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WO2024175999A2 - Dérivés de benzènesulfonamide et leurs utilisations - Google Patents

Dérivés de benzènesulfonamide et leurs utilisations Download PDF

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Publication number
WO2024175999A2
WO2024175999A2 PCT/IB2024/000099 IB2024000099W WO2024175999A2 WO 2024175999 A2 WO2024175999 A2 WO 2024175999A2 IB 2024000099 W IB2024000099 W IB 2024000099W WO 2024175999 A2 WO2024175999 A2 WO 2024175999A2
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WIPO (PCT)
Prior art keywords
substituted
compound
unsubstituted
polypeptide
protein
Prior art date
Application number
PCT/IB2024/000099
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English (en)
Other versions
WO2024175999A3 (fr
Inventor
Patrick T. GUNNING
Jeffrey O'meara
Siawash AHMAR
Graham L. SIMPSON
David Alexander ROSA
Ji Sung Park
Giles Albert Brown
Jeffrey David ST. DENIS
Original Assignee
Dunad Therapeutics Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Dunad Therapeutics Ltd. filed Critical Dunad Therapeutics Ltd.
Publication of WO2024175999A2 publication Critical patent/WO2024175999A2/fr
Publication of WO2024175999A3 publication Critical patent/WO2024175999A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/36—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/42—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • Protein binders such as covalent small molecule binder (e.g., inhibitors).
  • protein binders e.g., covalent small molecule binders (e.g., inhibitors of proteins) are considered to be useful in multiple applications, including therapeutics.
  • binders specifically the warhead group of such compounds, are susceptible to off-target (e.g., covalent) modification, such as before reaching a target protein.
  • a warhead group of such a binder covalently modifies a protein (e.g., an off-target protein) or is metabolized, such as via nucleophilic metabolism by glutathione (GSH), and is neutralized before it has a chance to (e.g., covalently) modify its target protein.
  • GSH glutathione
  • a warhead group that is more selective for a target protein and/or more stable to off-target (e.g., covalent) modification, such as modification via nucleophilic metabolism by glutathione (GSH), would help decrease off-target effects, such as resulting from covalent binding of the warhead to an off-target protein, and increase efficacy of (e.g., on-target effects of) covalent small molecule binders.
  • off-target e.g., covalent
  • protein binders e.g., covalent small molecule protein binders (e.g., inhibitors)
  • the protein binders provided herein comprise a warhead group.
  • the warhead group directs covalent and/or irreversible interaction with a (e.g., cysteine residue of a) protein (e.g., described herein, such as a target protein).
  • the warhead group directs covalent and/or irreversible interaction with a (e.g., cysteine residue of a) target protein and is stable to off-target (e.g., covalent) modification, such as modification via nucleophilic metabolism by glutathione (GSH).
  • GSH glutathione
  • the warhead group directs covalent and/or irreversible interaction of a (e.g., cysteine residue of a) protein (e.g., described herein, such as a target protein) to a position of the warhead group that is ortho or meta to a sulfur- containing group (e.g., sulfone, sulfide, sulfoxide, or the like).
  • a sulfur- containing group e.g., sulfone, sulfide, sulfoxide, or the like.
  • the protein does not covalently and/or irreversibly interact with the warhead group at a para-position.
  • the protein covalently and/or irreversibly interacts with the warhead group at either an ortho-position or a meta-position, such as a position of the warhead that is ortho or meta relative to the sulfur containing group.
  • the warhead comprises a blocking group (e.g., hydrogen, CN, NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or the like).
  • the blocking group is at a position of the warhead that is para relative to the sulfur-containing group.
  • the blocking group directs covalent and/or irreversible interaction of a (e.g., cysteine residue of a) protein (e.g., described herein) to a position of the warhead that is ortho or meta relative to the sulfur-containing group.
  • a compound provided herein does not substantially bind to glutathione (GSH).
  • GSH glutathione
  • a compound provided herein is stable.
  • a compound provided herein (or a warhead group thereof) is stable to GSH.
  • a warhead of a compound provided herein is stable (e.g., to metabolism by GSH).
  • a warhead of a compound provided herein is stable to GSH.
  • a compound provided herein (or a warhead group thereof) does not bind to GSH.
  • a warhead of a compound provided herein does not bind to GSH.
  • a compound provided herein has reduced reactivity with GSH.
  • a compound provided herein (or a warhead group thereof) forms covalent bond(s) with a polypeptide (e.g., a protein, such as Bruton’s tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), aurora kinase A (AURKA), proto- oncogene c-KIT (KIT), BMX non-receptor tyrosine kinase (BMX), transcriptional enhancer factor TEF (TEAD), Janus kinase 3 (JAK3), a KRAS protein or a mutant thereof (e.g., KRAS G12C, KRAS C118A, or KRAS G12C/C118A)) without substantially binding to GSH.
  • a polypeptide e.g., a protein, such as Bruton’s tyrosine kin
  • a compound provided herein forms covalent bond(s) with a sulfur atom of a cysteine residue of a target protein without substantially covalently binding to the sulfur-containing GSH.
  • a compound provided herein (or a warhead group thereof) is selective for a polypeptide, such as a (target) protein described herein, relative to GSH.
  • GSH has minimal to no reactivity with a compound described herein (or a warhead group thereof), such that GSH is unable to react with (e.g., a warhead of) a compound provided herein.
  • GSH has a binding affinity (e.g., Kd) with a compound described herein (or a warhead group thereof) of more than 0.1 ⁇ M (e.g., 1 pm, 10 pm, 100 pm, or 1000 pm or more). In some instances, GSH has a binding affinity (e.g., Kd) with a compound described herein (or a warhead group thereof) of more than 10 pm.
  • the compound (or a warhead group thereof) is selective for the polypeptide (e.g., a protein, such as Bruton’s tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), aurora kinase A (AURKA), proto- oncogene c-KIT (KIT), BMX non-receptor tyrosine kinase (BMX), transcriptional enhancer factor TEF (TEAD), Janus kinase 3 (JAK3), a KRAS protein or a mutant thereof (e.g., KRAS G12C, KRAS C118A, or KRAS G12C/C118A)).
  • a protein such as Bruton’s tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), aurora kinase A (AURKA), proto- oncogene
  • the compound (or a warhead group thereof) is selective for the polypeptide (e.g., a protein, such as Bruton’s tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), aurora kinase A (AURKA), proto-oncogene c-KIT (KIT), BMX non-receptor tyrosine kinase (BMX), transcriptional enhancer factor TEF (TEAD), Janus kinase 3 (JAK3), a KRAS protein or a mutant thereof (e.g., KRAS G12C, KRAS Cl 18A, or KRAS G12C/C118A)) relative to GSH.
  • a protein such as Bruton’s tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), aurora kinase A (AURKA), proto
  • the compound (or a warhead group thereof) is selective for (e.g., covalent) binding to the polypeptide relative to GSH. In some embodiments, the compound (or a warhead group thereof) is selective for the polypeptide relative to GSH at a ratio of at least 10: 1 (e.g., 20: 1 or more, 50: 1 or more, 100: 1 or more, 500: 1 or more, 1000: 1 or more). In some embodiments, the compound (or a warhead group thereof) is selective for the polypeptide relative to GSH at a ratio of about 10: 1 to about 100: 1.
  • the compound (or a warhead group thereof) is at least 2-fold (e.g., 2-fold or more, 5-fold or more, 10-fold or more, 25-fold or more) selective for the polypeptide relative to GSH.
  • the compound has an ICso for the polypeptide of at least 10 pM and a GSH half life of greater than about 10 minutes. In some embodiments, the compound has an ICso for the polypeptide of at least 1 ⁇ M and a GSH half life of greater than about 10 minutes. In some embodiments, the compound has an IC50 of at least 0.1 ⁇ M and a GSH half life of greater than about 100 minutes.
  • the compound (or a warhead group thereof) does not covalently bind with (e.g., the thiol of) GSH (e.g., at Y 2 or a position ortho or meta to Y 2 ). In some embodiments, the compound (or a warhead group thereof) does not covalently bind with (e.g., the thiol of) GSH.
  • a warhead group described herein is provided in Table A.
  • X 1 is absent or O
  • X is absent, O, or NR A ;
  • Q 1 is R x or L-G
  • Q 2 is L-G or Y 2 ;
  • Y 2 is a blocking group (e.g., a group that directs (e.g., covalent and/or irreversible) binding (of a cysteine residue) of a protein to a position other than Y 2 );
  • R x is substituted or unsubstituted alkyl or NR y R z ;
  • R A , R y , and R z are each independently hydrogen or substituted or unsubstituted alkyl
  • L is a linker
  • G is an organic residue; wherein one and only one of Q 1 or Q 2 is L-G.
  • Q 1 is not substituted or unsubstituted methoxy phenyl.
  • X 2 is absent, O, or NR A ;
  • R A is hydrogen or substituted or unsubstituted alkyl
  • Y 2 is a blocking group (e.g., a group that directs (e.g., covalent and/or irreversible) binding (of a cysteine residue) of a protein to a position other than Y 2 );
  • L is a linker
  • G is a protein-binding ligand (e.g., a radical of a compound that interacts with a protein or a mutant thereof, comprising one or more cyclic group wherein the one or more cyclic groups are individually linked by one or more linker).
  • a protein-binding ligand e.g., a radical of a compound that interacts with a protein or a mutant thereof, comprising one or more cyclic group wherein the one or more cyclic groups are individually linked by one or more linker.
  • G is or comprises a protein-binding ligand selected from a BTK-, EGFR-, FGFR-, AURKA-, TEAD-, JAK3- KRAS-, and BMX-binding ligand.
  • G is or comprises a BTK-binding ligand.
  • G is or comprises a EGFR-binding ligand.
  • G is or comprises a FGFR-binding ligand.
  • G is or comprises a AURKA-binding ligand.
  • G is or comprises a TEAD-binding ligand.
  • G is or comprises a JAK3-binding ligand.
  • G is or comprises KRAS-binding ligand.
  • G is or comprises a BMX-binding ligand.
  • X is absent, O, or NR A ;
  • R A is hydrogen or substituted or unsubstituted alkyl
  • Y is a blocking group (e.g., a group that directs (e.g., covalent and/or irreversible) binding (of a cysteine residue) of KRAS or a mutant thereof to a position other than Y 2 (e.g., a position ortho or meta to Y 2 ));
  • a blocking group e.g., a group that directs (e.g., covalent and/or irreversible) binding (of a cysteine residue) of KRAS or a mutant thereof to a position other than Y 2 (e.g., a position ortho or meta to Y 2 )
  • L is a linker
  • KRAS-binding ligand e.g., a radical of a compound that interacts with a KRAS protein or a mutant thereof (e.g., KRAS G12C, KRAS C118A, or KRAS G12C/C118A) (e.g., an (e.g., unsaturated) unsubstituted or substituted carbocycle or an (e.g., unsaturated) unsubstituted or substituted heterocycle)).
  • KRAS-binding ligand e.g., a radical of a compound that interacts with a KRAS protein or a mutant thereof (e.g., KRAS G12C, KRAS C118A, or KRAS G12C/C118A) (e.g., an (e.g., unsaturated) unsubstituted or substituted carbocycle or an (e.g., unsaturated) unsubstituted or substituted heterocycle)).
  • X is absent, O, or NR A ;
  • R A is hydrogen or substituted or unsubstituted alkyl
  • Y is a blocking group (e.g., a group that directs (e.g., covalent and/or irreversible) binding (of a cysteine residue) of JAK3 or a mutant thereof to a position other than Y 2 (e.g., a position ortho or meta to Y 2 ));
  • a blocking group e.g., a group that directs (e.g., covalent and/or irreversible) binding (of a cysteine residue) of JAK3 or a mutant thereof to a position other than Y 2 (e.g., a position ortho or meta to Y 2 )
  • L is a linker
  • G is a JAK3 -binding ligand (e.g., a radical of a compound that interacts with a JAK3 protein or a mutant thereof (e.g., an unsubstituted or substituted heterocycle)).
  • a JAK3 -binding ligand e.g., a radical of a compound that interacts with a JAK3 protein or a mutant thereof (e.g., an unsubstituted or substituted heterocycle)).
  • the JAK3-binding ligand is an unsubstituted or substituted pyrrolopyrimidine, an unsubstituted or substituted pyrrolopyridine, an unsubstituted or substituted pyrazolopyrimidine, an unsubstituted or substituted pyrazolopyridine, or an unsubstituted or substituted benzimidazole.
  • the JAK3-binding ligand is a pyrrolopyrimidine described herein, such as a 7H-pyrrolo[2,3-t/]pyrimidine described herein.
  • the JAK3 -binding ligand is a pyrrolopyridine described herein, such as a 1H- pyrrolo[2,3-b]pyridine described herein. In some embodiments, the JAK3-binding ligand is a pyrazolopyridine described herein, such as a pyrazolo[l,5-a]pyridine described herein.
  • X 2 is O. In some embodiments, at least one of X 1 or X 2 is O.
  • the compound e.g., covalently and/or irreversibly interacts with a protein or a mutant thereof (e.g., a cysteine residue of the protein or the mutant thereof) at a position other than Y 2 (e.g., a position ortho or meta to Y 2 ).
  • Y 2 is a group that directs (e.g., covalent and/or irreversible) binding (e.g., of a cysteine residue) of a protein (e.g., BTK, EGFR, FGFR, AURKA, BMX, TEAD, JAK3 KRAS) or a mutant thereof to a position other than Y 2 (e.g., a position ortho or meta to Y 2 ).
  • a protein e.g., BTK, EGFR, FGFR, AURKA, BMX, TEAD, JAK3 KRAS
  • Y 2 is not halo. In some embodiments, Y 2 is not fluoro.
  • Y 2 is hydrogen, CN, NO2, hydroxy, substituted or unsubstituted amino (e.g., -NR xa R ya -, where R xa is hydroxy or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo) and R ya is hydrogen or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo)), substituted or unsubstituted alkyl (e.g., fluoroalkyl), substituted or unsubstituted alkoxy (e.g., fluoroalkoxy), or substituted or unsubstituted heteroalkyl (e.g., alkylamine substituted with oxo and/or hydroxy)).
  • R xa is hydroxy or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo) and R ya is hydrogen or
  • Y 2 is hydrogen, CN, NO2, amino, hydroxy, substituted or unsubstituted alkoxy (e.g., methoxy), unsubstituted or substituted heteroalkyl (e.g., alkylamine or heteroalkyl substituted with oxo, such as Me2N(CO)O, MeNHCO-, Me2NCO-, and MeCONH-), unsubstituted alkyl (e.g., methyl), or substituted alkyl (e.g., alkyl substituted with hydroxy or amino (e.g., -NH2), alkyl substituted with oxo an amino (e.g., -C(O)NH2), alkyl substituted with hydroxy and oxo (e.g., -COOH), alkyl substituted with oxo and heterocyclyl (e.g., azetidinyl), alkyl substituted with halo (e.g., fluor
  • Y 2 is hydrogen, CN, NO2, or substituted alkyl (e.g., alkyl substituted with halo (e.g., fluoroalkyl (e.g., methyl substituted with one, two, or three fluoro))).
  • alkyl substituted with halo e.g., fluoroalkyl (e.g., methyl substituted with one, two, or three fluoro)
  • Y 2 is hydrogen, CN, NO2, or CF3.
  • Y 2 is CN, NO2, or CF3.
  • Y 2 is CN or NCh.
  • the compound e.g., covalently and/or irreversibly interacts with a protein or a mutant thereof (e.g., a cysteine residue of the protein or the mutant thereof) at a position other than Y 2 (e.g., a position ortho or meta to Y 2 ).
  • G comprises an optionally substituted cyclic group, optionally substituted with one or more L’-G’, wherein each L’ individually selected from a linker and is connected to another G’ .
  • G or G’ is a radical of a compound that interacts with a protein (e g., BTK, EGFR, FGFR, AURKA, BMX, TEAD, JAK3, KRAS) or a mutant thereof.
  • a protein e g., BTK, EGFR, FGFR, AURKA, BMX, TEAD, JAK3, KRAS
  • G or G’ is amino, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, alkoxy, or comprises one or more cyclic groups wherein the one or more cyclic groups are individually linked by one or more linker (e.g., L or L’).
  • G or G’ comprises one or more cyclic group wherein the one or more cyclic groups are individually linked by one or more linker (e.g., L or L’).
  • G or G’ comprises an optionally substituted cyclic group, optionally substituted with -(L’-G’)nL’-G’, wherein n is 0 to 4.
  • n 1 to 3.
  • G or G’ is or comprises an (e.g., unsaturated) unsubstituted or substituted carbocycle or an (e.g., unsaturated) unsubstituted or substituted heterocycle)).
  • G or G’ comprises a substituted or unsubstituted carbocycle.
  • G or G’ comprises a substituted or unsubstituted heterocycle. In some embodiments, G is a substituted heterocycle.
  • G or G’ comprises one or more (e.g., one, two, or three) nitrogen atoms (e.g., within its (e.g., fused) ring system).
  • G or G’ comprises one or more (e.g., fused) rings.
  • G or G’ is aromatic or partially aromatic.
  • G or G’ comprises one or more (e.g., one, two, or three) substituted or unsubstituted (e.g., fused) aromatic ring(s).
  • G or G’ comprises two or more substituted or unsubstituted aromatic or partially aromatic rings.
  • G or G’ comprises two or more substituted or unsubstituted aromatic or partially aromatic rings, each aromatic or partially aromatic ring independently being a carbocycle or a heterocycle.
  • G or G’ comprises one or more substituted or unsubstituted carbocycle and one or more substituted or unsubstitued heterocycle, each of the one or more substituted or unsubstituted carbocycle and the one or more substituted or unsubstitued heterocycle independently being linked (e.g., fused) to a substituted or unsubstituted carbocycle or a substituted or unsubstitued heterocycle by a bond.
  • G or G’ comprises two (or more) substituted or unsubstituted heteroaromatic rings, the heteroaromatic rings being linked (e.g., fused) by a bond, each heteroaromatic ring being aromatic or partially aromatic.
  • the heteroaromatic rings are selected from the group consisting of benzimidazole, indole, indolizine, pyridine, and pyridopyrimidinone (e.g., pyrido[2,3- d]pyrimidin-2(lH)-one).
  • G or G’ comprises two (or more) substituted or unsubstituted phenyl rings, the phenyl being linked by a bond.
  • G or G’ is or comprises a substituted or unsubsituted quinazoline, a substituted or unsubstituted tetrahydropyridopyrimidine (e.g., 5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidine), a substituted or unsubsituted quinoline, a substituted or unsubstituted pyridopyrazinone (e.g., pyrido[2,3-b]pyrazin-3(4H)-one), a substituted or unsubstituted benzimidazole, a substituted or unsubstituted pyrrolopyrimidine (e.g., a 7H- pyrrolo[2,3-t/]pyrimidine), a substituted or unsubstituted pyrazolopyridine (e.g., a pyrazolo[l,5- a]pyridine),
  • G or G’ is a substituted quinazoline, a substituted tetrahydropyridopyrimidine (e.g., 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine), a substituted quinoline, a substituted pyridopyrazinone (e.g., pyrido[2,3-b]pyrazin-3(4H)-one).
  • G is a substituted tetrahydropyridopyrimidine (e.g., 5,6,7,8-tetrahydropyrido[3,4- d]pyrimidine).
  • G or G’ has a structure shown in Table 1 A, Table IB, or Table 1C.
  • G or G’ is a substituted carbocycle. In some embodiments, G is a substituted phenyl. [0046] In some embodiments, G or G’ is a substituted heterocycle. In some embodiments, G or G’ is a substituted or unsubsituted quinazoline or a substituted pyrazolopyrimidine (e.g., 1H- pyrazolo[3,4-d]pyrimidine). In some embodiments, G or G’ is an unsubsituted quinazoline.
  • G is a substituted quinazoline or a substituted pyrazolopyrimidine (e.g., 1H- pyrazolo[3,4-d]pyrimidine).
  • G or G’ is a substituted pyridine.
  • G or G’ is a substituted pyrazole.
  • the linker (e.g., L or L’) is a bond, amino, substituted or unsubstituted alkyl(ene), substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl(ene), substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl.
  • the linker (e.g., L or L’) is amino, substituted or unsubstituted heteroalkyl(ene), or substituted or unsubstituted heterocyclyl.
  • the linker (e.g., L or L’) comprises substituted or unsubstituted C1-C6 alkylene. In some embodiments, the linker (e.g., L or L’) comprises substituted or unsubstituted C1-C6 heteroalkylene.
  • the linker (e.g., L or L’) comprises a carbonyl. In some embodiments, the linker (e.g., L or L’) comprises an ester. In some embodiments, the linker (e.g., L or L’) comprises a ketone. In some embodiments, the linker (e.g., L or L’) comprises an amide. [0050] In some embodiments, the linker (e.g., L or L’) comprises one or more N atom(s).
  • the linker (e.g., L or L’) is amino. In some embodiments, the linker (e.g., L or L’) is -NR 2 -, where R 2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl. In some embodiments, the linker (e.g., L or L’) is -NH- or -NCH3-.
  • the linker (e.g., L or L’) is substituted or unsubstituted alkylamine. In some embodiments, the linker (e.g., L or L’) comprises a C1-C6 alkylamine.
  • the linker (e.g., L or L’) is -NR 3 R 4 -, where R 3 is substituted or unsubstituted alkyl(ene), substituted or unsubstituted heteroalkyl(ene), substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocycyl and R 4 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl.
  • the linker (e.g., L or L’) is methylamine, ethylamine, propylamine, or butylamine.
  • the linker (e.g., L or L’) is methylamine, ethylamine, or propylamine.
  • L is - NH(heterocyclyl)-.
  • L is -NH(azetidinyl)-.
  • the linker (e.g., L or L’) is substituted or unsubstituted heterocyclyl.
  • the linker (e.g., L or L’) is -NR 5 R 6 -, where R 5 and R 6 are taken together to form a substituted or unsubstituted heterocyclyl.
  • L or L’ is substituted or unsubstituted piperazinyl or substituted or unsubstituted piperidinyl.
  • L is substituted or unsubstituted piperazinyl (e.g., piperazinyl substituted with methyl).
  • -NR 5 R 6 - is substituted or unsubstituted piperazinyl (e.g., piperazinyl substituted with methyl), substituted or unsubstituted piperidinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azepanyl, or diazepanyl (e.g., 1,4-diazepanyl).
  • piperazinyl e.g., piperazinyl substituted with methyl
  • piperazinyl substituted with methyl substituted or unsubstituted piperidinyl
  • substituted or unsubstituted azetidinyl substituted or unsubstituted pyrrolidinyl
  • diazepanyl e.g., 1,4-diazepanyl
  • -NR 5 R 6 - is substituted or unsubstituted piperidinyl or substituted or unsubstituted azetidinyl and -NR 7 - is -NH-, -NCH3-, -NC(O)CH3-, or -NCH2CH2OCH3-.
  • L or L’ is -NR 5 R 6 -C(O)- and -NR 5 R 6 - is unsubstituted 1,4-diazepanyl.
  • L or L’ is -C(O)NR 5 R 6 -NR 7 -, -NR 5 R 6 - is unsubstituted piperidinyl or unsubstituted pyrrolidinyl, and -NR 7 - is -NH-.
  • L or L’ is -NR 5 R 6 -CH2NR 7 C(O)-, -NR 5 R 6 - is unsubstituted pyrrolidinyl, and -NR 7 - is -NH-.
  • L or L’ is -NR 5 R 6 -CH2NR 7 - , -NR 5 R 6 - is unsubstituted azetidinyl or azepanyl, and -NR 7 - is -NH-.
  • L or L’ is -NR 5 R 6 -CH2NR 7 C(O)-, -NR 5 R 6 - is unsubstituted azetidinyl, and -NR 7 - is -NH-.
  • the linker (e.g., L or L’) comprises two N atom(s) (e.g., (substituted or unsubstituted) diaminoalkyl, (substituted or unsubstituted) diamino-cycloalkyl, (substituted or unsubstituted) amino-heterocyclyl (e.g., the heterocyclyl being nitrogen containing), (substituted or unsubstituted) heterocyclyl (e.g., containing 2 nitrogen atoms), the heterocyclyl being optionally fused or spirocyclic).
  • L or L’ is or comprises -C(O)-diaminoalkyl-, each amino group of the diaminoalkyl being independently unsubstituted or substituted, such as being substituted with methyl.
  • the linker (e.g., L or L’) comprises one or more (e.g., fused or spirocyclic) rings.
  • L or L’ is or comprises a spirocyclic ring, such as 1,7- diazaspiro[4.5]decane.
  • L or L’ is or comprises substituted or unsubstituted phenyl.
  • L or L’ is or comprises substituted phenyl, the phenyl being substituted with substitued halo, cyano, amino, alkylamino, heteroalkyl (e.g., substituted alkanolamine or substituted diaminoalkyl), -N-(substituted heterocyclyl), or substituted heterocyclyl, such as wherein the substituted heterocyclyl is piperidinyl or pyrrolidinyl substituted with amino or alkylamine.
  • L or L’ is -NH-(unsubstituted phenyl)-, -NH-(unsubstituted phenyl)-C(O)-, -NH-(substituted phenyl)-C(O)-, -NH-(unsubstituted phenyl)-C(O)NH-, or-NH- (substituted phenyl)-C(O)NH-.
  • the linker e.g., L or L’
  • the linker is a bond.
  • the compound is represented by a structure of Table 2A, Table
  • compositions comprising the compounds described herein, and methods for using said compounds for the treatment of diseases.
  • pharmaceutical compositions comprising the compounds provided herein.
  • pharmaceutical compositions that are at least partially stable to glutathione (GSH).
  • composition comprising a compound disclosed herein, or a salt, solvate, tautomer, or regioisomer thereof, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising a compound represented by a structure provided herein, such as the structure of Formula (A), Formula (I), Formula (I-A), Formula (I-B), or provided in Table 2A, Table 2B, Table 2C, or Table 2D.
  • a pharmaceutical composition comprising a compound represented by a structure provided herein, such as the structure of Formula (A), Formula (I), Formula (I-A), Formula (I-B), or provided in Table 2A, Table 2B, Table 2C, or Table 2D, wherein the compound is selective for a polypeptide (e.g., a protein) relative to glutathione (GSH).
  • a polypeptide e.g., a protein
  • GSH glutathione
  • a pharmaceutical composition that is (e.g., at least partially) stable to glutathione (GSH).
  • the pharmaceutical composition is (e.g., at least partially) stable to glutathione (GSH) in the presence of a polypeptide.
  • GSH glutathione
  • a pharmaceutical composition comprising a compound represented by a structure provided herein, such as the structure of Formula (A), Formula (I), Formula (I-A), Formula (I-B), or provided in Table 2A, Table 2B, Table 2C, or Table 2D, the compound having reduced reactivity with GSH.
  • methods of selectively modifying polypeptides in the presence of glutathione with the compounds provided herein comprising contacting the polypeptides with the compound.
  • a method of modifying e.g., attaching to and/or degrading a polypeptide with a compound, comprising contacting the polypeptide with a compound disclosed herein, or a salt, solvate, tautomer, or regioisomer thereof, to form a covalent bond with a sulfur atom of a cysteine residue of the polypeptide.
  • disclosed herein is a method of binding a compound to a polypeptide, comprising contacting the polypeptide with a compound disclosed herein, or a salt, solvate, tautomer, or regioisomer thereof.
  • a method of disrupting a polypeptide comprising contacting the polypeptide with a compound disclosed herein, or a salt, solvate, tautomer, or regioisomer thereof.
  • the compound contacts the polypeptide intracellularly (e.g., in an individual).
  • the present disclosure provides a KRAS protein or an active fragment thereof modified with a compound described herein, or a salt, solvate, tautomer, or regioisomer thereof, wherein the compound forms a covalent bond with a sulfur atom of a cysteine residue of the KRAS protein or an active fragment thereof (e.g., a polypeptide thereof).
  • the present disclosure provides a method of modifying (e.g., attaching to and/or degrading) KRAS protein or an active fragment thereof with a compound, comprising contacting the polypeptide with a compound described herein, or a salt, solvate, tautomer, or regioisomer thereof, to form a covalent bond with a sulfur atom of a cysteine residue of the KRAS protein or an active fragment thereof (e.g., polypeptide thereof).
  • a method of modifying (e.g., attaching to and/or degrading) KRAS protein or an active fragment thereof with a compound comprising contacting the polypeptide with a compound described herein, or a salt, solvate, tautomer, or regioisomer thereof, to form a covalent bond with a sulfur atom of a cysteine residue of the KRAS protein or an active fragment thereof (e.g., polypeptide thereof).
  • the present disclosure provides a method of binding a compound to KRAS protein or an active fragment thereof, comprising contacting the KRAS protein or an active fragment thereof (e.g., polypeptide thereof) with a compound described herein, or a salt or solvate or tautomer or regioisomer thereof.
  • the present disclosure provides a method of disrupting KRAS protein or an active fragment thereof (e.g., a function thereof), comprising contacting the KRAS protein or an active fragment thereof (e.g., polypeptide thereof) with a compound described herein, or a salt or solvate or tautomer or regioisomer thereof.
  • the compound contacts KRAS (or the mutant thereof) intracellularly (e.g., in an individual).
  • a method for (e.g., selectively) modifying a polypeptide e.g., a protein
  • a compound represented by a structure provided herein such as the structure of Formula (A) Formula (I), Formula (I- A), or Formula (I-B)
  • the method comprising contacting the polypeptide with the compound, the compound having reduced reactivity with glutathione (GSH).
  • a method for (e.g., selectively) modifying a polypeptide e.g., a protein
  • a compound represented by a structure provided herein such as the structure of Formula (A), Formula (I), Formula (I- A), or Formula (I-B)
  • the method comprising contacting the polypeptide with the compound (e.g., to form a covalent bond with (e.g., a sulfur atom of a cysteine residue of) the polypeptide) without the compound substantially covalently binding to GSH (e.g., as demonstrated by the lack of covalent binding of GSH to the compound).
  • a method for (e.g., selectively) modifying a polypeptide e.g., a protein
  • a compound represented by a structure provided herein such as the structure of Formula (A), Formula (I), Formula (I- A), or Formula (I-B)
  • the method comprising contacting the polypeptide with the compound, wherein the compound is selective for the polypeptide relative to GSH.
  • the polypeptide covalently binds to the compound (e.g., wherein the polypeptide comprises a thiol (e.g., a cysteine residue) that covalently binds to the compound).
  • the polypeptide contacts (e.g., covalently binds) the compound in the absence of covalent binding of GSH to the compound.
  • the polypeptide is a sulfur containing polypeptide, such as a cysteine containing polypeptide.
  • the polypeptide is Bruton’s tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), aurora kinase A (AURKA), proto-oncogene c-KIT (KIT), BMX non-receptor tyrosine kinase (BMX), transcriptional enhancer factor TEF (TEAD), Janus kinase 3 (JAK3), KRAS, or a mutant thereof (e.g., KRAS G12C, KRAS C118A, or KRAS G12C/C118A).
  • BTK tyrosine kinase
  • EGFR epidermal growth factor receptor
  • FGFR fibroblast growth factor receptor
  • AURKA aurora kinase A
  • KIT proto-oncogene c-KIT
  • the method further comprises inhibiting, deactivating, or degrading the polypeptide.
  • FIG. 1A illustrates an example of a warhead portion, a linker portion, and a protein- binding ligand portion of a compound provided herein.
  • FIG. IB illustrates an example of a warhead portion, a linker portion, and a KRAS- binding ligand portion of a compound provided herein.
  • FIG. 1C illustrates an example of a warhead portion, a linker portion, and a JAK3- binding ligand portion of a compound provided herein.
  • FIG. 2 shows the amino acid sequence of KRAS G12C.
  • FIG. 3 shows the amino acid sequence of KRAS G12C Commercial.
  • FIG. 4 shows the amino acid sequence of KRAS G12C Lite.
  • FIG. 5 shows an exemplary warhead reaction progress curve used to calculate 50% warhead reaction (WRso) values, as described herein.
  • ⁇ when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. In some embodiments, about is within 10% of the stated number or numerical range. In some embodiments, about is within 5% of the stated number or numerical range. In some embodiments, about is within 1% of the stated number or numerical range.
  • KRAS protein refers to a wild-type KRAS protein or a mutant thereof.
  • KRAS-binding ligand refers to a ligand binding to a KRAS protein or a mutant thereof, for example KRAS G12C, KRAS C118A, or KRAS G12C/C118A.
  • Amino refers to the -NH2 moiety.
  • Niro refers to the -NO2 radical.
  • Alkyl generally refers to a non-aromatic straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, partially or fully saturated, cyclic or acyclic, having from one to fifteen carbon atoms (e.g., C1-C14 alkyl). Unless otherwise state, alkyl is saturated or unsaturated (e.g., an alkenyl, which comprises at least one carbon-carbon double bond). Disclosures provided herein of an “alkyl” are intended to include independent recitations of a saturated “alkyl,” unless otherwise stated.
  • Alkyl groups described herein are generally monovalent, but may also be divalent (which may also be described herein as “alkylene” or “alkylenyl” groups).
  • an alkyl comprises one to thirteen carbon atoms (e.g., C1-C12 alkyl).
  • an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl).
  • an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl).
  • an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl).
  • an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl).
  • an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1 -propyl (//-propyl), 1 -methylethyl (/.w-propyl), 1 -butyl (//-butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (/.w-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (//-pentyl).
  • the alkyl is attached to the rest of the molecule by a single bond.
  • alkyl groups are each independently substituted or unsubstituted.
  • an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)C(O)C(O)OR a
  • an alkyl includes alkenyl, alkynyl, cycloalkyl, carbocycloalkyl, cycloalkylalkyl, haloalkyl, and fluoroalkyl, as defined herein.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (z.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -OC(O)- N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2),
  • Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ⁇ -butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene comprises one to eight carbon atoms (e.g., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene).
  • an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene).
  • an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SIU, -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , - N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is as defined above. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted, as defined above for an alkyl group.
  • Alkoxyalkyl refers to an alkyl moiety comprising at least one alkoxy substituent, where alkyl is as defined above. Unless stated otherwise specifically in the specification, an alkoxyalkyl group is optionally substituted, as defined above for an alkyl group.
  • Alkylamino refers to a moiety of the formula -NHR a or -NR a R b where R a and R b are each independently an alkyl group as defined above. Unless stated otherwise specifically in the specification, an alkylamino group is optionally substituted, as defined above for an alkyl group.
  • Alkylaminoalkyl refers to an alkyl moiety comprising at least one alkylamino substituent. The alkylamino substituent can be on a tertiary, secondary or primary carbon. Unless stated otherwise specifically in the specification, an alkylaminoalkyl group is optionally substituted, as defined above for an alkyl group.
  • aminoalkyl refers to an alkyl moiety comprising at least one amino substituent.
  • the amino substituent can be on a tertiary, secondary or primary carbon.
  • an aminoalkyl group is optionally substituted, as defined above for an alkyl group.
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-OR a , -R
  • Arylene refers to a divalent aryl group which links one part of the molecule to another part of the molecule. Unless stated specifically otherwise, an arylene is optionally substituted, as defined above for an aryl group.
  • Aralkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • carbocycle refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic group from a “heterocycle” or “heterocyclic” in which the ring backbone contains at least one atom which is different from carbon.
  • carbocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds.
  • Carbocycle includes aromatic and partially or fully saturated ring systems.
  • carbocycle comprises cycloalkyl and aryl.
  • a carboxycle provided herein is optionally substituted (e.g., carbocycle substituted with one or more carbocycle substitutent, each carbocycle substituent being independently selected from the group consisting of alkyl, oxo, halo, hydroxyl, heteroalkyl, alkoxy, aryl, and heteroaryl).
  • a heterocycle provided herein is optionally substituted (e.g., heterocycle substituted with one or more heterocycle substitutent, each heterocycle substituent being independently selected from the group consisting of alkyl, oxo, halo, hydroxyl, heteroalkyl, alkoxy, aryl, and heteroaryl).
  • Cyclic ring refers to a carbocycle or heterocycle, including aromatic, non- saturated, and saturated carbocycle and heterocycle.
  • a “cyclic ring” is optionally monocyclic or polycyclic (e.g., bicyclic).
  • Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms.
  • the cycloalkyl is attached to the rest of the molecule by a single bond.
  • Cycloalkyl is saturated (z.e., containing single C-C bonds only) or unsaturated (z.e., containing one or more double bonds or triple bonds).
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated cycloalkyl is also referred to as "cycloalkenyl.”
  • Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, norbomyl (z.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • cycloalkyl is meant to include cycloalkyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-OR a , -R
  • Cycloalkylalkyl refers to a radical of the formula -R c -cycloalkyl where R c is an alkylene chain as defined above. The alkylene chain and the cycloalkyl radical is optionally substituted as defined above.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo substituents.
  • a “haloalkyl” refers to an alkyl radical, as described herein, that is substituted with one or more halo radical, such as described above.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
  • heteroalkyl refers to an alkyl group as defined above in which one or more skeletal carbon atoms of the alkyl are substituted with a heteroatom (with the appropriate number of substituents or valencies - for example, -CH2- may be replaced with -NH- or -O-).
  • each substituted carbon atom is independently substituted with a heteroatom, such as wherein the carbon is substituted with a nitrogen, oxygen, sulfur, or other suitable heteroatom.
  • each substituted carbon atom is independently substituted for an oxygen, nitrogen (e.g.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a Ci -Ci 8 heteroalkyl. In some embodiments, a heteroalkyl is a C1-C12 heteroalkyl.
  • a heteroalkyl is a C1-C6 heteroalkyl. In some embodiments, a heteroalkyl is a Ci- C4 heteroalkyl. In some embodiments, heteroalkyl includes alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, heterocyclyl, and heterocycloalkylalkyl, as defined herein. Unless stated otherwise specifically in the specification, heteroalkyl does not include alkoxy as defined herein. Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted as defined above for an alkyl group.
  • Heteroalkylene refers to a divalent heteroalkyl group defined above which links one part of the molecule to another part of the molecule. Unless stated specifically otherwise, a heteroalkylene is optionally substituted, as defined above for an alkyl group.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) that includes at least one heteroatom selected from nitrogen, oxygen and sulfur, wherein each heterocyclic group has from 3 to 12 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
  • heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds.
  • Non-aromatic heterocyclic groups include rings having 3 to 12 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 12 atoms in its ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • the foregoing groups are either C-attached (or C-linked) or TV-attached where such is possible.
  • a group derived from pyrrole includes both pyrrol-l-yl (TV-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both TV-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • the heterocyclic groups include benzo-fused ring systems.
  • Heterocycle includes aromatic and partially or fully saturated ring systems. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.
  • Heterocycloalkyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated.
  • heterocycloalkyl is attached to the rest of the molecule through any atom of the ring(s).
  • heterocycloalkyl comprises 2-12 C atoms, 0-6 N atoms, 0-4 O atoms, and 0-4 S atoms.
  • heterocycloalkyl comprises 2-10 C atoms, 0-4 N atoms, 0-2 O atoms, and 0-2 S atoms.
  • heterocycloalkyl comprises 2-8 C atoms, 0-3 N atoms, 0-1 0 atoms, and 0-1 S atoms.
  • heterocycloalkyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic, or 13-16 membered polycyclic (e.g., tricyclic or tetracyclic) ring system having 1, 2, 3, or 4 heteroatom ring members each independently selected from N, O, and S.
  • heterocycloalkyl comprises 1 or 2 heteroatom ring members each independently selected from N, O, and S.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-
  • heterocycloalkyl is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -0R a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R
  • /'/-heterocycloalkyl or “TV-attached heterocycloalkyl” refers to a heterocycloalkyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a nitrogen atom in the heterocycloalkyl radical.
  • An A -heterocycloalkyl radical is optionally substituted as described above for heterocycloalkyl radicals.
  • A-heterocycloalkyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
  • C-heterocycloalkyl or “C-attached heterocycloalkyl” refers to a heterocycloalkyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a carbon atom in the heterocycloalkyl radical.
  • a C-heterocycloalkyl radical is optionally substituted as described above for heterocycloalkyl radicals. Examples of such C-heterocycloalkyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.
  • Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3 -benzodi oxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothieny
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -0R a , -R b -0C(0)-R a , -R b -0C(0)-R a , -R b -0
  • Heteroarylene refers to a divalent heteroaryl group which links one part of the molecule to another part of the molecule. Unless stated specifically otherwise, a heteroarylene is optionally substituted, as defined above for a heteroaryl group.
  • optionally substituted groups are each independently substituted or unsubstituted.
  • a substituted group provided herein is substituted by one or more substituent, each substituent being independently selected from the group consisting of halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , - N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where
  • the compounds disclosed herein in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
  • geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Exemplary pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A,A-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et
  • solvates refers to a composition of matter that is the solvent addition form.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms.
  • the term “individual,” “subject,” or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non- human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • treatment or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder.
  • compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • binders e.g., a (e.g., covalent) small molecule inhibitor.
  • binders e.g., covalent small molecule binders (e.g., inhibitors) of proteins
  • Covalent binding (e.g., inhibition) of a target protein may minimize the required systemic drug exposure.
  • protein (e.g., functional) activity can only be restored by de novo protein synthesis, resulting in a prolonged therapeutic effect long after the compound is cleared from the blood.
  • an electrophilic moiety on the protein binder e.g., inhibitor
  • the ability to form a covalent bond with the target enzyme has raised concerns about indiscriminate reactivity with off-target proteins, even though some of the most prescribed drugs are covalent irreversible binders.
  • binders e.g., to form covalent small molecule binders (e.g., inhibitors).
  • a protein binder such as a covalent small molecule binder (e.g., inhibitor).
  • a covalent small molecule protein binder which acts functionally as a protein.
  • a covalent small molecule binder which acts functionally as an inhibitor.
  • the warhead group directs covalent and/or irreversible interaction with a (e.g., cysteine residue of a) protein (e.g., described herein). In some embodiments, the warhead group directs covalent and/or irreversible interaction of a (e.g., cysteine residue of a) protein (e.g., described herein) to a position of the warhead group that is ortho or meta to a sulfur-containing group (e.g., sulfone, sulfide, sulfoxide, or the like). In some embodiments, the protein does not covalently and/or irreversibly interact with the warhead group at a para-position.
  • a sulfur-containing group e.g., sulfone, sulfide, sulfoxide, or the like.
  • the protein covalently and/or irreversibly interacts with the warhead group at either an ortho-position or a meta-position, such as a position of the warhead that is ortho or meta relative to the sulfur containing group.
  • the warhead comprises a blocking group (e.g., hydrogen, CN, NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or the like).
  • the blocking group is at a position of the warhead that is para relative to the sulfur-containing group.
  • the blocking group directs covalent and/or irreversible interaction of a (e.g., cysteine residue of a) protein (e.g., described herein) at a position of the warhead that is ortho or meta relative to the sulfur-containing group.
  • a pharmaceutical composition comprising a protein binder (e.g., a covalent small molecule binder (e.g., inhibitor) and one or more pharmaceutically acceptable excipients.
  • a protein binder e.g., covalent small molecule binder (e.g., inhibitor)
  • a protein binder e.g., covalent small molecule binder (e.g., inhibitor)
  • a protein binder e.g., covalent small molecule binder (e.g., inhibitor)
  • a protein binder provided herein such as a covalent small molecule binder (e.g., inhibitor) is a benzenesulfonamide derivative compound.
  • a benzenesulfonamide derivative compound as described herein is used to treat or prevent a disease or condition in a subject in need thereof.
  • a protein binder provided herein such as any compound provided herein, such as a compound of Table 1A, Table IB, or Table 1C, binds to, (e.g., covalently) interacts with, modulates (e.g., inhibits), destabilizes, imparts a conformational change, (functionally) disrupts a protein described herein, such as, for example, epidermal growth factor receptor (EGFR), Bruton’s tyrosine kinase (BTK), Fibroblast Growth Factor Receptor (FGFR) (e.g., FGFR4), Aurora kinase A (AURKA), tyrosine-protein kinase KIT (KIT), Cytoplasmic tyrosine-protein kinase (BMX)), transcriptional enhancer factor TEF (TEAD), Janus kinase 3 (JAK3), KRAS, or a mutant thereof (e.g., by interacting with EGFR
  • BTK
  • a protein binder provided herein binds to BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof (e.g., by interacting with the protein at a position of a warhead (e.g., of the compound) that is ortho or meta relative to a sulfur- containing group (e.g., of the compound)).
  • a protein binder provided herein interacts with BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof (e.g., by interacting with the protein at a position of a warhead (e.g., of the compound) that is ortho or meta relative to a sulfur-containing group (e.g., of the compound)).
  • a protein binder provided herein covalently interacts with BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof.
  • a protein binder provided herein modulates BTK, EGFR, FGFR, AURKA, KIT BMX, TEAD, JAK3, KRAS, or a mutant thereof (e.g., by interacting with the protein at a position of a warhead (e.g., of the compound) that is ortho or meta relative to a sulfur-containing group (e.g., of the compound)).
  • a protein binder provided herein inhibits BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof (e.g., by interacting with the protein at a position of a warhead (e.g., of the compound) that is ortho or meta relative to a sulfur- containing group (e.g., of the compound)).
  • a protein binder provided herein destabilizes BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a muta’t the’eof (e.g., by interacting with the protein at a position of a warhead (e.g., of the compound) that is ortho or meta relative to a sulfur-containing group (e.g., of the compound)).
  • a protein binder provided herein imparts a conformational change to BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof (e.g., by interacting with the protein at a position of a warhead (e.g., of the compound) that is ortho or meta relative to a sulfur-containing group (e.g., of the compound)).
  • a protein binder provided herein disrupts BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof (e g., by interacting with the protein at a position of a warhead (e.g., of the compound) that is ortho or meta relative to a sulfur-containing group (e.g., of the compound)).
  • a protein binder provided herein functionally disrupts BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof (e.g., by interacting with the protein at a position of a warhead (e.g., of the compound) that is ortho or meta relative to a sulfur-containing group (e.g., of the compound)).
  • an inhibitor is a protein binder that degrades and/or disrupts the functionality of a protein described herein, such as BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof (e.g., by interacting with the protein at a position of a warhead (e.g., of the compound) that is ortho or meta relative to a sulfur-containing group (e.g., of the compound)).
  • a protein binder that degrades and/or disrupts the functionality of a protein described herein, such as BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof (e.g., by interacting with the protein at a position of a warhead (e.g., of the compound) that is ortho or meta relative to a sulfur-containing group (e.g., of the compound)).
  • a warhead e.g., of
  • a compound provided herein interacts with the protein at a position of a warhead (e.g., of the compound) that is ortho or meta relative to a sulfur-containing group (e.g., of the compound).
  • a compound provided herein is an irreversible binder (e.g., inhibitor).
  • mass spectrometry, enzyme kinetics, discontinuous exposure (e.g., jump dilution), or any combination thereof are used to determine the amount a compound modifies a target protein.
  • mass spectrometry e.g., of the protein drug target modified (e g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof) in the presence of a compound provided herein
  • mass spectrometry e.g., of the protein drug target modified (e g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof) in the presence of a compound provided herein
  • a compound is an irreversible binder (e.g., inhibitor).
  • a protein e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof
  • modulated e.g., inhibited
  • mass spectral analysis e.g., to assess the formation of permanent, irreversible covalent adducts.
  • analytical methods to examine peptide fragments include, but are not limited to mass spectroscopy.
  • a protein e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof
  • mass spectroscopy e.g., mass spectroscopy.
  • such methods identify permanent, irreversible covalent protein adducts (e.g., by observing a mass peak that corresponds to the mass of a control sample plus the mass of an irreversible adduct).
  • binding of a protein described herein leads to functional inhibition of the protein target (e.g., in a cellular environment).
  • a compound provided herein modifies (e.g., covalently) a polypeptide (e.g., a protein) (e.g., intracellularly) (e.g., wherein the selectivity is for a sulfur-containing nucleophile of the protein over other (e.g., intracellular) sulfur-containing nucleophiles (e.g., in a biological system)).
  • a polypeptide e.g., a protein
  • intracellularly e.g., wherein the selectivity is for a sulfur-containing nucleophile of the protein over other (e.g., intracellular) sulfur-containing nucleophiles (e.g., in a biological system)
  • the compound contacts the polypeptide intracellularly (e.g., in an individual).
  • a measure of (e.g., GSH or protein) modification is relative (e.g., GSH or protein) modification over a period of time.
  • a measure of (e.g., GSH or protein) modification is relative (e.g., GSH or protein) modification over a period of time of at least 0.5 minutes (e.g., at least 1 minutes, at least 5 minutes, at least 10 minutes, at least 30 minutes).
  • a measure of (e.g., GSH or protein) modification is relative (e.g., GSH or protein) modification over a period of time of at most 200 minutes (e.g., at most 150 minutes, at most 100 minutes, at most 50 minutes).
  • the relative (e.g., GSH or protein) modification over a period of time is measured using a method described herein, such as a GSH or GST assay described in Example IV1.
  • a compound provided herein comprises a group (e.g., a warhead) that irreversibly or covalently binds to a protein (e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof).
  • a protein e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof.
  • a warhead provided herein is a functional group that covalently binds (e.g., at a position ortho or meta of the warhead that is ortho or meta to a sulfur-containing group of the compound) to an amino acid residue (such as cysteine, lysine, histidine, or other residues capable of being covalently modified), present in or near the binding pocket of a target protein (e g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof).
  • a target protein e g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof.
  • a warhead provided herein irreversibly inhibits BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof.
  • a warhead provided herein covalently and irreversibly inhibits BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof either alone or in combination with L (e.g., warhead-L-).
  • a compound provided herein is selective for a KRAS protein or a mutant thereof, e.g., selective for KRAS G12C, KRAS C118A, or KRAS G12C/C118A.
  • small molecule binders e.g., inhibitors
  • KRAS protein a.k.a., K-Ras
  • KRAS G12C a mutant thereof
  • pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases such as cancers.
  • provided herein is a compound that interacts with KRAS or a mutant thereof at a position other than Y 2 .
  • a compound provided herein irreversibly and covalent modifies KRAS G12C at cysteine-12 and/or cysteine-118 in the full-length protein.
  • a compound provided herein interacts with a protein as described in the Examples, such as shown in Tables 3-10F.
  • a compound e.g., of Formula (A), Formula (I), Formula (LA), or Formula (I-B)
  • the compound e.g., of Formula (A), Formula (I), Formula (LA), or Formula (I-B)
  • the warhead is the part of the compound identified with a box around it in FIG. 1 A, FIG. IB, or FIB. 1C.
  • the warhead comprises a para-activating group, such as a para- activating group that directs binding to, disruption of, and/or modification of a protein (e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof) either alone or in combination with the linker (e.g., L or L’).
  • a para-activating group such as a para- activating group that directs binding to, disruption of, and/or modification of a protein (e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof) either alone or in combination with the linker (e.g., L or L’).
  • a compound e.g., of Formula (A), Formula (I), Formula (I-A), or Formula (I-B)
  • the compound e.g., of Formula (A), Formula (I), Formula (I-A), or Formula (I-B)
  • comprises a protein-binding ligand e.g., G or G’
  • the protein-binding ligand e.g., G or G’
  • the protein-binding ligand e.g., G or G’
  • the protein-binding ligand is the part of the compound identified with a box around it in FIG. 1 A, FIG. IB, or FIB. 1C.
  • a compound of any one of the formulas provided herein such as Formula (A), Formula (I), Formula (I-A), or Formula (I-B) has a G or G’ as described in any of the compounds of Table 2A, Table 2B, Table 2C, or Table 2D.
  • a compound of any one of the formulas e.g., Formula (A), Formula (I), Formula (I-A), or Formula (I-B)
  • a compound of any one of the formulas e.g., Formula (A), Formula (I), Formula (I-A), or Formula (I-B)
  • a protein-binding ligand provided herein binds to, disrupts, and/or modifies a protein (e.g, BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof) either alone or in combination with a warhead radical provided herein and/or a linker (e.g, L or L’) provided herein.
  • a protein e.g, BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof
  • a linker e.g, L or L’
  • a protein-binding ligand provided herein has activity such that a compound provided herein binds to, disrupts, and/or modifies a protein (e g, BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof) at a concentration of about 10 mM or less (e.g, 500 uM or less, 100 uM or less, or 10 uM or less).
  • a protein e.g, BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof
  • a protein binding ligand provided herein has activity such that a compound provided herein has Ki to a protein (e.g, BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof) of about 250 uM or less (e.g, about 50 uM or less or about 1 uM or less).
  • a protein e.g, BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof
  • the linker (e.g, L or L’) is a non-releasable linker.
  • the linker (e.g, L or L’) does not decompose (e.g, hydrolyze) or release the warhead radical (or a free form thereof), the radical of the protein-binding ligand (or a free form thereof), or any other portion of the compound (e.g, a radical of any Formula provided herein) (or a free form thereof)).
  • the linker (e.g, L or L’) comprises one or more linker group, each linker group being independently selected from the group consisting of a bond, -O-, (substituted or unsubstituted) amino (e.g, -NH-, -NCEE-, methylamine, or dimethylamine), substituted or unsubstituted (e.g, acyclic (e.g, straight or branched) or cyclic) alkyl(ene) (e.g, straight unsubstituted alkyl (e.g, methylene, ethylene, or the like) or straight alkylene substituted with oxo, amino (e.g, -NH-, -NCEE-, or methylamine), heterocyclyl (e.g, (methylene) piperidinyl or piperazinyl), and/or aryl (e.g, (methylene) phenyl)), substituted or unsubstituted (
  • the linker (e.g., L or L’) comprises one or more linker group, each linker group being independently selected from the group consisting of -O-, substituted or unsubstituted amino, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, and substituted or unsubstituted alkoxy.
  • the linker (e.g., L or L’) comprises one or more linker group, each linker group being independently selected from the group consisting of -O-, substituted or unsubstituted amino and substituted or unsubstituted heteroalkylene.
  • the linker (e.g., L or L’) comprises one or more linker group, each linker group being independently selected from the group consisting of -O-, substituted or unsubstituted amino and substituted or unsubstituted acyclic (e.g., straight or branched) heteroalkylene.
  • the linker (e.g., L or L’) comprises one or more linker group, each linker group being independently selected from the group consisting of -O-, substituted or unsubstituted amino and substituted or unsubstituted cyclic heteroalkylene. In some embodiments, the linker (e.g., L or L’) comprises one or more linker group, each linker group being independently selected from the group consisting of -O-, substituted or unsubstituted amino and substituted or unsubstituted heterocyclyl.
  • the linker (e.g., L or L’) comprises one or more linker group, each linker group being independently selected from the group consisting of substituted or unsubstituted amino and substituted or unsubstituted heteroalkylene.
  • the linker (e.g., L or L’) comprises one or more linker group, each linker group being independently selected from the group consisting of substituted or unsubstituted amino and substituted or unsubstituted acyclic (e.g., straight or branched) heteroalkylene.
  • the linker (e.g., L or L’) comprises one or more linker group, each linker group being independently selected from the group consisting of substituted or unsubstituted amino and substituted or unsubstituted cyclic heteroalkylene. In some embodiments, the linker (e.g., L or L’) comprises one or more linker group, each linker group being independently selected from the group consisting of substituted or unsubstituted amino and substituted or unsubstituted heterocyclyl.
  • the linker (e.g., L or L’) comprises -O-.
  • the linker (e.g., L or L’) comprises substituted or unsubstituted amino.
  • the linker (e.g., L or L’) comprises -NH-.
  • the linker (e.g., L or L’) comprises substituted or unsubstituted alkylene. In some embodiments, the linker (e.g., L or L’) comprises substituted or unsubstituted C1-C6 alkylene. In some embodiments, the linker (e.g., L or L’) comprises substituted Ci-Ce alkylene. In some embodiments, the linker (e.g., L or L’) comprises unsubstituted C1-C6 alkylene. [00165] In some embodiments, the linker (e.g., L or L’) comprises substituted or unsubstituted heteroalkylene.
  • the linker (e.g., L or L’) comprises substituted or unsubstituted C1-C6 heteroalkylene. In some embodiments, the linker (e.g., L or L’) comprises substituted C1-C6 heteroalkylene. In some embodiments, the linker (e.g., L or L’) comprises unsubstituted C1-C6 heteroalkylene.
  • the linker (e.g., L or L’) comprises substituted or unsubstituted alkoxyalkyl. In some embodiments, the linker (e.g., L or L’) comprises substituted alkoxyalkyl. In some embodiments, the linker (e.g., L or L’) comprises unsubstituted alkoxyalkyl. In some embodiments, the linker (e.g., L or L’) comprises substituted or unsubstituted alkoxyheteroalkyl. In some embodiments, the linker (e.g., L or L’) comprises substituted or unsubstituted Ci-Ce alkoxyheteroalkyl. In some embodiments, the linker (e.g., L or L’) comprises substituted Ci-Ce alkoxyheteroalkyl .
  • the linker (e.g., L or L’) comprises substituted or unsubstituted amino. In some embodiments, the linker (e.g., L or L’) is -NH-. In some embodiments, the linker (e.g., L or L’) comprises an alkylamine. In some embodiments, the linker (e.g., L or L’) comprises a C1-C6 alkylamine.
  • the linker (e.g., L or L’) is a bond.
  • the linker (e.g., L or L’) comprises a carbonyl. In some embodiments, the linker (e.g., L or L’) comprises an ester. In some embodiments, the linker (e.g., L or L’) comprises a ketone. In some embodiments, the linker (e.g., L or L’) comprises an amide. [00170] In some embodiments, the linker (e.g., L or L’) comprises substituted or unsubstituted alkylene. In some embodiments, the linker (e.g., L or L’) comprises substituted or unsubstituted acyclic (e.g., straight or branched) alkylene. In some embodiments, the linker (e.g., L or L’) comprises substituted or unsubstituted cyclic alkylene.
  • the linker (e.g., L or L’) comprises substituted or unsubstituted heteroalkylene.
  • the linker e.g., L or L’
  • the linker comprises substituted or unsubstituted acyclic (e.g., straight or branched) heteroalkylene.
  • the linker e.g., L or L’
  • the linker (e.g., L or L’) comprises substituted or unsubstituted heterocycyl.
  • the linker (e.g., L or L’) comprises substituted or unsubstituted heterocycloalkyl. In some embodiments, the linker (e.g., L or L’) comprises substituted or unsubstituted C4-C7 heterocycloalkyl. In some embodiments, the linker (e.g., L or L’) comprises substituted C4-C7 heterocycloalkyl. In some embodiments, the linker (e.g., L or L’) comprises unsubstituted C4-C7 heterocycloalkyl.
  • the linker (e.g., L or L’) comprises substituted or unsubstituted piperazine (e.g., piperazine substituted with methyl). In some embodiments, the linker (e.g., L or L’) comprises substituted piperazine. In some embodiments, the linker (e.g., L or L’) comprises piperazine substituted with one or more methyl, alkoxy, alkoxyalkyl, alkoxyheteroalkyl, or heteroalkyl.
  • the linker (e.g., L or L’) comprises substituted or unsubstituted alkoxy.
  • a compound e.g., of Formula (A), Formula (I), Formula (I-A), or Formula (I-B)
  • the compound e.g., of Formula (A), Formula (I), Formula (I-A), or Formula (I-B)
  • comprises a linker e.g., L or L’
  • the linker e.g., L or L’ is the part of the compound identified with a box around it in FIG. 1 A, FIG. IB, or FIG. 1C.
  • linker e.g., L or L’
  • the linker is part of the protein-binding ligand and/or the warhead.
  • a covalent small molecule protein binder e.g., inhibitor
  • a covalent small molecule protein binder e.g., inhibitor
  • a benzenesulfonamide derivative compound as described herein is used to treat or prevent a disease or condition in a subject in need thereof.
  • a pharmaceutical composition comprising a benzenesulfonamide derivative compound as described herein and one or more pharmaceutically acceptable excipients is used to treat or prevent a disease or condition in a subject in need thereof.
  • a method of treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a benzenesulfonamide derivative compound as described herein.
  • a method of treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a benzenesulfonamide derivative compound as described herein and one or more pharmaceutically acceptable excipients.
  • a protein modified with a benzenesulfonamide derivative compound as described herein, wherein the compound forms a covalent bond with a sulfur atom of a cysteine residue of the protein e.g., as described elsewhere herein.
  • a method of binding a compound to a polypeptide comprising contacting the polypeptide with a benzenesulfonamide derivative compound as described herein (e.g., as described elsewhere herein).
  • a benzenesulfonamide derivative compound is a protein-binding compound. In some embodiments, a benzenesulfonamide derivative compound is a protein-binding ligand inhibitory compound.
  • the warhead comprises a para-activating group, such as a para- activating group that directs binding to, disruption of, and/or modification of KRAS or a mutant thereof either alone or in combination with L.
  • a para-activating group such as a para- activating group that directs binding to, disruption of, and/or modification of KRAS or a mutant thereof either alone or in combination with L.
  • the warhead is a selective warhead. In some embodiments, the warhead is a selective over other cysteine containing selectivity protein S0S1. In some embodiments, the warhead is selective for KRAS, such as over wild-type KRAS.
  • the warhead covalently modifies KRAS (e.g., KRAS G12C (SEQ ID NO: 1 or SEQ ID NO: 2) and/or a mutant KRAS G12C Lite (SEQ ID NO: 3)).
  • KRAS e.g., KRAS G12C (SEQ ID NO: 1 or SEQ ID NO: 2) and/or a mutant KRAS G12C Lite (SEQ ID NO: 3).
  • KRAS G12C Lite (SEQ ID NO: 3) is FL KRAS mutated at all the cysteines except G12C (K-Ras(C51S/C80L/C118S) described in reference : Ostrem, J. M. L.; Shokat, K. M. Direct Small- Molecule Inhibitors of KRAS: From Structural Insights to Mechanism-Based Design. Nature Reviews Drug Discovery. Nature Publishing Group November 1, 2016,
  • the warhead does not covalently modify KRAS WT protein. In some embodiments, the warhead does not substantially covalently modify KRAS WT protein.
  • KRAS G12C SEQ ID NO: 1 or SEQ ID NO: 2
  • SEQ ID NO: 3 a mutant KRAS G12C Lite
  • a compound e.g., of Formula (LA)
  • the compound e.g., of Formula (I- A)
  • a KRAS-binding ligand provided herein binds to, disrupts, and/or modifies KRAS either alone or in combination with a warhead radical provided herein and/or a linker provided herein.
  • a KRAS-binding ligand provided herein has activity such that a compound provided herein binds to, disrupts, and/or modifies KRAS (e.g., KRAS G12C) at a concentration of about 10 mM or less (e.g., 500 uM or less, 100 uM or less, or 10 uM or less).
  • a KRAS-binding ligand provided herein has activity such that a compound provided herein has Ki to KRAS (e.g., KRAS G12C) of about 250 uM or less (e.g., about 50 uM or less or about 1 uM or less).
  • Ki to KRAS e.g., KRAS G12C
  • the warhead comprises a para-activating group, such as a para- activating group that directs binding to, disruption of, and/or modification of JAK3 or a mutant thereof either alone or in combination with L.
  • a para-activating group such as a para- activating group that directs binding to, disruption of, and/or modification of JAK3 or a mutant thereof either alone or in combination with L.
  • the warhead covalently modifies JAK3.
  • DSF differential scanning fluorimetry
  • a compound e.g., of Formula (LB)
  • the compound e.g., of Formula (LB)
  • a JAK3 -binding ligand provided herein binds to, disrupts, and/or modifies JAK3 either alone or in combination with a warhead radical provided herein and/or a linker provided herein.
  • a JAK3 -binding ligand provided herein has activity such that a compound provided herein binds to, disrupts, and/or modifies JAK3 at a concentration of about 10 mM or less (e.g., 500 uM or less, 100 uM or less, or 10 uM or less).
  • a JAK3 -binding ligand provided herein has activity such that a compound provided herein has Ki to JAK3 of about 250 uM or less (e.g., about 50 uM or less or about 1 uM or less).
  • X 1 is absent or O. In some embodiments, X 1 is O. In some embodiments, X 2 is absent, O, or NR A . In some embodiments, X 2 is absent. In some embodiments, X 2 is O. In some embodiments, X 2 is NR A . In some embodiments, Q 1 is R x or L-G. In some embodiments, Q 1 is R x . In some embodiments, Q 1 is L-G. In some embodiments, Q 2 is L-G or Y 2 . In some embodiments, Q 2 is L-G. In some embodiments, Q 2 is Y 2 . In some embodiments, Y 2 is a blocking group.
  • a blocking group is a group that directs (e.g., covalent and/or irreversible) binding (e.g., of a cysteine residue) of a protein to a position other than Y 2 .
  • R x is substituted or unsubstituted alkyl or NR y R z .
  • R x is substituted or unsubstituted alkyl.
  • R x is substituted alkyl.
  • R x is unsubstituted alkyl.
  • R x is NR ⁇ R 2 .
  • R A , R y , and R z are each independently hydrogen or substituted or unsubstituted alkyl.
  • R A is hydrogen or unsubstituted alkyl.
  • R A is hydrogen.
  • R A is unsubstituted alkyl.
  • R y is hydrogen or substituted or unsubstituted alkyl.
  • R y is hydrogen.
  • R y is substituted alkyl.
  • R y is unsubstituted alkyl.
  • R z is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R z is hydrogen.
  • R z is substituted alkyl. In some embodiments, R z is unsubstituted alkyl. In some embodiments, L is a linker. In some embodiments, G is an organic residue. In specific embodiments, one and only one of Q 1 or Q 2 is L-G. In some embodiments, one of Q 1 or Q 2 is L-G.
  • R x is substituted or unsubstituted alkyl. In some embodiments, R x is unsubstituted alkyl. In some embodiments, R x is C1-C6 alkyl. In some embodiments, R x is methyl.
  • R x is substituted or unsubstituted aryl.
  • R x is substituted or unsubstituted heteroaryl.
  • R x is NR y R z .
  • R y and R z are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R y and R z are each independently hydrogen or substituted or unsubstituted alkyl.
  • R y and R z are hydrogen.
  • R y and R z are each independently substituted or unsubstituted alkyl.
  • R y is substituted or unsubstituted alkyl and R z is hydrogen.
  • X 1 is absent.
  • X 1 is O.
  • At least one of X 1 or X 2 is O.
  • Q 1 is not substituted or unsubstituted methoxy phenyl. In some instances, Q 1 is not phenyl, such as specifically not methoxy phenyl.
  • Q 2 is not substituted or unsubstituted methoxy phenyl. In some instances, Q 2 is not phenyl, such as specifically not methoxy phenyl.
  • X 2 is absent, O, or NR A .
  • R A is hydrogen or substituted or unsubstituted alkyl.
  • Y 2 is a blocking group (e.g., a group that directs (e.g., covalent and/or irreversible) binding (of a cysteine residue) of a protein to a position other than Y 2 ).
  • L is a linker.
  • G is a protein- binding ligand (e.g., a radical of a compound that interacts with a protein or a mutant thereof, comprising one or more cyclic group wherein the one or more cyclic groups are individually linked by one or more linker).
  • G is a KRAS-binding ligand.
  • the compound is a salt.
  • X 2 is O.
  • X 2 is absent.
  • X 2 is NR A .
  • R A is hydrogen or substituted or unsubstituted C1-C6 alkyl.
  • G or G’ is an organic residue. In some embodiments, G or G’ is a radical of a protein-binding ligand, such as a protein-binding ligand provided elsewhere herein. [00215] In some embodiments, G or G’ is a radical of a compound that interacts with a protein (e g., BTK, EGFR, FGFR, AURKA, BMX, TEAD, JAK3, KRAS) or a mutant thereof.
  • a protein e g., BTK, EGFR, FGFR, AURKA, BMX, TEAD, JAK3, KRAS
  • G or G’ is or comprises a protein-binding ligand selected from a BTK-, EGFR-, FGFR-, AURKA-, TEAD-, JAK3- KRAS-, and BMX-binding ligand.
  • G or G’ is a radical of a BTK-binding ligand. In some embodiments, G or G’ is a radical of an EGFR-binding ligand. In some embodiments, G or G’ is a radical of a FGFR-binding ligand. In some embodiments, G or G’ is a radical of a BMX-binding ligand. In some embodiments, G or G’ is a radical of an AURKA-binding ligand. In some embodiments, G or G’ is a radical of a TEAD-binding ligand.
  • G is a radical of a KRAS-binding ligand, such as a KRAS-binding ligand provided elsewhere herein.
  • G is a radical of a KRAS-binding protein.
  • X is absent, O, or NR A .
  • R A is hydrogen or 2 substituted or unsubstituted alkyl.
  • Y is a blocking group.
  • Y is a group that directs (e.g., covalent and/or irreversible) binding (of a cysteine residue) of KRAS or a mutant thereof to a position other than Y 2 (e.g., a position ortho or meta to Y 2 )).
  • L is a linker described herein.
  • G is a KRAS- binding ligand described herein, such as a radical of a compound that interacts with a KRAS protein or a mutant thereof (e.g., KRAS G12C, KRAS C118A, or KRAS G12C/C118A).
  • the compound is a salt.
  • G is a radical of a JAK3-binding ligand, such as a JAK3-binding ligand provided elsewhere herein.
  • G is a radical of a JAK3 -binding protein.
  • X is absent, O, or NR A .
  • R A is hydrogen
  • Y is a blocking group.
  • Y is a group that directs (e.g., covalent and/or irreversible) binding (of a cysteine residue) of KRAS or a mutant thereof to a position other than Y 2 (e.g., a position ortho or meta to Y 2 )).
  • L is a linker described herein.
  • G is a JAK3- binding ligand described herein, such as a radical of a compound that interacts with a JAK3 protein or a mutant thereof.
  • the compound is a salt.
  • the JAK3-binding ligand is an unsubstituted or substituted heterocycle. In some embodiments, the JAK3-binding ligand is an unsubstituted or substituted pyrrolopyrimidine, an unsubstituted or substituted pyrrolopyridine, an unsubstituted or substituted pyrazolopyrimidine, an unsubstituted or substituted pyrazolopyridine, or an unsubstituted or substituted benzimidazole. In some embodiments, the JAK3-binding ligand is an unsubstituted or substituted pyrrolopyrimidine.
  • the JAK3-binding ligand is an an unsubstituted or substituted pyrrolopyridine. In some embodiments, the JAK3-binding ligand is an unsubstituted or substituted pyrazolopyrimidine. In some embodiments, the JAK3-binding ligand is an unsubstituted or substituted pyrazolopyridine. In some embodiments, the JAK3- binding ligand is an unsubstituted or substituted benzimidazole. In some embodiments, the JAK3- binding ligand is a pyrrolopyrimidine described herein, such as a 7H-pyrrolo[2,3-J]pyrimidine described herein.
  • the JAK3-binding ligand is a pyrrolopyridine described herein, such as a lH-pyrrolo[2,3-b]pyridine described herein.
  • the JAK3- binding ligand is a pyrazolopyridine described herein, such as a pyrazolo[l ,5-a]pyridine described herein.
  • the JAK3-binding ligand is attached to a linker described herein. [00227]
  • G has a structure represented by any one of Formulas (II)-(VII).
  • G or G’ has a structure shown in Table 1 A, Table IB, or Table 1C.
  • G or G’ is or comprises one or more (e.g., unsaturated) unsubstituted or substituted carbocycle and/or one or more (e.g., unsaturated) unsubstituted or substituted heterocycle.
  • G or G’ is or comprises an (e.g., unsaturated) unsubstituted or substituted carbocycle or an (e.g., unsaturated) unsubstituted or substituted heterocycle.
  • G or G’ consists of an (e.g., unsaturated) unsubstituted or substituted carbocycle or an (e.g., unsaturated) unsubstituted or substituted heterocycle.
  • G or G’ is (e.g., unsaturated) unsubstituted or substituted carbocycle or an (e.g., unsaturated) unsubstituted or substituted heterocycle. In some embodiments, G or G’ is substituted or unsubstituted unsaturated carbocycle or substituted or unsubstituted unsaturated heterocycle. In some embodiments, G or G’ comprises one or more cyclic ring systems selected from substituted or unsubstituted unsaturated carbocycles and substituted or unsubstituted unsaturated heterocycles. In some embodiments, G or G’ comprises two or more cyclic ring systems selected from substituted or unsubstituted unsaturated carbocycles and substituted or unsubstituted unsaturated heterocycles.
  • G or G’ comprises one or more cyclic ring systems selected from substituted or unsubstituted carbocycles and substituted or unsubstituted heterocycles. In some embodiments, G or G’ comprises two or more cyclic ring systems selected from substituted or unsubstituted carbocycles and substituted or unsubstituted heterocycles.
  • G or G’ is amino, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or alkoxy. In some embodiments, G or G’ is amino. In some embodiments, G or G’ is hydroxyl. In some embodiments, G or G’ is substituted or unsubstituted alkyl. In some embodiments, G or G’ is substituted or unsubstituted heteroalkyl. In some embodiments, G or G’ is alkoxy.
  • G or G’ comprises one or more cyclic group.
  • G or G’ comprises one or more cyclic groups wherein the one or more cyclic groups are individually linked by one or more linker (e.g., L or L’).
  • G or G’ comprises one or more cyclic groups, wherein each of the one or more cyclic group are individually linked to another of the one or more cyclic groups by a linker, such as a bond.
  • FIG. IB shows a G’ that comprises a cyclic group (e.g., a heterocyclyl described herein) linked to another cyclic group (e.g., a heteroaryl described herein) via a bond.
  • G or G’ comprises an optionally substituted cyclic group, optionally substituted with one or more L’-G’, wherein each L’ is individually selected from a linker, such as a linker provided elsewhere herein, and is connected to another G’.
  • G’ comprises G as described elsewhere herein.
  • G’ and G are the same.
  • G’ and G are different.
  • G or G’ comprises an optionally substituted cyclic group, optionally substituted with -(L’-G’)nL’-G’, wherein n is 0 to 4. In some embodiments, n is 1 to 3.
  • G is substituted with L’-G’. In some instances, G is substituted with one or more, such as 2 or 3, L’-G’ on a single G. In some embodiments G is substituted with 2 L’-G’, such as on a single G. In some embodiments, G is substituted with -(L’-G’)n-L’-G’. In some embodiments, G is substituted with one or more, such as 2 or 3, -(L’-G’)n-L’-G’ on a single G. In some embodiments, G is substituted with 2 -(L’-G’)n-L’-G’ on a single G.
  • the two or more cyclic ring systems are connected via a bond. In some embodiments, the two or more cyclic ring systems are connected via one or more linker (e.g., L or L’) and/or bond.
  • linker e.g., L or L
  • the cyclic ring system comprises substituted or unsubstituted monocyclic aryl or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, the cyclic ring system comprises substituted or unsubstituted bicyclic aryl or substituted or unsubstituted bicyclic heteroaryl.
  • G or G’ comprises one or more nitrogen atoms. In some embodiments, G or G’ comprises one or more nitrogen ring atoms. In some embodiments, G or G’ comprises one or more nitrogen atoms within its ring system. In some embodiments, G or G’ comprises one or more nitrogen atoms within its fused ring system. In some embodiments, G or G’ comprises one, two, or three nitrogen atoms (e.g., within its (e.g., fused) ring system).
  • G or G’ comprises one or more (e.g., fused) rings. In some embodiments, G or G’ comprises one or more fused rings.
  • G or G’ is aromatic or partially aromatic. In some embodiments, G or G’ is aromatic. In some embodiments, G or G’ is partially aromatic.
  • G or G’ comprises one or more substituted or unsubstituted aromatic ring(s). In some embodiments, G or G’ comprises one substituted or unsubstituted aromatic ring. In some embodiments, G or G’ comprises two substituted or unsubstituted aromatic rings. In some embodiments, G or G’ comprises three substituted or unsubstituted aromatic rings. [00241] In some embodiments, G or G’ comprises two or more substituted or unsubstituted aromatic or partially aromatic rings. In some embodiments, each aromatic or partially aromatic ring independently is a carbocycle or a heterocycle.
  • G or G’ comprises one or more substituted or unsubstituted carbocycle and one or more substituted or unsubstitued heterocycle.
  • each of the one or more substituted or unsubstituted carbocycle and the one or more substituted or unsubstitued heterocycle are independently linked (e.g., fused) to a substituted or unsubstituted carbocycle or a substituted or unsubstitued heterocycle by amino or a bond.
  • G or G’ comprises one or more substituted or unsubstituted carbocycle and one or more substituted or unsubstitued heterocycle, each of the one or more substituted or unsubstituted carbocycle and the one or more substituted or unsubstitued heterocycle independently being linked (e.g., fused) to a substituted or unsubstituted carbocycle or a substituted or unsubstitued heterocycle by a bond.
  • G or G’ comprises a substituted or unsubstituted carbocycle and a substituted or unsubstitued heterocycle, the substituted or unsubstituted carbocycle and the substituted or unsubstitued heterocycle being linked (e.g., fused) by a bond.
  • G or G’ comprises two (or more) substituted or unsubstituted heteroaromatic rings, the heteroaromatic rings being linked (e.g., fused) by a bond, each heteroaromatic ring being aromatic or partially aromatic.
  • the heteroaromatic rings are selected from the group consisting of benzimidazole, indole, indolizine, pyridine, quinoline, indazole, pyrimidine, and pyridopyrimidinone (e.g., pyrido[2,3-d]pyrimidin- 2(lH)-one).
  • the heteroaromatic rings are selected from the group consisting of benzimidazole, indole, indolizine, pyridine, and pyridopyrimidinone (e.g., pyrido[2,3-d]pyrimidin-2(lH)-one).
  • G or G’ is a substituted benzimidazole linked to an unsubstituted indolizine by a bond.
  • G or G’ is a substituted benzimidazole linked to an unsubstituted phenyl by a bond.
  • G or G’ is a substituted pyrido[2,3-d]pyrimidin-2(lH)-one linked to a substituted pyridine by a bond.
  • G or G’ has a structure of:
  • G or G’ has a structure of:
  • G or G’ has a structure of:
  • G or G’ comprises two (or more) substituted or unsubstituted phenyl rings.
  • the phenyl is linked by a bond.
  • G or G’ has a structure of:
  • G or G’ comprises one or more (e.g., one, two, or three) substituted or unsubstituted heteroaromatic ring(s).
  • G or G’ comprises a substituted or unsubstituted carbocycle. In some embodiments, G or G’ comprises an unsubstituted carbocycle. In some embodiments, G or G’ comprises a substituted carbocycle.
  • G or G’ comprises a substituted or unsubstituted heterocycle. In some embodiments, G or G’ comprises a substituted heterocycle. In some embodiments, G or G’ comprises an unsubstituted heterocycle.
  • G or G’ is a substituted or unsubstituted N-heterocycle.
  • G or G’ is a substituted or unsubstituted pyridine. In some embodiments, G or G’ is unsubstituted pyridine.
  • G or G’ is a substituted or unsubstituted piperazine. In some embodiments, G or G’ is a substituted piperazine. In some embodiments, G or G’ is an unsubstituted piperazine. In some embodiments, G or G’ is piperazine substituted with methyl.
  • G or G’ is a substituted or unsubstituted piperidine. In some embodiments, G or G’ is a substituted or unsubstituted azetidine.
  • G or G’ is unsubstituted tetrahydrofuran. In some embodiments, G or G’ is unsubstituted tetrahydro-2H-pyran. [00258] In some embodiments, G or G’ is substituted or unsubstituted IH-pyrazole. In some embodiments, G or G’ is unsubstituted IH-pyrazole. In some embodiments, G or G’ is substituted IH-pyrazole.
  • G or G’ is substituted or unsubstituted isoxazole. In some embodiments, G or G’ is substituted isoxaole, such as isoxazole substituted with methyl. In some embodiments, G or G’ is unsubstituted isoxazole.
  • G or G’ is unsubstituted quinoline.
  • G or G’ is unsubstituted pyrimidine.
  • G or G’ is substituted or unsubstituted IH-indazole. In some embodiments, G or G’ is unsubstituted IH-indazole. In some embodiments, G or G’ is substituted IH-indazole, such as IH-indazole substituted with methyl.
  • G or G’ is a substituted carbocycle.
  • G or G’ is a substituted phenyl.
  • G or G’ is a substituted heterocycle.
  • G or G’ is a substituted or unsubstituted quinazoline or a substituted or unsubstituted pyrazolopyrimidine. In some embodiments, G or G’ is a substituted quinazoline or a substituted pyrazolopyrimidine. In some embodiments, G or G’ is an unsubstituted quinazoline or an unsubstituted pyrazolopyrimidine. In some embodiments, G or G’ is a substituted quinazoline. In some embodiments, G or G’ is an unsubstituted quinazoline. In some embodiments, G or G’ is a substituted pyrazolopyrimidine.
  • G or G’ is an unsubstituted pyrazolopyrimidine. In some embodiments, G or G’ is a substituted 1H- pyrazolo[3,4-d]pyrimidine. In some embodiments, G or G’ is an unsubstituted lH-pyrazolo[3,4- d]pyrimidine.
  • G or G’ is or comprises a substituted or unsubsituted quinazoline. In some embodiments, G or G’ is or comprises a substituted or unsubstituted tetrahydropyridopyrimidine (e.g., 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine). In some embodiments, G or G’ is or comprises a substituted or unsubsituted quinoline. In some embodiments, G or G’ is or comprises a substituted or unsubstituted pyridopyrazinone (e.g., pyrido[2,3-b]pyrazin-3(4H)-one).
  • pyridopyrazinone e.g., pyrido[2,3-b]pyrazin-3(4H)-one.
  • G or G’ is or comprises a substituted or unsubstituted benzimidazole. In some embodiments, G or G’ is or comprises a substituted or unsubstituted pyrrolopyrimidine (e.g., a 7H-pyrrolo[2,3-J]pyrimidine). In some embodiments, G or G’ is or comprises a substituted or unsubstituted pyrazolopyridine (e.g., a pyrazolo[l,5- a]pyridine). In some embodiments, G or G’ is or comprises an unsubstituted pyrrolopyridine (e.g., a lH-pyrrolo[2,3-Z>]pyridine).
  • G or G’ is or comprises a substituted pyrrolopyridine (e.g., a lH-pyrrolo[2,3-Z>]pyridine).
  • G or G’ is a substituted quinazoline, a substituted tetrahydropyridopyrimidine (e.g., 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine), a substituted quinoline, a substituted pyridopyrazinone (e.g., pyrido[2,3-b]pyrazin-3(4H)-one).
  • G or G’ is a substituted tetrahydropyridopyrimidine (e.g., 5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidine).
  • G or G’ is a substituted quinazoline.
  • G or G’ is a substituted tetrahydropyridopyrimidine (e.g., 5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidine).
  • G or G’ is a substituted quinoline.
  • G or G’ is a substituted pyridopyrazinone (e.g., pyrido[2,3- b]pyrazin-3(4H)-one).
  • G or G’ has a structure represented by Formula (II):
  • R lx , R 2x , R 3x , R 4x , R 5x , R 6x , and R 7x are each independently selected from the group consisting of hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • R lx , R 2x , R 3x , R 4x , R 5x , R 6x , and R 7x are each independently selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted alkyl.
  • R lx is hydrogen
  • R 2x is halogen. In some embodiments, R 2x is fluoro.
  • R 3x is halogen. In some embodiments, R 3x is chloro.
  • R 3x is substituted aryl. In some embodiments, R 3x is aryl substituted with halogen. In some embodiments, R 3x is aryl substituted with hydroxy. In some embodiments, R 3x is aryl substituted with halogen and hydroxy. In some embodiments, R 3x is aryl substituted with fluoro and hydroxy. [00281] In some embodiments, R 4x is substituted or unsubstituted alkyl. In some embodiments, R 4X is methyl.
  • R 5x is hydrogen
  • R 6x is hydrogen
  • R 7x is substituted or unsubstituted alkyl. In some embodiments, R 7X is isopropyl.
  • R lx is hydrogen
  • R 2x is fluoro
  • R 3x is aryl substituted with fluoro and hydroxy
  • R 4x is methyl
  • R 5x is hydrogen
  • R 6x is hydrogen
  • R 7x is isopropyl.
  • G or G’ has a structure represented by Formula (II-A):
  • R lx is hydrogen
  • R 2x is fluoro
  • R 3x is chloro
  • R 4x is methyl
  • R 5x is hydrogen
  • R 6x is hydrogen
  • R 7x is isopropyl.
  • G or G’ has a structure represented by Formula (II-B):
  • G or G’ has a structure represented by Formula (III):
  • R 8a is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • each R 9a is independently selected from the group consisting of halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • each R 10a is independently selected from the group consisting of halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • m is 0-6.
  • n is 0-7.
  • R 8a is hydrogen
  • n is 0 or 1.
  • m is 0.
  • R 10a is halogen, hydroxy, or unsubstituted alkoxy. In some embodiments, R 10a is chloro, hydroxy, or OMe. In some embodiments, R 10a is chloro. In some embodiments, R 10a is hydroxy. In some embodiments, R 10a is OMe.
  • R 8a is hydrogen, m is 0, n is 1, and R 10a is chloro.
  • G or G’ has a structure represented by Formula (III-A):
  • R 8a is hydrogen, m is 0, and n is 0.
  • G or G’ has a structure represented by Formula (III-B):
  • R 8a is hydrogen, m is 0, n is 1, and R 10a is hydroxy.
  • G or G’ has a structure represented by Formula (III-C):
  • R 8a is hydrogen, m is 0, n is 1, and R 10a is -OMe.
  • G or G’ has a structure represented by Formula (III-D):
  • G or G’ has a structure represented by Formula (IV):
  • R 11 and R 12 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • each R 13 is independently selected from the group consisting of halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • each R 14 is independently selected from the group consisting of halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • o is 0-3.
  • p is 0-5.
  • R 11 is hydrogen.
  • R 12 is hydrogen.
  • o is 0 or 1.
  • R 13 is halogen (e.g., chloro). In some embodiments, R 13 is chloro.
  • each R 14 is independently alkyl.
  • each R 14 is independently unsubstituted alkyl. In some embodiments, p is 2 and each R 14 is methyl.
  • R 11 is hydrogen
  • R 12 is hydrogen
  • G or G’ has a structure represented by Formula (IV-A):
  • R 11 is hydrogen
  • R 12 is hydrogen
  • o is 1
  • R 13 is chloro
  • p is 2
  • each R 14 is independently methyl
  • G or G’ has a structure represented by Formula (IV-B):
  • G or G’ has a structure represented by Formula (V):
  • R 15 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • each R 16 is independently selected from the group consisting of halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • each R 17 is independently selected from the group consisting of halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • r is 0-3.
  • s is 0-5.
  • R 15 is hydrogen
  • r is 1 or 2.
  • each R 16 is independently halogen. In some embodiments, each R 16 is independently chloro or fluoro.
  • r is 1 and R 16 is fluoro.
  • R 17 is independently halogen (e.g., fluoro) or hydroxyl. In some embodiments, R 17 is independently fluoro or hydroxyl.
  • R 15 is hydrogen, r is 1, R 16 is chloro, s is 1, and R 14 is fluoro.
  • G or G’ has a structure represented by Formula (V-A):
  • G or G’ has a structure represented by Formula (V-B):
  • G or G’ has a structure represented by Formula (VI):
  • each R 18 is independently selected from the group consisting of halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • each R 19 is independently selected from the group consisting of halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • each R 20 is independently selected from the group consisting of halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • R 21 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • t is 0-6.
  • u is 0-7.
  • v is 0-7.
  • t is 0.
  • u is 1.
  • R 19 is halogen (e.g., chloro). In some embodiments, R 19 is chloro. [00330] In some embodiments, v is 0.
  • R 21 is unsubstituted alkyl (e.g., methyl). In some embodiments, R 21 is methyl.
  • t and v are 0, u is 1, R 19 is chloro, and R 21 is methyl.
  • G or G’ has a structure represented by Formula (VI- A):
  • G or G’ has a structure represented by Formula (VI-B):
  • G or G’ has a structure represented by Formula (VI-C):
  • G or G’ has a structure represented by Formula (VII):
  • R 22 , R 23 , R 24 , R 25 , and R 26 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • R 22 is hydrogen, hydroxy, or substituted or unsubstituted heteroalkyl. In some embodiments, R 22 is hydrogen. In some embodiments, R 22 is hydroxy. In some embodiments, R 22 is substituted or unsubstituted heteroalkyl (e.g., alkylamine substituted with oxo and heterocyclyl, such as cyclopropyl). [00339] In some embodiments, R 23 is hydrogen or halogen. In some embodiments, R 23 is hydrogen. In some embodiments, R 23 is halogen. In some embodiments, R 23 is hydrogen or chloro. [00340] In some embodiments, R 24 is hydrogen or halogen. In some embodiments, R 24 is hydrogen. In some embodiments, R 24 is halogen. In some embodiments, R 24 is chloro or bromo. In some embodiments, R 24 is hydrogen, chloro or bromo.
  • R 25 is hydrogen, halogen (e.g., bromo), or substituted alkyl. In some embodiments, R 25 is hydrogen. In some embodiments, R 25 is halogen (e.g., bromo). In some embodiments, R 25 is chloro. In some embodiments, R 25 is substituted alkyl.
  • R 26 is hydrogen, halogen (e.g., chloro), unsubstituted alkoxy, or substituted alkyl. In some embodiments, R 26 is hydrogen. In some embodiments, R 26 is halogen. In some embodiments, R 26 is chloro. In some embodiments, R 26 is unsubstituted alkoxy. In some embodiments, R 26 is substituted alkyl.
  • halogen e.g., chloro
  • R 26 is hydrogen, halogen (e.g., chloro), unsubstituted alkoxy, or substituted alkyl.
  • R 22 is hydrogen
  • R 23 is hydrogen
  • R 24 is chloro
  • R 25 is hydrogen
  • R 26 is chloro
  • G or G’ has a structure represented by Formula (VII-A):
  • R 22 is hydrogen
  • R 23 is chloro
  • R 24 is hydrogen
  • R 25 is hydrogen
  • R 26 is chloro
  • G or G’ has a structure represented by Formula (VII-B):
  • R 22 is hydrogen
  • R 23 is hydrogen
  • R 24 is hydrogen
  • R 25 is bromo
  • R 26 is chloro
  • G or G’ has a structure represented by Formula (VII-C):
  • R 22 is hydrogen
  • R 23 is hydrogen
  • R 24 is alkylamine substituted with oxo and cycloalkyl (e.g., -C(O)NH-(cyclopropyl))
  • R 25 is hydrogen
  • R 26 is hydrogen.
  • G or G’ has a structure represented by Formula (VII-D):
  • G or G’ is substituted pyridine.
  • G or G’ is pyridine substituted with halo (e.g., chloro).
  • G or G’ is pyridine substituted with substituted alkyl (haloalkyl) and/or unsubstituted alkyl (e.g., methyl).
  • G or G’ has a structure represented by Formula (VII-E):
  • G or G’ has a structure represented by Formula (VII-F):
  • G or G’ is substituted pyrazole.
  • G or G’ is pyrazole substituted with heterocyclyl, such as pyrrolidin-2-one.
  • G or G’ has a structure represented by Formula (VII-G):
  • G or G’ is substituted or unsubstituted pyrrolopyridine (e.g., 1H- pyrrolo[2,3-Z>]pyridine). In some embodiments, G or G’ is substituted pyrrolopyridine. In some embodiments, G or G’ is lH-pyrrolo[2,3-Z>]pyridine substituted with substituted alkylamine, such as alkylamine substituted with oxo (e.g., -C(O)NH2). In some embodiments, G or G’ is a JAK3- binding ligand that is a substituted or unsubstituted pyrrolopyridine (e.g., lH-pyrrolo[2,3- Z>]pyridine).
  • G or G’ has a structure represented by Formula (VII-H):
  • G or G’ is unsubstituted or substituted pyrrolopyrimidine (e.g., a 7H-pyrrolo[2,3-J]pyrimidine). In some embodiments, G or G’ is unsubstituted pyrrolopyrimidine (e.g., a 7H-pyrrolo[2,3-J]pyrimidine). In some embodiments, G or G’ is unsubstituted 7H-pyrrolo[2,3-J]pyrimidine.
  • G or G’ is a JAK3-binding ligand that is an unsubstituted or substituted pyrrolopyrimidine (e.g., a 7H-pyrrolo[2,3- t/]pyrimidine).
  • G or G’ has a structure represented by Formula (VII-I):
  • G or G’ is unsubstituted or substituted pyrazolopyrimidine (e.g., lH-pyrazolo[3,4-d]pyrimidine).
  • G or G’ is substituted pyrazolopyrimidine (e.g., lH-pyrazolo[3,4-d]pyrimidine), such as pyrazolopyrimidine (e.g., lH-pyrazolo[3,4- d]pyrimidine) substituted with substituted amino (e.g., amino substituted with alkyl (e.g., methyl) or unsubstituted or substituted heterocyclyl, such as pyrazole substituted with alkoxy).
  • substituted amino e.g., amino substituted with alkyl (e.g., methyl) or unsubstituted or substituted heterocyclyl, such as pyrazole substituted with alkoxy.
  • G or G’ is substituted lH-pyrazolo[3,4-d]pyrimidine.
  • G or G’ is a JAK3-binding ligand that is an unsubstituted or substituted pyrazolopyrimidine (e.g., 1H- pyrazolo[3,4-d]pyrimidine).
  • G or G’ is substituted or unsubstituted pyrazolopyridine (e.g., a pyrazolo[l,5-a]pyridine). In some embodiments, G or G’ is unsubstituted pyrazolopyridine (e.g., a pyrazolo[l,5-a]pyridine). In some embodiments, G or G’ is unsubstituted a pyrazolo[l,5- a]pyridine. In some embodiments, G or G’ is a JAK3-binding ligand that is an unsubstituted or substituted pyrazolopyridine (e.g., a pyrazolo[l,5-a]pyridine).
  • G or G’ has a structure represented by Formula (VII- J):
  • G or G’ is unsubstituted or substituted benzimidazole. In some embodiments, G or G’ is substituted benzimidazole. In some embodiments, G or G’ is benzimidazole substituted with alkyl (e.g., methyl or fluoroalkyl).
  • alkyl e.g., methyl or fluoroalkyl
  • G or G’ has a structure represented by Formula (VII-K):
  • G’ is a radical of a protein-binding ligand, such as a protein- binding ligand provided elsewhere herein.
  • G’ is a radical of a compound that interacts with a protein (e.g., BTK, EGFR, KRAS, FGFR, TEAD, JAK3, or BMX) or a mutant thereof.
  • a protein e.g., BTK, EGFR, KRAS, FGFR, TEAD, JAK3, or BMX
  • G’ is or comprises a protein-binding ligand selected from a BTK-, EGFR-, FGFR-, KRAS-, TEAD-, JAK3-, or BMX-binding ligand.
  • G’ is a radical of a BTK-binding ligand. In some embodiments, G is a radical of an EGFR-binding ligand. In some embodiments, G is a radical of a FGFR-binding ligand. In some embodiments, G’ is a radical of a BMX-binding ligand. In some embodiments, G’ is a radical of a AURKA-binding ligand. In some embodiments, G’ is a radical of a TEAD- binding ligand. In some embodiments, G’ is a radical of a JAK3 -binding ligand. In some embodiments, G’ is a radical of a KRAS-binding ligand.
  • G’ has a structure represented in Table 1 A, Table IB, or Table 1C.
  • G’ is or comprises one or more (e.g., unsaturated) unsubstituted or substituted carbocycle and/or one or more (e.g., unsaturated) unsubstituted or substituted heterocycle.
  • G’ is or comprises an (e.g., unsaturated) unsubstituted or substituted carbocycle or an (e.g., unsaturated) unsubstituted or substituted heterocycle)).
  • G’ consists of an (e.g., unsaturated) unsubstituted or substituted carbocycle or an (e.g., unsaturated) unsubstituted or substituted heterocycle)). In some embodiments, G’ is (e.g., unsaturated) unsubstituted or substituted carbocycle or an (e.g., unsaturated) unsubstituted or substituted heterocycle. In some embodiments, G’ is substituted or unsubstituted unsaturated carbocycle or substituted or unsubstituted unsaturated heterocycle.
  • G’ comprises one or more cyclic ring systems selected from substituted or unsubstituted unsaturated carbocycles and substituted or unsubstituted unsaturated heterocycles. In some embodiments, G’ comprises two or more cyclic ring systems selected from substituted or unsubstituted unsaturated carbocycles and substituted or unsubstituted unsaturated heterocycles.
  • G’ comprises one or more cyclic ring systems selected from substituted or unsubstituted carbocycles and substituted or unsubstituted heterocycles. In some embodiments, G’ comprises two or more cyclic ring systems selected from substituted or unsubstituted carbocycles and substituted or unsubstituted heterocycles.
  • G’ comprises one or more cyclic group. In some embodiments, G’ comprises one or more cyclic groups wherein the one or more cyclic groups are individually linked by one or more linker (e.g., L or L’).
  • linker e.g., L or L
  • G’ comprises one or more nitrogen atoms. In some embodiments, G’ comprises one or more nitrogen ring atoms. In some embodiments, G’ comprises one or more nitrogen atoms within its ring system. In some embodiments, G’ comprises one or more nitrogen atoms within its fused ring system. In some embodiments, G’ comprises one, two, or three nitrogen atoms (e.g., within its (e.g., fused) ring system).
  • G’ comprises one or more (e.g., fused) rings. In some embodiments, G’ comprises one or more fused rings.
  • G’ is aromatic or partially aromatic. In some embodiments, G is partially aromatic. In some embodiments, G’ is partially aromatic.
  • G’ comprises one or more substituted or unsubstituted aromatic ring(s). In some embodiments, G’ comprises one substituted or unsubstituted aromatic ring. In some embodiments, G’ comprises two substituted or unsubstituted aromatic rings. In some embodiments, G’ comprises three substituted or unsubstituted aromatic rings.
  • G’ comprises one or more (e.g., one, two, or three) substituted or unsubstituted heteroaromatic ring(s).
  • G’ comprises a substituted or unsubstituted carbocycle. In some embodiments, G’ comprises an unsubstituted carbocycle. In some embodiments, G comprises a substituted carbocycle.
  • G’ comprises a substituted or unsubstituted heterocycle. In some embodiments, G’ comprises a substituted heterocycle. In some embodiments, G comprises an unsubstituted heterocycle.
  • G’ is a substituted carbocycle.
  • G’ is a substituted phenyl.
  • G’ is a substituted heterocycle.
  • G’ is a substituted quinazoline or a substituted pyrazolopyrimidine.
  • G’ is a substituted quinazoline.
  • G’ is a substituted pyrazolopyrimidine.
  • G is a substituted lH-pyrazolo[3,4-d]pyrimidine.
  • each instance of radical indicates that a hydrogen (i.e., a hydrogen radical (H*)) is removed from a free form of a compound provided herein, such as any protein-binding ligand (e.g., G or G’) or warhead described herein.
  • H* hydrogen radical
  • the removal of the hydrogen radical from the compound provided herein, such as any protein-binding ligand (e.g., G or G’) or warhead described herein provides a radical of a protein- binding ligand or a warhead that is taken together with any point of a linker provided herein (e.g., L or L’) to form a bond (e.g., between the linker and the radical of the protein-binding ligand or the warhead).
  • a carbon atom e.g., of any protein-binding ligand (e.g., a substituted heterocycle or a substituted carbocycle) or warhead described herein) loses an H* to become a point of attachment to L.
  • >NH loses an H* to become >N-(point of attachment), such as >N-L-G, >N-L-warhead, >N-DG, or >N-warhead.
  • -OH loses an H* to become -O-(point of attachment), such as -O-L-G, -O-L-warhead, -O-G, or -O- warhead.
  • the linker e.g., L or L’
  • G-L- is a protein-binding ligand.
  • the protein-binding ligand (e.g., G or G’) has or comprises a structure shown in Table 1 A:
  • the protein (e.g., KRAS)-binding ligand e.g., G or G’
  • the protein e.g., KRAS
  • G or G has or comprises a structure shown in Table IB:
  • the protein-binding ligand (e.g., G or G’) has or comprises a structure shown in Table 1C:
  • Y 2 is a blocking group. In some embodiments, Y 2 is a group that directs binding of a protein (e.g., a protein described herein) or a mutant thereof to a position other than Y 2 . In some embodiments, Y 2 is a group that directs covalent and/or irreversible binding of a cysteine residue of a protein (e.g., a protein described herein) or a mutant thereof to a position other than Y 2 .
  • Y 2 is a group that directs covalent and/or irreversible binding of a cysteine residue of a protein (e.g., a protein described herein) or a mutant thereof to a position ortho or meta to Y 2 . In some embodiments, Y 2 is a group that directs covalent and/or irreversible binding of a cysteine residue of a protein (e.g., a protein described herein) or a mutant thereof to a position ortho to Y 2 .
  • Y 2 is a group that directs covalent and/or irreversible binding of a cysteine residue of a protein (e.g., a protein described herein) or a mutant thereof to a position meta to Y 2 .
  • Y 2 is not a leaving group, such as halo (e.g., fluoro).
  • Y 2 is not halo. In some embodiments, Y 2 is not fluoro.
  • Y 2 is hydrogen, CN, NO2, hydroxy, substituted or unsubstituted amino (e.g., -NR xa R ya -, where R xa is hydroxy and R ya is hydrogen), substituted or unsubstituted amido (e.g., -CONR xa R ya -, where R xa is hydroxy or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo) and R ya is hydrogen or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo)), substituted or unsubstituted alkyl (e.g., fluoroalkyl), substituted or unsubstituted alkoxy (e.g., fluoroalkoxy), or substituted or unsubstituted heteroalkyl (e.g., alkylamine substituted with o
  • Y 2 is hydrogen, CN, NO2, hydroxy, substituted amino (e.g., - NR xa R ya -, where R xa is hydroxy or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo) and R ya is hydrogen or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo)), unsubstituted alkyl (e.g., methyl), substituted alkyl (e.g., alkyl substituted with halo (e.g., fluoroalkyl (e.g., methyl substituted with one, two, or three fluoro))), unsubstituted alkoxy (e.g., methoxy), substituted alkoxy (e.g., alkoxy substituted with halo (e.g., fluoroalkoxy (e.g., meth
  • Y 2 is CN, NO2, hydroxy, substituted or unsubstituted amino (e.g., -NR xa R ya -, where R xa is hydroxy and R y is hydrogen), substituted or unsubstituted amido (e.g., -CONR xa R ya -, where R xa is hydroxy or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo) and R ya is hydrogen or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo)), substituted or unsubstituted alkyl (e.g., fluoroalkyl), substituted or unsubstituted alkoxy (e.g., fluoroalkoxy), or substituted or unsubstituted heteroalkyl (e.g., alkylamine substituted with oxo and
  • Y 2 is CN, NO2, hydroxy, substituted or unsubstituted amino (e.g., -NR xa R ya -, where R xa is hydroxy or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo) and R ya is hydrogen or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo)), substituted or unsubstituted amido (e.g., -CONR x R y -, where R xa is hydroxy or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo) and R ya is hydrogen or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo)), substituted or unsubstituted alkyl (e.g., fluoroalky
  • Y 2 is hydrogen, CN, NO2, hydroxy, substituted or unsubstituted amino (e.g., -NR xa R ya -, where R xa is hydroxy and R y is hydrogen or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo)), substituted or unsubstituted alkyl (e.g., fluoroalkyl), substituted or unsubstituted alkoxy (e.g., fluoroalkoxy), or substituted or unsubstituted heteroalkyl (e.g., alkylamine substituted with oxo and/or hydroxy)).
  • substituted or unsubstituted amino e.g., -NR xa R ya -, where R xa is hydroxy and R y is hydrogen or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo)), substituted
  • Y 2 is hydrogen, CN, NO2, hydroxy, substituted or unsubstituted amino (e.g., -NR xa R ya -, where R xa is hydroxy or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo) and R ya is hydrogen or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo)), substituted or unsubstituted alkyl (e.g., fluoroalkyl), substituted or unsubstituted alkoxy (e.g., fluoroalkoxy), or substituted or unsubstituted heteroalkyl (e.g., alkylamine substituted with oxo and/or hydroxy)).
  • R xa is hydroxy or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo) and R ya is hydrogen or
  • Y 2 is hydrogen, CN, NO2, hydroxy, substituted amino (e.g., - NR xa R ya -, where R xa is hydroxy and R y is hydrogen or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo)), unsubstituted alkyl (e.g., methyl), substituted alkyl (e.g., alkyl substituted with halo (e.g., fluoroalkyl (e.g., methyl substituted with one, two, or three fluoro))), unsubstituted alkoxy (e.g., methoxy), substituted alkoxy (e.g., alkoxy substituted with halo (e.g., fluoroalkoxy (e.g., methoxy substituted with one, two, or three fluoro))), or substituted heteroalkyl (e.g., alkyl, methyl, methyl substituted
  • Y 2 is hydrogen, CN, NO2, substituted alkoxy (e.g., alkoxy substituted with halo (e.g., fluoroalkoxy (e.g., methoxy substituted with one, two, or three fluoro), or substituted alkyl (e.g., alkyl substituted with halo (e.g., fluoroalkyl (e.g., methyl substituted with one, two, or three fluoro))).
  • halo e.g., fluoroalkoxy (e.g., methoxy substituted with one, two, or three fluoro)
  • substituted alkyl e.g., alkyl substituted with halo (e.g., fluoroalkyl (e.g., methyl substituted with one, two, or three fluoro)
  • Y 2 is hydrogen, CN, NO2, amino (e.g., -NH2), hydroxy, substituted or unsubstituted alkoxy (e.g., methoxy), unsubstituted or substituted heteroalkyl (e.g., alkylamine or heteroalkyl substituted with oxo, such as Me2N(CO)O, MeNHCO-, Me2NCO-, and MeCONH-), unsubstituted alkyl (e.g., methyl), or substituted alkyl (e.g., alkyl substituted with hydroxy or amino (e.g., -NH2), alkyl substituted with oxo and amino (e.g., -C(O)NH2), alkyl substituted with hydroxy and oxo (e.g., -COOH), alkyl substituted with oxo and heterocyclyl (e.g., azetidinyl), alkyl substituted with oxo and
  • Y 2 is unsubstituted alkylamine (e.g., diaminoalkyl), such as -CH2NHMe, -CH2NMe2, and -NHCH2CH2Nme2.
  • Y 2 is heteroalkyl substituted with oxo, such as Me2N(CO)O, MeNHCO-, Me2NCO-, and MeCONH-.
  • Y 2 is substituted alkyl.
  • Y 2 is alkyl substituted with hydroxy or amino (e.g., -NH2).
  • Y 2 is alkyl substituted with oxo and amino (e.g., - C(O)NH2).
  • Y 2 is alkyl substituted with hydroxy and oxo (e.g., -COOH). In some embodiments, Y 2 is alkyl substituted with oxo and heterocyclyl (e.g., -O-C(O)- (azetidinyl)). In some embodiments, Y 2 is alkyl substituted with halo (e.g., fluoroalkyl (e.g., methyl substituted with one, two, or three fluoro))).
  • halo e.g., fluoroalkyl (e.g., methyl substituted with one, two, or three fluoro)
  • Y 2 is hydrogen, CN, NO2, or substituted alkyl (e.g., alkyl substituted with halo (e.g., fluoroalkyl (e.g., methyl substituted with one, two, or three fluoro))).
  • alkyl substituted with halo e.g., fluoroalkyl (e.g., methyl substituted with one, two, or three fluoro)
  • Y 2 is CN, NO2, substituted alkoxy (e.g., alkoxy substituted with halo (e.g., fluoroalkoxy (e.g., methoxy substituted with one, two, or three fluoro), or substituted alkyl (e.g., alkyl substituted with halo (e.g., fluoroalkyl (e.g., methyl substituted with one, two, or three fluoro))).
  • halo e.g., fluoroalkoxy (e.g., methoxy substituted with one, two, or three fluoro)
  • substituted alkyl e.g., alkyl substituted with halo (e.g., fluoroalkyl (e.g., methyl substituted with one, two, or three fluoro)
  • Y 2 is hydrogen, CN, NO2, or CF3.
  • Y 2 is CN, NO2, or CF3.
  • Y 2 is CN or NO2.
  • Y 2 is hydrogen
  • Y 2 is CN
  • Y 2 is NO2.
  • Y 2 is CF3.
  • Y 2 is OCH3.
  • Y 2 is unsubstituted amino.
  • Y 2 is substituted alkoxy. In some embodiments, Y 2 is substituted C1-C3 alkoxy. In some embodiments, Y 2 is -O(CH2)2N(CH3)2.
  • Y 2 is heterocyclyl. In some embodiments, Y 2 is N-heterocyclyl. In some embodiments, Y 2 is pyrrolidine.
  • Y 2 is heteroalkyl. In some embodiments, Y 2 is C1-C3 heteroalkyl. In some embodiments, Y 2 is SCH3.
  • Y 2 is hydrogen, thiol, substituted thioether, substituted alkoxy (e.g., fluoroalkoxy), substituted amino, or NO2
  • the compound interacts with a protein or a mutant thereof at a position other than Y 2 .
  • thiol, substituted thioether, substituted alkoxy (e.g., fluoroalkoxy), substituted amino, or NCh the compound covalently and/or irreversibly interacts with a cysteine residue of the protein or the mutant thereof at a position other than Y 2 .
  • the compound covalently and/or irreversibly interacts with a cysteine residue of the protein or the mutant thereof at a position ortho or meta to Y 2 .
  • K directs binding of a protein (e.g., BTK, EGFR, FGFR, BMX, TEAD, JAK3, KRAS) or a mutant thereof to a position ortho or meta to L or L’ .
  • a protein e.g., BTK, EGFR, FGFR, BMX, TEAD, JAK3, KRAS
  • K directs binding of a protein (e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS) or a mutant thereof to a position ortho to L or L’.
  • K directs binding of a protein (e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS) or a mutant thereof to a position meta to L or L’ .
  • a protein e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS
  • covalently and/or irreversibly directs binding of a cysteine residue of a protein (e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS) or a mutant thereof to a position ortho or meta to L or L’.
  • a cysteine residue of a protein e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS
  • a mutant thereof e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS
  • ⁇ S ⁇ X 2 K covalently and/or irreversibly directs binding of a cysteine residue of a protein (e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS) or a mutant thereof to a position p ortho to L or L’ .
  • Rx covalently and/or irreversibly directs binding of a cysteine residue of a protein (e g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS) or a mutant thereof to a position meta to L or L’ .
  • a warhead group described herein has or comprises a structure shown in Table A:
  • L or L’ is a linker.
  • L or L’ is a bond, -O- , amino (e.g., -NR 2 -, where R 2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl), substituted or unsubstituted alkyl(ene), substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl(ene) (e.g., alkylamine (e.g., -NR 3 R 4 -, where R 3 is substituted or unsubstituted alkyl(ene), substituted or unsubstituted heteroalkyl(ene), substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocycyl and R 4 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl, or substituted or unsub
  • L or L’ is a bond, amino (e.g., -NR 2 -, where R 2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl), substituted or unsubstituted alkyl(ene), substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl(ene) (e.g., alkylamine (e.g., -NR 3 R 4 -, where R 3 is substituted or unsubstituted alkyl(ene), substituted or unsubstituted heteroalkyl(ene), substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocycyl and R 4 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl)), substituted or unsubstituted carbocyclyl, or substituted or unsub
  • L or L’ is a bond, -O-, amino, substituted or unsubstituted alkyl(ene), substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl(ene), substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl.
  • L or L’ is amino, substituted or unsubstituted heteroalkyl(ene), or substituted or unsubstituted heterocyclyl.
  • L or L’ is amino, -O-, substituted or unsubstituted heteroalkyl(ene), or substituted or unsubstituted heterocyclyl.
  • L orL’ is a bond, amino, substituted or unsubstituted alkyl(ene), substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl(ene), substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl. In some embodiments, L or L’ is amino, substituted or unsubstituted heteroalkyl(ene), or substituted or unsubstituted heterocyclyl.
  • L or L’ is amino (e.g., -NR 2 -, where R 2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl), substituted or unsubstituted heteroalkyl(ene) (e.g., alkylamine (e.g., -NR 3 R 4 -, where R 3 is substituted or unsubstituted alkyl(ene), substituted or unsubstituted heteroalkyl(ene), substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocycyl and R 4 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl)), or substituted or unsubstituted heterocyclyl (e.g., - NR 5 R 6 -, where R 5 and R 6 are taken together to form a substituted
  • L or L’ is amino. In some embodiments, L or L’ is -NR 2 -, where R 2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl. In some embodiments, L or L’ is -NH- or -NCH3-. In some embodiments, L or L’ is -NH-.
  • L or L’ is substituted or unsubstituted alkylamine.
  • L or L’ is substituted alkylamine (e.g., alkylamine substituted with oxo, such as - NHC(O)-).
  • L or L’ is unsubstituted alkylamine.
  • L or L’ is methylamine, ethylamine, propylamine, or butylamine.
  • L or L’ is methylamine, ethylamine, or propylamine.
  • the linker (e.g., L or L’) is -NR 4 -R 3 -, -NR 4 -R 3 -NR 7a -, -NR 4 -R 3 - O-, or -C(O)NR 4 -R 3 -, where R 3 is substituted or unsubstituted alkyl(ene), substituted or unsubstituted heteroalkyl(ene), substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocycyl, R 4 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl, and R 7a is H or substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo).
  • L or L’ is -C(O)NH(unsubstituted alkyl)-. In some embodiments, L or L’ is -C(O)NH(methyl)-, -C(O)NH(ethyl)-, or -C(O)NH(propyl)-.
  • L or L’ is -NR 3 R 4 -, where R 3 is substituted or unsubstituted alkyl(ene), substituted or unsubstituted heteroalkyl(ene), substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocycyl and R 4 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl.
  • L or L’ is -NH(heterocyclyl)-. In some embodiments, L is - NH(azetidinyl)-.
  • L or L’ is substituted or unsubstituted heterocyclyl.
  • the linker e.g., L or L’
  • the linker is -NR 5 R 6 -, -NR 5 R 6 -NR 7 -, -NR 5 R 6 -C(O)-, -NR 5 R 6 - CH2NR 7 -, -NR 5 R 6 -CH 2 NR 7 C(O)-, -C(O)NR 5 R 6 -NR 7 -, -C(O)NR 5 R 6 -O-, -NR 5 R 6 -O-, or - C(O)NR 5 R 6 CH2-NR 7 -, where R 5 and R 6 are taken together to form a substituted or unsubstituted heterocyclyl, and R 7 is H, substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo), or alkoxy.
  • R 5 and R 6 are taken together to form a substituted or unsubstituted heterocyclyl
  • R 7 is H, substituted or unsubstituted alkyl (e.g., alkyl substituted with oxo), or alkoxy.
  • L or L’ is -NR 5 R 6 -, where R 5 and R 6 are taken together to form a substituted or unsubstituted heterocyclyl.
  • L or L’ (or -NR 5 R 6 -) is substituted or unsubstituted piperazinyl or substituted or unsubstituted piperidinyl.
  • L or L’ (or -NR 5 R 6 -) is substituted or unsubstituted piperidinyl.
  • L or L’ (or -NR 5 R 6 -) is substituted or unsubstituted piperazinyl.
  • L or L’ (or -NR 5 R 6 -) is piperazinyl substituted with methyl.
  • -NR 5 R 6 - is substituted or unsubstituted piperazinyl (e.g., piperazinyl substituted with methyl), substituted or unsubstituted piperidinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azepanyl, or diazepanyl (e.g., 1,4-diazepanyl).
  • piperazinyl e.g., piperazinyl substituted with methyl
  • piperazinyl substituted with methyl substituted or unsubstituted piperidinyl
  • substituted or unsubstituted azetidinyl substituted or unsubstituted pyrrolidinyl
  • diazepanyl e.g., 1,4-diazepanyl
  • -NR 5 R 6 - is substituted or unsubstituted piperidinyl or substituted or unsubstituted azetidinyl and -NR 7 - is -NH-, -NCH3-, -NC(O)CH3-, or -NCH2CH2OCH3-.
  • L or L’ is -NR 5 R 6 -C(O)- and -NR 5 R 6 - is unsubstituted 1,4- diazepanyl.
  • L or L’ is -C(O)NR 5 R 6 -NR 7 -, -NR 5 R 6 - is unsubstituted piperidinyl or unsubstituted pyrrolidinyl, and -NR 7 - is -NH-.
  • L or L’ is -NR 5 R 6 -CH2NR 7 C(O)-, -NR 5 R 6 - is unsubstituted pyrrolidinyl, and -NR 7 - is -NH-.
  • L or L’ is -NR 5 R 6 -CH2NR 7 -, -NR 5 R 6 - is unsubstituted azetidinyl or azepanyl, and -NR 7 - is -NH-.
  • L or L’ is -NR 5 R 6 -CH2NR 7 C(O)-, -NR 5 R 6 - is unsubstituted azetidinyl, and -NR 7 - is -NH-.
  • L or L’ comprises two N atom(s).
  • L or L’ comprises or is (substituted or unsubstituted) diaminoalkyl, (substituted or unsubstituted) diamino-cycloalkyl, (substituted or unsubstituted) amino-heterocyclyl (e.g., the heterocyclyl being nitrogen containing), (substituted or unsubstituted) heterocyclyl (e.g., containing 2 nitrogen atoms).
  • the heterocyclyl is optionally fused or spirocyclic.
  • L or L’ is or comprises -C(O)-diaminoalkyl-.
  • each amino group of the diaminoalkyl is independently unsubstituted or substituted.
  • each amino group of the diaminoalkyl is independently unsubstituted or substituted with methyl.
  • L or L’ comprises one or more rings. In some embodiments, L or L’ comprises one or more fused or spirocyclic rings.
  • L or L’ is or comprises a spirocyclic ring. In some embodiments, L or L’ is or comprises l,7-diazaspiro[4.5]decane.
  • L or L’ is or comprises substituted or unsubstituted phenyl. In some embodiments, L or L’ is or comprises substituted phenyl. In some embodiments, the phenyl is substituted with substitued with one or more substituent selected from the group consisting of halo, cyano, amino, alkylamino, heteroalkyl (e.g., substituted alkanolamine or substituted diaminoalkyl), -N-(substituted heterocyclyl), and substituted heterocyclyl.
  • substituent selected from the group consisting of halo, cyano, amino, alkylamino, heteroalkyl (e.g., substituted alkanolamine or substituted diaminoalkyl), -N-(substituted heterocyclyl), and substituted heterocyclyl.
  • the phenyl is substituted with substitued halo, cyano, amino, alkylamino, heteroalkyl (e.g., substituted alkanolamine or substituted diaminoalkyl), -N-(substituted heterocyclyl), or substituted heterocyclyl, such as wherein the substituted heterocyclyl is piperidinyl or pyrrolidinyl substituted with amino or alkylamine.
  • L or L’ is -NH-(unsubstituted phenyl)-, -NH-(unsubstituted phenyl)-NH-, -NH-(unsubstituted phenyl)-C(O)-, -CH2NH- (unsubstituted phenyl)-C(O)-, -CH2-(unsubstituted phenyl)-NH-, -NHCH2-(unsubstituted phenyl)-C(O)-, -NHC(O)-(unsubstituted phenyl)-C(O)-, -NH-(substituted phenyl)-C(O)-, - C(O)NH-(substituted phenyl)-C(O)-, -C(O)NH-(substituted phenyl)-C(O)NH-, -NH- (unsubstituted phenyl)-
  • L or L’ is -NH-(unsubstituted phenyl)-, -NH- (unsubstituted phenyl)-C(O)-, -NH-(substituted phenyl)-C(O)-, -NH-(unsubstituted phenyl)- C(O)NH-, or-NH-(substituted phenyl)-C(O)NH-.
  • L or L’ is:
  • L or L’ is a bond
  • a compound e.g., of Formula (I-A) or Formula (I-B)
  • the compound e.g., of Formula (I-A) or Formula (I-B)
  • L is part of G and/or the warhead.
  • a compound e.g., of Formula (I-A) or Formula (I-B)
  • the compound e.g., of Formula (I-A) or Formula (I-B)
  • a compound provided herein has a structure shown in Table 2A, Table 2B, Table 2C, or Table 2D.
  • a compound provided herein such a compound of Formula (A), Formula (I), Formula (I-A), or Formula (I-B) or provided in Table 1A, Table IB, or Table 1C, forms a bond, such as a covalent bond with a polypeptide provided herein.
  • the polypeptide covalently binds to the compound.
  • the polypeptide covalently binds to the compound, wherein the polypeptide comprises a thiol that covalently binds to the compound.
  • the polypeptide covalently binds to the compound, wherein the polypeptide comprises a thiol, such a thiol of a cysteine residue of the polypeptide, that covalently binds to the compound.
  • a compound provided herein has reduced reactivity with GSH. In some embodiments, a compound provided herein has reduced reactivity with GSH (and GSH/GST catalyzed reactions) while still retaining the ability to bind to a (target) polypeptide. In some embodiments, a compound provided herein has increased stability to GSH, such as GSH metabolism in vitro and/or in vivo, such as in liver cells and whole blood. In some embodiments, a compound provided herein has a higher affinity to (e.g., and covalently modifying) the polypeptide (e.g., a target protein described herein) than GSH.
  • GSH has a binding affinity for a compound provided herein (e.g., Kd) of more than 0.1 ⁇ M (e.g., 1 pM, 10 pM, 100 pM, or 1000 ⁇ M or more). In some instances, GSH has a binding affinity for a compound provided herein (e.g., Kd) of more than 10 pM. In some instances, GSH has a binding affinity (e.g., Kd) for a compound provided herein of no less than 10 pM.
  • a compound provided herein e.g., Kd
  • a compound provided herein has reduced reactivity with glutathione (GSH).
  • GSH glutathione
  • a compound provided herein has a reduced reactivity with the sulfur (e.g., thiol) of glutathione (GSH), such as relative to that of a (e.g., sulfur- containing) polypeptide.
  • a compound provided herein is inert glutathione (GSH) metabolism.
  • a compound provided herein does not substantially covalently bind to glutathione (GSH).
  • the lack of substantial covalent binding of the compound to glutathione is demonstrated by the lack of binding of glutathione to the compound, such as measured by glutathione S-trasferase (GST) assay described herein, such as at Example IV.
  • GST glutathione S-trasferase
  • Tables 10A-10F of the Examples demonstrate reactivity (expressed as ICso and WRso values) and selectivity of compounds described herein.
  • Tables 10A-10F show, in some instances, that compounds described herein have reduced reactivity with glutathione (GSH), such as in comparison to a target protein, such as a target protein described herein (e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof).
  • GSH glutathione
  • Tables 10A-10F demonstrate that compounds described herein lack covalent binding to GSH.
  • Tables 10A-10F demonstrate, in some instances, that compounds described herein bind to and/or (e.g., covalently) modify a target protein, such as a target protein described herein (e.g, BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof), without the compound substantially covalently binding to GSH.
  • a target protein described herein e.g, BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof
  • a target protein described herein e.g, BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof
  • the compounds provided herein contact, bind to, and/or modify a target protein, such as a target protein described herein (e g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof), in the absence of any binding, including covalent binding, of GSH to the compounds.
  • a target protein described herein e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof
  • compounds described herein are 10-fold or more selective for a target protein, such as a target protein described herein (e.g, BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof), relative to GSH.
  • compounds described herein are 100-fold or more selective for a target protein, such as a target protein described herein (e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof), relative to GSH.
  • a target protein described herein e.g., BTK, EGFR, FGFR, AURKA, KIT, BMX, TEAD, JAK3, KRAS, or a mutant thereof
  • GSH a target protein described herein
  • a compound provided herein is selective for the polypeptide (e.g., a target protein described herein) relative to glutathione (GSH). In some embodiments, a compound provided herein is selective for binding to the polypeptide (e.g., a target protein described herein) relative to GSH. In some embodiments, a compound provided herein is selective for covalent binding to the polypeptide (e.g, a target protein described herein) relative to GSH.
  • compound provided herein is selective for the polypeptide (e.g, a target protein described herein) relative to GSH at a ratio of at least 10: 1 (e.g, 10: 1 or more, 20: 1 or more, 50: 1 or more, 100: 1 or more, 500: 1 or more, 1000: 1 or more). In some embodiments, the compound is selective for the polypeptide (e.g, a target protein described herein) relative to GSH at a ratio of about 2: 1 to about 1000: 1. In some embodiments, the compound is selective for the polypeptide (e.g, a target protein described herein) relative to GSH at a ratio of about 10: 1 to about 100: 1.
  • a compound provided herein is at least 2-fold more (e.g, 2- fold or more, 5-fold or more, 10-fold or more, 25-fold or more) selective for the polypeptide (e.g, a target protein described herein) relative to GSH. In some embodiments, a compound provided herein is 2-fold to about 100-fold more selective for the polypeptide (e.g., a target protein described herein) relative to GSH. In some embodiments, a compound provided herein is 2-fold to about 50-fold more selective for the polypeptide (e.g., a target protein described herein) relative to GSH.
  • a compound provided herein has a structure represented in Table 2A, Table 2B, Table 2C, or Table 2D.
  • a compound provided herein is stable to GSH modification, such as described herein.
  • a compound provided herein is stable to GSH modification and bind (e.g., covalently) to a polypeptide (e.g., a target protein).
  • a compound provided herein is stable to GSH modification and modifies a polypeptide (e.g., a target protein).
  • a compound provided herein e.g., Compounds 53-61 is stable to GSH modification but does not (e.g., necessarily) bind (e.g., covalently) to a polypeptide (e.g., a target protein).
  • a compound provided herein e.g., Compounds 53-61 is stable to GSH modification but does not (e.g., necessarily) modify a polypeptide (e.g., a target protein).
  • GSH stability is demonstrated in Table 7.
  • Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J.
  • the benzenesulfonamide derivative compound described herein is administered as a pure chemical.
  • the benzenesulfonamide derivative compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • a pharmaceutical composition comprising at least one benzenesulfonamide derivative compound as described herein, or a salt, solvate, tautomer, or regioisomer thereof, and one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (A), Formula (I), Formula (I- A), or Formula (I-B), or a compound disclosed in Table 2A, Table 2B, Table 2C, or Table 2D, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof.
  • a pharmaceutical composition comprising a compound provided herein, such as a compound of Formula (A), Formula (I), Formula (I- A), or Formula (I-B), or a compound disclosed in Table 2A, Table 2B, Table 2C, or Table 2D, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof.
  • a pharmaceutical composition comprising a compound provided herein, such as a compound of Formula (A), Formula (I), Formula (I- A), or Formula (I-B), or a compound disclosed in Table 2A Table 2B, Table 2C, Table 2D, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof.
  • the compound has reduced reactivity with glutathione. In some embodiments, reduced reactivity is described elsewhere herein.
  • a pharmaceutical composition comprising a compound provided herein, such as a compound of Formula (A), Formula (I), Formula (I- A), or Formula (I-B), or a compound disclosed in Table 2A, Table 2B, Table 2C, Table 2D, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof.
  • the compound is selective for a polypeptide relative to glutathione.
  • the compound is selective for a protein relative to glutathione.
  • selectivity for a polypeptide relative to glutathione is described elsewhere herein.
  • a pharmaceutical composition that is (e.g., at least partially) stable to glutathione.
  • the pharmaceutical composition comprises a compound provided herein, such as a compound of Formula (A), Formula (I), Formula (I-A), or Formula (I-B), or a compound disclosed in Table 2A, Table 2B, Table 2C, Table 2D, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof.
  • the pharmaceutical compositions provided herein are stable to glutathione (GSH) in the presence of a polypeptide. In some embodiments, the pharmaceutical compositions are at least partially stable to glutathione (GSH) in the presence of a polypeptide.
  • a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (A), Formula (I), Formula (I-A), or Formula (I-B), or a compound disclosed in Table 2A, Table 2B, or Table 2C, Table 2D, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, and a pharmaceutically acceptable carrier.
  • the benzenesulfonamide derivative compound as described by Formula (A), Formula (I), Formula (I-A), or Formula (I-B), or a compound disclosed in Table 2A, Table 2B, Table 2C, or Table 2D is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract.
  • suitable nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • the compound as described by Formula (A), Formula (I), Formula (I-A), or Formula (I-B), or a compound disclosed in Table 1A, Table IB, or Table 1C, or pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, is formulated for administration by injection.
  • the injection formulation is an aqueous formulation.
  • the injection formulation is a non-aqueous formulation.
  • the injection formulation is an oil-based formulation, such as sesame oil, or the like.
  • the dose of the composition comprising at least one compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.
  • compositions are administered in a manner appropriate to the disease to be treated (or prevented).
  • An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
  • a polypeptide e.g., a target protein described herein
  • a compound provided herein such as in the absence of the compound reacting with glutathione or being metabolized by glutathione.
  • a polypeptide e.g., a target protein described herein
  • GST glutathione S- transferase
  • the method comprises contacting the polypeptide (e.g., a protein) with a compound provided herein, such as a compound of Formula (A), Formula (I), Formula (I- A), or Formula (I-B), or represented in Table 2A, Table 2B, Table 2C, or Table 2D or a pharmaceutically acceptable salt thereof.
  • the method comprises contacting the polypeptide with the compound to form a covalent bond with the polypeptide.
  • the compounds provided herein have reduced reactivity to GSH.
  • the compounds provided herein are selective for the polypeptide over GSH.
  • provided herein are methods of modifying a polypeptide (e.g., a target protein described herein) with a compound provided herein, such as a compound of Formula (A), Formula (I), Formula (I-A), or Formula (I-B), or represented in Table 2A, Table 2B, Table 2C, or Table 2D or a pharmaceutically acceptable salt thereof.
  • a compound provided herein such as a compound of Formula (A), Formula (I), Formula (I-A), or Formula (I-B), or represented in Table 2A, Table 2B, Table 2C, or Table 2D or a pharmaceutically acceptable salt thereof.
  • provided herein are methods of selectively modifying a polypeptide with a compound provided herein.
  • the method comprises contacting the polypeptide with any of the compounds provided herein.
  • the compound has reduced reactivity with glutathione (GSH).
  • provided herein are methods of modifying a polypeptide (e.g., a target protein described herein) with a compound provided herein in the presence of glutathione (GSH).
  • the method comprises contacting the polypeptide with a compound provided herein, such as a compound of Formula (A), Formula (I), Formula (I- A), or Formula (I- B), or represented in Table 2A, Table 2B, Table 2C, or Table 2D, or a pharmaceutically acceptable salt thereof.
  • the method comprises contacting the polypeptide with the compound (or a warhead group thereof) to form a covalent bond with the polypeptide.
  • the method comprises contacting the polypeptide with the compound (or a warhead group thereof) to form a covalent bond with a sulfur atom of a cysteine residue of the polypeptide. In some embodiments, the method comprises contacting the polypeptide with the compound (or a warhead group thereof) without the compound substantially covalently binding to GSH. In some embodiments, the method comprises contacting the polypeptide with the compound (or a warhead group thereof) to form a covalent bond polypeptide without the compound substantially covalently binding to GSH. In some embodiments, the method comprises contacting the polypeptide with the compound (or a warhead group thereof) to form a covalent bond with a sulfur atom of a cysteine residue of the polypeptide, without substantially covalently binding to GSH.
  • provided herein is a method of modifying a polypeptide in the presence of glutathione (GSH) with a compound provided herein, such as a compound of Formula (A), Formula (I), Formula (I-A), or Formula (I-B), or represented in Table 2A, Table 2B, Table 2C, or Table 2D, or a pharmaceutically acceptable salt thereof.
  • a compound provided herein such as a compound of Formula (A), Formula (I), Formula (I-A), or Formula (I-B), or represented in Table 2A, Table 2B, Table 2C, or Table 2D, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of selectively modifying a polypeptide in the presence of glutathione (GSH) with a compound provided herein, such as a compound of Formula (A), Formula (I), Formula (I- A), or Formula (I-B), or represented in Table 2A, Table 2B, Table 2C, or Table 2D, or a pharmaceutically acceptable salt thereof.
  • the method comprises contacting the polypeptide with any of the compounds provided herein.
  • the compound is selective for the polypeptide relative to GSH.
  • the selectivity for the polypeptide relative to GSH is described elsewhere herein.
  • modifying herein comprises forming a bond. In some embodiments, modifying comprises forming a bond between the polypeptide and the compound. In some embodiments, modifying comprises forming a covalent bond. In some embodiments, modifying comprises forming a covalent bond between the polypeptide and the compound. In some embodiments, forming a bond comprises forming a non-covalent bond. In some embodiments, non-covalent bonding comprises electrostatic interactions, hydrogen bonding, Van der Waals interactions, or depletion interactions. In some embodiments, forming a bond comprises an electrostatic interaction. In some embodiments, forming a bond comprises forming a non- covalent bond between the compound and polypeptide and the compound.
  • the method comprises contacting the compound (or a warhead group thereof) with the polypeptide to form a covalent bond with the polypeptide.
  • the method comprises forming a covalent bond with a heteroatom (e.g., a sulfur atom, a nitrogen atom, or an oxygen atom) of the polypeptide.
  • the method comprises forming a covalent bond with a sulfur atom of the polypeptide.
  • the method comprises forming a covalent bond with an oxygen or nitrogen atom of the polypeptide.
  • the method comprises forming a covalent bond with a sulfur atom of a cysteine residue of the polypeptide.
  • the polypeptide covalently binds to the compound (or a warhead group thereof).
  • the method comprises contacting the polypeptide with a compound (or a warhead group thereof) provided herein without the compound substantially covalently binding to glutathione (GSH).
  • GSH glutathione
  • the lack of substantial binding to GSH is demonstrated by the lack of covalent binding of GSH to the compound (as measured using a GST assay described elsewhere herein).
  • the polypeptide contacts the compound (or a warhead group thereof) in the absence of covalent binding of GSH to the compound.
  • the polypeptide covalently binds to the compound (or a warhead group thereof) in the absence of covalent binding of GSH to the compound.
  • glutathione has a half life of at least 1 minute (e.g., 10 minutes or more, 30 minutes or more, 60 minutes or more, 100 minutes or more, or 200 minutes or more), such as in the presence of a compound provided herein.
  • GSH has a half life of at least 10 minutes in the presence of a compound provided herein.
  • GSH has a half life of at least 30 minutes in the presence of a compound provided herein.
  • GSH has a half life of at least 60 minutes in the presence of a compound provided herein.
  • GSH has a half life at least 100 minutes in the presence of a compound provided herein.
  • GSH has a half life of at least 200 minutes in the presence of a compound provided herein. In some embodiments, GSH has a half life of 1 minutes to 200 minutes, such as in the presence of a compound provided herein. In some embodiments, GSH has a half life of about 10 minutes to about 100 minutes, such as in the presence of a compound provided herein. In some embodiments, GSH half-life is measured using a glutathione S-transferase (GST) assay described herein, such as in Example IV.
  • GST glutathione S-transferase
  • a compound provided herein such as a compound of Formula (A), Formula (I), Formula (I-A), or Formula (I-B), or represented in Table 2A, Table 2B, Table 2C, or Table 2D or a pharmaceutically acceptable salt thereof, has an IC50 for a polypeptide (e.g., a target protein described herein) of at least 10 ⁇ M (e.g., 10 ⁇ M or less, 1 ⁇ M or less, 0.1 ⁇ M or less).
  • a polypeptide e.g., a target protein described herein
  • a compound provided herein has an IC50 for a polypeptide (e.g., a target protein described herein) of at least 10 ⁇ M (e.g., 10 ⁇ M or less, 1 ⁇ M or less, 0.1 ⁇ M or less, or 0.01 ⁇ M or less). In some embodiments, a compound provided herein has an IC50 for a polypeptide (e.g., a target protein described herein) of 1 ⁇ M or less. In some embodiments, a compound provided herein has an IC50 for a polypeptide (e.g., a target protein described herein) of 0.1 ⁇ M or less.
  • a compound provided herein has an IC50 for a polypeptide (e.g., a target protein described herein) of 0.01 ⁇ M or less. In some embodiments, a compound provided herein has an IC50 for a polypeptide (e.g., a target protein described herein) of about 0.01 ⁇ M to about 10 pM.
  • a compound provided herein such as a compound of Formula (A), Formula (I), Formula (I-A), or Formula (I-B), or represented in Table 2A, Table 2B, Table 2C, or Table 2D or a pharmaceutically acceptable salt thereof has an IC50 for a polypeptide (e.g., a target protein described herein) of at least 10 ⁇ M and a GSH half life of greater than about 10 minutes (e.g., IC50 of at least 1 ⁇ M and a GSH half life of greater than about 10 minutes (e.g., IC50 of at least 0.1 ⁇ M and a GSH half life of greater than about 100 minutes)).
  • a polypeptide e.g., a target protein described herein
  • a GSH half life of greater than about 10 minutes e.g., IC50 of at least 1 ⁇ M and a GSH half life of greater than about 10 minutes (e.g., IC50 of at least 0.1 ⁇ M and a GSH half life of
  • a compound provided herein has a an IC50 for a polypeptide (e.g., a target protein described herein) of 1 ⁇ M or less and a GSH half life of about 10 minutes or more. In some embodiments, a compound provided herein has a IC50 for a polypeptide (e.g., a target protein described herein) of 0.1 ⁇ M or less and a GSH half life of about 100 minutes or more. In some embodiments, a compound provided herein has a IC50 for a polypeptide (e.g., a target protein described herein) of 0.01 ⁇ M or less and a GSH half life of about 200 minutes or more.
  • a polypeptide e.g., a target protein described herein
  • a compound provided herein has an IC50 for a polypeptide (e.g., a target protein described herein) of about 0.01 ⁇ M to about 10 ⁇ M (e.g., about 0.1 ⁇ M to about 10 pM, about 0.1 ⁇ M to about 1 pM) and a GSH half life of about 10 minutes to about 200 minutes (e.g., about 30 minutes to about 100 minutes, e.g., about 50 minutes to about 100 minutes).
  • a polypeptide e.g., a target protein described herein
  • a GSH half life e.g., about 10 minutes to about 200 minutes (e.g., about 30 minutes to about 100 minutes, e.g., about 50 minutes to about 100 minutes).
  • the polypeptides described herein is a protein.
  • the polypeptide comprises natural and/or non-natural amino acid residues.
  • the polypeptide comprises natural amino acid residues.
  • the polypeptide comprises cysteine (e.g., a cysteine residue), such as a nucleophilic cysteine.
  • the polypeptide comprises methionine (e.g., a methionine residue).
  • the polypeptide comprises non-natural amino acids.
  • the polypeptide comprises non-natural amino acid residues.
  • the polypeptide comprises homocysteine.
  • the polypeptide comprises sulfur containing amino acids. In some embodiments, the polypeptide comprises a thiol, such as a nucleophilic thiol. [00484] In some embodiments, the polypeptides described herein comprise a nucleophile. In some embodiments, the polypeptide (e.g., target protein provided herein) comprises a sulfur, oxygen, or nitrogen containing nucleophile. In some embodiments, the polypeptide (e.g., target protein provided herein) comprises a sulfur containing nucleophile. In some embodiments, the polypeptide (e.g., target protein provided herein) comprises a cysteine nucleophile.
  • the polypeptide comprises a cysteine residue, such as cysteine nucleophile.
  • the polypeptide e.g., target protein provided herein
  • the polypeptide comprises a methionine nucleophile.
  • the polypeptide e.g., target protein provided herein
  • the polypeptide comprises an oxygen containing nucleophile.
  • the polypeptide e.g., target protein provided herein
  • the polypeptide e.g., target protein provided herein
  • the polypeptide (e.g., target protein provided herein) comprises a tyrosine nucleophile. In some embodiments, the polypeptide (e.g., target protein provided herein) comprises a nitrogen containing nucleophile. In some embodiments, the polypeptide (e.g., target protein provided herein) comprises an amino containing nucleophile, such as an amino of a lysine residue. In some embodiments, the polypeptide (e.g., target protein provided herein) comprises a lysine nucleophile.
  • a polypeptide provided herein is Bruton’s tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), aurora kinase A (AURKA), proto-oncogene c-KIT (KIT), or BMX non-receptor tyrosine kinase (BMX).
  • the polypeptide is Bruton’s tyrosine kinase (BTK).
  • the polypeptide is epidermal growth factor receptor (EGFR).
  • the polypeptide is fibroblast growth factor receptor (FGFR).
  • the polypeptide is aurora kinase A (AURKA). In some embodiments, the polypeptide is proto- oncogene c-KIT (KIT). In some embodiments, the polypeptide is BMX non-receptor tyrosine kinase (BMX). In some embodiments, the polypeptide is transcriptional enhancer factor TEF (TEAD). In some embodiments, the polypeptide is Janus kinase 3 (JAK3).
  • the polypeptide reacts (e.g., forms a bond with) with a compound provided herein. In some embodiments, the polypeptide reacts (e.g., forms a bond with) with a compound of Formula (A), or Formula (I), Formula (I-A), or Formula (I-B), or represented in Table 2A, Table 2B, Table 2C, or Table 2D.
  • the thiol of the polypeptide reacts (e.g., forms a bond with) with a compound provided herein. In some embodiments, the thiol of the polypeptide reacts (e.g., forms a bond) with a compound of Formula (A), or Formula (I), Formula (I-A), or Formula (I-B), or represented in Table 2A, Table 2B, Table 2C, or Table 2D.
  • the methods provided herein further comprise inhibiting, deactivating, or degrading the polypeptide. In some embodiments, the method further comprises inhibiting the polypeptide. In some embodiments, the method further comprises deactivating the polypeptide. In some embodiments, the method further comprises degrading the polypeptide. In some instances, contacting of the polypeptide with any of the compounds provided herein inhibits, deactivates, or degrades the polypeptide. In some embodiments, binding of the polypeptide inhibits, deactivates, or degrades the polypeptide.
  • covalent binding of the polypeptide inhibits, deactivates, or degrades the polypeptide.
  • the polypeptide is inhibited or deactivated by a factor of at least 2 (e.g., 2 or more, 3 or more, 4 or more, 5 or more).
  • a method of modifying comprising contacting the polypeptide with the compound to form a covalent bond with a sulfur atom of a cysteine residue of the polypeptide.
  • the method provides for selectively modifying a polypeptide with a compound.
  • the selectivity is for a sulfur-containing nucleophile of the protein over other (e.g., intracellular) sulfur-containing nucleophiles (e.g., in a biological system).
  • modifying comprises covalent modification of the polypeptide, such as a protein.
  • modifying a polypeptide occurs intracellularly.
  • a method of binding a compound to a polypeptide comprising contacting the polypeptide with a benzenesulfonamide derivative compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof.
  • the protein is BTK.
  • the protein is EGFR.
  • the protein is FGFR.
  • the protein is AUKRA.
  • the protein is KIT.
  • the protein is BMX.
  • the protein is TEAD.
  • the protein is JAK3.
  • the protein is KRAS.
  • a method of disrupting a protein, or an active fragment thereof comprising contacting the protein or an active fragment thereof (e.g., polypeptide thereof) with a compound described herein, or a salt, solvate, tautomer, or regioisomer thereof.
  • described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (A), Formula (I), Formula (I-A), or Formula (I-B), or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof.
  • described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound disclosed in Table 2A, Table 2B, Table 2C, or Table 2D, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof.
  • a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (A), Formula (I), Formula (I-A), or Formula (I-B), or provided in Table 2A, Table 2B, Table 2C, or Table 2D, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (A), Formula (I), Formula (I-A), or Formula (I-B), or provided in Table 2A, Table 2B, Table 2C, or Table 2D, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, and a pharmaceutically acceptable excipient.
  • a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound disclosed in Table 2A, Table 2B, Table 2C, or Table 2D, or a pharmaceutically acceptable salt, solvate, tautomer, or regioisomer thereof, and a pharmaceutically acceptable excipient.
  • the cancer is selected from chronic and acute myeloid leukemia.
  • the cancer is selected from chronic lymphocytic leukemia and small lymphocytic lymphoma.
  • the protein is BTK.
  • the protein is EGFR.
  • the protein is FGFR.
  • the protein is AURKA.
  • the protein is KIT.
  • the protein is BMX.
  • the protein is TEAD.
  • the protein is JAK3.
  • the protein is KRAS.
  • a method of modifying comprising contacting the polypeptide with the compound to form a covalent bond with a sulfur atom of a cysteine residue of the polypeptide.
  • a method of binding a compound to KRAS or an active fragment thereof comprising contacting the polypeptide with a benzenesulfonamide derivative compound as described herein.
  • the benzenesulfonamide derivative compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the specification, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:
  • NMR nuclear magnetic resonance pH potential of hydrogen a measure of the acidity or basicity of an aqueous solution
  • THF tetrahydrofuran [00506]
  • Exemplary compounds of the application are synthesized using the methods described herein, or other methods, which are known in the art. Unless otherwise noted, reagents and solvents are obtained from commercial suppliers.
  • Anhydrous solvents methanol, acetonitrile, dichloromethane, tetrahydrofuran and dimethylformamide, are purchased from Sigma Aldrich and used directly from Sure-Seal bottles. Reactions are performed under an atmosphere of dry nitrogen in oven-dried glassware and are monitored for completeness by thin-layer chromatography (TLC) using silica gel (visualized by UV light, or developed by treatment with KMnCh stain and ninhydrin stain) or by LC/MS.
  • TLC thin-layer chromatography
  • LCMS Method I Mobile phase is a linear gradient consisting of a changing solvent composition of 5 % to 98% ACN in H2O with 10 mM NH4HCO3 over 2.5 minutes. Method was run on a Phenomenex Kinetex EVO C18 (50 x 3.0 mm), 2.6 pm column; column maintained at a temperature of 30°C; flow rate of 0.8 mL/min.
  • LCMS Method II Mobile phase is a linear gradient consisting of a changing solvent composition of 5 % to 95% ACN in H2O with 0.1 % Formic acid (v/v) over 2.5 minutes. Method was run on an Agilent ZORBAX ECLIPSE PLUS C18 (50 x 2.1 mm), 1.8 pm column; column maintained at a temperature of 30°C; flow rate of 0.7 mL/min.
  • rpHPLC reversed-phase HPLC
  • HPLC was performed with a Shimadzu LC Prominence-I series with PDA (210 - 400 nm) and ELSD detectors or Agilent 6120 Mass detector and Diode array Detector. The following conditions were employed for analysis by rpHPLC, UPLC, HPLC, and LCMS:
  • Method I Mobile phase is a linear gradient consisting of a changing solvent composition of 10 % to 90% ACN in H2O with 0.1 % TFA (v/v) over 9 minutes, followed by 5 minutes of 100% ACN. Method was run on a Welch Xtimate 5 pm C18, 150 mm x 4.6 mm column; maintained at a temperature of 30°C; flow rate of 1.0 mL/min.
  • Method II Mobile phase is a linear gradient consisting of a changing solvent composition of 10 % to 90% ACN in H2O with 0.1 % Ammonia (v/v) over 7 minutes, followed by 5 minutes of 100% ACN. Method was run on a Waters Atlantis 5 pm C18, 150 mm x 4.6 mm column; maintained at a temperature of 30°C; flow rate of 1.0 mL/min.
  • Method III Mobile phase is a linear gradient consisting of a changing solvent composition of 15 % to 100% ACN in H2O with 0.1 % TFA (v/v) over 15 minutes. Method was run on a Phenom enex Luna ⁇ m C18 150 mm x 4.6 mm column; column maintained at a temperature of 25°C; flow rate of 1.0 mL/min.
  • Method IV Mobile phase is a linear gradient consisting of a changing solvent composition of 5 % to 100% ACN in FLO with 0.1 % Formic acid (v/v) over 10 minutes. Method was run on a X-Select C18 (4.6 * 150mm), 5 ⁇ m column; column maintained at a temperature of 25°C; flow rate of 2.0 mL/min.
  • Sulfonyl chloride 1 Synthesis of 4-cyano-2,3,5,6-tetrafluorobenzenesulfonyl chloride. Benzyl mercaptan Trichloraisocyanuric DtPEA. Dioxane add. ACN, ACOH 100 X*, 2h Water, RT, 2h sw5 *
  • Step-2 Synthesis of 4-cyano-2,3,5,6-tetrafluorobenzenesulfonyl chloride
  • Sulfonyl chloride 2 Synthesis of 2,3,5,6-tetrafluoro-4-(methylcarbamoyl)benzenesulfonyl chloride
  • Step-2 Synthesis of 2,3,5,6-tetrafluoro-4-(methylcarbamoyl)benzenesulfonyl chloride
  • Step-2 Synthesis of benzyl(4-(difluoromethoxy)-2,3,5,6-tetrafluorophenyl)sulfane
  • Step-1 Synthesis of benzyl(2,3,5,6-tetrafluorophenyl)sulfane
  • Step-2 Synthesis of benzyl(2,3,5,6-tetrafluoro-4-methylphenyl)sulfane
  • Step-3 Synthesis of 2,3,5,6-tetrafluoro-4-methylbenzenesulfonyl chloride [00527] Prepared by a method analogous to Sulfonyl chloride 2, Step-2 using benzyl(2, 3,5,6- tetrafluoro-4-methylphenyl)sulfane (0.500 g, 1.736 mmol). Yield (223 mg, crude).
  • Step-2 Synthesis of methyl 4-(benzylthio)-2,3,5,6-tetrafluorobenzoate
  • Step-3 Synthesis of methyl 4-(chlorosulfonyl)-2,3,5,6-tetrafluorobenzoate.
  • methyl 4-(benzylthio)-2,3,5,6-tetrafluorobenzoate (0.500 g, 1.515 mmol) was dissolved in a solution of Acetic acid (8 mL) and Water (2 mL) at room temperature. The above solution was cooled to 0 °C. l,3-Dichloro-5,5-dimethylhydantoin (0.587 g, 0.303 mmol) was added portion wise to the above solution. The reaction mixture was gradually brought to room temperature and stirred for 1 hour. After completion, the reaction mixture was diluted with IN aqueous HC1 (100 mL) and the aqueous layer was extracted with Ethyl acetate (2 x 100 mL).
  • Step-1 Synthesis of benzyl(2,3,5,6-tetrafluoro-4-nitrophenyl)sulfane
  • Step-4 Synthesis of 4-acetamido-2,3,5,6-tetrafluorobenzenesulfonyl chloride
  • Step-2 Synthesis of 4-(benzylthio)-2,3,5,6-tetrafluorophenyl dimethylcarbamate
  • Step-2 Synthesis of benzyl(2,3,5,6-tetrafluoro-4-methoxyphenyl)sulfane
  • Sulfonyl chloride 10 Synthesis of 4-(chlorosulfonyl)-2,3,5,6-tetrafluorophenyl azetidine-1- carboxylate
  • Step-1 Synthesis of 4-bromo-2,3,5,6-tetrafluorophenyl azetidine-l-carboxylate
  • Step-2 Synthesis of 4-(benzylthio)-2,3,5,6-tetrafluorophenyl azetidine-l-carboxylate
  • Step-3 Synthesis of 4-(chlorosulfonyl)-2,3,5,6-tetrafluorophenyl azetidine-l-carboxylate
  • Step-3 Synthesis of benzyl(3-(difluoromethoxy)-2,4,5,6-tetrafluorophenyl)sulfane
  • Step-4 Synthesis of 3-(difluoromethoxy)-2,4,5,6-tetrafluorobenzenesulfonyl chloride
  • Sulfonyl chloride 12 Synthesis of 2,3,6-trifluoro-5-(methylcarbamoyl)benzenesulfonyl chloride
  • Sulfonyl chloride 13 Synthesis of 2,3,5,6-tetrafluoro-4-(trifluoroniethyl)benzenesulfonyl chloride
  • Step-1 Synthesis of benzyl(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)sulfane
  • Step-2 Synthesis of 2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzenesulfonyl chloride
  • Sulfonyl chloride 14 2,3,5,6-tetrafluoro-4-nitrobenzenesulfonyl chloride
  • the prepared lithium thiolate was added slowly via cannula to a solution of l,2,3,4,5-pentafluoro-6-nitro- benzene (3.43 g, 16.1 mmol, 2.0 eq.) in THF (17.5 M) at -78 °C and the reaction stirred while gradually warming to rt over 12 hrs. The mixture was quenched with water, and the aqueous phase extracted twice with EtOAc. The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude material was purified via reverse-phase column chromatography, eluting with 5% ACN in Water (0.1% FA), to yield the product as a brown solid (0.66 g, 2.1 mmol, 26% yield).
  • Neat l,3-dichloro-5,5-dimethyl-imidazolidine-2, 4-dione (830 mg, 4.2 mmol, 2 eq.) was added to an ice cold solution of benzyl(2,3,5,6-tetrafluoro-4-nitrophenyl)sulfane (668 mg, 2.11 mmol, 1 eq.) in CH3CN/ACOH/H2O (12.5 mL/0.54 mL/0.37 mL). The resulting pale yellow mixture was stirred at 0 °C for 4 hours, then warmed to r.t. overnight.
  • Step-1 Synthesis of 2,3,5,6-tetrafluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide
  • Step-2 Synthesis of 4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2,3,5,6-tetrafluorobenzoic acid
  • Step-4 Synthesis of 2,3,5,6-tetrafluoro-N,N-bis(4-methoxybenzyl)-4-((methylamino) methyl) benzene sulfonamide
  • Step-6 Synthesis of tert-butyl methyl(2,3,5,6-tetrafluoro-4-sulfamoylbenzyl)carbamate
  • Step-1 Synthesis of 2,3,5,6-tetrafluoro-4-(hydroxymethyl)-N,N-bis(4-methoxybenzyl) benzene sulfonamide
  • Step-2 Synthesis of 2,3,5,6-tetrafluoro-4-(hydroxymethyl)benzenesulfonamide:
  • Step-2 Synthesis of tert-butyl (tert-butoxycarbonyl)(2,3,5,6-tetrafluoro-4- sulfamoylbenzyl)carbamate
  • Sulfonyl Fluoride F Synthesis of 2-(2,3,5,6-tetrafluoro-4-pyrrolidin-l-yl- phenyl)sulfonylpyridine (Compound 24)
  • Step-1 Synthesis of l,2,4,5-tetrafluoro-3-((4-nitrophenyl)sulfonyl)benzene
  • Step-2 Synthesis of l,2,4,5-tetrafluoro-3-((4-nitrophenyl)sulfonyl)benzene
  • Step-4 Synthesis of di-tert-butyl (4-((2,3,5,6-tetrafluorophenyl)sulfonyl)phenyl)carbamate
  • TEA 4-((2,3,5,6-tetrafluorophenyl)sulfonyl)aniline (3.19g, 10.45mmol) in THF (100mL) were sequentially added TEA (2.11g, 20.91mmol), boc anhydride (4.56g, 20.91mmol) and DMAP (0.127g, 1.05mmol) at 0°C temperature.
  • TEA TEA
  • boc anhydride 4.56g, 20.91mmol
  • DMAP 0.127g, 1.05mmol
  • Step-5 Synthesis of tert-butyl (4-((2,3,5,6-tetrafluoro-4- (methylthio)phenyl)sulfonyl)phenyl)carbamate
  • Step-6 Synthesis of 4-((2,3,5,6-tetrafluoro-4-(methylthio)phenyl)sulfonyl)aniline
  • Step 1 Synthesis of tert-butyl 4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-l- carboxylate
  • Step-1 Synthesis of tert-butyl(R)-4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)azepane-l- carboxylate
  • Step-1 Synthesis of tert-butyl ((ls,4s)-4-((7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)carbamate
  • Step-2 Synthesis of (ls,4s)-Nl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-l,4-diamine
  • tert-butyl ((ls,4s)-4-((7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)carbamate 1.0 g, 3.017 mmol
  • DCM 10 mL
  • TFA 3 mL
  • Step-1 Synthesis of tert-butyl (l-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidin-4-yl)carbamate
  • Step-2 Synthesis of l-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-4-amine
  • Step-1 Synthesis of tert-butyl (l-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidizetidinen-4-yl)azetidin-3-yl)carbamate
  • Step-2 Synthesis of l-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidizetidinen-4-yl)azetidin-3-amine
  • Step-1 Synthesis of tert-butyl (l-(6-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylazetidin-3-yl)carbamate
  • Step-2 Synthesis of l-(6-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylazetidin-3-amine
  • Step-1 Synthesis of ethyl 8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolizine-3- carboxylate
  • Step-2 Synthesis of ethyl 8-(l-methyl-6-(trifluoromethyl)-lH-benzo[d]imidazol-5- yl)indolizine-3-carboxylate
  • Step-3 Synthesis of tert-butyl 4-(8-(l-methyl-6-(trifluoromethyl)-lH-benzo[d]imidazol-5- yl)indolizine-3-carbonyl)piperazine-l-carboxylate
  • reaction mixture was stirred at 0°C temperature for 30 min under N2 atm followed by addition of ethyl 8-(l-methyl-6-(trifluoromethyl)-lH- benzo[d]imidazol-5-yl) indolizine-3 -carboxylate (1.0g, 2.58mmol) in toluene (5mL).
  • the reaction mixture was stirred at 90°C temperature for Ih.
  • the reaction mixture was cooled to room temperature and diluted with sat. NaHCO 3 (100mL).
  • the resulting suspension was extracted with ethyl acetate (3xl00mL).
  • Step-4 Synthesis of (8-(l-methyl-6-(trifluoromethyl)-lH-benzo[d]imidazol-5-yl)indolizin- 3-yl)(piperazin-l-yl)methanone
  • Step-1 Synthesis of 8-(l-methyl-6-(trifluoromethyl)-lH-benzo[d]imidazol-5-yl)indolizine- 3-carboxylic acid
  • Step-2 Synthesis of tert-butyl (2-(8-(l-methyl-6-(trifluoromethyl)-lH-benzo[d]imidazol-5- yl)indolizine-3-carboxamido)ethyl)carbamate
  • Step-3 Synthesis of N-(2-aminoethyl)-8-(l-methyl-6-(trifluoromethyl)-lH- benzo[d]imidazol-5-yl)indolizine-3-carboxamide
  • Step-1 Synthesis of tert-butyl (3-(8-(l-methyl-6-(trifluoromethyl)-lH-benzo[d]imidazol-5- yl)indolizine-3-carboxamido)propyl)carbamate
  • Step-2 Synthesis of N-(3-aminopropyl)-8-(l-methyl-6-(trifluoromethyl)-lH- benzo [d] imidazol-5-yl)indolizine-3-carboxamide hydrochloride
  • Step-1 Synthesis of tert-butyl ((l-(8-(l-methyl-6-(trifluoromethyl)-lH-benzo[d]imidazol-5- yl)indolizine-3-carbonyl)azetidin-2-yl)methyl)carbamate
  • Step-2 Synthesis of (2-(aminomethyl)azetidin-l-yl)(8-(l-methyl-6-(trifluoromethyl)-lH- benzo [d] imidazol-5-yl)indolizin-3-yl)methanone
  • Step-1 Synthesis of 3-bromo-2-methyl-l-(2-(4-nitrophenyl)-2-oxoethyl)pyridin-l-ium bromide salt
  • 2-bromo-l-(4-nitrophenyl)ethan-l-one (20.0g, 81.95mmol) in THF (200mL) was added 3-bromo-2-methylpyridine (28.2g, 163.90mmol) at room temperature.
  • the reaction mixture was heated at 80°C for 32h. After completion of the reaction, the reaction mixture was cooled to room temperature.
  • the resulting suspension was filtered and washed with hexane.
  • reaction mixture was stirred for Ih at room temperature followed by addition of DIPEA (23.52mL, 135.29mmol) over a period of Ih. After completion of the reaction, the reaction mixture was poured into ice-cold water to precipitate out the product. The obtained precipitate was filtered off and washed with hexane to afford the title compound as an orange solid (11g, 31.87mmol, 94% yield).
  • Step-3 Synthesis of (4-nitrophenyl)(8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indolizin-3-yl)methanone
  • the resulting suspension was filtered through celite bed and washed with ethyl acetate (100mL).
  • the obtained filtrate was concentrated under reduced pressure to obtain the crude.
  • the obtained crude was purified by flash column chromatography, product eluted with 10-15% ethyl acetate in hexane to afford the title compound as a yellow solid (1.2g, 3.06mmol, 42% yield).

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Abstract

L'invention concerne des composés de benzènesulfonamide, des compositions pharmaceutiques comprenant des composés de benzènesulfonamide, et des méthodes d'utilisation desdits composés pour modifier des polypeptides, lesdits composés ayant une réactivité réduite avec le glutathion.
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WO2021084765A1 (fr) 2019-10-31 2021-05-06 Taiho Pharmaceutical Co., Ltd Dérivés de 4-aminobut-2-enamide et sels de ces derniers
WO2021085653A1 (fr) 2019-10-31 2021-05-06 Taiho Pharmaceutical Co., Ltd. Dérivés de 4-aminobut-2-enamide et sels de ces derniers

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LT6064B (lt) * 2012-10-15 2014-08-25 Vilniaus Universitetas Fluorinti benzensulfonamidai kaip karboanhidrazės inhibitoriai
WO2020047042A1 (fr) * 2018-08-28 2020-03-05 University Of Louisville Research Foundation Polymères organiques en tant que photocatalyseurs
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WO2022204536A1 (fr) * 2021-03-26 2022-09-29 Bolt Biotherapeutics, Inc. Immunoconjugués de 2-amino-4-carboxamide-benzazépine et leurs utilisations
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WO2021084765A1 (fr) 2019-10-31 2021-05-06 Taiho Pharmaceutical Co., Ltd Dérivés de 4-aminobut-2-enamide et sels de ces derniers
WO2021085653A1 (fr) 2019-10-31 2021-05-06 Taiho Pharmaceutical Co., Ltd. Dérivés de 4-aminobut-2-enamide et sels de ces derniers

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