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WO2024255795A1 - Inhibiteurs de kras et leurs utilisations - Google Patents

Inhibiteurs de kras et leurs utilisations Download PDF

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Publication number
WO2024255795A1
WO2024255795A1 PCT/CN2024/098986 CN2024098986W WO2024255795A1 WO 2024255795 A1 WO2024255795 A1 WO 2024255795A1 CN 2024098986 W CN2024098986 W CN 2024098986W WO 2024255795 A1 WO2024255795 A1 WO 2024255795A1
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Prior art keywords
heterocycloalkyl
alkyl
heteroaryl
cycloalkyl
aryl
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Defeng SHEN
Luoheng QIN
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InSilico Medicine IP Ltd
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InSilico Medicine IP Ltd
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    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems

Definitions

  • KRAS mutations e.g. amino acids G12, G13, Q61, A146 are found in a variety of human cancers including lung cancer, colorectal cancer and pancreatic.
  • KRAS mutations mediate immune escape by regulating the intrinsic characteristics of tumor cells. In KRAS-driven tumors, mutant KRAS mediates tumor immune escape by upregulating PD-L1 expression.
  • KRAS (G12C) , KRAS (G12V) , KRAS (G12D) , and KRAS (G13D) mutations are often associated with high PD-L1 expression.
  • Carboxyl refers to -COOH.
  • Cyano refers to -CN.
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1-10 alkyl.
  • the alkyl is a C 1-6 alkyl.
  • the alkyl is a C 1 - 5 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6-to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl) .
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • arylene refers to a bivalent aryl radical as described herein. An arylene can be bonded through the aryl at any suitable position. In some embodiments, when an arylene comprises an aryl fused with a cycloalkyl or heterocycloalkyl ring, the arylene is bonded at the aryl and the cycloalkyl, or the aryl and the heterocycloalkyl. In some embodiments, when an arylene comprises an aryl fused with a cycloalkyl or heterocycloalkyl ring, the arylene is bonded only at the aryl.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (e.g., C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (e.g., C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (e.g., C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (e.g., C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four
  • the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • cycloalkylene refers to a bivalent cycloalkyl radical as described herein.
  • a cycloalkylene when a cycloalkylene comprises a cycloalkyl fused with an aryl or a heteroaryl ring, the cycloalkylene is bonded at the cycloalkyl and the aryl, or the cycloalkyl and the heteroaryl. In some embodiments, when a cycloalkylene comprises a cycloalkyl fused with an aryl or a heteroaryl ring, the cycloalkylene is bonded only at the cycloalkyl.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH (CH 3 ) OCH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N (CH 3 ) 2 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocyclyl refers to a heterocycloalkyl or a heteroaryl, as described herein. Unless stated otherwise specifically in the specification, a heterocyclyl is optionally substituted. In some embodiments, the heterocyclyl is a heterocycloalkyl. In some embodiments, the heterocyclyl is a heteroaryl.
  • Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (e.g., C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (e.g., C 2 -C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (e.g., C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (e.g., C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 6 heterocycloalkenyl) , from two to five carbon
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
  • the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • heterocycloalkylene refers to a bivalent heterocycloalkyl radical as described herein. In some embodiments, when a heterocycloalkylene comprises a heterocycloalkyl fused with an aryl or a heteroaryl ring, the heterocycloalkylene is bonded at the heterocycloalkyl and the aryl, or the heterocycloalkyl and the heteroaryl. In some embodiments, when a heterocycloalkylene comprises a heterocycloalkyl fused with an aryl or a heteroaryl ring, the heterocycloalkylene is bonded only at the heterocycloalkyl.
  • Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4- benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzo
  • heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • heteroarylene refers to a bivalent heteroaryl radical as described herein. In some embodiments, when a heteroarylene comprises a heteroaryl fused with a cycloalkyl or heterocycloalkyl ring, the heteroarylene is bonded at the heteroaryl and the cycloalkyl, or the heteroaryl and the heterocycloalkyl. In some embodiments, when a heteroarylene comprises a heteroaryl fused with a cycloalkyl or heterocycloalkyl ring, the heteroarylene is bonded only at the heteroaryl.
  • an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ) , fully substituted (e.g., -CF 2 CF 3 ) , mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc. ) .
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • Treatment of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell.
  • treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.
  • X 1 is C (R 1a ) (R 1b ) , O, S, or N (R 1c ) ;
  • X 2 is C (R 2a ) (R 2b ) , O, S, or N (R 2c ) ;
  • X 3 is C (R 3a ) (R 3b ) , O, S, or N (R 3c ) ;
  • R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3a , R 3b , and R 3c are independently selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13
  • R 1a , R 1b , and R 1c and one of R 2a , R 2b , and R 2c together with the atom they are attached to form a 3-7 membered ring; or one of R 2a , R 2b , and R 2c and one of R 3a , R 3b , and R 3c together with the atom they are attached to form a 3-7 membered ring; or one of R 1a , R 1b , and R 1c and one of R 3a , R 3b , and R 3c form a bond, a C 1-4 alkylene, or C 1-3 heterolkylene; and optionally,
  • R 1a and R 1b together with the carbon atom they are attached to form a optionally substituted C3-6cycloalkyl or optionally substituted 3-to 6-membered heterocycloalkyl; and/or R 2a and R 2b together with the carbon atom they are attached to form a optionally substituted C 3-6 cycloalkyl or optionally substituted 3-to 6-membered heterocycloalkyl; and/or R 3a and R 3b together with the carbon atom they are attached to form a optionally substituted C3-6cycloalkyl or optionally substituted 3-to 6-membered heterocycloalkyl; wherein each of the C 3 - 6 cycloalkyl is optionally substituted with one, two or three groups selected from halogen, oxo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocyclo
  • R 4 is selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) , -
  • R 5 is absent or is selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 )
  • Ring A is a 5-8 membered ring optionally substituted with 1-3 R A ;
  • Ring B is a 5-8 membered ring optionally substituted with 1-4 R B ; or one of R B and R 5 together with the atoms they are attached to form a 5-8 membered ring optionally substituted with 1-4 R C ;
  • each R A is independently selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) ,
  • each R B is independently selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -C 1-9 heteroaryl-C 1- 9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C
  • each R C is independently selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) ,
  • each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, -CH 2 -C 6- 10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -CH 2 -C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, -CH 2 -C 6-10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -CH 2 -C 1-9 heteroaryl
  • each R B10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -C 1- 3 alkylene-C 2-9 heterocycloalkyl, -C 1-3 alkylene-C 6-10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -C 1- 3 alkylene-C 1-9 heteroaryl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -C 1- 3 alkylene-C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -C 1-3 alkylene-C 2-9 heterocycloalkyl, -C 1-3 alkylene-C 6-10
  • each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • R 10 and R 11 together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl which is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy;
  • each R 12 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • each R 13 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • Ring A is a 5-8 membered heteroaryl ring optionally substituted with 1, 2, or 3 R A ; (2) Ring A is a 5-8 membered heteroaryl ring substituted with 1, 2, or 3 R A ; and/or (3) Ring A is selected from furan, pyrrole, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, thiadiazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine, azepine, diazepine, and triazepine.
  • ring A is optionally substituted 5-6 membered heteroaryl. In some embodiments, ring A is optionally substituted 6 membered heteroaryl. In some embodiments, ring A is optionally substituted 5 membered heteroaryl.
  • a compound of Formula (I) is a compound of Formula (I) , (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (VI-1) , (VI-2) , (VI-3) , (VI-4) , (VI-5) , (VI-6) , (VI-7) , (VI-8) , (VI-9) , (VI-10) , (V) , (Va) , (Vb) , (Vc) , (Vd) , (Ve) , (Vf) ,
  • R 10 is C 1-6 alkyl. In some embodiments, R 10 is methyl. In some embodiments, R 10 is optionally substituted C 2-9 heterocycloalkyl. In some embodiments, R 10 is optionally substituted 4-6 membered heterocycloalkyl. In some embodiments, R 10 is -CH 2 -C 3-6 cycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, -CH 2 -C 6-10 aryl, or -CH 2 -C 1- 9 heteroaryl, each of which is optionally substituted.
  • R 10 when R 10 is -CH 2 -C 3- 6 cycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, -CH 2 -C 6-10 aryl, or -CH 2 -C 1-9 heteroaryl, R 10 is optionally substituted at the -CH 2 -position.
  • R 10 is -CH 2 -C 3-6 cycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, -CH 2 -C 6-10 aryl, or -CH 2 -C 1-9 heteroaryl, each of which is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl , wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6
  • a compound of Formula (I) is a compound of Formula (I) , (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (VI-1) , (VI-2) , (VI-3) , (VI-4) , (VI-5) , (VI-6) , (VI-7) , (VI-8) , (VI-9) , (VI-10) , (V) , (Va) , (Vb) , (Vc) , (Vd) , (Ve) , (Vf) or (
  • the compounds disclosed herein may have a Ring A selected from:
  • each hydrogen on a ring atom is independently and optionally replaced by a R A group.
  • the compounds disclosed herein may have a Ring A selected from:
  • each hydrogen on a ring atom is independently and optionally replaced by a R A group.
  • the compounds disclosed herein may have a structure of:
  • n is independently 0, 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
  • a compound of Formula (I) (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (V) , (Va) , (Vb) , (Vc) , (Vd) , (Ve) , (Vf) , or (Vg) , wherein Ring B is a 5-8 membered ring substituted with 1-3 R B .
  • ring B is optionally substituted 5-6 membered heteroaryl. In some embodiments, ring B is optionally substituted 5 membered heteroaryl. In some embodiments, ring B is optionally substituted thiazolyl. In some embodiments, ring B is optionally substituted 6 membered heteroaryl. In some embodiments, ring B is optionally substituted pyrimidinyl. In some embodiments, ring B is optionally substituted pyridinyl.
  • Ring B is selected from:
  • each hydrogen on a ring atom is independently and optionally replaced by a R B group.
  • Ring B is selected from:
  • Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is in some embodiments, Ring B is
  • a compound of Formula (I) is a compound of Formula (I) , (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (VI-1) , (VI-2) , (VI-3) , (VI-4) , (VI-5) , (VI-6) , (VI-7) , (VI-8) , (VI-9) , (VI-10) , (V) , (Va) , (Vb) , (Vc) , (Vd) , (Ve) , (Vf) ,
  • a compound of Formula (I) (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (V) , (Va) , (Vb) , (Vc) , (Vd) , (Ve) , (Vf) , (Vg) , (VI-1) , (VI-2) , (VI-3) , (VI-4) , (VI-5) , (VI-6) , (VI-7) , (VI-8) , (VI-9) or (VI-
  • a compound of Formula (I) (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (V) , (Va) , (Vb) , (Vc) , (Vd) , (Ve) , (Vf) , (Vg) , (VI-1) , (VI-2) , (VI-3) , (VI-4) , (VI-5) , (VI-6) , (VI-7) (VI-8) , (VI-9) or (VI-10) where
  • each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, -CH 2 -C 6- 10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -CH 2 -C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, -CH 2 -C 6-10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -CH 2 -C 1-9 heteroaryl
  • each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 10 and R 11 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl which is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl;
  • R B is R B’ , wherein R B’ is selected from optionally substituted C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -N (R 10 ) (R 11 ) ;
  • R B is R B’ , wherein R B’ is selected from optionally substituted C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR B10 , -SR B10 , -N (R 10 ) (R 11 ) ;
  • R B is R B’ , wherein R B’ is selected from optionally substituted C 2-9 heterocycloalkyl, and -OR 10 ;
  • R B is R B’ , wherein R B’ is selected from optionally substituted C 2-9 heterocycloalkyl, and -OR B10 ;
  • R B is R B” , wherein R B” is C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1- 9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -C (O) N (R 10 ) (R 11 ) , -C (O) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) R 13 , -S (O) 2 R 13 , -S (O) 2 N (R 10 )
  • each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, -CH 2 -C 6- 10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -CH 2 -C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, - CH 2 -C 6-10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -CH 2 -C 1-9 heteroaryl
  • each R 11 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 10 and R 11 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl which is optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy;
  • At least one R B is R B” , wherein R B” is optionally substituted C 1-9 heteroaryl;
  • R B is R B” , wherein R B” is optionally substituted thiazolyl;
  • Ring B is substituted by one, two, or three R B that is not hydrogen; and/or
  • Ring B is selected from:
  • R B1 , R B2 , R B3 , and R B4 are independently selected from R B ;
  • X 2 is C (R 2a ) (R 2b ) , O, S, or N (R 2c ) ;
  • Y 1 is C (R 1Ya ) (R 1Yb ) , O, S, or N (R 1Yc ) ;
  • Y 2 is C (R 2Ya ) (R 2Yb ) , O, S, or N (R 2Yc ) ;
  • Y 3 is C (R 3Ya ) (R 3Yb ) , O, S, or N (R 3Yc ) ;
  • R 1Ya , R 2Ya and R 3Ya are independently selected from R 1a ;
  • R 1Yb , R 2Yb and R 3Ya are independently selected from R 1b ;
  • R 1Yc , R 2Yc and R 3Yc are independently selected from R 1c .
  • R B4 is not hydrogen, halogen and OMe.
  • X 1 , X 2 , Y 1 , Y 2 and Y 3 is not C (R 1a ) (R 1b ) .
  • At least one of X 1 , X 2 , Y 1 , Y 2 and Y 3 is O. In some embodiments, at least one of X 1 , X 2 , Y 1 , Y 2 and Y 3 is S. In some embodiments, at least one of Y 1 , Y 2 and Y 3 is O. In some embodiments, at least one of Y 1 and Y 2 is O.
  • At least one of the following conditions are satisfied: (i) X 1 is not C (R 1a ) (R 1b ) ; (ii) X 2 is not C (R 2a ) (R 2b ) ; (iii) Y 1 is not C (R 1Ya ) (R 1Yb ) ; (iv) Y 2 is not C (R 2Ya ) (R 2Yb ) ; or (v) Y 3 is not C (R 3Ya ) (R 3Yb ) .
  • X 1 is not C (R 1a ) (R 1b ) .
  • X 2 is not C (R 2a ) (R 2b ) .
  • Y 1 is not C (R 1Ya ) (R 1Yb ) .
  • Y 2 is not C (R 2Ya ) (R 2Yb ) .
  • Y 3 is not C (R 3Ya ) (R 3Yb ) .
  • Y 1 is O or S
  • Y 2 is C (R 2Ya ) (R 2Yb )
  • Y 3 is C (R 3Ya ) (R 3Yb ) .
  • Y 1 is C (R 1Ya ) (R 1Yb )
  • Y 2 is O or S
  • Y 3 is C (R 3Ya ) (R 3Yb )
  • Y 1 is C (R 1Ya ) (R 1Yb )
  • Y 2 is C (R 2Ya ) (R 2Yb )
  • Y 3 is O or S
  • X 1 is O or S
  • X 2 is C (R 2a ) (R 2b ) .
  • X 1 is C (R 1a ) (R 1b ) and X 2 is O or S.
  • Y 1 is O
  • Y 2 is C (R 2Ya ) (R 2Yb )
  • Y 3 is C (R 3Ya ) (R 3Yb )
  • X 1 is C (R 1a ) (R 1b )
  • X 2 is C (R 2a ) (R 2b )
  • Y 1 is C (R 1Ya ) (R 1Yb )
  • Y 2 is O
  • Y 3 is C (R 3Ya ) (R 3Yb )
  • X 1 is C (R 1a ) (R 1b )
  • X 2 is C (R 2a ) (R 2b ) .
  • Y 1 is C (R 1Ya ) (R 1Yb )
  • Y 2 is C (R 2Ya ) (R 2Yb )
  • Y 3 is O
  • X 1 is C (R 1a ) (R 1b )
  • X 2 is C (R 2a ) (R 2b )
  • X 1 is O
  • X 2 is C (R 2a ) (R 2b )
  • Y 1 is C (R 1Ya ) (R 1Yb )
  • Y 2 is C (R 2Ya ) (R 2Yb )
  • Y 3 is C (R 3Ya ) (R 3Yb ) .
  • X 1 is C (R 1a ) (R 1b )
  • X 2 is O
  • Y 1 is C (R 1Ya ) (R 1Yb )
  • Y 2 is C (R 2Ya ) (R 2Yb )
  • Y 3 is C (R 3Ya ) (R 3Yb ) .
  • X 1 is C (R 1a ) (R 1b )
  • X 2 is C (R 2a ) (R 2b )
  • Y 1 is C (R 1Ya ) (R 1Yb )
  • Y 2 is C (R 2Ya ) (R 2Yb )
  • Y 3 is C (R 3Ya ) (R 3Yb ) .
  • R B4 is halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR B10 , -SR B10 , -SF 5 , or -N (R 10 ) (R 11 ) .
  • a compound of Formula (I) (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (V) , (Va) , (Vb) , (Vc) , (Vd) , (Ve) , (Vf) , (Vg) , (VI-1) , (VI-2) , (VI-3) , (VI-4) , (VI-5) , (VI-6) , (VI-7) , (VI-8) , (VI-9) or (VI-
  • R 4 is selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, oxo, -CN, -OH, -SH, -SF 5 , and -NH 2 ;
  • R 4 together with one of R 1a , R 1b , and R 1c form a group selected from -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 -optionally substituted by one, two, or three groups selected from halogen, oxo, -CN, -OH, -SH, -SF 5 , and -NH 2 ;
  • R 4 together with one of R 2a , R 2b , and R 2c form a group selected from -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 -optionally substituted by one, two, or three groups selected from halogen, oxo, -CN, -OH, -SH, -SF 5 , and -NH 2 ;
  • R 4 together with one of R 3a , R 3b , and R 3c form a group selected from -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 -optionally substituted by one, two, or three groups selected from halogen, oxo, -CN, -OH, -SH, -SF 5 , and -NH 2 ;
  • R 5 is selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OH, -SH, -SF 5 , and -NH 2 ; and/or
  • R 4 and R 5 together with the atoms they are attached to form a C5-7cycloalkyl or a 5-7 membered heterocyclyl optionally substituted with 1-3 R 4a , wherein each R 4a is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OH, -SH, -SF 5 , and -NH 2 .
  • disclosed herein is a compound having a structure of Formula (VI-5) , or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a compound having a structure of Formula (VI-1) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a compound having a structure of Formula (Ve) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a compound having a structure of Formula (Vf) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • disclosed herein is a compound having a structure of Formula (Vg) , or a pharmaceutically acceptable salt or stereoisomer thereof.
  • disclosed herein is a compound having a structure of Formula (Vb) , or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, disclosed herein is a compound having a structure of Formula (Vc) , or a pharmaceutically acceptable salt or stereoisomer thereof.
  • X 1 is C (R 1a ) (R 1b ) . In some embodiments, X 1 is CH 2 . In some embodiments, X 1 is O. In some embodiments, X 2 is C (R 2a ) (R 2b ) . In some embodiments, X 2 is CH 2 . In some embodiments, X 2 is O. In some embodiments, X 3 is C (R 3a ) (R 3b ) . In some embodiments, X 3 is CH 2 . In some embodiments, X 3 is O. In some embodiments, R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3a , R 3b , and R 3c are hydrogen.
  • Y 1 is C (R 1Ya ) (R 1Yb ) . In some embodiments, Y 1 is CH 2 . In some embodiments, Y 1 is O. In some embodiments, Y 1 is S. In some embodiments, Y 1 is N (R 1Yc ) . In some embodiments, Y 2 is C (R 2Ya ) (R 2Yb ) . In some embodiments, Y 2 is CH 2 . In some embodiments, Y 2 is O. In some embodiments, Y 2 is S. In some embodiments, Y 2 is N (R 2Yc ) . In some embodiments, Y 3 is C (R 3Ya ) (R 3Yb ) .
  • Y 1 is CH 2 . In some embodiments, Y 3 is O. In some embodiments, Y 3 is S. In some embodiments, Y 3 is N (R 3Yc ) . In some embodiments, at least one of Y 1 , Y 2 and Y 3 is O.
  • R 1a is hydrogen. In some embodiments, R 1a is C 1-6 alkyl. In some embodiments, R 1b is hydrogen. In some embodiments, R 1b is C 1-6 alkyl. In some embodiments, R 1a and R 1b together with the carbon atom they are attached to form an optionally substituted C 3 - 6 cycloalkyl (e.g., a cyclopropyl) or optionally substituted 3-to 6-membered heterocycloalkyl.
  • C 3 - 6 cycloalkyl e.g., a cyclopropyl
  • R 2a is hydrogen. In some embodiments, R 2a is C 1-6 alkyl. In some embodiments, R 2b is hydrogen. In some embodiments, R 2b is C 1-6 alkyl. In some embodiments, R 2a and R 2b together with the carbon atom they are attached to form an optionally substituted C 3 - 6 cycloalkyl (e.g., a cyclopropyl) or optionally substituted 3-to 6-membered heterocycloalkyl.
  • C 3 - 6 cycloalkyl e.g., a cyclopropyl
  • R 3a is hydrogen. In some embodiments, R 3a is C 1-6 alkyl. In some embodiments, R 3b is hydrogen. In some embodiments, R 3b is C 1-6 alkyl. In some embodiments, R 3a and R 3b together with the carbon atom they are attached to form an optionally substituted C 3 - 6 cycloalkyl (e.g., a cyclopropyl) or optionally substituted 3-to 6-membered heterocycloalkyl.
  • C 3 - 6 cycloalkyl e.g., a cyclopropyl
  • R 1a and R 3a together form a C 1-4 alkylene. In some embodiments, R 1a and R 3a together form -CH 2 -CH 2 -or -CH 2 -CH 2 -CH 2 -.
  • R 4 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments, R 4 is hydrogen, R 4 is C 1-3 alkyl. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 and R 1a together form a -CH 2 CH 2 -or -CH 2 CH 2 CH 2 -. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 and R 1a together form a -CH 2 CH 2 -.
  • R 5 is absent. In some embodiments, R 4 and R 5 together with the atoms they are attached to form a C 5 - 7 cycloalkyl or a 5-7 membered heterocyclyl, each of which is optionally substituted with 1-3 R 4a . In some embodiments, R 4 and R 5 together with the atoms they are attached to form an optionally substituted C 5 - 7 cycloalkyl. In some embodiments, R 4 and R 5 together with the atoms they are attached to form an optionally substituted C 6 cycloalkyl.
  • R 4 and R 5 together with the atoms they are attached to form an optionally substituted 5-7 membered heterocycloalkyl. In some embodiments, R 4 and R 5 together with the atoms they are attached to form an optionally substituted 6 membered heterocycloalkyl. In some embodiments, R 4 and R 5 together with the atoms they are attached to form an optionally substituted 6 membered heterocycloalkyl comprising an oxygen.
  • ring A is substituted.
  • each R A is independently selected from hydrogen, halogen, -CN, C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments, ring A is unsubstituted.
  • ring A is 5-6 membered heteroaryl. In some embodiments, ring A is 5 membered heteroaryl. In some embodiments, ring A is isoxazole. In some embodiments, ring A is oxadiazole. In some embodiments, ring A is furan.
  • ring A is 6 membered heteroaryl. In some embodiments, ring A is pyridine.
  • ring B is substituted with one or two R B . In some embodiments, ring B is substituted by 1-3 R B . In some embodiments, each R B is independently selected from halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, or -OR B10 , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted.
  • each R B is independently selected from halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, or -OR 10 , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted.
  • each R B is independently selected from halogen, C 1-6 alkyl, C 1- 6 haloalkyl, or -OR 10 , wherein the C 1-6 alkyl is optionally substituted. In some embodiments, each R B is independently selected from halogen, C 1-6 alkyl and -OR 10 . In some embodiments, each R B is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR B10 , wherein the C 1-6 alkyl is optionally substituted. In some embodiments, each R B is independently selected from halogen, C 1-6 alkyl and -OR B10 .
  • each R B is independently selected from halogen, C 1-6 alkyl, -OR B10 , and optionally substitued C 1-9 heteroaryl. In some embodiments, each R B is independently selected from C 1-6 alkyl and -OR B10 . In some embodiments, each R B is independently selected from -OR B10 and optionally substitued C 1-9 heteroaryl. In some embodiments, one or more R B is halogen. In some embodiments, one or more R B is optionally substituted C 1-6 alkyl. In some embodiments, one or more R B is optionally substituted C 1-3 alkyl. In some embodiments, one or more R B is methyl.
  • one or more R B is optionally substituted C 1-9 heteroaryl. In some embodiments, one or more R B is optionally substituted 5-6 membered heteroaryl. In some embodiments, one or more R B is optionally substituted 5 membered heteroaryl. In some embodiments, one or more R B is optionally substituted bicyclic heteroaryl. In some embodiments, one or more R B is optionally substituted -C 1- 9 heteroaryl-C 1-9 heteroaryl. In some embodiments, one or more R B is optionally substituted -5 to 6 membered heteroaryl-5 to 6-membered heteroaryl (e.g., optionally substituted ) .
  • one or more R B is optionally substituted -5 membered heteroaryl-5-membered heteroaryl (e.g., ) . In some embodiments, one or more R B is -OR 10 . In some embodiments, one or more R B is -OR B10 . In some embodiments, one or more R B is optionally substituted C 2-9 heterocycloalkyl. In some embodiments, one or more R B is optionally substituted 5-7 membered heterocycloalkyl. In some embodiments, one or more R B is optionally substituted bicyclic heterocycloalkyl. In some embodiments, two or more R B are independently -OR B10 . In some embodiments, two R B are independently -OR B10 .
  • R B is substituted with one, two, or three groups selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 heteroalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 1-9 heteroaryl, -CH 2 -C 1-9 heteroaryl, -OR 10 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -C (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) R 13 , wherein the C 1-6 alkyl, C 1-6 heteroalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocyclo
  • R B is substituted with one or more C 1-6 heteroalkyl, which is optionaly substituted. In some embodiments, R B is substituted with one or more C 1-6 heteroalkyl, which is optionaly substituted with one, two, or three groups selected from halogen, -CN, hydroxy, oxo, C 1-6 alkyl, -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) R 13 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy.
  • the C 1-6 heteroalkyl is In some embodiments, R B is In some embodiments, R B is substituted with one or more -CH 2 -C 2-9 heterocycloalkyl, which is optionaly substituted.
  • each R B is independently selected from hydrogen, halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1- 9 heteroaryl, -OR B10 , -SR B10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 10 )
  • each R B is independently selected from hydrogen, halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1- 9 heteroaryl, -OR B10 , -SR B10 , -SF 5 , -N (R 10 ) (R 11 ) , -C (O) OR 10 , -OC (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) OR 13 , -N (R 12 ) S (O) 2 R 13 , -C (O) R 13 , -S (O) R 13 , -OC (O) R 13 , -C (O) N (R 10 ) (R 10 )
  • each R B10 is independently selected from hydrogen, C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -C 1-3 alkylene-C 2-9 heterocycloalkyl, -C 1-3 alkylene-C 6-10 aryl, C 6-10 aryl, C 1-9 heteroaryl, and -C 1-3 alkylene-C 1-9 heteroaryl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -C 1- 3 alkylene-C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -C 1-3 alkylene-C 2-9 heterocycloalkyl, -C 1-3 alkylene
  • R B10 is optionally substituted C 1-6 alkyl. In some embodiments, R B10 is optionally substituted C 1-6 heteroalkyl. In some embodiments, R B10 is optionally substituted C 3-6 cycloalkyl or -C 1-3 alkylene-C 3-6 cycloalkyl. In some embodiments, R B10 is optionally substituted C 2-9 heterocycloalkyl. In some embodiments, R B10 is optionally substituted 5-6 membered heterocycloalkyl. In some embodiments, R B10 is optionally substituted -C 1-3 alkylene-C 2-9 heterocycloalkyl. In some embodiments, R B10 is optionally substituted -CH 2 -C 2-9 heterocycloalkyl.
  • R B10 is optionally substituted -CH 2 -5-6 membered heterocycloalkyl. In some embodiments, R B10 is optionally substituted -C 1-3 alkylene-C 6-10 aryl or C 6-10 aryl. In some embodiments, R B10 is optionally substituted C 1-9 heteroaryl. In some embodiments, R B10 is optionally substituted 5-6 membered heteroaryl. In some embodiments, R B10 is optionally substituted -C 1-3 alkylene-C 1-9 heteroaryl.
  • R B10 is substituted with one or more selected from halogen, -CN, hydroxy, -C (O) R 13 , oxo, C 1-6 alkyl, C 1- 6 heteroalkyl, -N (R 10 ) (R 11 ) , -C (O) OR 10 , -C (O) N (R 10 ) (R 11 ) , -N (R 12 ) C (O) R 13 , and -OR 10 .
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H (D) , 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the substituents disclosed herein.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • a method of treating a disease in which inhibition of KRAS mutation is beneficial comprising administering a compound of Formula (I) , (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (VI-1) , (VI-2) , (VI-3) , (VI-4) , (VI-5) , (VI-6) , (VI-7) , (VI-8) , (VI-9) , (VI-10) , (V) , (Va) , (Vb) , (Vc
  • a method of treating a disease in which inhibition of KRAS mutation is beneficial comprising administering a compound of Formula (I) , (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (VI-1) , (VI-2) , (VI-3) , (VI-4) , (VI-5) , (VI-6) , (VI-7) , (VI-8) , (VI-9) , (VI-10) , (V) , (Va) , (Vb) , (Ia) , (Ib)
  • a method of treating a disease in which inhibition of KRAS mutation is beneficial comprising administering a compound of Formula (I) , (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (VI-1) , (VI-2) , (VI-3) , (VI-4) , (VI-5) , (VI-6) , (VI-7) , (VI-8) , (VI-9) , (VI-10) , (V) , (Va) , (Vb) , (Ia) , (Ib)
  • a method of treating a disease in which inhibition of KRAS mutation is beneficial comprising administering a compound of Formula (I) , (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (VI-1) , (VI-2) , (VI-3) , (VI-4) , (VI-5) , (VI-6) , (VI-7) , (VI-8) , (VI-9) , (VI-10) , (V) , (Va) , (Vb) , (Ia) , (Ib)
  • a method of treating a disease or disorder associated with KRAS mutation comprising administering to the subject a compound disclosed herein, e.g., a compound of Formula (I) , (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (VI-1) , (VI-2) , (VI-3) , (VI-4) , (VI-5) , (VI-6) , (VI-7) , (VI-8) , (VI-9) , (VI-10) , (V) , (
  • a method of treating a disease or disorder associated with KRAS mutation comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating a disease or disorder associated with KRAS mutation the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating a disease or disorder associated with KRAS mutation the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating cancer in a subject comprising administering to the subject a compound disclosed herein, e.g., a compound of Formula (I) , (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (VI-1) , (VI-2) , (VI-3) , (VI-4) , (VI-5) , (VI-6) , (VI-7) , (VI-8) , (VI-9) , (VI-10) , (V) , (Va) , (Va) , (Ia
  • a method of treating cancer in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the cancer is selected from intra-hepatic cholangiocarcinoma, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.
  • the method of treating intra-hepatic cholangiocarcinoma in a subject the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating urothelial cancer in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating gastric cancer in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating bladder cancer in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating breast cancer in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating endometrial cancer in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating kidney cancer in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating liver cancer in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating lung cancer in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating melanoma in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating pancreatic cancer in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating prostate cancer in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating thyroid cancer in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • compositions containing the compound (s) described herein are administered for prophylactic and/or therapeutic treatments.
  • 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 at least one of the symptoms of the disease or condition. Amounts effective for this use 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.
  • Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition.
  • 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. ”
  • 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.
  • prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds of this disclosure may be administered to animals.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.
  • compositions comprising a compound disclosed here, e.g., a compound of Formula (I) , (A-1) , (A-2) , (A-3) , (Ia) , (Ib) , (Ic) , (Id) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IIIa) , (IIIb) , (IIIc) , (IIId) , (IV) , (IVa) , (IVb) , (IVc) , (IVd) , (VI-1) , (VI-2) , (VI-3) , (VI-4) , (VI-5) , (VI-6) , (VI-7) , (VI-8) , (VI-9) , (VI-10) , (V) , (Va) , (Vb) , (Vc) , (Vd) , (VI-1)
  • compositions comprising a compound of Formula (I) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical compositions comprising a compound of Formula (Ia) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical compositions comprising a compound of Formula (Ib) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • compositions comprising a compound of Formula (Ic) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • pharmaceutical compositions comprising a compound of Formula (Id) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be 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; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins1999) , herein incorporated by reference for such disclosure.
  • non-exemplified compounds according to the present disclosure may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art other than those described, and/or by making routine modifications of reaction conditions.
  • persons skilled in the art will also understand that individual steps described herein or in the separate batches of a compound may be combined.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure, but rather is specified by the claims appended hereto..
  • SC-18-4 was separated by SFC (DAICEL CHIRALPAK AS (250mm*30mm, 10um) (eluent: 15%to 15%(v/v) CO 2 -i-PrOH (0.1%NH 3 H 2 O) to SC-18-4A (peak with earlier retention time, single unknown configuration) and SC-18-4B (peak with later retention time, single unknown configuration) both as colorless oil.
  • SFC DICEL CHIRALPAK AS (250mm*30mm, 10um) (eluent: 15%to 15%(v/v) CO 2 -i-PrOH (0.1%NH 3 H 2 O)
  • A IC 50 > 0 nM and ⁇ 200 nM;
  • Example B KRAS_GDP nucleotide exchange HTRF assay
  • KRAS WT_GDP Biotin marker
  • KRAS WT-GTP GTP marker BODIPY
  • KRAS WT-GDP (ICE, Cat #E2207T-H15HA) , SOS1 (ICE, Cat #E2204T-H10G) , GDP (Sigma, Cat #G7127) , and BODIPY-GTP (Invitrogen, Cat #G12411) solutions in reaction buffer (25 mM HEPES, pH 7.4, 120 mM NaCl, 5 mM MgCl2, 1 mM DTT (fresh) , 0.01%Tween 20, 0.1%BSA) .
  • the final concentrations of KRAS WT-GDP, GDP, SOS1, and BODIPY-GTP in the reaction mixture were 0.5 nM, 5 nM, 500 nM, and 200 nM, respectively.
  • the initial concentration of the positive reference MRTX1133 was 1 ⁇ M, 3 times diluted, 10 dose.
  • the 100%DMSO-diluted compound was transferred 0.1 ⁇ L to a 384-well plate with Echo655.
  • a mixture of 5 ⁇ L 2 ⁇ BODIPY-GTP, SOS1, and SA-Tb (Cisbio, Cat#610SATLB) was transferred to 384 reaction plates, centrifuged at 1000 rpm for 1 min, and incubated at 25 °C for 180 min.
  • the HTRF signal (665/620) is read by BMG.
  • KRAS G12V_GDP exchange experiment and KRAS G12D_GDP exchange experiment were also conducted following the same steps described previously, except that KRAS G12V-GDP (ICE, Cat #E2207T-H17HA) was utilized in KRAS G12V_GDP exchange experiment and KRAS G12D-GDP (ICE, Cat #E2203T-H48HA) was utilized in KRAS G12D_GDP exchange experiment.
  • IC50 values and nonlinear regression curve fitting were obtained using GraphPad Prism software.
  • the objective of this study was to determine the kinetic solubility of in 50 mM phosphate buffer solution (pH 7.4) at room temperature for 24 hours with shake plate method.
  • Compound sample 1 and Compound sample 2 were prepared according to the synthetic route reported in patent WO2023099624. Amiodarone hydrochloride, carbamazepine and chloramphenicol were used as control compounds in these assays. Test compound and control compounds (amiodarone hydrochloride, carbamazepine and chloramphenicol) were dissolved in DMSO. The stock solutions were kept stored at -80 °C freezer until used. The detailed information of control compounds is shown in the following table.
  • the preparation of 50 mM Na2HPO4 Dissolved 3.549 g of Na2HPO4 with 500 mL of water, and the pH measured was about 9.4.
  • the preparation of 50 mM NaH2PO4 Dissolved 3.000 g of NaH2PO4 with 500 mL of water, and the pH measured was about 4.5.
  • the preparation of 50 mM PB (pH 7.4) 15 mL of 50 mM Na2HPO4 was added into a 50 mL tube, and then adjusted pH to 7.4 ⁇ 0.05 with 50 mM NaH2PO4.
  • Animal or human liver microsomes were purchased from IPHASE or Corning and stored in a freezer (lower than -60°C) before use.
  • ⁇ -nicotinamide adenine dinucleotide phosphate reduced form, tetrasodium salt.
  • Control compounds Testosterone, diclofenac and propafenone.
  • a total of two sample plates with 96-well format were prepared for incubation, labeled as 'Incubation' T60 and 'Incubation' NCF60.
  • Empty 'Incubation' T60 and NCF60 plates were pre-warmed for 10 min minutes. Liver microsomes were diluted to 0.56 mg/mL in 100 mM phosphate buffer. Microsome working solutions (0.56 mg/mL) were transferred (445 uL) into pre-warmed 'Incubation' T60 and NCF60 plates, followed by incubation for 10 min at 37°C with constant shaking.
  • Liver microsomes (54 ⁇ L) were transferred to a Blank60 plate, followed by the addition of 6 ⁇ L NAPDH cofactor and 180 ⁇ L stop solution (acetonitrile containing internal standards) into each well.
  • For the 'Incubation' NCF60 plate 50 uL of buffer was added and mixed 3 times thoroughly. The plates were incubated at 37°C for 60 min while shaking. samples were mixed once and 60 ⁇ L was transferred from the NCF60 incubation plate to the stop plate containing stop solution after the 60-min incubation.
  • Stop solution 180 ⁇ L
  • NAPDH cofactor 6 ⁇ L
  • Stop solution 180 ⁇ L
  • NAPDH cofactor 44 ⁇ L
  • the plate was incubated at 37°C for 60 min while shaking.
  • 180 ⁇ L stop solution was added to the 'Quenching' plates, samples were mixed once, and 60 ⁇ L was serially transferred from 'Incubation' T60 plate per time point.
  • the final concentration was 1 ⁇ M for test compounds, testosterone, diclofenac and propafenone, 0.5 mg/mL for animal or human liver microsomes, 0.01% (v/v) for DMSO and 0.99% (v/v) for acetonitrile. All sampling plates were shaken for 10 min, then centrifuged at 3220 ⁇ g for 20 minutes at 4°C. Supernatant (80 ⁇ L) was transferred into 240 ⁇ L pure water, and mixed by plate shaker for 10 min. Each bioanalysis plate was sealed and shaken for 10 minutes prior to LC-MS/MS analysis.
  • hepatic intrinsic clearance and hepatic clearance can be calculated by the following formula.

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Abstract

Des inhibiteurs de mutation de KRAS et des compositions pharmaceutiques comprenant lesdits inhibiteurs sont utiles pour le traitement d'une maladie ou d'un trouble associé à une mutation de KRAS.
PCT/CN2024/098986 2023-06-14 2024-06-13 Inhibiteurs de kras et leurs utilisations Pending WO2024255795A1 (fr)

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WO2025190342A1 (fr) * 2024-03-15 2025-09-18 苏州浦合医药科技有限公司 Composé spiro en tant qu'inhibiteur mutant de kras
WO2025201480A1 (fr) * 2024-03-28 2025-10-02 苏州浦合医药科技有限公司 Composé spiro en tant qu'inhibiteur de mutation de kras
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WO2025190342A1 (fr) * 2024-03-15 2025-09-18 苏州浦合医药科技有限公司 Composé spiro en tant qu'inhibiteur mutant de kras
WO2025201480A1 (fr) * 2024-03-28 2025-10-02 苏州浦合医药科技有限公司 Composé spiro en tant qu'inhibiteur de mutation de kras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
CN119751476A (zh) * 2025-03-05 2025-04-04 苏州共康医药科技有限公司 螺环类化合物及其在医药上的应用
CN119751476B (zh) * 2025-03-05 2025-06-03 苏州共康医药科技有限公司 螺环类化合物及其在医药上的应用

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