WO2024259169A1 - Modulateurs à base de pyrimidine et leurs utilisations - Google Patents

Modulateurs à base de pyrimidine et leurs utilisations Download PDF

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WO2024259169A1
WO2024259169A1 PCT/US2024/033907 US2024033907W WO2024259169A1 WO 2024259169 A1 WO2024259169 A1 WO 2024259169A1 US 2024033907 W US2024033907 W US 2024033907W WO 2024259169 A1 WO2024259169 A1 WO 2024259169A1
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compound
salt
alkyl
optionally substituted
heterocycle
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Hong Lin
Juan Luengo
Audrey HOSPITAL
Jin Zeng
Pei Gan
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Quanta Therapeutics Inc
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Quanta Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/20—Spiro-condensed systems
    • 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
    • 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

Definitions

  • KRAS The small GTPase protein Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
  • MAPK mitogen-activated protein kinase
  • Ras has been recognized as a target in cancer for about 40 years, Ras-driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies.
  • Ras encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP-bound state.
  • KRAS G12D The most common Ras mutation found across human tumor types is KRAS G12D (e.g., see The AACR Project GENIE Consortium. Cancer Discovery, 2017. 7(8): p. 818-831. Dataset Version 4).
  • Activating mutations in codon 12 impair the small GTPases’ ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression.
  • GAP GTPase activating protein
  • GEF guanine nucleotide exchange factor
  • SOS guanine nucleotide exchange factor
  • KRAS G12C mutations most common in lung adenocarcinoma, have been clinically shown to be susceptible to direct inhibition by covalent modification with small molecule inhibitors trapping the protein in the inactive GDP -bound state.
  • KRAS G12D mutation confers a significantly slower intrinsic rate of GTP hydrolysis than G12C, resulting in more constitutive activation.
  • the present disclosure provides a compound represented by the structure of Formula (I): Formula (I), or a pharmaceutically acceptable salt thereof wherein:
  • R 100 is selected from
  • R 1A is selected from Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of R 1A come together to form a C3-C6 carbocycle or 3- to 8- membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 11A ;
  • R 1B is selected from hydrogen, Ci-6 alkyl, C3-C6 carbocycle, 4- to 6-membered heterocycle, wherein the Ci-6 alkyl and C3-C6 carbocycle, and 4- to 6-membered heterocycle, are each independently optionally substituted with one or more R 10 ;
  • R 1C is selected from hydrogen, Ci-6 alkyl, C3-Ci 2 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 12 , and wherein optionally two R 12 on the same atom of R 1C come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 12A ;
  • R 1D is selected from hydrogen, Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 13 , and wherein optionally two R 13 on the same atom of R 1D come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 13A ;
  • Y is selected from a bond, -0-, -S-, and -N(R 5 )-;
  • R 100 is selected from
  • R 1A is selected from Ci-6 alkyl, Cs-Ci 2 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of R 1A come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 11A ;
  • R 1B is selected from hydrogen, Ci-6 alkyl, C3-C6 carbocycle, wherein the Ci-6 alkyl and C3- C ⁇ > carbocycle are each independently optionally substituted with one or more R 10 ;
  • R 1C is selected from hydrogen, Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 12 , and wherein optionally two R 12 on the same atom of R 1C come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 12A ;
  • R 1D is selected from hydrogen, Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 13 , and wherein optionally two R 13 on the same atom of R 1D come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C -C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 13A ;
  • Y is selected from a bond, -O-, -S-, and -N(R 5 )-;
  • Formula (I) is represented by Formula (I-A): Formula (I-A), or a pharmaceutically acceptable salt thereof.
  • Formula (I) is represented by Formula (I-B): or a pharmaceutically acceptable salt thereof.
  • Formula (I) is represented by Formula (I-C): Formula (I-C), or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), and a pharmaceutically acceptable excipient.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I- C). In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), and a pharmaceutically acceptable excipient. In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a pharmaceutical composition compromising a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C).
  • the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (I), Formula (I-A), Formula (I- B), or Formula (I-C). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a pharmaceutical composition compromising a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), and a pharmaceutically acceptable excipient.
  • C x-y or “C x -C y ” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • a chemical moiety such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • Ci-ealkyl or “Ci.Cealkyl” refers to saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.
  • -Ci-6 alkyl or Ci-Cg alkyl may be selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl, any one of which is optionally substituted.
  • the term -C x.y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain.
  • -Ci-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (i.e., C1-C13 alkyl).
  • an alkyl comprises one to eight carbon atoms i.e., Ci-Cs alkyl).
  • an alkyl comprises one to five carbon atoms (i.e., C1-C5 alkyl).
  • an alkyl comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms i.e., Cs-Cs alkyl).
  • an alkyl comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1 -propyl (//-propyl), 1 -methylethyl (z'so-propyl), 1 -butyl (//-butyl), 1 -methylpropyl (s c-butyl), 2-methylpropyl (/.w-butyl), 1,1 -dimethylethyl (Z / Z-butyl).
  • 1-pentyl (//-pentyl). The alkyl is attached to the rest of the molecule by a single bond.
  • 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 preferably having from two to twelve carbon atoms (i.e., C2-C12 alkenyl).
  • an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl).
  • an alkenyl comprises two to six carbon atoms (i.e., C2-G, alkenyl).
  • an alkenyl comprises two to four carbon atoms (i.e., C2-C4 alkenyl).
  • alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-1, 4-dienyl, and the like.
  • ethenyl i.e., vinyl
  • prop-l-enyl i.e., allyl
  • but-l-enyl i.e., pent-l-enyl, penta-1, 4-dienyl, and the like.
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl).
  • an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl).
  • an alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl).
  • an alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl).
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • C x -yalkenyl and “Cx- y alkynyl” as used herein refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • the term -C x.y alkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain.
  • -C2-salkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted.
  • An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain.
  • the term -C x-y alkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain.
  • -C2-ealkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted.
  • An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.
  • Alkylene refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably 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 the terminal carbons respectively.
  • an alkylene comprises one to five carbon atoms (z.e., C1-C5 alkylene).
  • an alkylene comprises one to four carbon atoms (ie., Ci- C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom i.e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene).
  • an alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more substituents such as those substituents described herein.
  • alkenylene refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms.
  • the alkenylene 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 alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively.
  • an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene).
  • an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., Cj-Cs alkenyl ene).
  • an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene) Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more substituents such as those substituents described herein.
  • Alkynylene refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms.
  • the alkynylene 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 alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively.
  • an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (z.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms i.e., C5- C « alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5 alkynylene).
  • alkynylene chain is optionally substituted by one or more substituents such as those substituents described herein.
  • substituents such as those substituents described herein.
  • Halo or "halogen” as used herein refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • haloalkanes examples include halom ethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., tri chloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens.
  • each halogen may be independently selected, for example I-chloro,2-bromoethane.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane- 1,2-diamine, pentane- 1, 2, 4-triamine and the like
  • Hydroxy alkyl refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-l-ol, butane- 1 ,4-diol, pentane- 1, 2, 4-triol, and the like.
  • Alkoxyalkyl refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1 -methoxypropane, 2-ethoxypentane, and the like.
  • Cyanoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3-methylsuccinonitrile, butyronitrile, and the like.
  • Carbocycle refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon atom.
  • Carbocycle includes 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings.
  • Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • an aromatic ring e.g., phenyl
  • a bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits.
  • a bicyclic carbocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl.
  • Bicyclic carbocycles may be fused, bridged, or spiro-ring systems. In some cases, spiro-ring carbocycles have at least two molecular rings with only one common atom.
  • Aryl refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.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.
  • unsaturated carbocycle refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles.
  • unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.
  • Cycloalkyl refers to a fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve 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 may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • C x-y carbocycle is meant to include groups that contain from x to y carbons in the cycle.
  • C3-6 carbocycle refers to a saturated, unsaturated, or aromatic ring comprising from 3 to 6 carbons.
  • -C3-6 carbocycle- may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any one of which is optionally substituted.
  • Carbocyclene refers to a divalent ring, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen atoms.
  • the carbocyclene 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 carbocyclene are to the rest of the molecule and to the radical group are through any two carbons respectively.
  • Carbocyclene includes arylene and cycloalkylene. The term therefore distinguishes carbocyclene from heterocyclene in which the divalent ring comprises at least one atom that is different from a carbon atom.
  • heterocyclene 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 heterocyclene are to the rest of the molecule and to the radical group through any two atoms respectively, valency permitting.
  • Heterocyclene includes heteroarylene and heterocycloalkylene. Carbocyclene and heterocyclene may each be optionally substituted by one or more substituents such as those substituents described herein.
  • heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms.
  • exemplary heteroatoms include N, O, Si, P, B, Se, and S atoms.
  • the heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle.
  • Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings.
  • a bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits.
  • an aromatic ring e.g., pyridyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene.
  • a bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5- 6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems.
  • Bicyclic heterocycles may be fused, bridged, or spiro-ring systems.
  • a spiro-ring system may be referred as a “spiroheterocycle”, “spiro heterocycle”, or “spiro-heterocycle”.
  • spiro-heterocycles, spiro heterocycles, or spiroheterocycles have at least two molecular rings with only one common atom.
  • the spiroheterocycle, spiro heterocycle, or spiroheterocycle comprises one or more heteroatoms.
  • Heteroaryl or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S.
  • the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) K-electron system in accordance with the Hiickel theory.
  • the heteroatom(s) in the heteroaryl radical may be optionally oxidized.
  • unsaturated heterocycle refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles.
  • unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine.
  • Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein.
  • “Substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the term “optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.
  • electrophile or “electrophilic moiety” is any moiety capable of reacting with a nucleophile (e g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge and/or an excess of electrons, for example an — SH group).
  • Electrophiles typically are electron poor or comprise atoms which are electron poor.
  • an electrophile contains a positive charge or partial positive charge, has a resonance structure which contains a positive charge or partial positive charge, or is a moiety in which delocalization or polarization of electrons results in one or more atoms which contains a positive charge or partial positive charge.
  • an electrophile comprises a conjugated double bond, for example an a,P-unsaturated carbonyl or a,P-unsaturated thiocarbonyl compound.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • the terms "subject,” “individual,” and “patient” may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like).
  • the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context.
  • the subject may not be under the care or prescription of a physician or other health worker.
  • a subject in need thereof' refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.
  • the terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration.
  • oral routes of administering a composition can be used.
  • the terms “administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.
  • the term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein.
  • the specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • treatment refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and/or a prophylactic benefit.
  • treatment or treating involves administering a compound or composition disclosed herein to a subject.
  • a therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.
  • the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • sum frequency generation is a nonlinear, optical technique whereby light at one frequency (QI) is mixed with light at another frequency (Q2) to yield a response at the sum frequency (Q1+Q2) (Shen, 1984, 1989).
  • QI light at one frequency
  • Q2 another frequency
  • SFG is particularly useful for the detection of molecules at surfaces through their characteristic vibrational transitions and, in this case, is essentially a surface-selective infrared spectroscopy with I and Q2 at visible and infrared frequencies.
  • SHG or “second harmonic generation” are used herein, it is understood that SFG and “sum frequency generation” can substitute and be used in place of SHG with methods well known to one skilled in the art.
  • Second harmonic-active moiety refers to a nonlinear-active moiety, particle or molecule which can be attached (covalently or non-covalently) to a molecule (e.g., a protein, such as an enzyme), particle or phase (e.g., lipid bilayer) in order to render it more nonlinear optical active.
  • a molecule e.g., a protein, such as an enzyme
  • particle or phase e.g., lipid bilayer
  • a “nonlinear active moiety,” as used herein, is a substance which possesses a hyperpolarizability.
  • “Hyperpolarizability” or “Nonlinear Susceptibility” as used herein refer to the properties of a molecule, particle, interface, or phase which allow for generation of nonlinear light.
  • the terms “hyperpolarizability,” “second-order nonlinear polarizability,” and “nonlinear susceptibility” are some-times used interchangeably.
  • Allosteric refers to a molecule, moiety or substance which binds predominantly to a site other than the active site and causes conformational change, which can be determined by SHG or SFG, and thus exert their effect via an allosteric mechanism of action.
  • the term “inhibit”, “selective inhibition” or “selectively inhibit” as referred to a biologically active agent refers to the agent’s ability to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or interact interaction with the target.
  • targeted agent or “targeted therapy” as described herein referred to a therapy that uses specific drugs to target specific genes, protein, or active sites involved in the development, survival, and proliferation of cancer cells.
  • the present disclosure provides a compound represented by the structure of Formula (I): Formula (I), or a pharmaceutically acceptable salt thereof wherein:
  • R 100 is selected from
  • R 1A is selected from C1-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of R 1A come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 11A ;
  • R 1B is selected from hydrogen, C1-6 alkyl, C3-C6 carbocycle, 4- to 6-membered heterocycle, wherein the C1-6 alkyl and C3-C6 carbocycle, and 4- to 6-membered heterocycle, are each independently optionally substituted with one or more R 10 ;
  • R 1C is selected from hydrogen, Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 12 , and wherein optionally two R 12 on the same atom of R 1C come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 12A ;
  • R 1D is selected from hydrogen, Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 13 , and wherein optionally two R 13 on the same atom of R 1D come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 13A ;
  • Y is selected from a bond, -O-, -S-, and -N(R 5 )-;
  • R 100 is selected from
  • R 1A is selected from Ci-6 alkyl, C3-Ci 2 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of R 1A come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 11A ;
  • R 1B is selected from hydrogen, Ci-6 alkyl, C3-C6 carbocycle, wherein the Ci-6 alkyl and C3- C'e carbocycle are each independently optionally substituted with one or more R 10 ;
  • R 1C is selected from hydrogen, Ci-6 alkyl, C3-Ci 2 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 12 , and wherein optionally two R 12 on the same atom of R 1C come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 12A ;
  • R 1D is selected from hydrogen, Ci-6 alkyl, C3-Ci 2 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 13 , and wherein optionally two R 13 on the same atom of R 1D come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 13A ;
  • Y is selected from a bond, -O-, -S-, and -N(R 5 )-;
  • Formula (I) is represented by Formula (II).
  • the present disclosure provides a compound of Formula (II) Formula (II), or a pharmaceutically acceptable salt thereof wherein:
  • R 100 is selected from
  • R 1A is selected from an C1-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of C1-4 alkyl come together to form a C3-C4 carbocycle;
  • R 1C is selected from an C1-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R 12 , and wherein optionally two R 12 on the same atom of C1-4 alkyl come together to form a C3-C4 carbocycle;
  • R 2 is selected from heterocycle, -L-heterocycle, -L-aryl, -L-heteroaryl, and -L-N(R 20 )2, wherein the heterocycle, the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R 6 , and wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R 7 ; each R 6 is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl; each R 7 is independently selected from halogen, and C1-C4 haloalkyl; each L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on
  • each R 21 is independently selected from hydrogen; and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle; and n is 0.
  • R 100 is R 1A R 1 B R 1C RI B R1A selected from -J-- and ⁇ L ⁇ . In some cases, R 100 is ⁇ -L ⁇
  • R 100 is selected from:
  • R 1A is selected from Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of R 1A come together to R 1C
  • R 1C is selected from Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more R 12 , and wherein optionally two R 12 on the same atom of R 1C come together to form an unsubstituted C3 carbocycle.
  • R 1A N is selected from: — I—
  • R 1A is selected from Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12- membered heterocycle, each of which is optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of R 1A come together to form a C3-C6 carbocycle or 3- to 8- membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more R 11A .
  • Formula (I) is represented by Formula (I-A): Formula (I-A), or a pharmaceutically acceptable salt thereof.
  • R 100 for a compound or salt of Formula (I) or Formula (I-A), R 100 , . In some cases,
  • R 1A is selected from Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of R 1A come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more R 11A .
  • R 1A is selected from Cn
  • J- ofR 100 , or -L is selected from: some cases, R 1A is selected from
  • R 1B is hydrogen.
  • R 1B is selected from an optionally substituted Ci-6 alkyl.
  • R 1B is selected from an optionally substituted C3-C6 carbocycle.
  • R 1A is selected from an optionally substituted Ci-6 alkyl.
  • R 11 is -N(R 20 )2. In some cases,
  • R 1A is C4- Cc, carbocycle, wherein the C4-C6 carbocycle is optionally with one or more R 11 .
  • each R 11 is selected from -N(R 20 )2, wherein each R 20 is selected from hydrogen and optionally
  • R 1A is selected from 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is optionally with one or more R 11 .
  • each R 11 is selected from halogen, -N(R 20 )2, - C(O)R 20 , -C(O)N(R 20 )2, C1-6 aminoalkyl, Ci-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally with one or more R 11 .
  • the heterocycle has at least one oxygen atom In some cases, the heterocycle has one oxygen atom.
  • R 1A is selected from which is optionally substituted.
  • each R 11 is selected from -OH and Ci-6 hydroxyalkyl. In some cases, each R 11 is -
  • R 1A is selected f
  • N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , - OC(O)N(R 20 )2, -NO 2 , -O, NO(R 20 ), -CN, -NHCN, Ci- 6 alkyl-N(R 20 ) 2 , Ci- 6 aminoalkyl, Ci- 6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.
  • each R 11 is independently selected from halogen, -OR 20 , -N(R 20 )2, -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, Ci-shydroxyalkyl, C1-6 cyanoalkyl, and C 1-6 haloalkyl.
  • R 1B is selected from hydrogen, optionally substituted Ci-6 alkyl, and optionally substituted C3-C6 carbocycle.
  • R 1B is hydrogen, Ci-6 alkyl, C 1-6 cyanoalkyl, Ci-6 hydroxyalkyl, and C3- C ⁇ > carbocycle.
  • R 1B is hydrogen, methyl, ethyl, C2 hydroxyalkyl, and cyclopropyl.
  • R 1B is hydrogen.
  • R 1B is selected from an optionally substituted Ci-6 alkyl.
  • R 1B is selected from methyl and ethyl.
  • R 1B is methyl. In some cases, R 1B is selected from an optionally substituted C3-C6 carbocycle. In some cases, R 1B is In some cases, R 1B is selected from Ci-6 cyanoalkyl. In some cases, R 1B is selected from Ci-6 hydroxy alkyl.
  • R 1A is selected from an optionally substituted C1-3 alkyl, and wherein optionally two R 11 on the same atom of R 1A come together to form a C3 carbocycle.
  • R 11 is selected from halogen, - N(R 20 ) 2 , C3 carbocycle, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N(R 21 ) 2 , C MO alkyl, and -Ci-io haloalkyl.
  • each R 21 is independently selected from hydrogen; and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle.
  • R 1A is
  • R 100 for a compound or salt of Formula (I) or Formula (I-A), R 100 ,
  • R 1A is selected from an optionally substituted Ci-6 alkyl. In some cases, R 1A is selected from an optionally substituted C1-3 alkyl, and wherein optionally two R 11 on the same atom of R 1A come together to form a C3 carbocycle. In some cases, R 1A is selected from cases, R 1A is selected from
  • R 1A is selected from . In some cases, R 1A is selected from . , . In some cases, R 1A is some cases, R 11 is selected from an optionally substituted 5- to 12-membered heterocycle. In some cases, R 11 is selected from an optionally substituted 5- to 8-membered heterocycle. In some cases, R 11 is selected from an optionally substituted 5- to 6-membered heterocycle. In some cases, R 11 is selected from an optionally substituted 5- to 6-membered heteroaryl. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least two nitrogen atoms. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heterocycle has only 1 nitrogen atom and no other heteroatoms. In some cases, the heterocycle has only 2 nitrogen atoms and no other heteroatoms.
  • R 11 which is optionally substituted. In some cases, R 11 , which is optionally substituted. In some cases, each of which is optionally substituted. In some cases, R 11 is selected from each of which is optionally substituted. In some cases, the optional one or more substituents independently selected from halogen, -OH, -CN, -N(R 21 )2, -C(O)N(R 21 )2, CMO alkyl, and -Ci-io haloalkyl.
  • R 21 is independently selected from hydrogen; and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle.
  • the optional one or more substituents of R 11 is selected from halogen, Ci-6 haloalkyl, -NH2, -NH(CI-6 alkyl), -N(Ci- one or more substituents of R 11 is selected from -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, and Ci-io alkyl.
  • the optional one or more substituents of R 11 is selected from -NH2, and Ci-io alkyl.
  • the optional one or more substituents of R 11 is selected from -NH2.
  • R 100 for a compound or salt of Formula (I) or Formula (I-A), R 100 ,
  • R 100 for a compound or salt of Formula (I) or Formula (I-A), R 100 ,
  • R 100 for a compound or salt of Formula (I) or Formula (I-A), R 100 ,
  • R 1B is selected from hydrogen and Ci-s alkyl. In some cases, R 1B is selected from Ci-6 alkyl. In some cases, R 1B is a cyclopropyl. In some cases, R 1B is methyl. In some cases, R 1B is ethyl. In some cases, R 100 is [0091] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), R 100 ,
  • R 1A is selected from an C1-3 alkyl, which is optionally substituted with one or more R 11 , wherein each R 11 is selected from C3-C6 carbocycle, and 5- to 6-membered heterocycle, wherein the 5- to 6- membered heterocycle and C3-C6 carbocycle are each optionally substituted.
  • R 1A is selected from an C1-3 alkyl, which is substituted with one or more R 11 , wherein each R 11 is selected from phenyl, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle and phenyl are each optionally substituted.
  • R 11 is phenyl, which is optionally substituted.
  • R 11 is selected from a 5- to 6-membered heterocycle, which is optionally substituted.
  • R 11 is pyridine, which is optionally substituted.
  • R 1A is selected from , . , y y . n some cases, the one or more substituents are independently selected from halogen, -P(O)(R 21 )2, -S(O)2F, -OH, -CN, -N(R 21 )2, - C(O)N(R 21 ) 2 , CI -io alkyl, and -C1-10 haloalkyl.
  • the one or more substituents are independently selected from halogen, -P(O)(R 21 )2, -OH, -CN, -N(R 21 )2, -C(O)N(R 21 )2, Ci-io alkyl, and -Ci-10 haloalkyl. In some cases, the one or more substituents are independently selected from -P(O)(R 21 )2, -N(R 21 )2, and Ci -10 alkyl. In some cases, the one or more substituents are independently selected from -P(O)(R 21 )2, and -N(R 21 )2. In some cases, the one or more substituents are independently selected from -P(O)(R 21 )2. In some cases, each R 21 is independently selected from hydrogen and Ci-6 alkyl. In some cases, each R 21 is independently selected from C1.3 alkyl. In
  • R 1B is selected from hydrogen and Ci-6 alkyl.
  • R 100 is selected from In some cases, some cases, R 100 is —J— . In some cases, R 100 is selected from —I— .
  • B is selected from an 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, and Ci-6 alkyl. In some cases, B is selected from an 8-membered heterocycle, wherein the 8-membered heterocycle is substituted with one or more substituents independently selected from halogen, -CN, -NH2, and Ci-6 alkyl.
  • the heterocycle of B has one sulfur atom and no other heteroatoms. In some cases, the heterocycle of B is an unsaturated heterocycle. In some cases, B is selected from each of which is optionally substituted. In some cases, B is selected from , each of which is substituted with at least one substituent. . In some cases, Y is O. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from an unsubstituted Ci alkylene.
  • two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle.
  • two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle.
  • R 2 is selected from optionally substituted -L-heterocycle, wherein the heterocycle is a saturated heterocycle.
  • the heterocycle is selected from , each of which is optionally substituted with one or more R 6 .
  • each R 6 is independently selected from halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some cases, each R 6 is independently selected from halogen. In some cases, Y-R 2 is selected from ,
  • B is an optionally substituted 8- to 15-membered fused heterocycle, wherein B contains at least one heteroatom selected from nitrogen, sulfur, and selenium.
  • B is an optionally substituted 8- to 15-membered fused heterocycle, wherein B contains at least one heteroatom selected from nitrogen, and selenium.
  • B is an optionally substituted 8- to 15-membered fused heterocycle, wherein B contains at least one heteroatom selected from selenium.
  • B is an optionally substituted 8- to 15-membered fused heterocycle, wherein B contains at least one heteroatom selected from sulfur and selenium. In some cases, B is an optionally substituted 8- to 10-membered fused heterocycle, wherein B contains at least one heteroatom selected from nitrogen, sulfur, and selenium. In some cases, B is an optionally substituted 8-membered fused heterocycle, wherein B contains at least one heteroatom selected from nitrogen, sulfur, and selenium.
  • R 1B is hydrogen. In some cases, R 1B is selected from an optionally substituted Ci-6 alkyl. In some cases, R 1B is selected from an optionally substituted C3-C6 carbocycle. In some cases, R 1B is selected from hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, and C3-C6 carbocycle. In some cases, R 1B is hydrogen, methyl, ethyl, and cyclopropyl. In some cases, R 1B is hydrogen. In some cases, R 1B is selected from an optionally substituted C1-6 alkyl.
  • R 1B is selected from an optionally substituted C1-2 alkyl. In some cases, R 1B is selected from methyl and ethyl. In some cases, R 1B is methyl. In some cases, R 1B is selected from an optionally substituted C3-C6 carbocycle. In some cases, R 1B is
  • R 1A is selected from an optionally substituted C1.3 alkyl, and wherein optionally two R 11 on the same atom of R 1A come together to form a C3 carbocycle.
  • R 11 is selected from halogen, -N(R 20 ) 2 , C3 carbocycle, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N(R 21 ) 2 , Ci-io alkyl, and -C1-10 haloalkyl.
  • each R 21 is independently selected from hydrogen; and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle.
  • R 1A is selected from
  • R 1A is selected from an optionally substituted Ci-6 alkyl. In some cases, R 1A is selected from an optionally substituted C1-3 alkyl, and wherein optionally two R 11 on the same atom of R 1A come together to form a C3 carbocycle. In some cases, R 1A is selected from an optionally substituted C1-2 alkyl. In some cases,
  • R 11 R 11 R 11 In some cases, R 1A is selected from In some cases, R 1A is selected from
  • R 11 is selected from an optionally substituted 5- to 12-membered heterocycle. In some cases, R 11 is selected from an optionally substituted 5- to 8-membered heterocycle. In some cases, R 11 is selected from an optionally substituted 5- to 6-membered heterocycle. In some cases, R 11 is selected from an optionally substituted 5- to 6-membered heteroaryl.
  • the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least two nitrogen atoms. In some cases, the heterocycle has one nitrogen atom and no other heteroatoms. In some cases, the heterocycle has two nitrogen atoms and no other heteroatoms. In some cases, the heteroaryl has at least one nitrogen atom.
  • the heteroaryl has at least two nitrogen atoms. In some cases, the heteroaryl has one nitrogen atom and no other heteroatoms. In some cases, the heteroaryl has two nitrogen atoms and no other heteroatoms.
  • R 11 is each of which is optionally substituted. In some cases, each of which is optionally substituted. In some cases, R 11 is selected from each of which is optionally substituted. In some cases, the optional one or more substituents of R 11 are each independently selected from halogen, -OH, -CN, -N(R 21 )2, -C(O)N(R 21 )2, Ci-io alkyl, and -Ci-io haloalkyl. In some cases, each R 21 is independently selected from hydrogen; and Ci-6 alkyl,
  • the optional one or more substituents of R 11 is selected from halogen, Ci-6 haloalkyl, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, , and Ci-io alkyl.
  • the optional one or more substituents of R 11 is selected from -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, and Ci -10 alkyl.
  • the optional one or more substituents of R 11 is selected from -NH2, and Ci-io alkyl.
  • the optional one or more substituents of R 11 is selected from -NH2.
  • R 11 is selected from
  • R 1B is selected from hydrogen and Ci-6 alkyl. In some cases, R 1B is selected from Ci-6 alkyl. In some cases, R 1B is a cyclopropyl. In some cases, R 1B is methyl. In some cases, R 1B is ethyl. In some cases, R 100
  • R 100 is selected from
  • R 100 is selected from some cases, R 100 is selected from some cases, R 1B is selected from hydrogen and Ci-6 alkyl. In some cases, R 100 is selected from In some cases, some cases, R 100 is — I— . In some cases, R 100 is selected from —I— . In some cases, B is selected from an 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, and C1-6 alkyl.
  • B is selected from an 8-membered heterocycle, wherein the 8-membered heterocycle is substituted with one or more substituents independently selected from halogen, -CN, -NH2, and Ci-6 alkyl.
  • the heterocycle of B has one sulfur atom and no other heteroatoms.
  • the heterocycle of B is an unsaturated heterocycle.
  • B is selected from each of which is optionally substituted.
  • B is selected from each of which is substituted with at least one substituent.
  • R 3 is selected from hydrogen, -CN, -C(O)H, Ci hydroxyalkyl, and Ci-
  • R 3 is selected from hydrogen, fluorine, and -CN. In some cases, R 3 is selected from fluorine. In some cases, R 3 is selected from hydrogen. In some cases, R 3 is selected from -
  • Y is O.
  • L is selected from C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from an unsubstituted Ci alkylene.
  • two substituents on the same carbon atom ofL come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle.
  • each L is selected from . , s selected from optionally substituted -L-heterocycle.
  • R 2 is selected from optionally substituted -L-heterocycle, wherein the heterocycle is a saturated heterocycle.
  • the heterocycle is selected from each of which is optionally substituted with one or more R 6 .
  • each R 6 is independently selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, -N(R 5 )S(O)2(R 5 ), -
  • each R 6 is independently selected from halogen, C1-C3 alkyl, and C1-C3 haloalkyl.
  • each R 6 is independently selected from halogen.
  • Y-R 2 is selected from ,
  • R 1A is selected from an optionally substituted C1-6 alkyl.
  • R 11 is -N(R 20 )2. In some cases,
  • R 1A is selected
  • R 11 is selected from an optionally substituted 5- to 6- membered heteroaryl. In some cases, R 11 is selected from an optionally substituted 6-membered heteroaryl. In some cases, R 11 is selected from an optionally substituted pyridine. In some cases, the heteroaryl (e.g., pyridine) is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -NH 2 , -NH(CI-6 alkyl), - N(CI-6 alkyl) 2 , C1-10 alkyl, and -Ci-10 haloalkyl.
  • substituents independently selected from halogen, -CN, -OH, -NH 2 , -NH(CI-6 alkyl), - N(CI-6 alkyl) 2 , C1-10 alkyl, and -Ci-10 haloalkyl.
  • the heteroaryl e.g., pyridine
  • the heteroaryl is optionally substituted with one or more substituents independently selected from -NH2, -NH(CI-6 alkyl), and -N(Ci-s alkyl)2.
  • the heteroaryl e.g., pyridine
  • the heteroaryl is substituted with at least one -NH2.
  • there heteroaryl has at least one nitrogen atom.
  • there heteroaryl has one nitrogen atom and no other heteroatoms.
  • R 1A is selected from
  • R 1A is C4-C6 carbocycle, wherein the C4-C6 carbocycle is optionally with one or more R 11 .
  • the carbocycle is a saturated carbocycle.
  • each R 11 is selected from -N(R 20 )2, wherein each R 20 is selected from hydrogen and optionally substituted Ci-6 alkyl.
  • R 1A is selected
  • R 1A is selected from 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is optionally with one or more R 11 .
  • the heterocycle is a saturated heterocycle.
  • each R 11 is selected from halogen, -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl.
  • R 1A is [00104]
  • R 100 is selected from
  • R 1B is hydrogen. In some cases, R 1B is selected from an optionally substituted Ci-6 alkyl. In some cases, R 1B is selected from an unsubstituted Ci-6 alkyl. In some cases, R 1B is methyl. In some cases, R 1B is selected from an optionally substituted C3-C6 carbocycle.
  • R 1A is selected from an optionally substituted C1-6 alkyl.
  • R 11 is -N(R 20 )2.
  • the C4-C6 carbocycle is optionally with one or more R 11 .
  • R 11 is selected from -N(R 20 ) 2 , and wherein each R 20 is selected from hydrogen and optionally substituted C1-6 selected from 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is optionally with one or more R 11 .
  • each R 11 is independently selected from C1-6 aminoalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, -C(O)R 20 , C3-C12 carbocycle and 5- to 12- membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, and oxo.
  • each R 11 is selected from halogen, -OH, -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, Ci-
  • R 1A is selected from , , y . ,
  • R 1A is selected from which is optionally substituted.
  • each R 11 is independently selected from Ci-6 aminoalkyl, Ci-g cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, -C(O)R 20 ,
  • C3-C12 carbocycle and 5- to 12-membered heterocycle wherein the C3-C12 carbocycle and 5- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(CI-6 alkyl), -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-io alkyl, and oxo.
  • substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -NH(CI-6 alkyl), -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-io alkyl, and oxo.
  • each R 11 is selected from halogen, -N(R 20 )2, - C(O)R 20 , -C(O)N(R 20 )2, CI-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, each R 11 is selected from halogen, -N(R 20 )2,
  • R 1A is selected from
  • R 11 is selected from -OH and -CN, and wherein two R 11 on the same atom of R 1A come together to form an unsubstituted C3 carbocycle. In some cases,
  • R 1A is selected from 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally with one or more R 11 .
  • the heterocycle has at least one oxygen atom.
  • the heterocycle has one oxygen atom.
  • R 1A is selected from , which is optionally substituted.
  • each R 11 is selected from -OH and C1-6 hydroxyalkyl.
  • each R 11 is -OH.
  • R 1A is selected from
  • R 100 is from [00110] In some embodiments, for a compound or salt of Formula (I), R 100 is selected from
  • R 1A is selected from In some cases, R 1A is selected from In some cases, R 1A is selected from
  • R 1A is selected from an optionally substituted Ci-6 alkyl, and wherein optionally two R 11 on the same atom of R 1A come together to form an optionally substituted C3-C6 carbocycle.
  • R 11 is selected from -OH, -CN, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -NH(CI-6 alkyl), -N(Ci-6 alkyl)2, Ci- 10 alkyl, -Ci-io haloalkyl, and -O-Ci- 10 alkyl; and wherein two R 11 on the same atom of R 1A come together to form an unsubstituted C3
  • R 11 is selected from , which is optionally substituted. In some cases, R 11 is selected from which is optionally substituted.
  • R 100 for a compound or salt of Formula (I) or Formula (I-A), R 100
  • R 1A is selected from an Ci-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of R 1A come together to form a C3 carbocycle.
  • R 1A is selected from an C1-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of R 1A come together to form a C3 carbocycle.
  • each R 21 is independently selected from hydrogen; and Ci-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered [00116]
  • R 1A for a compound or salt of Formula (I) or Formula (I-A), R 1A
  • R 1B is
  • R 100 for a compound or salt of Formula (I) or Formula (I-A), R 100
  • R 100 for a compound or salt of Formula (I) or Formula (I-A), R 100 or
  • R 1A is selected from an optionally substituted Ci-6 alkyl.
  • R 1A is selected from an optionally substituted C1-3 alkyl, and wherein optionally two R 11 on the same atom of R 1A come together to form a C3 carbocycle.
  • R 1A is selected from an optionally substituted C1.3 alkyl.
  • R 1A is selected from an optionally substituted C1-2 alkyl.
  • R 1A is selected from an optionally substituted Ci alkyl.
  • R 1A is selected from an optionally substituted C2 alkyl.
  • R 1A is not a C2 alkyl.
  • R 1A is not a linear C2 alkyl.
  • R 1A is not a branched C3 alkyl. In some cases, R 1A is not . In some cases,
  • R 1A is not . In some cases, R 1A is not some cases, R 1A is selected from
  • R 1A is not selected from . In some cases, R 1A is not . In some cases, R 1A is not not a heteroaryl. In some cases, R 1A is not a linear C2 alkyl or a branched C3 alkyl. In some cases, R 1A is not a linear C2 alkyl or a branched C3 alkyl, and R 11 is not a heteroaryl. In some cases, R 1A is not a linear C2 alkyl or a branched C3 alkyl, and R 11 is not a 5- to 6-membered heteroaryl. In some cases, R 11 is selected from an optionally substituted 5- to 12- membered heterocycle.
  • R 11 is selected from an optionally substituted 5- to 8- membered heterocycle. In some cases, R 11 is selected from an optionally substituted 5- to 6- membered heterocycle. In some cases, R 11 is selected from an optionally substituted 5- to 6- membered heteroaryl. In some cases, R 11 each of which is optionally substituted. In some cases,
  • R 11 is selected from , each of which is optionally substituted. In some cases, R 11 is selected from , each of which is optionally substituted. In some cases, the optional one or more substituents independently selected from halogen, -OH, -CN, -N(R 21 )2, Ci-io alkyl, and -CMO haloalkyl. In some cases, each R 21 is independently selected from hydrogen; and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle.
  • the optional one or more substituents of R 11 is selected from halogen, C1-6 haloalkyl, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, , , , and Ci -io alkyl. In some cases, the optional one or more substituents ofR 11 is selected from -NH2, -NH(CI-6 alkyl), -N(Ci-e alkyl)2, and Ci-io alkyl. In some cases, the optional one or more substituents of R 11 is selected from -NH2, and Ci-io alkyl. In some cases, the optional one or more substituents of R 11 is selected from -NH2. In some cases, R 11
  • R 100 for a compound or salt of Formula (I) or Formula (I-A), R 100
  • R 100 for a compound or salt of Formula (I) or Formula (I-A), R 100 or
  • R 100 for a compound or salt of Formula (I) or Formula (I-A), R 100 or
  • R 11 is selected from each of which is optionally substituted.
  • the optional one or more substituents independently selected from halogen, oxo, -OH, -OCH3, -CN, -N(R 21 )2, - C(O)N(R 21 )2, -P(O)(R 21 )2, -SCH3, Ci-10 alkyl, and -Ci-io haloalkyl.
  • the optional one or more substituents of R 11 is selected from halogen, oxo, -OH, -OCH3, C1-6 haloalkyl, -NH2, - [00136]
  • R 1A is selected from Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of C1-6 alkyl come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 11A .
  • R 1C is selected from hydrogen, Ci-6 alkyl, C3-C12 carbocycle, and 4- to 12-membered heterocycle, each of which is independently optionally substituted with one or more R 12 , and wherein optionally two R 12 on the same atom of Ci-6 alkyl come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each independently optionally substituted with one or more R 12A ;
  • R 1A is selected from 4- to 12-membered heterocycle, wherein the 4- to 12-membered heterocycle is optionally with one or more R 11 .
  • R 1A is selected from , each of which is optionally substituted with one or more R 11 , and wherein each R 11 is independently selected from -OH, C 1.6 aminoalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, C1-6 alkyl, -C(O)R 20 , C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NHz, -NH(CI-6 alkyl), -N(CI-6 alkyl h, C1-10 alkyl, -Ci-io haloalkyl, -O-Ci-10 alkyl, and oxo.
  • R 11 is selected from halogen, -OH, -N(R 20 )2, - C(O)R 20 , -C(O)N(R 20 )2, CI-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl.
  • R 1A is selected from
  • R 100 is selected from
  • Formula (I) is represented by Formula (I-B): Formula (I-B), or a pharmaceutically acceptable salt thereof [00144] In some embodiments, for a compound or salt of Formula (I), R 100 is different than
  • —I— is different than Y-R 2 .
  • R 1C is selected from an optionally substituted Ci-6 alkyl.
  • R 1C is selected from an optionally substituted Ci-6 alkyl, and wherein optionally two R 12 on the same atom of R 1C come together to form an optionally substituted C3-C6 carbocycle.
  • R 12 is selected from -OH and -CN, and wherein two R 12 on the same atom of R 1C come together to form an unsubstituted C3
  • R 1C is selected from an optionally substituted C1-6 alkyl. In some cases, R 1C is selected from an optionally substituted C1-6 alkyl, and wherein optionally two R 12 on the same atom of R 1C come together to form an optionally substituted C3-C6 carbocycle.
  • R 12 is selected from -OH, -CN, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-10 alkyl, -Ci-io haloalkyl, and -O-Ci-io alkyl; and wherein two R 12 on the same atom of R 1C come together to form an unsubstituted C3 carbocycle.
  • substituents independently selected from halogen, -OH, -CN, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-10 alkyl, -Ci-io haloalkyl, and -O-Ci-io alkyl.
  • R 1C is selected from an optionally substituted C1.3 alkyl. In some cases, R 1C is selected from
  • R 1C is
  • R 12 selected from In some cases, R 12 is selected from an optionally substituted 5- to 12-membered heterocycle. In some cases, R 12 is selected from an optionally substituted 5- to 8- membered heterocycle. In some cases, R 12 is selected from an optionally substituted 5- to 6- membered heterocycle. In some cases, R 12 is selected from an optionally substituted 5- to 6- membered heteroaryl. In some cases, R 12
  • R 12 is selected from the optional one or more substituents of R 12 is selected from -NH2, -NH(CI-6 alkyl), -N(Ci-6alkyl)2, and Ci-io alkyl. In some cases, the optional one or more substituents of R 12 is selected from -NH2,
  • R 12 is selected from -NH2, and C1-10 alkyl. In some cases, the optional one or more substituents of R 12 is selected from -NH2. In some cases, R 12 is selected from some embodiments, for a compound or salt of Formula (I), R 100 is selected from
  • R 1C is selected from an optionally substituted 5- to 6-membered heterocycle. In some cases, R 1C is selected from an optionally substituted 5-membered heterocycle having at least one oxygen atom, o- ⁇
  • R 1C is selected , which is optionally substituted.
  • each R 12 is selected from halogen, -OR 20 , Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl.
  • R 12 is selected from -OH.
  • R 1C is HO
  • R 1C is selected from an optionally substituted 5- to 6-membered heterocycle. In some cases, R 1C is selected from an optionally substituted 5-membered heterocycle. In some cases, R 1C is selected from an optionally substituted 5-membered heterocycle having at least one oxygen atom. In some cases, R 1C is selected which is optionally substituted. In some cases, R 12 is selected from halogen, -OR 20 , C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C1-6 haloalkyl, and Ci-6 alkyl. In some cases, each R 12 is selected from -OH. In some cases, R 1C 1S HO
  • R 100 is selected from
  • R 1C is selected from an optionally substituted Ci-6 alkyl. In some cases, R 1C is selected from an optionally substituted C1-3 alkyl, and wherein optionally two R 11 on the same atom of R 1C come together to form a C3 carbocycle. In some cases, R 1C is selected from an optionally substituted C1-3 alkyl.
  • R 1C is selected from . In some cases, R 1C is selected from In some cases, R 1C is selected from
  • R 1C is selected from an C1-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R 12 , and wherein optionally two R 12 on the same atom of R 1C come together to form a C3 carbocycle.
  • R 1C is selected from an C1-4 alkyl, C3 carbocycle, and 5- to 9-membered heterocycle, each of which is optionally substituted with one or more R 12 , and wherein optionally two R 12 on the same atom of R 1C come together to form a C3 carbocycle.
  • each R 21 is independently selected from hydrogen; and Ci-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, C3-6 carbocycle, and 3- to 6-membered heterocycle.
  • R 1C is
  • R 1C is selected from C1.3 alkyl, and 5- to 6-membered heterocycle, each of which is independently optionally substituted with one or more R 12 , and wherein optionally two R 12 on the same atom of R 1C come together to form a C3-C4 carbocycle or 4-membered heterocycle.
  • each R 12 is independently selected from -OH, -CN, 5- to 6-membered heterocycle, wherein the 5- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, and Ci-io alkyl.
  • R 1C is
  • Formula (I) is represented by Formula (I-C): Formula (I-C), or a pharmaceutically acceptable salt thereof.
  • R 1D is selected from an optionally substituted Ci-6 alkyl.
  • R is selected from some cases, R 13 is selected from an optionally substituted 5- to 12-membered heterocycle.
  • R 13 is selected from an optionally substituted 5- to 8-membered heterocycle.
  • R 13 is selected from an optionally substituted 5- to 6-membered heterocycle.
  • R 13 is selected from an optionally substituted 5- to 6-membered heteroaryl.
  • R 13 is selected from each of which is optionally substituted. In some cases, selected from each of which is optionally substituted.
  • the optional one or more substituents of R 12 is selected from -NH 2 , -NH(CI-6 alkyl), -N(CI-6 alkyl)2, and Ci-io alkyl. In some cases, the optional one or more substituents of R 12 is selected from -NH 2 ,
  • R 12 is selected from -NH 2 , and C1-10 alkyl. In some cases, the optional one or more substituents of R 12 is selected from -NIL. In some cases, R 13 is selected from
  • R 1D is selected from an optionally substituted C1-6 alkyl, and wherein optionally two R 13 on the same atom of R 1D come together to form an optionally substituted C3-C6 carbocycle.
  • R 13 is selected from -OH, -CN, and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH 2 , -NH(CI- 6 alkyl), -N(Ci- 6 alkyl) 2 , Ci-io alkyl, -C1-10 haloalkyl, and -O-Ci- 10 alkyl; and wherein two R 13 on the same atom of R 1D come together to form an unsubstituted C3 carbocycle.
  • R 1D is selected from
  • B is selected from an optionally substituted 7- to 15-membered fused heterocycle and optionally substituted C7-C15 fused carbocycle. In some cases, and optionally substituted C7-C15 fused carbocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle. In some cases, B is an optionally substituted unsaturated 7- to 15-membered fused heterocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heteroaryl.
  • B is selected from an optionally substituted 7- to 15-membered fused heteroaryl and optionally substituted C7-C15 fused aryl. In some cases, B is an optionally substituted unsaturated C7-C15 fused carbocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle, wherein the fused heterocycle is partially unsaturated. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle, wherein the fused heterocycle is partially saturated.
  • B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Ci5 fused carbocycle. In some cases, and optionally substituted Cs-Cis fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted unsaturated 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heteroaryl.
  • B is selected from an optionally substituted 8- to 15-membered fused heteroaryl and optionally substituted Cs-Cis fused aryl. In some cases, B is an optionally substituted unsaturated Cs-Ci5 fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is partially unsaturated. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is partially saturated.
  • B is selected from an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is formed by combining three rings (e.g., tricyclic).
  • B is selected from an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is formed by combining two rings (e.g., bicyclic).
  • the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Ci5 fused carbocycle are each independently bicyclic or tricyclic.
  • the optionally substituted 8- to 15-membered fused heterocycle is bicyclic.
  • for B the optionally substituted 8- to 15-membered fused heterocycle is tricyclic.
  • the heterocycle or carbocycle of B is bicyclic. In some cases, the heterocycle or carbocycle of B is tricyclic. In some cases, the tricyclic heterocycle contains three interconnected rings of atoms.
  • the heterocycle and carbocycle are each independently selected from bicyclic and tricyclic. In some cases, for B, the heterocycle and carbocycle are each independently tricyclic. In some cases, for B, the heterocycle and carbocycle are each independently bicyclic.
  • the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle are selected from more substituents.
  • the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Ci5 fused carbocycle are selected
  • B is selected from which is optionally substituted with one or more substituents.
  • the one or more optional substituents of the heterocycle and carbocycle are each independently selected from oxo, -NH2, halogen, C1-C3 alkyl.
  • the optionally substituted 8- to 15- membered fused heterocycle and optionally substituted C8-C15 fused carbocycle are selected from
  • B is selected from an optionally substituted 7- to 12-membered fused heterocycle and optionally substituted C9-10 fused carbocycle.
  • the heterocycle of B has at least one sulfur atom.
  • the heterocycle of B has one or sulfur atoms.
  • the heterocycle of B has at least one nitrogen atom.
  • B is
  • B is selected from an optionally substituted 8- to 10-membered fused heterocycle having at least one sulfur atom.
  • B is selected from , each of which is optionally substituted.
  • the one or more optional substituents of B are independently selected at each occurrence from halogen, Ci- C 3 alkyl, -NH 2 , and -CN.
  • B is substituted.
  • B is substituted with at least one -NH 2 .
  • B is selected from .
  • B is substituted with at least one -NH 2 at least one -CN.
  • B is selected from
  • B is an optionally substituted 7- to 11-membered fused heterocycle.
  • B is an optionally substituted 8- to 10-membered fused heterocycle.
  • B is an optionally substituted 7-membered fused heterocycle.
  • B is an optionally substituted 8-membered fused heterocycle.
  • B is an optionally substituted 9-membered fused heterocycle.
  • B is an optionally substituted 10-membered fused heterocycle.
  • the heterocycle of B is an unsaturated heterocycle.
  • the heterocycle of B is a non-aromatic heterocycle.
  • B has at least one sulfur atom.
  • B has at two sulfur atoms.
  • B has at least one sulfur atom and at least one nitrogen atom.
  • B has at least one sulfur atom and at least one oxygen atom.
  • B has only 1 heteroatom.
  • B has at least 2 heteroatoms.
  • S sulfur atom
  • the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least three substituents. In some cases, B is substituted with at least two substituents. In some cases, B is substituted with at least one substituent. In some cases, B is substituted with at least one substituent selected from halogen,
  • B is substituted with at least one substituent selected from halogen. In some cases, B is substituted with at least one substituent selected from -NH2. In some cases, B is substituted with at least one substituent selected from -CN. In some cases, B is
  • B is an optionally substituted 8- to 10-membered fused carbocycle. In some cases, B is a substituted 8- to 10-membered fused carbocycle. In some cases, B is an optionally substituted 9-membered fused carbocycle. In some cases, B is a substituted 9- membered fused carbocycle. In some cases, , which is optionally substituted with one or more substituents. In some cases, , which is substituted with one or more substituents.
  • B is substituted with at least one halogen.
  • B is substituted with at least one chlorine.
  • B is substituted with at least one fluorine.
  • B is selected from
  • B is , which is substituted with one or more substituents selected from halogen. In some selected from fluorine. In some cases, B is selected from
  • B is selected from
  • a compound or salt of Formula (I), Formula (I- A), Formula (I-B), or Formula (I-C), B is selected from an 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, and Ci-6 alkyl.
  • the heterocycle of B is selected is optionally substituted with one or more substituents independently selected from halogen, -CN,
  • B is an optionally substituted 7- to 11-membered fused heterocycle. In some cases, B is an optionally substituted 8- to 10-membered fused heterocycle. In some cases, the heterocycle of B is an unsaturated heterocycle. In some cases, the heterocycle of B is a non-aromatic heterocycle. In some cases, B has at least one sulfur atom. In some cases, B has at two sulfur atoms. In some cases, B has at least one sulfur atom and at least one nitrogen atom. In some cases, B has at least one sulfur atom and at least one oxygen atom. In some cases, B has only 1 heteroatom. In some cases, B has at least 2 heteroatoms. In some cases, B is selected each of which is optionally substituted. In some cases, B is selected from , which is optionally substituted.
  • B is selected from which is optionally substituted.
  • the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN.
  • B is substituted with at least one substituent selected from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least one substituent selected from halogen. In some cases, B is substituted with at least one substituent selected from -NH2. In some cases, B is substituted with at least one substituent selected from CN. In some cases, B is substituted with at least one substituent. In some cases, B is selected
  • R 3 is selected from hydrogen, halogen, -CN, -NO2, -N(R 20 )2, - OR 20 , -SR 20 , -S(O) 2 (R 20 ), -S(O) 2 N(R 20 )2, -NR 20 S(O)2R 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , - N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)R 20 , C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 )2, C1-6 aminoalkyl, Ci-6 alkoxy, Ci-e alkoxyalkyl, Ci-6 hydroxyalkyl
  • R 3 is selected from hydrogen, halogen, -CN, - NO2, -N(R 20 ) 2 , -OR 20 , -SR 20 , -C(O)N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , CI-6 aminoalkyl, Ci-6 alkoxy, C 1-6 alkoxy alkyl, Ci-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl.
  • R 3 is selected from hydrogen, halogen, -CN, -NO2, -NH2, - N(Ci.6 alkyl)H -N(Ci. 6 alkyl) 2 ,-OH, -C(O)N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , Ci- 6 aminoalkyl, Ci-6 alkoxy, Ci-e alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, C 1-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.
  • R 3 is selected from hydrogen, -CN, -C(O)R 20 , -C(O)OR 20 , C 1-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, Ci- 6 haloalkyl, and Ci-6 alkyl.
  • R 3 is selected from hydrogen, -CN, -C(O)R 20 , - C(O)OR 20 , Ci-6 hydroxyalkyl, and Ci-6 alkyl.
  • R 3 is selected from hydrogen, -CN, - C(O)H, -C(O)OCH3, CI hydroxyalkyl, and Ci-6 alkyl.
  • R 3 is selected from hydrogen, -F, -CN, -C(O)H, -C(O)OCH3, Ci hydroxyalkyl, and Ci-6 alkyl. In some cases, R 3 is selected from hydrogen, -CN, -C(O)H, Ci hydroxyalkyl, and Ci-6 alkyl. In some cases, R 3 is selected from hydrogen, fluorine, and -CN. In some cases, R 3 is selected from fluorine. In some cases, R 3 is selected from hydrogen. In some cases, R 3 is selected from -CN. In some cases, R 3 is selected from -NO2. In some cases, R 3 is selected from C1.3 haloalkyl. In some cases, R 3 is selected from -CF3.
  • a compound or salt of Formula (I), Formula (I- A), Formula (I-B), or Formula (I-C), R 3 is -CN.
  • Y is -O-. In some cases, Y is a bond. In some cases, Y is -S-. In some cases, Y is -N(R 5 )-.
  • L is selected from C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from an unsubstituted Ci alkylene.
  • two substituents on the same carbon atom ofL come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle.
  • two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle.
  • L is selected from C1-C4 alkylene. In some cases, L is selected from unsubstituted C1-C4 alkylene.
  • the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl.
  • L is selected , each L is independently selected from a substituted
  • each L is independently selected from a substituted C2-3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle or 4-membered heterocycle, wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen.
  • each L is independently selected from , and .
  • each L is independently selected from .
  • each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen and C1-C4 alkyl. In some cases, L is selected from
  • each L is independently selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from ' ' . In some cases, L is selected from
  • R 2 is selected from heterocycle, -L-heterocycle, -L-aryl, -L- heteroaryl, and -L-N(R 20 ) 2 , wherein the heterocycle, the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R 6 , and wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R 7 .
  • R 2 is -L-heterocycle, wherein the heterocycle portion is optionally substituted.
  • R 2 is -L-heterocycle, wherein the heterocycle portion is a bicyclic heterocycle.
  • R 2 is -L-heterocycle, wherein the heterocycle portion is a monocyclic heterocycle.
  • R 2 is -L-heterocycle, wherein the heterocycle portion is a saturated heterocycle.
  • R 2 is selected from a -L-5- to 10-membered heterocycle.
  • R 2 is selected from a -(Ci-C 2 alkylene)-5- to 10-membered heterocycle. In some cases, R 2 is selected from a -L-5- to 8-membered heterocycle. In some cases, R 2 is selected from a -L-5- to 8-membered saturated heterocycle. In some cases, R 2 is a -L-5-membered heterocycle. In some cases, R 2 is a -L-8-membered heterocycle. In some cases, the heterocycle contains at least 1 nitrogen atom. In some cases, the heterocycle contains at most 1 nitrogen atom. In some cases, the heterocycle contains 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at least 1 nitrogen atom.
  • the bicyclic heterocycle contains at most 1 nitrogen atom.
  • the heterocycle has a silicon atom.
  • the heterocycle portion of -L- heterocycle has at least one heteroatom selected from nitrogen, oxygen, silicon, and sulfur.
  • the bicyclic heterocycle contains 1 nitrogen atom.
  • Y-R 2 is selected optionally substituted In some cases, Y-R 2 is selected from wherein the heterocycle portion is optionally substituted.
  • the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl
  • the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, -CN, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 aminoalkyl.
  • the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3 alkyl and halogen.
  • Y-R 2 is selected from
  • R 2 is selected from optionally substituted -L-heterocycle.
  • the heterocycle is a bicyclic heterocycle.
  • the heterocycle is a monocyclic heterocycle.
  • the heterocycle has only 1 nitrogen atom.
  • the heterocycle has only 1 nitrogen atom and no other heteroatoms.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • Y-R 2 is selected from wherein the heterocycle portion is optionally substituted.
  • Y-R 2 is selected from
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • the heterocycle is optionally substituted.
  • Y-R 2 is selected from
  • R 2 is -L-heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R 7
  • the heteroaryl is selected from a 5- to 6- membered heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R 7 .
  • the heteroaryl is selected from a 5-membered heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R 7 .
  • the heteroaryl has at least one nitrogen atom.
  • the heteroaryl has two nitrogen atoms.
  • the heteroaryl has three nitrogen atoms.
  • the heteroaryl is selected from -which i s optionally substituted.
  • the heteroaryl is , which is optionally substituted.
  • R 2 is selected from , wherein the heteroaryl portion is optionally substituted with one or more R 7 .
  • each R 7 is independently selected from C1-C4 alkyl, halogen, and C1-C4 haloalkyl.
  • Y-R 2 is selected from In some cases, Y-
  • R 2 is selected from j n some caseSj Y-R 2 is selected from
  • R 2 is -L-aryl, optionally substituted with one or more R 7 In some cases, wherein Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 7 . In some cases, Y-R 2 is selected from [00192] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), R 2 is -L-N(R 20 )2. In some cases, Y-R 2 is selected from
  • R 2 is heterocycle, optionally substituted with one or more R 6 .
  • the heterocycle which is optionally substituted.
  • the heterocycle some cases,
  • R 2 is heterocycle, optionally substituted with one
  • the heterocycle of R 6 is , which is optionally substituted. In some cases, the heterocycle some cases,
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • each R 6 is selected from -(CH2)o-iS-heterocycle, and -
  • (CH2)o-i-0-heterocycle wherein the heterocycle of -(CH2)o-i-0-heterocycle and -(CH2)O-I-S- heterocycle are each optionally substituted with one or more substituents selected from Ci-6 alkyl, Ci-ehaloalkyl, Ci-6 alkyl-OR 20 , and -OR 20 .
  • each R 6 is selected from -CH2-S- heterocycle, and -CI b-O-heterocycle, wherein the heterocycle of -CH2-O-heterocycle and -CH2- S-heterocycle are each optionally substituted with one or more substituents selected from C1-6 alkyl, Ci-e haloalkyl, Ci-6 alkyl-OR 20 , and -OR 20 .
  • each R 20 is independently selected from hydrogen; and Ci-6 alkyl, each of which is optionally substituted with one or more substituents independently selected from halogen.
  • each R 20 is independently selected from Ci-6 alkyl, each of which is optionally substituted with one or more substituents independently selected from halogen.
  • the heterocycle has one or two nitrogen atoms. In some cases, the heterocycle is a heteroaryl. In some cases, the heterocycle is selected heterocycle, and -CH2-O-heterocycle, wherein the heterocycle of -CH2-O-heterocycle and -CH2- S-heterocycle are each optionally substituted with one or more substituents selected from
  • R 6 is selected from -CH2O-C1-C6 alkyl, wherein the alkyl of -CH2O-C1-C6 alkyl is optionally substituted with one or more substituents selected
  • R 2 is selected from heterocycle, -L-heterocycle, wherein the heterocycle, and the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R 6 ; -L-aryl, and -L-heteroaryl, wherein the aryl of the -L-aryl, and the heteroaryl of - L-heteroaryl are each optionally substituted with one or more R 7 ; and -L-N(R 20 )2.
  • the heterocycle of R 2 is selected from , wherein the heterocycle of
  • R 2 is optionally substituted with one or more R 6 ; wherein the aryl and heteroaryl of R 2 is selected from , wherein the aryl and the heteroaryl are each optionally substituted with one or more R 7 ; In some cases, the heterocycle of R 2 is heterocycle is optionally substituted with one or more R 6 ; wherein the aryl and heteroaryl of R 2 is selected from wherein the aryl and the heteroaryl are each optionally substituted with one or more R 7 ; and . In some cases, each R 6 is independently selected from halogen, hydroxy, Ci-C 3 alkyl, C1-C3 haloalkyl, -
  • the heterocycle of R 2 , the aryl and heteroaryl of R 2 , and -N(R 20 ) 2 of R 2 is selected from ; wherein the heterocycle, and the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R 6 ; the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more
  • L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from hydroxy, C1-C4 hydroxyalkyl and C1-C4 alkyl. In some cases, L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from C1-C4 alkyl. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from C1-C2 alkylene.
  • L is . In some cases, L is
  • the optional substituents ofL are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl.
  • each L is independently selected from a substituted C1-C4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle.
  • each L is independently selected from a substituted C1-C4 alkylene, and two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. In some cases, each L is independently selected from
  • R 2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R 6 .
  • the heterocycle is a saturated heterocycle.
  • the heterocycle has at least one nitrogen atom and at least one sulfur atom.
  • the heterocycle has at least one nitrogen atom.
  • the heterocycle has at least one sulfur atom.
  • R 2 is selected from wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more
  • R 2 is selected from -L-saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R 6 , and contains one nitrogen atom and one sulfur atom.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3 alkyl and oxo. In some cases, Y-R 2 is selected from
  • Y is a bond.
  • R 2 is selected from an optionally substituted heteroaryl and optionally substituted aryl.
  • R 2 is selected from an optionally substituted heteroaryl.
  • the heteroaryl has at least one nitrogen atom.
  • the heteroaryl has at least two nitrogen atoms.
  • the heteroaryl only contain nitrogen atom(s).
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • the heteroaryl is selected from each of which is optionally substituted.
  • the heteroaryl is selected each of which is optionally substituted.
  • R 2 is selected from an optionally substituted aryl.
  • the aryl is a phenyl.
  • the heteroaryl is optionally substituted with one or more R 6 , wherein each R 6 is selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, - CH2 heterocycle, -C1-C3 alkyl-N(R 5 )2, and -C(O)N(R 5 )2.
  • R 6 is selected from C1-C3 alkyl, -CHiheterocycle, and -C(O)N(R 5 )2.
  • the aryl is optionally substituted with one
  • each R 6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, each R 6 is independently selected from halogen, C1-C3 alkyl, and C1-C3 haloalkyl.
  • each R 6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R 5 )2, and oxo. In some cases, each R 6 is independently selected from -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R 5 )2.
  • R 6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, R 6 is selected from halogen and C1-C3 alkyl. In some cases, R 6 is halogen. In some cases, R 6 is C1-C3 alkyl. In some cases, R 6 is selected from halogen and C1-C3 alkyl. In some cases, R 6 is selected from methyl and fluorine.
  • R 2 is selected from
  • Formula (I-B), or Formula (I-C), L is selected from unsubstituted C1-C4 alkylene.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R 6 of R 2 is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and Ci- C3 aminoalkyl.
  • R 6 of R 2 is independently selected at each occurrence from Ci-
  • n is selected from 0 to 4. In some cases, n is selected from 0 to
  • n is selected from 0 to 2. In some cases, n is selected from 0 and 1. In some cases, n is 0. In some cases, n is 1. In some cases, n is 2.
  • each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, and C1-C4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 4- to 6-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen.
  • each L is selected from ⁇ ,
  • each R 6 is selected from -(CH2)o-iS-heterocycle, and - (CH2)o-i-0-heterocycle, wherein the heterocycle of -(CH2)o-i-0-heterocycle and -(CH2)O-I-S- heterocycle are each optionally substituted with one or more substituents selected from Ci-6 alkyl, Ci-ehaloalkyl, Ci-6 alkyl-OR 20 , and -OR 20 .
  • each R 6 is selected from -CH2-S- heterocycle, and -CH2-O-heterocycle, wherein the heterocycle of -CH2-O-heterocycle and -CH2- S-heterocycle are each optionally substituted with one or more substituents selected from C1-6 alkyl, Ci-e haloalkyl, Ci-6 alkyl-OR 20 , and -OR 20 .
  • each R 20 is independently selected from hydrogen; and C1-6 alkyl, each of which is optionally substituted with one or more substituents independently selected from halogen.
  • each R 20 is independently selected from Ci-6 alkyl, each of which is optionally substituted with one or more substituents independently selected from halogen.
  • the heterocycle has one or two nitrogen atoms.
  • the heterocycle is a heteroaryl.
  • the heterocycle is selected from: .
  • each R 6 is selected from -CH2-S- heterocycle, and -CJfr-O-heterocycle, wherein the heterocycle of -CHa-O-heterocycle and -CH2- S-heterocycle are each optionally substituted with one or more substituents selected from substituted with one or more R 6 .
  • R 6 is selected from -CH2O-C1-C6 alkyl, wherein the alkyl of -CH O-C1-C6 alkyl is optionally substituted with one or more substituents selected from halogen and C3-C6 carbocycle.
  • Y-R 2 is selected from [00229]
  • R 1B is selected from hydrogen and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen
  • R 1A is selected from Ci-6 alkyl, and 5- membered heterocycle, each of which is independently optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of Ci-6 alkyl come together to form a C3-C4 carbocycle
  • the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OR 20 , -N(R 20 )2, -CN, C1-6 aminoalkyl, Ci-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.
  • the optional substituents of B are independently selected at each occurrence from C1-C3 alkyl, -NH2, and -CN.
  • B is selected , an d , , .
  • Y is -O-.
  • R 2 is selected from -L-heterocycle, and -L-N(CH3)2, wherein the heterocycle portion of -L- heterocycle, is optionally substituted with one or more R 6 .
  • R 2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle, is optionally substituted with one or more R 6 .
  • each R 6 is independently selected from halogen. .
  • at least one R 6 is independently selected from C1-C3 alkyl.
  • L is selected from C1-C4 alkylene.
  • L is selected from an unsubstituted C1-C4 alkylene.
  • L is selected from an unsubstituted Ci alkylene.
  • two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle.
  • two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle.
  • each L is selected from In some cases, Y-R 2 is In some cases, Y-R 2 is
  • Y-R 2 is In some cases,
  • Y-R 2 is I .
  • R 1B is selected from hydrogen and Ci-6 alkyl, wherein the Ci-
  • R 6 alkyl is optionally substituted with one or more halogen
  • R 1A is selected from C1-6 alkyl, and 5- membered heterocycle, each of which is independently optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of Ci-6 alkyl come together to form a C3-C4 carbocycle or 4-membered heterocycle
  • 6-membered heterocycle are each optionally substituted with one or more substituents
  • R 3 is selected from hydrogen. In some cases, R 3 is selected from halogen. In some cases, R 3 is selected from -CN. In some cases, R 3 is selected from -NO2. In some cases, R 3 is selected from -C(O)R 20 . In some cases, R 3 is selected from -C(O)OR 20 . In some cases, R 3 is selected from Ci-6 haloalkyl. In some cases, each R 20 is independently selected from hydrogen; and C1-6 alkyl.
  • R 1B is selected from hydrogen and Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen;
  • R 100 or cases, some cases, B is selected from an optionally substituted 8- to 10-membered fused heterocycle having at least one sulfur atom.
  • the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OR 20 , -N(R 20 )2, -CN, C1-6 aminoalkyl, Ci-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.
  • the optional substituents of B are independently selected at each occurrence from C1-C3 alkyl, -NH2, cases, some cases, some cases, Y is -O-.
  • R 2 is selected from -L-heterocycle, and -L-N(CH3)2, wherein the heterocycle portion of -L- heterocycle, is optionally substituted with one or more R 6 .
  • R 2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle, is optionally substituted with one or more R 6 .
  • each R 6 is independently selected from halogen. .
  • at least one R 6 is independently selected from C1-C3 alkyl.
  • L is selected from C1-C4 alkylene.
  • L is selected from an unsubstituted C1-C4 alkylene.
  • L is selected from an unsubstituted Ci alkylene.
  • two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle.
  • two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle.
  • Y-R is , In some cases, Y-R 2 is
  • Y-R 2 is In some cases, In some cases, R 1B is selected from hydrogen and Ci-6 alkyl, wherein the Ci-
  • R 6 alkyl is optionally substituted with one or more halogen
  • R 1A is selected from Ci-6 alkyl, and 5- membered heterocycle, each of which is independently optionally substituted with one or more R 11 , and wherein optionally two R 11 on the same atom of Ci-6 alkyl come together to form a C3-C4 carbocycle or 4-membered heterocycle
  • 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from -NH2, -OH, and -C1-3 alkyl.
  • R 3 is selected from hydrogen, halogen, -CN, -NO2, -C(O)R 20 , -
  • R 3 is selected from hydrogen. In some cases, R 3 is selected from halogen. In some cases, R 3 is selected from -CN. In some cases, R 3 is selected from -NCh. In some cases, R 3 is selected from -C(O)R 20 . In some cases, R 3 is selected from -C(O)OR 20 . In some cases, R 3 is selected from Ci-6 haloalkyl. In some cases, each R 20 is independently selected from hydrogen; and C1-6 alkyl. [00231] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), a substituent is selected from a compound in Table 1.
  • each R 20 is independently selected from hydrogen; and Ci-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-io alkyl, -Ci -10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 20 is independently selected from hydrogen and C1-6 alkyl.
  • each R 20 is independently selected from C1-6 alkyl.
  • each R 21 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-io alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 21 is independently selected from hydrogen; and Ci-e alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH 2 , -N(CI. 6 alkyl) 2 , Ci -io alkyl, “C i- 10 haloalkyl, — O— C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 21 is independently selected from hydrogen; and C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NH2, -N(Ci-6alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 21 is independently selected from hydrogen; and C1-6 alkyl, C3-6 carbocycle.
  • each R 21 is independently selected from hydrogen and Ci -e alkyl.
  • R 1A is not C3-C12 carbocycle or 4- to 12-membered heterocycle.
  • Y-R 2 is: In some cases, Y-R 2 is:
  • a compound or salt of Formula (I), Formula (I-A), Formula (LB), Formula (II), or Formula (I-C), does not contain an electrophile moiety.
  • the compound or salt does not include an electrophilic substituent.
  • the compound or salt does include an electrophilic moiety.
  • a compound or salt of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), the compound or salt is not a covalent modifier of KRAS G12D and/or other G12 mutants.
  • a compound or salt of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), the compound or salt is a covalent modifier of KRAS G12D and/or other G12 mutants.
  • a compound or salt of Formula (I), Formula (I- A), Formula (I-B), Formula (II), or Formula (I-C), the compound or salt is capable of reacting with a cysteine.
  • a compound or salt of Formula (I), Formula (I- A), Formula (I-B), Formula (II), or Formula (I-C), the compound or salt is not a covalent inhibitor for KRAS G12D and/or other G12 mutants.
  • “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.
  • stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
  • Formula (I-C), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H.
  • Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration.
  • a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds or salts for Formula (I), Formula (I- A), Formula (I-B), or Formula (I-C), exist as tautomers.
  • a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH.
  • tautomeric [00253] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, n C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine- 125 ( 125 I) or carbon-14 ( 14 C).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine- 125 ( 125 I) or carbon-14 ( 14 C).
  • Isotopic substitution with 2 H, n C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 0, 17 0, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 C1, 37 C1, 79 Br, 81 Br, and 125 I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present
  • the compounds disclosed herein have some or all of the J H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • the compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.
  • the methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs).
  • the compounds described herein may be in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester.
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure.
  • One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal.
  • esters or carbonates e g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.
  • the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus etal., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J.
  • the present disclosure provides methods of producing the above-defined compounds.
  • the compounds may be synthesized using conventional techniques.
  • these compounds are conveniently synthesized from readily available starting materials.
  • compositions comprising a therapeutically effective amount of any compound or salt of Formula (I), Formula (LA), Formula (LB), Formula (II), or Formula (LC) (also referred to herein as “a pharmaceutical agent”).
  • compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;
  • compositions and methods of the present disclosure may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the pharmaceutical agent is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient.
  • Pharmaceutically acceptable carriers include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • a pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop.
  • the compound may also be formulated for inhalation.
  • a pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion.
  • the excipients described herein are examples and are in no way limiting.
  • An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein.
  • Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and/or in the urine, and/or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.
  • the dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art.
  • Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts.
  • suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted 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.
  • Optimal doses of an agent may generally be determined using experimental models and/or clinical trials.
  • the optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art.
  • the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy.
  • two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone.
  • An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg/kg and 100 mg/kg, e.g., between about 0.1 to 1 mg/kg, between about 1 to 10 mg/kg, between about 10-50 mg/kg, between about 50-100 mg/kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg/kg and 1000 mg/kg, between about 100-500 mg/kg, or between about 500-1000 mg/kg body weight.
  • the optimal dose, per day or per course of treatment may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.
  • compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art.
  • the composition may be in the form of a solid, e.g., tablet, capsule, semisolid, e.g., gel, liquid, or gas, e.g., aerosol.
  • the pharmaceutical composition is administered as a bolus infusion.
  • compositions are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used.
  • compositions described herein may be formulated as a lyophilizate.
  • a composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and/or diluting the pharmaceutical agent(s) of the composition upon administration.
  • the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art.
  • a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries.
  • compositions may be formulated for any appropriate manner of administration described herein and in the art.
  • a pharmaceutical composition e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid.
  • a liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile.
  • a liquid pharmaceutical composition may be applied to the eye in the form of eye drops.
  • a liquid pharmaceutical composition may be delivered orally.
  • At least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents.
  • the pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating.
  • a pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating.
  • a pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release.
  • Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site.
  • Sustained-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane.
  • Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release
  • the amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.
  • the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration.
  • the compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe- like applicator, as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste.
  • This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e g., intradermally or subcutaneously.
  • the active compositions can also be delivered via iontophoresis.
  • Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.
  • Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid.
  • the emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.
  • Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients.
  • the oil phase may contain other oily pharmaceutically approved excipients.
  • Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants.
  • Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure.
  • Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.
  • the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway.
  • the pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles.
  • the pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof.
  • Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles.
  • Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.
  • Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 p.
  • the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent.
  • the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.
  • Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 p. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 p range.
  • a jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate.
  • An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
  • suitable devices including, for example, AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Wales, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and AerosonicTM (DeVilbiss Medizinische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffetechnik (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.
  • AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc.
  • the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape.
  • these semisolid compositions can contain dissolved and/or suspended bactericidal agents, preservatives and/or a buffer system.
  • a petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes.
  • Absorption bases can be used with an oleaginous system.
  • Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.
  • lanolin lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.
  • Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art.
  • the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film.
  • the formulation can comprise a cross-linked polycarboxylic acid polymer formulation.
  • a cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.
  • An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time.
  • the article, transdermal patch or insert comprises water- soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.
  • PEG polyethylene glycol
  • Transdermal devices may also comprise a water insoluble polymer.
  • Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound.
  • the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.
  • a polymer formulation can also be utilized to provide controlled or sustained release.
  • Bioadhesive polymers described in the art may be used.
  • a sustained- release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix.
  • a polymeric matrix include a microparticle.
  • the microparticles can be microspheres, and the core may be of a different material than the polymeric shell.
  • the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel.
  • the polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent.
  • the matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.
  • Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses are provided.
  • kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition.
  • the present disclosure provides compounds that inhibit KRas G12 mutants.
  • the method may inhibit KRas G12 mutants activity in a cell.
  • inhibitng KRas G12 mutants activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants activity is desired with an effective amount of a compound of Formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical compositions containing a compound or salt of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C) and a pharmaceutically acceptable excipient.
  • the contacting is in vitro. In some cases, the contacting is in vivo.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" a KRas G12D and/or other G12 mutants with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12D and/or other G12 mutants, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12D and/or other G12 mutants.
  • a cell in which inhibition of KRas G12D and/or other G12 mutants activity is desired is contacted with an effective amount of a compound or salt of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutical composition of any one thereof to negatively modulate the activity of KRas G12D and/or other G12 mutants.
  • a compound or salt of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutical composition of any one thereof to negatively modulate the activity of KRas G12D and/or other G12 mutants.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12D and/or other G12 mutants activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12D and/or other G12 mutants.
  • the ability of compounds to bind KRas G12D and/or other G12 mutants may be monitored in vitro using well known methods.
  • the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12D and/or other G12 mutants activity of the amount of phosphorylated ERK.
  • methods of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a pharmaceutically acceptable excipient are provided.
  • compositions and methods provided herein may be used for the treatment of a KRas G12D and/or other G12 mutants-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided.
  • the KRas G12D and/or other G12 mutants associated cancer is lung cancer.
  • the compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc.
  • cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
  • the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In some cases, the cancer is non-small cell lung cancer.
  • the concentration and route of administration to the patient will vary depending on the cancer to be treated.
  • the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be coadministered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • Also provided herein is a compound of Formula (I), Formula (LA), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, for use in therapy.
  • Also provided herein is a compound of Formula (I), Formula (LA), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, for use in the treatment of cancer.
  • Also provided herein is a compound of Formula (I), Formula (LA), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, for use in the inhibition of KRas G12D and/or other G12 mutants.
  • Also provided herein is a compound of Formula (I), Formula (LA), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, for use in the treatment of a KRas G12D and/or other G12 mutants associated disease or disorder.
  • Also provided herein is the use of a compound of Formula (I), Formula (LA), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cancer.
  • Also provided herein is the use of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, in the manufacture of a medicament for the treatment of a KRas G12D and/or other G12 mutants-associated disease or disorder.
  • the present disclosure provides a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12D mutation and/or other G12 mutants (e g., a KRas G12D and/or other G12 mutants- associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA- approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (II), or Formula (I-C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a KRas G12D mutation and/or other G12 mutants e.g., a KRas G12D and/or other G12 mutants- associated cancer
  • a regulatory agency-approved e.g., FDA- approved, assay or kit
  • the compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
  • the compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
  • a patient susceptible to or otherwise at risk of a particular disease, disorder or condition is defined to be a "prophylactically effective amount or dose.”
  • dose a pharmaceutically effective amount or dose.
  • the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 - about 1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Nonlimiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LDso and ED50.
  • Compounds exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the invention provides a method of treating or preventing a disease, state or condition in a patient in need thereof comprising administering to the patient an effective amount of a compound of any one of embodiments of the invention or a pharmaceutically acceptable salt thereof.
  • the disease, state or condition may be selected from a group as described elsewhere herein.
  • compounds herein can adopt to selectively eliminate an over activated KRas signaling which is induced by KRas mutations by directly binding with the mutated KRas protein, either by stabilizing its GDP bound form (the inactive form) or by blocking the interaction between GTP bound form and its downstream target protein.
  • another way is to hijack the protein degradation mechanism in a cell and leverage E3 ligases’ (like VHL, CRBN or IAPS) substrate specificity through a bi-functional molecule called Proteolysis targeting chimera (PROTAC) (Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE.
  • a bifunctional compound composed of a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety, which may induce proteasome-mediated degradation of selected proteins.
  • the bifunctional compound comprises a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety known in the art.
  • disclosed herein is the use of the compound disclosed herein in the preparation of degrading a target protein compound by using chemical modification of the compound disclosed herein.
  • the target proteinbinding moiety is derived from a compound of Formula (I), Formula (I-A), Formula (LB), Formula (II), or Formula (LC).
  • the compounds of the present disclosure can generally be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • compounds of the present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art.
  • Step 1 Preparation of 01 -tert-butyl O3-methyl 3-bromoazetidine-l,3-dicarboxylate (Int-la).
  • Step 2 Preparation of 01-tert-butyl O3-methyl 3 -(3 -m ethoxy-3 -oxo- propyl)sulfanylazeti dine- 1,3 -dicarboxylate (Int-lb).
  • 01-tert-butyl O3-methyl 3- bromoazetidine-l,3-di carboxylate (Int-la, 1.5g, 5.1mmol) in DMF (16 mL) was added methyl 3- sulfanylpropanoate (1348.2 mg, 11.22 mmol) and K2CO3 (2819.27 mg, 20.4 mmol) at 20 °C under N2.
  • Step 3 Preparation of 02-tert-butyl O7-methyl 8-oxo-5-thia-2-azaspiro[3.4]octane- 2,7-dicarboxylate (Int-lc).
  • 01-tert-butyl O3-methyl 3-(3-methoxy-3-oxo- propyl)sulfanylazeti dine- 1,3 -dicarboxylate (Int-lb, 200 mg, 3.6 mmol) in THF (20 mL) was added t-BuONa (691.78 mg, 7.2 mmol) by portions at 0 °C under N2. The mixture was stirred at 0 °C for 2 h.
  • Step 4 Preparation of tert-butyl 8-oxo-5-thia-2-azaspiro[3.4]octane-2-carboxylate (Int-ld).
  • 02-tert-butyl 07-methyl 8-oxo-5-thia-2-azaspiro[3.4]octane-2,7- dicarboxylate (Int-lc, 800 mg, 2.65 mmol) in DMSO (12 mL) was added LiCl (225.06 mg, 5.31 mmol) and water (1.2 mL) at rt under N2.
  • Step 5 Preparation of tert-butyl 2-amino-3-cyano-spiro[6H-thieno[2,3-c]thiophene- 4,3'-azetidine]-l'-carboxylate (Int-le).
  • a solution of tert-butyl 8-oxo-5-thia-2- azaspiro[3.4]octane-2-carboxylate (480 mg, 1.97 mmol), Sulfur (94.93 mg, 2.96 mmol), ammonium acetate (228.08 mg, 2.96mmol) in Ethanol (7 mL) was added to propanedinitrile (195.48 mg, 2.96 mmol) at RT.
  • Step 6 Preparation of 2-aminospiro[6H-thieno[2,3-c]thiophene-4,3'-azetidine]-3- carbonitrile;methanesulfonic acid (Intermediate 1).
  • Step 1 Synthesis of 2-(bis(4-methoxybenzyl)amino)nicotinaldehyde (Int-2b)
  • Step 2 Synthesis of (S,E)-N-((2-(bis(4-methoxybenzyl)amino)pyridin-3- yl)methylene)-2-methylpropane-2-sulfinamide (Int-2c). To the solution of (S)-2-methylpropane- 2-sulfinamide (32037.3 mg, 264.33 mmol) and 2-[bis[(4-methoxyphenyl)methyl]amino]pyridine-
  • Step 3 Synthesis of (S)-N-((R)-l-(2-(bis(4-methoxybenzyl)amino)pyridin-3- yl)ethyl)-2-methylpropane-2-sulfinamide (Int-2d).
  • Step 4 Synthesis of (S)-N-((R)-l-(2-(bis(4-methoxybenzyl)amino)pyridin-3- yl)ethyl)-N,2-dimethylpropane-2-sulfmamide (Int-2e).
  • Step 5 Synthesis of (R)-3-(l-(methylamino)ethyl)pyridin-2-amine (Intermediate 2A)
  • (S)-N-[(lR)-l-[2-[bis[(4-methoxyphenyl)methyl]amino]-3- pyridyl]ethyl]-N,2-dimethyl-propane-2-sulfinamide (43.8 g, 88.36 mmol) in TFA (120 mL, 1568.15 mmol) was added Trifluoromethanesulfonic acid (1800.92 mg, 12.0 mmol) at rt under N2.
  • Step 2 Preparation of 3-(l-aminoethyl)pyridin-2-amine (Intermediate 3) .
  • l-(2-amino-3-pyridyl)ethanone oxime 996 mg, 6.59 mmol
  • zinc 1723.05 mg, 26.35 mmol
  • hydrochloric acid (16.8 mL, 201.6 mmol)
  • the reaction mixture was heated at 90 °C overnight.
  • the reaction mixture was concentrated under reduced pressure to remove solvent.
  • Step 1 Synthesis of 01 -tert-butyl O3-methyl 3-[3-[tert-butyl(dimethyl)silyl]oxy-l- hydroxy-propyl]azetidine-l,3-dicarboxylate (Int-4a).
  • LDA 99.55mL, 199.1 Immol
  • THF 500mL
  • a solution of 01 -tert-butyl O3-methyl azetidine- 1,3-dicarboxylate (21.43g, 99.55mmol) in THF (30mL) was added dropwise over Ih.
  • Step 2 Synthesis of 3-[l-benzyloxy-3-[tert-butyl(dimethyl)silyl]oxy-propyl]-l-tert- butoxycarbonyl-azetidine-3-carboxylic acid (Int-4b).
  • Step 4 Synthesis of tert-butyl 3-(l-benzyloxy-3-hydroxy-propyl)-3-formyl-azetidine- 1-carboxylate (Int-4d).
  • tert-butyl 9-benzyloxy-5-oxo-6-oxa-2- azaspiro[3.5]nonane-2-carboxylate 23 g, 66.2 mmol
  • DCM dimethyl methyl
  • DIBAL-H in hexane 99.31 mL, 99.31 mmol
  • Step 5 Synthesis of tert-butyl 3-(l-benzyloxy-3-hydroxy-propyl)-3-vinyl-azetidine-l- carboxylate (Int-4e).
  • Methyltriphenylphosphonium Bromide 40.89 g, 114.47 mmol
  • THF 600 mL
  • t-BuOK t-BuOK
  • THF 114.47 mL, 114.47 mmol
  • tert-butyl 3-(l-benzyloxy-3-hydroxy- propyl)-3-formyl-azetidine-l -carboxylate (20 g, 57.24 mmol) was added. The mixture was stirred for another 1 h. Upon completion, the mixture was quenched with sat. NH4CI aq. (1000 mL), extracted with EtOAc (800 mLx2). The combined organic layer was dried over Na2SO4, fdtered, and concentrated to afford the crude product.
  • Step 6 Synthesis of tert-butyl 3-(l-benzyloxy-3-oxo-propyl)-3-vinyl-azetidine-l- carboxylate (Int-4f). To a solution of tert-butyl 3-(l-benzyloxy-3-hydroxy-propyl)-3-vinyl- azetidine-1 -carboxylate (11 g, 31.66 mmol) in DCM (350 mL) was added DMP (26.86 g, 63.32 mmol). The resulting mixture was stirred at r.t. for 6 h.
  • Step 7 Synthesis of tert-butyl 3-[(3E)-l-benzyloxy-3-(p- tolylsulfonylhydrazono)propyl]-3-vinyl-azetidine-l-carboxylate (Int-4g). To a solution of tertbutyl 3-(l-benzyloxy-3-oxo-propyl)-3-vinyl-azetidine-l-carboxylate (2 g, 5.79 mmol) in THF (60 mL) was added TsNHNEE (1.62 g, 8.68 mmol). The resulting mixture was stirred at -20 °C for 0.2 h.
  • Step 8 Synthesis of tert-butyl 3'-benzyloxyspiro[azetidine-3,2'-bicyclo[3.1.0]hexane]- 1-carboxylate (Int-4h).
  • tert-butyl 3-[(3E)-l-benzyloxy-3-(p- tolylsulfonylhydrazono)propyl]-3-vinyl-azetidine-l-carboxylate (2 g, 3.89 mmol) and MeONa (420 mg, 7.79 mmol) in DMF (60 mL) was added Pd2(dba)3 (1.07 g, 1.17 mmol) under Ar.
  • Step 9 Synthesis of tert-butyl 3'-hydroxyspiro[azetidine-3,2'-bicyclo[3.1.0]hexane]-l- carboxylate & tert-butyl 5-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (Int-4i and by-product).
  • tert-butyl 3'-benzyloxyspiro[azetidine-3,2'-bicyclo[3.1.0]hexane]-l-carboxylate 300 mg, 0.91 mmol
  • Methanol (10 mL) was added Pd/C (150 mg, 1.41 mmol).
  • Step 10 Synthesis of tert-butyl 3'-oxospiro[azetidine-3,2'-bicyclo[3.1.0]hexane]-l- carboxylate & tert-butyl 5-oxo-2-azaspiro[3.5]nonane-2-carboxylate (Int-4j and by-product).
  • Step 11 Synthesis of tert-butyl 8-amino-7-cyano-spiro[9-thiatricyclo[4.3.0.02,4]nona- l(6),7-diene-5,3'-azetidine]-l'-carboxylate and tert-butyl 2-amino-3-cyano-spiro[6,7-dihydro-5H- benzothiophene-4,3'-azetidine]-l'-carboxylate (Int-4k and by-product).
  • Step 12 Synthesis of 8-aminospiro[9-thiatricyclo[4.3.0.02, 4]nona-l(6),7-diene-5, 3'- azetidine]-7-carbonitrile;methanesulfonic acid & 2-aminospiro[6,7-dihydro-5H-benzothiophene- 4,3'-azetidine]-3-carbonitrile;methanesulfonic acid (Intermediate 4 and by-product).
  • Step 1 Synthesis of 1 -(tert-butyl) 3-methyl 3 -azidoazetidine- 1,3 -dicarboxylate (Int- 5a).
  • the mixture of 1 -(tert-butyl) 3-methyl 3-bromoazetidine-l,3-dicarboxylate (2.00 g, 6.80 mmol) and azidosodium (1.33 g, 20.4 mmol) in anhydrous DMSO (20.0 mL) was stirred at 50 °C for 18 h under N2.
  • the reaction mixture was cooled to r.t and diluted with EtOAc (200 mL).
  • Step 2 Synthesis of 1 -(tert-butyl) 3-methyl 3 -aminoazetidine- 1,3 -dicarboxylate (Int- 5b).
  • the mixture of 1 -(tert-butyl) 3-methyl 3-azidoazetidine-l,3-dicarboxylate (1.66 g, 6.48 mmol) and 10% Pd/C (55% wt, 300 mg) in Ethanol (20.0 mL) was stirred at r.t under H2 atmosphere overnight.
  • Step 3 Synthesis of 1 -(tert-butyl) 3-methyl 3-((3-methoxy-3- oxopropyl)amino)azetidine-l,3-dicarboxylate (Int-5c).
  • Step 4 Synthesis of 5-benzyl 2-(tert-butyl) 7-methyl 8-oxo-2,5-diazaspiro[3.4]octane- 2,5,7-tricarboxylate (Int-5d).
  • Step 5 Synthesis of 5-benzyl 2-(tert-butyl) 8-oxo-2,5-diazaspiro[3.4]octane-2,5- dicarboxylate (Int-5e).
  • Step 6 Synthesis of tert-butyl 8-oxo-2,5-diazaspiro[3.4]octane-2-carboxylate (Int-5f).
  • Step 7 Synthesis of tert-butyl 5-methyl-8-oxo-2,5-diazaspiro[3.4]octane-2- carboxylate (Int-5g).
  • the mixture of tert-butyl 8-oxo-2,5-diazaspiro[3.4]octane-2-carboxylate (60.0 mg, 0.27 mmol), Methyl Iodide (0.05 mL, 0.80 mmol) and DIEA (0.12 mL, 0.66 mmol) in THF (2 mL) was stirred at 60 °C for 16 h under N2. The mixture was cooled to r.t and diluted with water (10 mL), extracted with EtOAc (10 m).
  • Step 8 Synthesis of tert-butyl 2-amino-3-cyano-5-methyl-spiro[6H-thieno[2,3- c]pyrrole-4,3'-azetidine]-l'-carboxylate (Int-5h).
  • Sulfur (31.6 mg, 0.99 mmol)
  • ammonium acetate 76.
  • Step 9 Synthesis of 2-amino-5-methyl-spiro[6H-thieno[2,3-c]pyrrole-4,3'-azetidine]- 3-carbonitrile (Intermediate 5).
  • Step 2 Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[4- [methoxy(methyl)carbamoyl]-l,2,5-thiadiazol-3-yl]carbamate (Int-6b).
  • Step 4 Synthesis of tert-butyl N-[4-[l-(ethylamino)ethyl]-l,2,5-thiadiazol-3- yl]carbamate (Intermediate 6).
  • tert-butyl N-(4-acetyl-l,2,5-thiadiazol-3- yl)carbamate 500 mg, 2.06 mmol
  • Ethylamine in THF 2.06 mL, 4.11 mmol
  • Methanol 10 mL
  • Titanium tetraisopropanolate (1168.28 mg, 4.11 mmol
  • Step 1 Synthesis of l-(3-chloropyrazin-2-yl)ethenone (Int-7a).
  • Step 2 Synthesis of l-(3-aminopyrazin-2-yl)ethenone (Int-7b).
  • Step 3 Synthesis of 3-[l-(methylamino)ethyl]pyrazin-2-amine (Intermediate 7). To a stirred solution of l-(3-aminopyrazin-2-yl)ethanone (402.91 mg, 2.94 mmol) in THF (5mL). Methylamine in MeOH (608.35 mg, 5.88 mmol) was added at 0°C followed by the drop wise addition of titanium(IV)isopropoxide (2.61 mL, 8.81 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, added Methanol (5mL) and cooled to 0°C.
  • Step 1 Synthesis of N,N-bis[(4-methoxyphenyl)methyl]-3-[(lR)-l- (methylamino)ethyl]pyridin-2-amine (Int-9a).
  • N-[(lR)-l-[2-[bis[(4- methoxyphenyl)methyl]amino]-3-pyridyl]ethyl]-N,2-dimethyl-propane-2-sulfinamide (Int-2e, 24. g, 46. mmol) in Methanol (200mL) was added HC1 in MeOH (34.5mL, 137.99mmol) at 0 °C.
  • Step 2 Synthesis of 4-[[(lR)-l-[2-[bis[(4-methoxyphenyl)methyl]amino]-3- pyridyl]ethyl]-methyl-amino]-6-chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (Int-9b) [00377] To the solution of N,N-bis[(4-methoxyphenyl)methyl]-3-[(lR)-l-(methylamino)ethyl]pyridin- 2-amine (1.78g, 4.54mmol) and 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (l.g, 4.54mmol) in DCM (20mL) was added DIEA (2.37mL, 13.63mmol) at 25 °C.
  • the mixture was stirred at 25 °C for 4 h.
  • the mixture was diluted with water (50 mL), and then extracted with DCM (80 mL x 3).
  • the combined organic phases were washed with brine (80 mL), dried overNa2SO 4 , filtered and concentrated.
  • the crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 0% to 30%).
  • Step 3 Synthesis of 4-[[(lR)-l-[2-[bis[(4-methoxyphenyl)methyl]amino]-3- pyridyl]ethyl]-methyl-amino]-6-chloro-2-methylsulfonyl-pyrimidine-5-carbonitrile (Intermediate 9).
  • Step 1 Synthesis of (R)-3-(l-((2,2-difluoroethyl)amino)ethyl)-N,N-bis(4- methoxybenzyl)pyridin-2-amine (Int-lla).
  • Step 2 Synthesis of (R)-3-(l-((2,2-difluoroethyl)amino)ethyl)pyridin-2-amine (Intermediate 11).
  • Step 1 Preparation of 4-chloro-6-[(l-cyanocyclopropyl)methoxy]-2- methylsulfanyl-pyrimidine-5-carbonitrile (la).
  • 1- (hydroxymethyl)cyclopropanecarbonitrile 220.65 mg, 2.27 mmol
  • LiHMDS LiHMDS
  • the reaction was stirred at -78 °C for 2h.
  • the mixture was extracted with EtOAc, washed with brine.
  • Step 2 Preparation of 2-amino-T-[5-cyano-6-[(l-cyanocyclopropyl)methoxy]-2- methylsulfanyl-pyrimidin-4-yl]spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3- carbonitrile (lb).
  • Step 3 Preparation of 2-amino-l'-[5-cyano-6-[(l-cyanocyclopropyl)methoxy]-2- methylsulfinyl-pyrimidin-4-yl]spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3- carbonitrile (lc).
  • Step 1 Preparation of 4-chloro-2-methylsulfanyl-6-(lH-pyrazol-5- ylmethylamino)pyrimidine-5-carbonitrile (4a).
  • Step 2 Preparation of tert-butyl 5-[[(6-chloro-5-cyano-2-methylsulfanyl- pyrimidin-4-yl)amino]methyl]pyrazole-l -carboxylate (4b).
  • 4-chloro-2- methylsulfanyl-6-(lH-pyrazol-5-ylmethylamino)pyrimidine-5-carbonitrile (4a, 200 mg, 0.71 mmol) and BOC2O (0.21 mL, 1.57 mmol) in MeCN (6mL) and DCM (4mL) were added DMAP (17.41mg, 0.14mmol) at 25 °C. The mixture was stirred at 25 °C for 2 h.
  • Step 3 Preparation of tert-butyl 5-[[(6-chloro-5-cyano-2-methylsulfmyl-pyrimidin- 4-yl)amino]methyl]pyrazole-l -carboxylate (4c).
  • Step 4 Preparation of tert-butyl 5-[[[6-chloro-5-cyano-2-[[(2R,8S)-2-fluoro- 1,2, 3,5,6, 7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4-yl]amino]methyl]pyrazole-l- carboxylate (4d).
  • Step 5 Preparation of tert-butyl 5-[[[6-(2-amino-3-cyano-spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-l'-yl)-5-cyano-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4-yl]amino]methyl]pyrazole-l -carboxylate (4e).
  • Step 2 Preparation of 2-amino-r-(6-chloro-5-cyano-2-methylsulfinyl-pyrimidin-4- yl)spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile (5b).
  • Step 3 Preparation of 2-amino-l'-[6-chloro-5-cyano-2-[[(2R,8S)-2-fluoro- l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4-yl]spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile (5c).
  • Step 4 Preparation of 2-amino-T-[6-[l-(2-amino-3-pyridyl)ethylamino]-5-cyano- 2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4-yl]spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile (Compound 5).
  • Step 1 Synthesis of 4-[l-(2-amino-3-pyridyl)ethyl-methyl-amino]-6-chloro-2- methylsulfanyl-pyrimidine-5-carbonitrile (15a). To a solution of 4,6-dichloro-2-methylsulfanyl- pyrimidine-5-carbonitrile (100.
  • Step 2 Synthesis of 4-[l-(2-amino-3-pyridyl)ethyl-methyl-amino]-6-chloro-2- methylsulfmyl-pyrimidine-5-carbonitrile (15b). To a solution of 4-[l-(2-amino-3-pyridyl)ethyl- methyl-amino]-6-chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (150.
  • Step 3 Synthesis of afford 4-[l-(2-amino-3-pyridyl)ethyl-methyl-amino]-6-chloro- 2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrimidine-5-carbonitrile (15c).
  • 4-[l-(2-amino-3-pyridyl)ethyl-methyl-amino]-6-chloro-2-methylsulfinyl- pyrimidine-5-carbonitrile (36. mg, O. lmmol) in 1,4-Dioxane (ImL) was added [(2R,8S)-2-fluoro-
  • Step 4 Synthesis of 2-amino-l'-[6-[l-(2-amino-3-pyridyl)ethyl-methyl-amino]-5- cyano-2-[[(2R, 8S)-2-fluoro- 1,2, 3,5,6, 7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4- yl]spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile (compound 15).
  • Step 1 Preparation of 6-chloro-5-fluoro-N-(l-(2-((4- methoxybenzyl)amino)pyri din-3 -yl)ethyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (22a). To a solution of N-[(4-methoxyphenyl)methyl]-3-[l-(methylamino)ethyl]pyridin-2-amine (prepared similarly to that of Intermediate 2.
  • Step 2 Preparation of 6-chloro-5-fluoro-N-(l-(2-((4- methoxybenzyl)amino)pyridin-3-yl)ethyl)-N-methyl-2-(methylsulfonyl)pyrimidin-4-amine (22b).
  • Step 3 Preparation of 6-chloro-5-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-N-(l-(2-((4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-N- methylpyrimidin-4-amine (22c)
  • 6-chloro-5-fhioro-N-[l-[2-[(4- methoxyphenyl)methylamino]-3-pyridyl]ethyl]-N-methyl-2-methylsulfonyl-pyrimidin-4-amine 750 mg, 1.56 mmol
  • [(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol 248.77 mg, 1.56 mmol) in THF (10 mL)
  • Step 4 Preparation of N-(l-(2-aminopyridin-3-yl)ethyl)-6-chloro-5-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-N-methylpyrimidin-4-(22d).
  • Step 5 Preparation of 2'-amino-l-(6-((l-(2-aminopyridin-3- yl)ethyl)(methyl)amino)-5-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrimidin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'- carbonitrile (Compound 22).
  • Example 6 Exemplary synthesis of 2-amino-T-[6-[[(lR)-l-(2-amino-3- pyridyl)ethyl]-methyl-amino]-5-fluoro-2-[[l-
  • Step 1 Preparation of (R)-6-chloro-5-fluoro-N-(l-(2-((4- methoxybenzyl)amino)pyri din-3 -yl)ethyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (28a). To a solution ofN-[(4-methoxyphenyl)methyl]-3-[(lR)-l-(methylamino)ethyl]pyridin-2- amine;hydrochloride (prepared similarly to that of Intermediate 2A.
  • Step 2 Preparation of (R)-6-chloro-5-fluoro-N-(l-(2-((4- methoxybenzyl)amino)pyridin-3-yl)ethyl)-N-methyl-2-(methylsulfonyl)pyrimidin-4-amine (28b).
  • Step 3 Preparation of (R)-6-chloro-5-fluoro-N-(l-(2-((4- methoxybenzyl)amino)pyridin-3-yl)ethyl)-N-methyl-2-((l- (morpholinomethyl)cyclopropyl)methoxy)pyrimidin-4-amine (28c).
  • Step 4 Preparation of (R)-N-(l-(2-aminopyridin-3-yl)ethyl)-6-chloro-5-fluoro-N- methyl-2-((l-(morpholinomethyl)cyclopropyl)methoxy)pyrimidin-4-amine (28d).
  • Step 5 Preparation of (R)-2'-amino-l-(6-((l-(2-aminopyridin-3- yl)ethyl)(methyl)amino)-5-fluoro-2-((l-(morpholinomethyl)cyclopropyl)methoxy)pyrimidin-4- yl)-6'H-spiro[azetidine-3,4'-thieno[3,4-b]thiophene]-3'-carbonitrile (Compound 28).
  • Example 7 l-(l-((6-(2'-amino-3'-cyano-6'H-spiro[azetidine-3,4'-thieno[3,4- b]thiophen]-l-yl)-5-cyano-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrimidin-4-yl)(methyl)amino)ethyl)cyclopropane-l -carboxamide (Compound 31)
  • Step 1 Preparation of 2-amino-l'-(2,6-dichloro-5-cyano-pyrimidin-4-yl)spiro[6H- thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile (31a).
  • Step 2 Preparation of 2'-amino-l-(6-chloro-5-cyano-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrimidin-4-yl)-6'H-spiro[azetidine-3,4'- thieno[3,4-b]thiophene]-3'-carbonitrile (31b).
  • Step 3 Preparation of l-(l-((6-(2'-amino-3'-cyano-6'H-spiro[azetidine-3,4'- thieno[3,4-b]thiophen]-l-yl)-5-cyano-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrimidin-4-yl)(methyl)amino)ethyl)cyclopropane-l -carboxamide (Compound 31).
  • Example 8 Exemplary synthesis of 2-amino-l'-[6-[l-(3-aminopyrazin-2-yl)ethyl- methyl-amino]-5-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrimidin-4-yl]spiro[6H-thieno[2,3-c]thiophene-4,3'-azetidine]-3-carbonitrile (Compound 33)
  • Step 1 Synthesis of 4,6-dichloro-5-fluoro-2-methylsulfonyl-pyrimidine (33a) To a solution of 4,6-dichloro-5-fluoro-2-methylsulfanyl-pyrimidine (300. mg, 1.41mmol) in Methanol (4mL) was added OXONE (2.6g, 4.22mmol) in Water (2mL) at 0°C. The reaction mixture was allowed to warm to rt and stirred for 16 hours. The reaction was quenched with H2O and extracted with EtOAc.
  • Step 2 Synthesis of (2R,8S)-8-[(4,6-dichloro-5-fluoro-pyrimidin-2-yl)oxymethyl]- 2-fluoro-l,2,3,5,6,7-hexahydropyrrolizine (35b).
  • Step 3 Synthesis of 2-amino-l'-[6-[l-(3-aminopyrazin-2-yl)ethyl-methyl-amino]- 5-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4- yl]spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile (Compound 33).
  • Step 1 Preparation of 4-[[(lR)-l-[2-[bis[(4-methoxyphenyl)methyl]amino]-3- pyridyl]ethyl]-ethyl-amino]-6-chloro-2-[[(2R,8S)-2-fluoro- 1,2, 3,5,6, 7-hexahydropyrrolizin-8- yl]methoxy]pyrimidine-5-carbonitrile (52a).
  • Step 2 Preparation of 4-[[(lR)-l-(2-amino-3-pyridyl)ethyl]-ethyl-amino]-6- chloro-2-[[(2R,8S)-2-fluoro- 1,2, 3,5,6, 7-hexahydropyrrolizin-8-yl]methoxy]pyrimidine-5- carbonitrile (52b).
  • Step 3 Preparation of 2-amino-r-[6-[[(lR)-l-(2-amino-3-pyridyl)ethyl]-ethyl- amino]-5-cyano-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin- 4-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile (Compound 52).
  • Step 1 Synthesis of 2-amino-l'-[6-[[(lR)-l-[2-[bis[(4- methoxyphenyl)methyl]amino]-3-pyridyl]ethyl]-methyl-amino]-5-cyano-2-[[2,2-difluoro-l- (hydroxymethyl)cyclopropyl]methoxy]pyrimidin-4-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'- azetidine]-3-carbonitrile (53a).
  • Step 3 Synthesis of 2-amino-l'-[6-[[(lR)-l-[2-[bis[(4- methoxyphenyl)methyl]amino]-3-pyridyl]ethyl]-methyl-amino]-5-cyano-2-[[l-
  • Step 4 Synthesis of 2-amino-l'-[6-[[(lR)-l-(2-amino-3-pyridyl)ethyl]-methyl- amino]-5-cyano-2-[[l-[(dimethylamino)methyl]-2,2-difluoro-cyclopropyl]methoxy]pyrimi din-4- yl]spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile (Compound 53).

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Abstract

L'invention concerne des composés, tels que des composés de formule (I), de formule (l-A), de formule (l-B), ou de formule (l-C), ou des sels pharmaceutiquement acceptables de l'un quelconque de ceux-ci, utiles pour moduler KRAS GD12 et/ou d'autres mutants G12.
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WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026035945A1 (fr) 2024-08-07 2026-02-12 Tesseract Medicines Us, Llc Conjugués médicamenteux induits par covalence ciblant kras et comprenant une charge utile de topoisomérase
WO2026035947A1 (fr) 2024-08-07 2026-02-12 Tesseract Medicines Us, Llc Conjugués médicamenteux à induction par liaison covalente ciblant kras comprenant une charge utile de topo-isomérase
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026064520A1 (fr) 2024-09-19 2026-03-26 Tesseract Medicines Us, Llc Conjugués médicamenteux à induction covalente ciblant kras et comprenant une charge utile inhibitrice de tubuline
WO2026064527A1 (fr) 2024-09-19 2026-03-26 Tesseract Medicines Us, Llc Conjugués médicamenteux à induction covalente ciblant kras comprenant une charge utile d'inhibiteur de tubuline
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon

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WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026035945A1 (fr) 2024-08-07 2026-02-12 Tesseract Medicines Us, Llc Conjugués médicamenteux induits par covalence ciblant kras et comprenant une charge utile de topoisomérase
WO2026035947A1 (fr) 2024-08-07 2026-02-12 Tesseract Medicines Us, Llc Conjugués médicamenteux à induction par liaison covalente ciblant kras comprenant une charge utile de topo-isomérase
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026064520A1 (fr) 2024-09-19 2026-03-26 Tesseract Medicines Us, Llc Conjugués médicamenteux à induction covalente ciblant kras et comprenant une charge utile inhibitrice de tubuline
WO2026064527A1 (fr) 2024-09-19 2026-03-26 Tesseract Medicines Us, Llc Conjugués médicamenteux à induction covalente ciblant kras comprenant une charge utile d'inhibiteur de tubuline
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon

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