amino)-6-methylpyrimidine-2-carboxylate: Pd(dppf)C12 (103 mg, 140 pmol) and triethylamine (567 mg, 5.61 mmol) were added to a mixture of 2-chloro-/V-( I -(3,4- dichlorophenyl)-4,5-dihydro-lf/-pyrazol-3-yl)-6-methylpyrimidin-4-amine (A-22) (0.5 g, 1.4 mmol) in methanol (15 mL) in a pressure vessel. The vessel was degassed and purged 3 times with CO and the resulting mixture was stirred at 60 °C for 12 h under CO atmosphere (50 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash chromatography (SiO?, PE/EtOAc=3/l to 1/1) to give methyl 4-((l- (3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-6-methylpyrimidine-2-carboxylate (0.3 g, 789 pmol, 56% yield) as a brown solid. LCMS: [M+H]+: calculated, 380.1, observed, 379.9. 'H NMR (400 MHz, DMSO-rftf) δ = 10.69 (s, 1H), 7.80 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 2.4, 8.8 Hz, 1H), 3.87 (s, 3H), 3.72 (t, J = 9.6 Hz, 2H), 3.21 (t, J = 9.6 Hz, 2H), 2.54 (s, 3H).
[00289] Synthesis of 4-((l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3-yl)amino)-6- methylpyrimidine-2-carboxylic acid (A-23): lithium hydroxide (63 mg, 2.63 mmol) was added to a mixture of methyl 4-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-6- methylpyrimidine-2-carboxylate (0.2 g, 526 pmol) in a mixture of tetrahydrofuran (2 mL) and water (2 mL). After Ih at 25 °C, the reaction mixture was quenched by IN HC1 solution and extracted with EtOAc (10 mL x 3). The combined organic layers were concentrated under reduced pressure to give 4-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-6- methylpyrimidine-2-carboxylic acid (A-23) (150 mg, 410 pmol, 77.87% yield) as a brown solid. LCMS: [M+H]+: calculated, 366.1, observed, 366.0.
[00290] Synthesis of tert-butyl 4-(4-((l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3- yl)amino)-6-methylpyrimidine-2-carbonyl)piperazine-l-carboxylate: HATU (187 mg, 1.2 eq., 492 pmol) was added to a solution of 4-(( 1 -(3,4-dichlorophenyl)-4,5-dihydro-l //-pyrazol-3- yl)amino)-6-methylpyrimidine-2-carboxylic acid (150 mg, 410 pmol) in dimethylacetamide (3 mL) at 0 °C. After 0.5h at 0 °C, tert-butyl piperazine- 1 -carboxylate (91.5 mg, 492 pmol) and DIEA (212 mg, 4 eq., 1.64 mmol) were added, and the resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were concentrated under reduced pressure to give tert-butyl 4-(4- ((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-6-methylpyrimidine-2- carbonyl)piperazine-l -carboxylate (160 mg, 299 pmol, 73% yield) as a brown solid. LCMS: [M+H]+: calculated, 534.2, observed, 534.1.
[00291] Synthesis of (4-((l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3-yl)amino)-6- methylpyrimidin-2-yl)(piperazin-l-yl)methanone hydrochloride: hydrogen chloride (4M in dioxane, 0.5 mL, 2 mmol) was added to a mixture of tert-butyl 4-(4-((l-(3,4-dichlorophenyl)-4,5- dihydro-l H-pyrazo]-3-yl)amino)-6-methylpyrimidine-2-carbonyl)pi perazine- 1 -carboxylate (150 mg, 281 pmol) in dichloromethane (1 mL). After 0.5h at 25 °C, the reaction mixture was concentrated under reduced pressure to give (4-(( I -(3,4-dichlorophenyl)-4,5-dihydro- 1 H-pyrazol- 3-yl)amino)-6-methylpyrimidin-2-yl)(piperazin-l-yl)methanone hydrochloride (120 mg, 255 pmol) as a yellow solid, which was used directly in the next step. LCMS: [M+H]+: calculated, 434.1, observed, 434.1.
[00292] Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- /][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-A^-(2-(2-(2-(4-(4-((l-(3,4-dichlorophenyl)-4,5- dihydro-l//-pyrazol-3-yl)amino)-6-methylpyrimidine-2-carbonyl)piperazin-l-yl)-2- oxoethoxy)ethoxy)ethyl)acetamide (8): HATU (38.8 mg, 102 pmol) was added to a solution of (S)-2-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2-/][l,2,4]triazolo[4,3- cz][l,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)acetic acid (46.4 mg, 85 pmol) in dimethylacetamide (928 pL) at 0 °C. After 0.5 h at 0 °C, (4-((l-(3,4-dichlorophenyl)-4,5-dihydro- I H-pyrazo]-3-y 1 )am i no)-6-methy 1 pyri m idi n-2-y 1 )(pi perazi n- 1 -yl)methanone hydrochloride (40 mg, 85 pmol) and DIEA (54.9 mg, 425 pmol) were added. The reaction was allowed to warm to 25 °C and stirred for another 1 h. The reaction mixture was filtered, concentrated under reduced pressure to give a residue which was purified by Preparative-HPLC (CDOl-Phenomenex luna C18 150*25*10pm water(FA)-ACN, B%, 47-77, 10 min) and lyophilized to give (S)-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-A-(2-(2- (2-(4-(4-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-6-methylpyrimidine-2- carbonyl)piperazin-l-yl)-2-oxoethoxy)ethoxy)ethyl)acetamide (8) (6.75 mg, 6.46 pmol, 8% yield) as a yellow solid. LCMS: [M+H]+: calculated, 961.3, observed, 961.2. NMR (400 MHz, CD3OD) δ = 7.90-7.64 (m, 1H), 7.50-7.37 (m, 4H), 7.29 (s, 1H), 7.08 (s, 1H), 6.87 (s, 1H), 4.71-4.66 (m, 1H), 4.38-4.22 (m, 2H), 3.81-3.69 (m, 5H), 3.68-3.56 (m, 9H), 3.50-3.33 (m, 8H), 2.70-2.65 (m, 3H), 2.52 (s, 3H), 2.41 (d, J = 15.2 Hz, 3H), 1.78-1.56 (m, 3H).
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6//-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-
6-yl)-V-(2-(2-(2-(( l-((4-(( l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3-yl)amino)-6- methylpyrimidin-2-yl)methyl)pyrrolidin-3-yl)oxy)ethoxy)ethoxy)ethyl)acetamide (11)
[00293] Synthesis of benzyl 3-((2,2-dimethyl-4-oxo-3,8,ll-trioxa-5-azatridecan-13- yl)oxy)pyrrolidine-l-carboxylate: sodium hydride (542 mg, 13.6 mmol) was added to a solution of benzyl 3-hydroxypyrrolidine-l-carboxylate (2 g, 9.04 mmol) in tetrahydrofuran (20 mL) at 0 °C. After 0.5 h at 0 °C, tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (3.39 g, 10.8 mmol) was added and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 3), the combined organic layers were concentrated under reduced pressure to give a residue which was purified by reverse phase chromatography (Cis, 80 g; condition: H2O/CH3CN = 95:5 to 40:60, 0.1% FA) to give benzyl 3-((2,2-dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan-13-yl)oxy)pyrrolidine-l- carboxylate (1.5 g, 10.6 mmol, 37% yield) as a colorless oil. LCMS: [M+H]+: calculated, 453.3, observed, 453.3. 'H NMR (400 MHz, CDCI3) 8 = 7.51-7.30 (m, 5H), 5.35-4.85 (m, 3H), 4.12 (s, 1H), 3.73-3.48 (m, 14H), 3.33 (s, 2H), 2.24-1.84 (m, 2H), 1.46 (s, 9H).
[00294] Synthesis of tert-butyl (2-(2-(2-(pyrrolidin-3- yloxy)ethoxy)ethoxy)ethyl)carbamate: A mixture of benzyl 3-((2,2-dimethyl-4-oxo-3,8,l 1- trioxa-5-azatridecan-13-yl)oxy)pyrrolidine-l-carboxylate (0.5 g, 1.1 mmol) and palladium over charcoal (118 mg) in methanol (10 mL, 247 mmol) was stirred at 25 °C for 2 h under an hydrogen atmosphere (15 psi). The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give tert-butyl (2-(2-(2-(pyrrolidin-3- yloxy)ethoxy)ethoxy)ethyl)carbamate (340 mg, 1.07 mmol, 97% yield) as a colorless oil, which was used directly in the next step. LCMS: [M+H]+: calculated, 319.2, observed, 319.2.
[00295] Synthesis of 4-((l-(3,4-dichlorophenyl)-4,5-dihydro-LH-pyrazol-3-yl)amino)-6- methylpyrimidine-2-carbaldehyde (A-25): DIBAL (281 mg, 1.97 mmol) was added to a solution of methyl 4-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-6- methylpyrimidine-2-carboxylate (0.3 g, 789 pmol) in tetrahydrofuran (2.81 mL) -78 °C under N2 atmosphere, and the resulting mixture was stirred at -78 °C for 1 h. The reaction was diluted with H2O (10 mL), filtered, and the filtrate was extracted with ethyl acetate (15 mLx3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 4-((l-(3,4-dichlorophenyl)-4,5- dihydro-17/-pyrazol-3-yl)amino)-6-methylpyrimidine-2-carbaldehyde (A-25) (0.5 g, 657 pmol, 83% yield), which was used directly in the following step. LCMS: [M+H]+: calculated, 350.1, observed, 350.2.
[00296] Synthesis of tert-butyl (2-(2-(2-(( l-((4-(( l-(3,4-dichlorophenyl)-4,5-dihydro- 1H- pyrazol-3-yl)amino)-6-methylpyrimidin-2-yl)methyl)pyrrolidin-3- yl)oxy)ethoxy)ethoxy)ethyl)carbamate: acetic acid (3.6 pL, 62.8 pmol) was added to a mixture of 4-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-6-methylpyrimidine-2- carbaldehyde (A-25) (220 mg, 628 pmol) and tert-butyl (2-(2-(2-(pyrrolidin-3- yloxy)ethoxy)ethoxy)ethyl)carbamate (240 mg, 754 pmol) in methanol (4 mL) at 0 °C. After 0.5h at 0 °C, sodium cyanoborohydride (59.2 mg, 942 pmol) was added and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated under reduced pressure to give tert-butyl (2-(2-(2-((l-((4-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3-yl)amino)-6- methylpyrimidin-2-yl)methyl)pyrrolidin-3-yl)oxy)ethoxy)ethoxy)ethyl)carbamate (320 mg, 490 pmol, 79% yield) as a yellow solid, which was used in the following step without any further purification. LCMS: [M+H]+: calculated, 652.3, observed, 652.2.
[00297] Using an analogous procedure, the following compounds were prepared:
[00298] Synthesis of 2-((3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)pyrrolidin-l-yl)methyl)-A- (l-(3,4-dichlorophenyl)-4,5-dihydro-l//-pyrazol-3-yl)-6-methylpyrimidin-4-amine hydrochloride (A-26): hydrogen chloride (4M in dioxane, 1 mL, 4 mmol) was added to a solution of tert-butyl (2-(2-(2-((l-((4-((l-(3,4-dichlorophenyl)-4,5-dihydro-17/-pyrazol-3- yl)amino)-6-methylpyrimidin-2-yl)methyl)pyrrolidin-3-yl)oxy)ethoxy)ethoxy)ethyl)carbamate (0.2 g, 306 pmol) in dichloromethane (2 mL) and the reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by RP flash chromatography (HC1 condition) to give 2-((3-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)pyrrolidin- 1 -yl)methyl)- N-( 1 -(3 ,4-dichlorophenyl)-4,5-dihydro- 1 H- pyrazol-3-yl)-6-methylpyrimidin-4-amine hydrochloride (1/1) (A-26) (50 mg, 84.9 pmol, 28% yield) as a yellow solid. LCMS: [M+H]+: calculated, 552.2, observed, 552.2.
[00299] Using an analogous procedure, the following compounds were prepared:
[00300] Synthesis of 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- /][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-A^-(2-(2-(2-((l-((4-((l-(3,4-dichlorophenyl)-4,5- dihydro-l//-pyrazol-3-yl)amino)-6-methylpyrimidin-2-yl)methyl)pyrrolidin-3- yl)oxy)ethoxy)ethoxy)ethyl)acetamide (11): A mixture of 2-((3-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)pyrrolidin- 1 -yl)methyl)- N-( 1 -(3 ,4-dichlorophenyl)-4,5-dihydro- 1 H- pyrazol-3-yl)-6-methylpyrimidin-4-amine hydrochloride (1/1) (A-26) (42 mg, 71.3 pmol) and 2,5-dioxopyrrolidin-l-yl (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6Z/-thieno[3,2-
/][l,2,4]triazolo[4,3-cz][l,4]diazepin-6-yl)acetate (39.1 mg, 78.4 pmol) in dimethylacetamide (634 pL) was stirred at 25 °C for 1 h. after concentration under reduced pressure, the reaction mixture was purified by reverse phase chromatography (CD02-Waters Xbidge BEH C18 150*25*10pm, water(FA)-ACN, B%, 30-52, 10 min) and lyophilized to give 2-((S)-4-(4-chlorophenyl)-2,3,9- tri methyl -6H-thieno| 3, 2;/] [ 1 ,2,4]triazolo[4,3-cz] [ 1 ,4]diazepin-6-yl)-A-(2-(2-(2-(( 1 -((4-(( 1 -(3,4- dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)amino)-6-methylpyrimidin-2-yl)methyl)pyrrolidin- 3-yl)oxy)ethoxy)ethoxy)ethyl)acetamide formate salt (1/1) (11) (33.7 mg, 31.3 pmol, 44% yield) as a yellow solid. LCMS: [M+H]+: calculated, 934.3, observed, 934.2. 'H NMR (400 MHz, CD3OD) δ = 8.52 (s, IH), 7.65 (s, IH), 7.43-7.36 (m, 4H), 7.30 (d, 7 = 8.4 Hz, IH), 7.07-7.02 (m, IH), 6.84 (dd, 7 = 2.0, 9.2 Hz, IH), 4.61 (td, 7 = 5.6, 9.2 Hz, IH), 4.26 (s, IH), 4.20-4.03 (m, 2H), 3.73-3.54 (m, 13H), 3.47-3.40 (m, 3H), 3.29-3.25 (m, 4H), 3.20 (t, 7 = 9.6 Hz, 2H), 2.66 (s, 3H), 2.47 (s, 3H), 2.42 (s, 3H), 2.23-2.13 (m, IH), 2.13-2.04 (m, IH), 1.67 (s, 3H).
(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-
6-yl)-N-(2-(2-(2-(4-((4-((l-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)amino)-6- methylpyrimidin-2-yl)methyl)piperazin-l-yl)-2-oxoethoxy)ethoxy)ethyl)acetamide (9)
[00301] HATU (29.1 mg, 76.6 pmol) was added to a mixture of (S)-2-(2-(2-(2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)ethoxy)ethoxy)acetic acid (41.8 mg, 76.6 pmol) in dimethylacetamide (2.14 mL) at 0 °C. After 0.5 h at 0 °C, A-(l-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)-6-methyl-2- (piperazin-l-ylmethyl)pyrimidin-4-amine hydrochloride (1/1) (A-27) (50 mg, 76.6 pmol) and DIEA (49.5 mg, 383 pmol) were added. After Ih at 0 °C, the reaction mixture was concentrated under reduced pressure to give a residue which was purified by reverse phase chromatography (Cis, 80 g; condition: H2O/CH3CN = 95:5 to 40:60, 0.1% FA) to give (S)-2-(4-(4-chlorophenyl)- 2,3,9-trimethyl-6H-thieno[3,2-/][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-A-(2-(2-(2-(4-((4-((l- (3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-3-yl)amino)-6-methylpyrimidin-2- yl)methyl)piperazin-l-yl)-2-oxoethoxy)ethoxy)ethyl)acetamide (9) (14.5 mg, 13.8 pmol) as a yellow solid. LCMS: [M+H]+: calculated, 947.3, observed, 947.2. 'H NMR (400 MHz, CD3OD) 5 = 7.88 (s, 2H), 7.21 (s, IH), 7.10-6.96 (m, 5H), 6.90 (d, J = 8.8 Hz, IH), 6.64 (d, J = 2.5 Hz, IH), 6.43 (dd, J = 2.4, 8.8 Hz, IH), 4.26 (dd, 7= 5.2, 8.8 Hz, IH), 3.90 (s, 2H), 3.35 (s, 2H), 3.29-3.21 (m, 6H), 3.15-3.11 (m, IH), 3.09 (d, 7 = 6.0 Hz, IH), 3.07 (d, 7 = 2.8 Hz, IH), 2.99- 2.93 (m, 4H), 2.87-2.77 (m, 2H), 2.40-2.30 (m, 4H), 2.28 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H), 1.29 (s, 3H).
[00302] Using an analogous procedure, the following compound was prepared:
Biological Assays
Measurement of binding to ABL1 by FP
[00303] Compounds were titrated in 1 to 3-dilution in 100% DMSO and 50 nl of compound or DMSO were dispensed to a black Corning Low Volume 384-well plate (Cat #3820). A fluorescent probe was diluted in assay buffer (50 mM HEPES pH 7.5, lOmM MgCh, 0.05 mM TCEP, 0.01% CHAPS) and added to each well for a final concentration of 50 nM fluorescent probe. ABLlb[46-534, (D382N)] was diluted in assay buffer and added to all wells except positive control wells for a final concentration of 100 nM. 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 ICsos were determined by fitting the data based on a sigmoidal dose-response equation. Results are shown in Table 1.
Table 1 Measurement of binding to ABL1 by HTRF
[00304] Compounds were titrated in 1 to 3-dilution 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, lOmM MgCh, 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 of the fluorescent probe. ABLlb[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 ICsos were determined by fitting the data based on a sigmoidal dose -response equation. Results are shown in Table 2.
Table 2.
Measurement of binding to BRD4 by Alpha screen
[00305] Compounds are assessed for BRD4 binding in the BRD4 AlphaScreen Assay at Reaction Biology (Malvern, PA). Compounds are titrated 1:3 in 100% DMSO and dispensed to the reaction plate using acoustic technology (Echo550, Labcyte) containing His-BRD4[2-1362] in reaction buffer containing 50 mM HEPES pH 7.5, 100 mM NaCl, 0.05% CHAPS, 0.1% BSA. Histone H4 peptide (1-21) K5/8/12/16Ac-Biotin is prepared in reaction buffer and dispensed to the plate following the addition of compound, and the plate is incubated for 30 minutes at room temperature. Subsequently, 5X donor beads (Streptavidin- coated) in reaction buffer are added, followed by the addition of 5X acceptor beads (AlphaScreen Ni beads) in reaction buffer. The plate is incubated with gentle shaking in the dark for 60 minutes. The plate is read using the Alpha measurement in Enspire (Ex/EM=680/520-620 nm). Data is normalized to wells which contain only DMSO and IC50S are determined by fitting the data based on a sigmoidal doseresponse equation. Results are shown in Table 3.
Table 3.
Measurement of binding to ABL1 into cells by NanoBRET
[00306] To demonstrate binding of the compounds of the disclosure to AB LI in cells, the following assay is performed. 40 mL of HEK293 cell suspension at 20000 cells/mL were transfected with 2 pg of NanoLuc-ABLl plasmid. 100 pl of the cell suspension are plated per 96- well and cells were incubated over night at 37°C, 5% CO2. The next day, compounds are added in a 1 to 3-dilution 10-point dose curve followed by the addition of IpM Bodipy-tracer. The cells are incubated for 4h at 37°C at 5% CO2. To read out luciferase signal, NanoBret NanoGio substrate and Extracellular NanoLuc inhibitor (Promega) reagent are added to the wells and incubated for 2 min at room temperature. Donor and acceptor emission are read out at 480 nm and 610 nm, respectively. The mBret ratio was calculated using the formula [(Acceptorsample / Donorsample) - (AcceptorDMSO/DonorDMSO)] x 1000. Results are shown in Table 4.
Table 4.
Intact Mass Spectrometry: Measurement of compound-mediated phosphorylation ofBRD4 by ABL [00307] Compounds of the disclosure are plated in an Eppendorf LoBind 384-well plate (Cat # 951040589) for a final concentration of 1 pM in 1% DMSO. Recombinant BRD4 (residues 49- 460, BPS Bioscience Cat #31047) and Abl (residues 46-534, produced in-house) are diluted in assay buffer (50 mM HEPES, pH 7.4, 10 mM MgC12, 0.5 mM TCEP) and added to each well for a final concentration of 700 nM BRD4 and 300 nM Abl. The plate is 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 are 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 2pl of the reaction onto a Waters ACQUITY UPLC Protein BEH C4 column (300 A, 1.7 pm, 2.1 x 50 mm, Cat #186004495) held at 80°C. Samples are 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 is 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 are deconvoluted into intact mass using the MaxEntl 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. To assess phosphorylation, the measured mass of BRD4 after incubation with Abl+/- PHICS is compared to the mass of BRD4 alone. Quantification of the modification is performed using deconvoluted peak height. Each phosphorylation state is expressed as a percentage of the total BRD4 protein detected in the LCMS run. Results are shown in FIG. 1.
Crkll phosphorylation profile on nanopro to assess Abl cellular activity
[00308] On day 1, plate ASPC-1 cells in TC treated 96wp at 50k cells/well in 200 pl/well of RPMI + 10% FBS. On day 2, prepare 3X test compounds in RPMI + 10% FBS and add lOOpl/well then incubate for 4h (0.3% DMSO in media for negative control for 0.1% final in well). Prepare lysis buffer (3ml of MPER + 30pl PPI + lOpl DNAse). After 4h incubation, aspirate the media from the well and rinse them with lOOpl PBS then lyse with 20pl lysis buffer/well. Put on the shaker for 20min at room temperature, then aspirate up and down lOpl with a multichannel pipette 10 times and check under the microscope that cells are lysed. Prepare nanopro mix by mixing 176 pl of Premix G2 3-10 with 2 pl of each standard 4.8 and 7. Mix 12pl of the premix with 4pl of the lysis for each sample. Vortex then spin down the tubes before transferring to the Nanopro plate. Run the nanopro using total Crkll antibody (Abeam, ab45136) for detection. Identify the 4 peaks (around PI 4.8, 4.95, 5.1 and 5.4, main peaks being 4.95 and 5.4, 4.95 being identified by p-Crkll Y221 antibody as well) and export the area under the curve for each peak of each sample. The percentage area per peak can be plotted in graphpad prism as an a grouped/stacked bar graph. The PI score (average PI for the whole unphosphorylated/phosphorylated Crkll species) can be calculated: PI score = (4.8 x W%) + (4.95 x X%) + (5.1 x Y%) + (5.4 x Z%). PI score can then be plotted as bar graph in graphpad.
EQUIVALENTS AND SCOPE
[00309] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
[00310] Furthermore, 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. For example, 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. Where 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. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
[00311] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
[00312] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMS What is claimed is:
1. A compound of Formula (I):
(I), or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, - n is an integer selected from 0, 1, 2, 3, 4, and 5;
R2 is hydrogen, or substituted or unsubstituted alkyl;
R3 is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group;
A is -X'-X2-X3-X4-;
X1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
X2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
X3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
X4 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene;
L is a bond or a linker;
B is a targeting moiety or a detectable moiety; and each occurrence of RA 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 RA groups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
2. A compound of Formula (II):
(II), or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA, -SRA, -N(RA)2, -NO2, -CN, -SCN, -C(=O)RA, -C(=O)ORA, -OC(=O)RA, -C(=O)N(RA)2, -N(RA)C(=O)RA, -SO2RA, or -SO2N(RA)2; n is an integer selected from 0, 1, 2, 3, 4, and 5;
R2 is hydrogen, or substituted or unsubstituted alkyl;
R3 is hydrogen, substituted or unsubstituted alkyl, or nitrogen protecting group;
A is -X'-X2-X3-X4-;
X1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ;
X2 is a substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
X3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene ; X4 is a bond, substituted or unsubstituted heterocyclylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene;
L is a bond or a linker;
T is hydrogen, a nucleophilic group, an electrophilic group, a leaving group, or a click chemistry handle; and each occurrence of RA 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 RA groups are attached to the same atom to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
3. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
X1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene comprising -O- or -NRA-.
4. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
X1 is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, or substituted or unsubstituted hetero-Ci alkylene comprising -O- or -NRA-.
5. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein
X1 is a bond.
6. The compound of any one of the preceding claims, wherein X2 is substituted or unsubstituted phenylene, substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, substituted or unsubstituted pyrazinylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, or substituted or unsubstituted triazolylene.
7. The compound of any one of the preceding claims, wherein X2 is substituted or unsubstituted pyridinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted pyrimidinylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, or substituted or unsubstituted triazolylene.
8. The compound of any one of the preceding claims, wherein X2 is a substituted or unsubstituted pyrazolylene, or substituted or unsubstituted pyrimidinylene.
9. The compound of any one of the preceding claims, wherein X2 is
The compound of any one of the preceding claims, wherein X2 is
11. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
X3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted heteroalkylene.
12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted heteroalkylene comprising -O- or -NRA-.
13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
X3 is substituted or unsubstituted alkylene, or substituted or unsubstituted alkenylene.
14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
X3 is a bond, substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted ethenylene, or substituted or unsubstituted hetero Ci alkylene comprising -O- or -NRA-.
15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
X3 is substituted or unsubstituted methylene, substituted or unsubstituted ethylene, or substituted or unsubstituted ethenylene.
16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
X3 is unsubstituted methylene, methylene substituted with =O, unsubstituted ethylene, or unsubstituted ethenylene.
17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
X4 is a bond, or substituted or unsubstituted heterocyclylene.
18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
X4 is a bond, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene.
19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt
21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
R1 is substituted or unsubstituted alkyl, halogen, hydroxy, or -©-(substituted or unsubstituted alkyl).
22. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
R1 is chloro, methyl, fluoro, bromo, trifluoromethyl, or trifluoromethoxy.
23. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: is 3,4-dichlorophenyl, 3-methyl-4-chlorophenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 3-bromophenyl, 2-fluoro-5-chlorophenyl, 3,5-dichlorophenyl, 2,4- dichlorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-5-fluorophenyl, 2,5-dichlorophenyl, 2-fluoro- 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, or 2,3- dichlorophenyl.
24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
R2 is hydrogen or substituted or unsubstituted alkyl.
25. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
R2 is hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, or substituted or unsubstituted butyl.
26. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
R2 is hydrogen, methyl, 2-hydroxyethyl, 2-methoxy ethyl, sec -butyl, or isopropyl.
27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
R3 is hydrogen or substituted or unsubstituted methyl.
28. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is a chain of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous atoms.
29. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -N(RA)-, -O-, -S-, - C(=O)O-, -OC(=O)-, -C(=O)NRA-, -NRAC(=O)-, -C(=O)-, -NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2N(RA)-, or -NRAS(O)2-, or a combination thereof; and each occurrence of RA 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 a nitrogen protecting group.
30. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted heteroarylene, -N(RA)-, -O-, -C(=O)NRA-, -NRAC(=O)-, or -C(=O)-, or a combination thereof; ; and each occurrence of RA 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 a nitrogen protecting group.
31. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is substituted or unsubstituted alkylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted triazolylene,
-N(CH3)C(=O)-, -C(=O)-, or a combination thereof.
32. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is of formula: wherein:
Z1 is a bond, -O-, -N(RA)-, -C(=O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; Z2 is a bond, -N(RA)-, -NRAC(=O)-, -C(=O)-, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted alkylene;
Q is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene;
Q1 is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene;
Z3 is a bond, -C(=O)-, -O-, or -N(RA)-;
Z4 is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-30; and u is 0-30; provided that L comprises at least one atom.
33. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is of formula:
AZ’-zfyQ-z<Q-z3y wherein:
Z3 is a bond, -C(=O)-, -O-, or -N(RA)-;
Z4 is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.
34. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is of formula: wherein:
Z1 is a bond, -O-, -N(RA)-, -C(=O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
Z2 is a bond, -N(RA)-, -NRAC(=O)-, -C(=O)-, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted alkylene;
Q is a bond, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene;
Z3 is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-30; and u is 0-30; provided that L comprises at least one atom.
35. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is of formula: wherein:
Z3 is a bond, -C(=O)-, -O-, or -N(RA)-; t is 0-20; and u is 0-6; provided that L comprises at least one atom.
36. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is of formula:
37. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is of formula:
38. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is any one of formula L1-L60 and L161-L177:
39. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is of formula:
40. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is any one of formula L61-L241:
41. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is of formula:
42. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:
L is of formula:
43. The compound of any one of claims 1 and 3-42, wherein the compound of Formula (I) is of Formula (I-A):
(I-A), or a pharmaceutically acceptable salt thereof.
44. The compound of any one of claims 1 and 3-42, wherein the compound of Formula (I) is of Formula (I-B):
(I B) or a pharmaceutically acceptable salt thereof.
45. The compound of any one of claims 1 and 3-42, wherein the compound of Formula (I) is of Formula (I-B-l):
(I-B-l) or a pharmaceutically acceptable salt thereof.
46. The compound of any one of claims 1 and 3-42, wherein the compound of Formula (I) is of Formula (I-B-2):
(I-B-2) or a pharmaceutically acceptable salt thereof.
47. The compound of any one of claims 1 and 3-46, or a pharmaceutically acceptable salt thereof, wherein:
B is a targeting moiety.
48. The compound of any one of claims 1 and 3-46, or a pharmaceutically acceptable salt thereof, wherein:
B is a bioactive moiety.
49. The compound of any one of claims 1 and 3-46, or a pharmaceutically acceptable salt thereof, wherein:
B is a protein-binding moiety.
50. The compound of any one of claims 1, 3-46, and 49, or a pharmaceutically acceptable salt thereof, wherein:
B is a BTK-binding moiety, bromodomain and extra-terminal domain (BET)-binding moiety, BRD2-binding moiety, BRD3-binding moiety, BRD4-binding moiety, BRDT-binding moiety, a kinase -binding moiety, KRAS-binding moiety, TRIM24-binding moiety, CAII-binding moiety, or a phosphatase -binding moiety.
51. The compound of any one of claims 1, 3-46, and 48-50, or a pharmaceutically acceptable salt thereof, wherein B is of formula:
52. The compound of any one of claims 1 and 3-46, or a pharmaceutically acceptable salt thereof, wherein:
B is a dye.
53. The compound of any one of claims 1, 3-46, and 52, or a pharmaceutically acceptable salt thereof, wherein:
B is of formula:
54. The compound of claim 1, wherein the compound is selected from:
(2),
or a pharmaceutically acceptable salt thereof.
55. The compound of any one of claims 2-42, wherein the compound of Formula (II) is of Formula (II-A): or a pharmaceutically acceptable salt thereof.
56. The compound of any one of claims 2-42, wherein the compound of Formula (II) is of Formula (II-B):
(II-B) or a pharmaceutically acceptable salt thereof.
57. The compound of any one of claims 2-42, wherein the compound of Formula (II) is of Formula (II-B-1):
(II-B-1) or a pharmaceutically acceptable salt thereof.
58. The compound of any one of claims 2-42, wherein the compound of Formula (II) is of Formula (II-B-2):
(II-B-2) or a pharmaceutically acceptable salt thereof.
59. The compound of any of claims 2-42 and 55-58, or a pharmaceutically acceptable salt thereof, wherein:
T is hydrogen, a nucleophilic group, a leaving group, or a nitrogen protecting group.
60. The compound of any of claims 2-42 and 55-59, or a pharmaceutically acceptable salt thereof, wherein:
T is hydrogen, -ORA, -N3, -COORA, -C=CH, halogen, or a nitrogen protecting group.
61. The compound of claim 2, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
62. A pharmaceutical composition comprising a compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
63. A method of phosphorylating a target substrate, the method comprising administering a compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 62, to a mixture that comprises ABL1 and the target substrate.
64. The method of claim 63, wherein the compound causes phosphorylation of the target substrate at a rate or amount that is increased over the rate or amount of phosphorylation in the same mixture comprising the ABL1 and the target substrate but without the compound.
65. The method of claim 63 or 64, wherein the amount of phosphorylation is measured at a specified time.
66. A method of promoting the phosphorylation of a target substrate, the method comprising contacting the target substrate with a compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 62.
67. The method of claim 66, wherein the target substrate is a protein.
68. A method of modulating a protein kinase, the method comprising contacting the protein kinase with a compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 62.
69. The method of claim 68, wherein the protein kinase is ABL1.
70. The method of any of claims 63-69, wherein the phosphorylation or modulation is in a cell.
71. The method of any of claims 63-69, wherein the phosphorylation or modulation is in a biological sample.
72. The method of any of claims 63-71, wherein the target substrate is a kinase or a phosphatase.
73. The method of any of claims 63-72, wherein the target substrate is KRAS or mutant thereof, BRD4, BRD2, BRD3, BET, BRDT, CAII, TRIM24, or BTK.
74. A kit comprising a compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 62; and instructions for use.
PCT/US2025/013801 2024-02-02 2025-01-30 Bifunctional abl1-binding compounds and uses thereof Pending WO2025166015A2 (en)

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