Fused ring compounds

Abstract

To provide compositions comprising compounds for use in the inhibition of Ras proteins, and methods of treatment by their administration.SOLUTION: Compounds such as 1-[4-[7-(3-amino-1-isoquinolyl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one are provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to International Application Serial No. PCT / CN2018 / 114788, filed November 9, 2018, which is incorporated herein by reference in its entirety.

[0002] The present invention relates to fused ring compounds of formula (I), as further described herein, for use in inhibiting Ras proteins, such as K-Ras, H-Ras, and N-Ras, and compositions comprising these compounds and methods of treatment by administering them. [Background technology]

[0003] Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch in central growth signaling pathways. In response to extracellular signals, Ras undergoes GDP-bound (Ras) exchange, catalyzed by guanine nucleotide exchange factors (GEFs), particularly the SOS1 protein. GDP ) state to GTP-bound (Ras GTP ) state. Active Ras GTP Ras mediates its diverse growth-stimulatory functions through direct interaction with effectors, including Raf, PI3K, and the Ral guanine nucleotide dissociation stimulator. The intrinsic GTPase activity of Ras then hydrolyzes GTP to GDP, terminating Ras signaling. Ras GTPase activity can be further accelerated by interaction with GTPase-activating proteins (GAPs), including the neurofibromin 1 tumor suppressor.

[0004] Mutant Ras has reduced GTPase activity, which sustains the activated form of Ras, thereby promoting Ras-dependent signaling and cancer cell survival or proliferation. Mutations in Ras that affect its ability to interact with GAPs or convert GTP back to GDP result in sustained activation of the protein, resulting in sustained signals that promote continued growth and division. Because these signals lead to cell growth and division, overactive RAS signaling can ultimately lead to cancer. Mutations in any one of the three major RAS isoforms (H-Ras, N-Ras, or K-Ras) are common events in human tumorigenesis. Of the three Ras isoforms (K, N, and H), K-Ras is the most frequently mutated.

[0005] The most common K-Ras mutations are found at residues G12 and G13 in the P loop and at residue Q61. G12C is a frequently observed mutation in the K-Ras gene (glycine-12 to cysteine). G12D and G13D are other frequently observed mutations. Ras mutations in cancer are associated with poor prognosis. Inactivation of oncogenic Ras in mice results in tumor regression. Thus, Ras is widely considered to be an exceptionally important oncological target. Summary of the Invention

[0006] In one aspect, the present disclosure provides a compound of formula (I): TIFF2025026853000001.tif67170 or a pharmaceutically acceptable salt thereof. [In the formula, R1, R2, R3, R4, R5, X, Y, U, V, W, and n are as defined herein.

[0007] Another aspect of the present disclosure is a compound of formula (II): TIFF2025026853000002.tif77170 or a pharmaceutically acceptable salt thereof. wherein R2, R3, R4, R5, R7, R8, R9, X, Y, U, V, W, and n are as defined herein.

[0008] A compound of formula (III), TIFF2025026853000003.tif68170, or a pharmaceutically acceptable salt thereof, is also disclosed. [In the formula, R2, R3, R4, R5, R 10 , X, Y, U, V, W, and n are as defined herein.]

[0009] In another aspect, the present disclosure provides a compound of formula (IV): TIFF2025026853000004.tif67170 or a pharmaceutically acceptable salt thereof. [In the formula, R1, R 11 , X, Y, U, V, W, and n are as defined herein.]

[0010] Also provided is a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] Another aspect includes a method of treating cancer, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0012] Another embodiment includes a method of regulating the activity of a mutant K-Ras G12C protein, comprising reacting the mutant protein with a compound of the invention or a pharmaceutically acceptable salt thereof.

[0013] Another aspect includes a method of treating a disease mediated by a K-Ras G12C mutation in an individual in need of such treatment, comprising determining whether the individual has the mutation, and, if the individual is determined to have the mutation, administering to the individual a therapeutically effective amount of a pharmaceutical composition of the invention.

[0014] Another aspect includes a method of inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0015] definition The terms "halogen" or "halo" mean F, Cl, Br, or I. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl.

[0016] The term "alkyl" means a monovalent saturated straight or branched chain hydrocarbon group. In one example, an alkyl group has 1 to 18 carbon atoms (C 1~18 In another example, the alkyl group is C 1~12 , C 1~10 , C 1~8 , C 1~6 , C 1~5 , C 1~4 , or C 1~3Examples of alkyl groups include methyl (Me-CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH 3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-(C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl ( -CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH 3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 1-heptyl, and 1-octyl.

[0017] The term "amino" means -NH2.

[0018] The term "alkylamino" refers to -NH-alkyl.

[0019] The term "dialkylamino" refers to -N(alkyl)2.

[0020] The term "oxo" means =O.

[0021] The term "carboxy" refers to -C(=O)OH.

[0022] The term "carbamoyl" refers to -C(=O)NH2.

[0023] The term "alkanoyl" refers to -C(=O)-alkyl.

[0024] The term "hydroxyalkanoyl" refers to -C(=O)-hydroxyalkyl.

[0025] The term "alkanoylamino" refers to -NH-C(=O)-alkyl.

[0026] The term "alkoxy" refers to --O-alkyl.

[0027] The term "alkoxyalkyl" means an alkyl substituted with one alkoxy substituent.

[0028] The term "dialkylaminocyclopropyl" means a cyclopropyl substituted with one dialkylamino substituent.

[0029] The term "alkylsulfanyl" refers to -S(=O)-alkyl.

[0030] The term "alkylsulfonyl" refers to -S(=O)2-alkyl.

[0031] The term "alkylsulfonylamino" refers to -NH-S(=O)2-alkyl.

[0032] The term "alkylthio" refers to -S-alkyl.

[0033] The term "haloalkylthio" refers to -S-haloalkyl.

[0034] The term "aminoalkyl" refers to an alkyl substituted with one amino substituent.

[0035] The term "carbamoylalkyl" means an alkyl substituted with one carbamoyl substituent.

[0036] The term "carboxyalkyl" refers to an alkyl substituted with one carboxy substituent.

[0037] The term "cyano" or "nitrile" refers to -C≡N or -CN.

[0038] The term "cyanoalkyl" means an alkyl substituted with one cyano substituent.

[0039] The term "haloalkoxy" refers to an --O-haloalkyl.

[0040] The term "heterocyclylamino" refers to -NH-heterocyclyl.

[0041] The term "hydroxy" means --OH.

[0042] The term "hydroxyalkyl" means an alkyl substituted with one hydroxy substituent.

[0043] The term "alkenyl" means a straight- or branched-chain monovalent hydrocarbon having at least one carbon-carbon double bond, including groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one example, an alkenyl group has 2 to 18 carbon atoms (C 2~18 In another example, the alkenyl group is C 2~12 , C 2~10 , C 2~8 , C 2~6 , or C 2~3Examples include, but are not limited to, ethenyl or vinyl (-CH=CH), prop-1-enyl (-CH=CHCH), prop-2-enyl (-CHCH=CH), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl.

[0044] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond. In one example, an alkynyl group has 2 to 18 carbon atoms (C 2~18 In another example, the alkynyl group is C 2~12 , C 2~10 , C 2~8 , C 2~6 , or C 2~3 Examples include, but are not limited to, ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH), prop-2-ynyl (propargyl, -CHC≡CH), but-1-ynyl, but-2-ynyl, and but-3-ynyl.

[0045] The term "alkylene" refers to a saturated, branched, or straight-chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. In one example, a divalent alkylene group has 1 to 18 carbon atoms (C 1~18 In one example, the divalent alkylene group is C 1~12 , C 1~10 , C 1~ 8. C 1~6 , C 1~5 , C 1~4 , or C 1~3Exemplary alkylene groups include methylene (-CH-), 1,1-ethyl (-CH(CH)-), 1,2-ethyl (-CHCH-), 1,1-propyl (-CH(CHCH)-), 2,2-propyl (-(C(CH)-), 1,2-propyl (-CH(CH)CH-), 1,3-propyl (-CHCHCH-), 1,1-dimethyleth-1,2-yl (-(C(CH)CH-), 1,4-butyl (-CHCHCHCHCH-), and the like.

[0046] The term "aryl" refers to a carbocyclic aromatic group having the specified number of carbon atoms, or up to 14 carbon atoms if no number is specified, whether fused to one or more groups. An example is an aryl group having 6 to 14 carbon atoms. Another example is an aryl group having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, and the like (see, e.g., Lang's Handbook of Chemistry (Dean, J.A., ed.) 13). th ed. Table 7-2

[1985] ). A particular aryl is phenyl.

[0047] The term "cycloalkyl" refers to a saturated hydrocarbon ring group. Cycloalkyl includes mono-, bi-, tricyclic, spiro-, and bridged saturated ring systems. In one example, a cycloalkyl group contains 3 to 12 carbon atoms (C 3~12 In another example, cycloalkyl is C 3~7 , C 3~8 , C 3~10 , or C 5~10 In another example, the cycloalkyl group as a single ring is C 3~8 , C3 ~6 , or C 5~6 In another example, the cycloalkyl group for the bicycle is C7-C 12 In another example, the cycloalkyl group as a spiro system is C5~12 Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary configurations of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Examples of spirocycloalkyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane.

[0048] The term "cycloalkenyl" refers to a non-aromatic hydrocarbon ring group having at least one carbon-carbon double bond. Cycloalkenyl includes mono-, bi-, tricyclic, spiro-, or bridged saturated ring systems. Examples of monocyclic cycloalkenyls include 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and cyclohexadienyl. Exemplary configurations of bicyclic cycloalkenyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary bridged bicyclic cycloalkenyls include, but are not limited to, bicyclo[2.2.1]heptene, bicyclo[2.2.2]octene, and bicyclo[3.2.2]nonene. Examples of spirocycloalkyls include spiro[2.2]pentene, spiro[2.3]hexene, spiro[2.4]heptene, spiro[2.5]octene, and spiro[4.5]decene.

[0049] The terms "heterocyclic group," "heterocyclic," "heterocycle," "heterocyclyl," or "heterocyclo" are used interchangeably and refer to any mono-, bi-, tricyclic, spiro-, or bridged, saturated, partially saturated, or unsaturated non-aromatic ring system having 3 to 20 ring atoms, in which the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. If any ring atom in the ring system is a heteroatom, the system is heterocyclic, regardless of the point of attachment of the ring system to the rest of the molecule. In one example, a heterocyclyl contains 3 to 11 ring atoms ("members"), including mono-, bi-, tricyclic, spiro-, and bridged ring systems in which the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, a heterocyclyl contains 4 to 10, or 5 to 10 ring atoms. In one example, a heterocyclyl contains 1 to 4 heteroatoms. In one example, a heterocyclyl contains 1 to 3 heteroatoms. In another example, a heterocyclyl contains 3 to 7 membered monocyclic rings having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclyl contains 4 to 6 membered monocyclic rings having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclyl contains 3 membered monocyclic rings. In another example, a heterocyclyl contains 4 membered monocyclic rings. In another example, a heterocyclyl contains 5 to 6 membered monocyclic rings. In some embodiments, a heterocycloalkyl contains at least one nitrogen. In one example, a heterocyclyl group contains 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO), and any nitrogen heteroatom may be optionally quaternized (e.g., [NR]). + Cl - , [NR4] + OH -Exemplary heterocycles include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothio ... Dropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, 1,1-dioxoisothiazolyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydro Benzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl , pyrimidinonyl, pyrimidindionyl, pyrimidine-2,4-dionyl, piperazinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranyl.

[0050] The term "methylheterocyclyl" refers to a heterocyclyl substituted with a methyl group.

[0051] The term "heteroaryl" refers to any mono-, bi-, or tricyclic aromatic ring system containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur; in exemplary embodiments, at least one heteroatom is nitrogen. See, e.g., Lang's Handbook of Chemistry (Dean, J.A., ed.) 13 th ed. Table 7-2

[1985] . This definition includes any bicyclic group in which any of the above heteroaryl rings is fused to an aryl ring, and either the aryl ring or the heteroaryl ring is attached to the remainder of the molecule. In one embodiment, heteroaryl includes 5- to 6-membered monocyclic aromatic groups in which one or more ring atoms is nitrogen, sulfur, or oxygen. Exemplary heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl, and purinyl, as well as benzo-fused derivatives such as benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indazolyl, and indolyl.

[0052] In certain embodiments, the heterocyclyl or heteroaryl group is bonded at a carbon atom of the heterocyclyl or heteroaryl group. For example, carbon-bonded heterocyclyl groups include those bonded at the 2-, 3-, 4-, 5-, or 6-positions of the pyridine ring, the 3-, 4-, 5-, or 6-positions of the pyridazine ring, the 2-, 4-, 5-, or 6-positions of the pyrimidine ring, the 2-, 3-, 5-, or 6-positions of the pyrazine ring, the 2-, 3-, 4-, or 5-positions of the furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole ring, the 2-, 4-, or 5-positions of the oxazole, imidazole, or thiazole ring, the 3-, 4-, or 5-positions of the isoxazole, pyrazole, or isothiazole ring, the 2-, or 3-positions of the aziridine ring, the 2-, 3-, or 4-positions of the azetidine ring, the 2-, 3-, 4-, 5-, 6-, 7-, or 8-positions of the quinoline ring, or the 1-, 3-, 4-, 5-, 6-, 7-, or 8-positions of the isoquinoline ring.

[0053] In certain embodiments, the heterocyclyl or heteroaryl group is N-linked. For example, nitrogen-linked heterocyclyl or heteroaryl groups include those linked at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, 2-position of isoindole or isoindoline, 4-position of morpholine, and 9-position of carbazole or β-carboline.

[0054] "Fused" means any cyclic structure described herein that shares one or more atoms (e.g., carbon or nitrogen atoms) with an existing cyclic structure in the compounds of the invention.

[0055] The term "acyl" refers to a carbonyl containing a substituent represented by the formula -C(=O)-R, where R is a substituent such as hydrogen, alkyl, cycloalkyl, aryl, or heterocyclyl, where alkyl, cycloalkyl, aryl, and heterocyclyl are as defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl (e.g., pyridinoyl).

[0056] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by halogen. Examples of haloalkyl include trifluoromethyl, difluoromethyl, and fluoromethyl.

[0057] Unless otherwise specified, the term "compound(s) of the invention / compound(s) of the present invention" and the like includes compounds of formula (I), formula (II), formula (III), formula (IV), formulas (Ia) to (Ik), and the compounds listed in the tables herein (including stereoisomers (including atropisomers), geometric isomers, tautomers, isotopes, and salts (e.g., pharmaceutically acceptable salts) thereof).

[0058] Unless otherwise specified, the term "optionally substituted" means that a group can be unsubstituted or substituted with one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range variable thereof) substituents listed for that group, which can be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In another embodiment, an optionally substituted group has five substituents.

[0059] As used herein, a wavy line crossing a bond in a chemical structure TIFF2025026853000005.tif7170 shows the attachment point of an atom in a chemical structure where a wavy bond connects it to the rest of the molecule, or to the rest of a fragment of a molecule.

[0060] In certain embodiments, a divalent group is described generically without a specific bond structure. Unless otherwise specified, the generic description is understood to be meant to include both bond structures. For example, the group R 1 -R 2 -R 3 In the formula, the group R 2 When is depicted as -CHC(O)-, unless otherwise specified, this group is represented by R 1 -CH2C(O)-R 3 and R 1 -C(O)CH2-R 3 It is understood that both are combinable.

[0061] The term "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other side effects when properly administered to an animal, such as a human.

[0062] The compounds of the present invention can be in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" includes both acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refers to salts which retain the biological effectiveness and properties of the free base and which are biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and the organic acids can be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0063] The term "pharmaceutically acceptable base addition salts" includes salts derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Specific base addition salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, and substituted amines, including basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Specific organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0064] In some embodiments, the salt is selected from the group consisting of hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate or 3-furoate), napadisylate (naphthalene-1,5-disulfonate or naphthalene-1(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonic acid), salt, or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethylsulfonate), 2-mesitylenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-mesitylenesulfonate), napsylate (2-naphthalenesulfonate) phthalenesulfonate), camsylate (camphor 10-sulfonate, e.g., (1S)-(+)-10-camphor-sulfonate), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulfonate), and pamoate (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylate).

[0065] A "sterile" preparation is aseptic or free of all viable microorganisms and their spores.

[0066] The term "stereoisomers" means compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers, etc.

[0067] The term "chiral" refers to molecules that possess the property of being non-superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0068] The term "diastereomer" refers to a stereoisomer with two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectroscopic properties, or biological activity. Mixtures of diastereomers can be separated under high-resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0069] The term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0070] Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l, or (+) and (-), are used to designate the indication of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers can be called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0071] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0072] "Atropisomers" are stereoisomers resulting from sterically hindered rotation about a single bond, where the energy difference due to steric strain or other factors creates a barrier to rotation high enough to allow isolation of individual conformers.

[0073] Certain compounds of the present invention can exist in unsolvated and solvated forms, including hydrated forms. The term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. Generally, all physical forms are intended to be within the scope of the present invention. The term "hydrate" refers to a complex where the solvent molecule is water.

[0074] "Metabolite" means a product produced through metabolism in the body of a specified compound or salt thereof. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.

[0075] The metabolites are typically radiolabeled (e.g., 14 C or 3H) Identification is accomplished by providing an isotope, administering the isotope to animals such as rats, mice, guinea pigs, monkeys, or humans at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time (typically about 30 seconds to 30 hours) for metabolism to occur, and isolating the transformation products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (otherwise isolated by the use of antibodies capable of binding epitopes surviving in the metabolites). The structures of the metabolites are determined in conventional manner, for example, by MS, LC / MS, or NMR analysis. Metabolite analysis is generally performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolite products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.

[0076] The invention described herein also encompasses isotopically labeled compounds of the invention, which are identical to those cited herein, except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those usually found in nature.All isotopes of any particular atom or element designated are contemplated within the scope of the compounds of the invention and their applications.Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, e.g. 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14C-labeled compounds) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon 14 ( 14 C) isotopes are useful for their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferable in some circumstances. 15 O. 13 N, 11 C, and 18 Positron-emitting isotopes such as F are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those described in the Examples set forth herein below, substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0077] As used herein, the term "amino-protecting group" refers to a derivative of a group commonly used to block or protect an amino group, while a reaction is carried out at another functional group in the compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, and imines, as well as many N-heteroatom derivatives that can be removed to regenerate the desired amine group. Specific amino-protecting groups are Pmb (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), and Cbz (carbobenzyloxy). Further examples of these groups can be found in T.W. Greene and P.G.M.Wuts, "Protecting Groups in Organic Synthesis, 3 rd ed., John Wiley & Sons, Inc., 1999. The term "protected amino" means an amino group substituted with one of the amino-protecting groups described above.

[0078] As used herein, the term "carboxy-protecting group" refers to a group that is stable to the conditions of subsequent reactions elsewhere in the molecule and can be removed at the appropriate location to yield an unprotected carboxy group without destroying the remainder of the molecule. Examples of carboxy-protecting groups include ester and heterocyclyl groups. Ester derivatives of the carboxylic acid group can be used to block or protect the carboxylic acid group while the reaction is carried out at another functional group in the compound. Examples of such ester groups include substituted aryl alkyl, including substituted benzyl, such as 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, alkyl or substituted alkyl esters, such as methyl, ethyl, t-butyl, allyl or t-amyl, triphenylmethyl (trityl), 4- Included are methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4''-trimethoxytrityl, 2-phenylprop-2-yl, thioesters such as t-butylthioester, silyl esters such as trimethylsilyl, t-butyldimethylsilyl ester, phenacyl, 2,2,2-trichloroethyl, β-(trimethylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and similar moieties. Another example of a carboxy protecting group is a heterocyclyl group such as 1,3-oxazole. Further examples of these groups are found in T.W. Greene and P.G.M.Wuts, "Protecting Groups in Organic Synthesis, 3 rd ed., John Wiley & Sons, Inc., 1999. The term "protected carboxy" means a carboxy group substituted with one of the carboxy-protecting groups described above.

[0079] The compounds of the present invention may contain one or more asymmetric carbon atoms. Therefore, the compounds can exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds can use racemates, diastereomers, or enantiomers as starting materials or intermediates. A mixture of specific diastereomeric compounds can be separated or enriched into one or more specific diastereomers by chromatographic or crystallization techniques. Similarly, enantiomeric mixtures can be separated or enantiomerically enriched using the same techniques, or other techniques known in the art. Each asymmetric carbon or nitrogen atom can exist in either the R or S configuration, and both of these configurations are within the scope of the present invention.

[0080] In the structures depicted herein, where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included as compounds of the present invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, that stereoisomer is so specified and defined. Unless otherwise stated, relative stereochemistry is intended when a solid wedge or dashed line is used.

[0081] Another embodiment includes prodrugs of compounds of the invention that contain known amino- and carboxy-protecting groups that are released, eg, hydrolyzed, under physiological conditions to yield compounds of the invention.

[0082] The term "prodrug" refers to a precursor or derivative form of a pharmaceutically active substance that is less available to the patient than the parent drug and that can be activated or converted to the more active parent form by enzymes or hydrolysis. See, for example, Wilman, "Prodrugs in Cancer Chemotherapy," Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast (1986), and Stella et al., "Prodrugs: A Chemical Approach to Targeted Drug Delivery," Directed Drug Delivery, Borchardt et al., (ed.), pp. 247-267, Humana Press (1985). Prodrugs include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid modified prodrugs, glycosylated prodrugs, β-lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, and 5-fluorocytosine and 5-fluorouridine prodrugs.

[0083] A specific class of prodrugs are compounds in which the nitrogen atom of an amino, amidino, aminoalkyleneamino, iminoalkyleneamino, or guanidino group is replaced with a hydroxy group, -CO-R, -CO-OR, or -CO-ORO-CO-R (where R is a monovalent or divalent group, such as alkyl, alkylene, or aryl), or a group having the formula -C(O)-O-CP1P2-haloalkyl (where P1 and P2 are the same or different and are hydrogen, alkyl, alkoxy, cyano, halogen, alkyl, or aryl). In certain embodiments, the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of the invention. Prodrugs can be prepared by reacting the compounds of the invention with an activated group, such as an acyl group, for example, by binding the nitrogen atom in the compound to the exemplary carbonyl of the activated acyl group. Examples of activated carbonyl compounds are compounds containing a leaving group attached to the carbonyl group, such as acyl halides, acylamines, acylpyridinium salts, acylalkoxides, and acylphenoxides (e.g., p-nitrophenoxyacyl, dinitrophenoxyacyl, fluorophenoxyacyl, and difluorophenoxyacyl). The reaction is typically carried out in an inert solvent at a temperature such as about -78°C to about 50°C. The reaction can also be carried out in the presence of an inorganic base, such as potassium carbonate or sodium bicarbonate, or an organic base, such as an amine, including pyridine, trimethylamine, triethylamine, triethanolamine, and the like.

[0084] Additional types of prodrugs are also encompassed. For example, free carboxyl groups of compounds of the invention can be derivatized as amides or alkyl esters. As another example, compounds of the invention containing free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group to groups such as, but not limited to, phosphate esters, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl groups, as outlined in Fleisher, D. et al. (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs (Advanced Drug Delivery Reviews, 19:115). Carbamate prodrugs of hydroxy and amino groups are also included, as are carbamate prodrugs, sulfonate esters, and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers is also encompassed, as are alkyl esters where the acyl group is optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above. This type of prodrug is described in J. Med. Chem., (1996), 39:10. More specific examples include those in which the hydrogen atom of the alcohol group is substituted with (C 1~6 ) alkanoyloxymethyl, 1-((C 1~6 )alkanoyloxy)ethyl, 1-methyl-1((C 1~6 )alkanoyloxy)ethyl, (C1 ~6 )alkoxycarbonyloxymethyl, N-(C 1~6 ) alkoxycarbonylaminomethyl, succinoyl, (C 1~6 ) Alkanoyl, α-amino (C 1~4 ) alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl (each α-aminoacyl group is a naturally occurring L-amino acid, P(O)(OH)2, -P(O)(O(C 1~6) alkyl) 2, or glycosyl (independently selected from groups resulting from removal of the hydroxyl group of the hemiacetal form of a carbohydrate).

[0085] The term "leaving group" refers to a portion of a first reactant in a chemical reaction that is displaced from that first reactant. Examples of leaving groups include, but are not limited to, halogen atoms, alkoxy, and sulfonyloxy groups. Exemplary sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (e.g., methylsulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (triflate group)), and arylsulfonyloxy groups (e.g., p-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylate group)).

[0086] A "subject," "individual," or "patient" is a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (such as cows), sport animals, pets (such as guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In certain embodiments, the mammal is a human. In embodiments involving administering a compound described herein to a patient, the patient is typically in need of administration of the compound.

[0087] The terms "inhibit" and "reduce," or any variation of these terms, include any measurable reduction or complete inhibition to achieve a desired result. For example, there may be a decrease in activity compared to normal of about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any variable of these ranges.

[0088] A "therapeutically effective amount" refers to an amount of a compound of the present invention, such as a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, that (i) treats or prevents a particular disease, condition, or disorder, or (ii) attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, and, optionally, (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. In the case of cancer, a therapeutically effective amount of an agent can reduce the number of cancer cells, decrease tumor size, inhibit (i.e., slow to a certain extent, and preferably stop) cancer cell invasion into peripheral organs, inhibit (i.e., slow to a certain extent, and preferably stop) tumor metastasis, inhibit tumor growth to a certain extent, or alleviate one or more symptoms associated with cancer to a certain extent. To the extent the agent may prevent growth of or kill existing cancer cells, the agent can be cytostatic or cytotoxic. With respect to cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) or determining the response rate (RR).

[0089] "Treatment" (and variations such as "treat" or "treating") refers to a clinical intervention to alter the natural course of the individual or cell being treated, and can be carried out for the prevention of, or during, a clinical disease state. Desirable effects of treatment include prevention of disease onset or recurrence, alleviation of symptoms, reduction of any direct or indirect pathological consequences of the disease, stable (i.e., not worsening) disease, slowed rate of disease progression, amelioration or palliation of disease state, increased survival compared to expected survival in the absence of treatment, and remission or improved prognosis. In some embodiments, the compounds of the invention are used to delay the development of a disease or disorder or to slow the progression of a disease or disorder. Subjects in need of treatment include those already with the condition or disorder, as well as those predisposed to having the condition or disorder (e.g., due to a genetic mutation) or those in whom the condition or disorder is to be prevented.

[0090] The term "therapeutic effect," as used herein, encompasses the therapeutic effect and / or prophylactic effect described above. 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.

[0091] The terms "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass the administration of two or more agents to an animal, including a human, such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration of separate compositions, administration of separate compositions at different times, or administration of a composition in which both agents are present.

[0092] The terms "antagonist" and "inhibitor" are used interchangeably to refer to compounds capable of inhibiting the biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as K-Ras, H-Ras, or N-Ras G12C. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit the biological activity of a target protein by interacting with other elements of a signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with tumor progression, growth, or spread. As used herein, the term "agonist" refers to a compound that has the ability to initiate or enhance the biological function of a target protein, whether by inhibiting the activity or expression of the target protein.

[0093] Thus, the term "agonist" is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, also specifically included within this definition are compounds that initiate or enhance the biological activity of the target polypeptide by interacting with other elements of a signal transduction pathway of which the target polypeptide is a member.

[0094] The terms "cancer," "cancerous," "neoplasm," and "tumor," and related terms, refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" contains one or more cancerous cells. Examples of cancers include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinomas (e.g., epithelial squamous cell carcinoma) and lung cancers (such as small cell lung carcinoma, non-small cell lung carcinoma ("NSCLC"), lung adenocarcinoma, and lung squamous cell carcinoma). Other cancers include skin cancer, keratoacanthoma, follicular carcinoma, hairy cell leukemia, oral cavity cancer, pharyngeal (mouth) cancer, lip cancer, tongue cancer, mouth cancer, salivary gland cancer, esophageal cancer, laryngeal cancer, hepatocellular carcinoma, gastric cancer, stomach cancer, gastrointestinal cancer, small intestine cancer, colon cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, genitourinary cancer, biliary tract cancer, thyroid cancer, papillary cancer, liver cancer, uterine cancer, uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, testicular cancer, vulvar cancer, peritoneal cancer, anal cancer, penile cancer, bone cancer, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system, brain cancer, head and neck cancer, Hodgkin's disease, and related metastases. Examples of neoplastic diseases include myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, myelofibrosis such as primary myelofibrosis, and chronic myelogenous leukemia (CML).

[0095] A "chemotherapeutic agent" is an agent useful in the treatment of a given disease, e.g., cancer or inflammatory disease. Examples of chemotherapeutic agents are known in the art and include examples such as those described in U.S. Patent Application Publication No. 2010 / 0048557, which is incorporated herein by reference. Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids, or derivatives of any chemotherapeutic agent, as well as combinations of two or more thereof.

[0096] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Isotopically labeled compounds (e.g., 3 H and 14 C) can be useful in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes can be useful for their ease of preparation and detectability. Additionally, heavier isotopes, such as deuterium (i.e., 2 Substitution with, for example, H, may result in greater metabolic stability and may confer certain therapeutic advantages (e.g., longer in vivo half-life or reduced dosage requirements). In some embodiments, in the compounds of the invention, one or more carbon atoms may be 13 C or 14It is replaced by C-enriched carbon. 15 O. 13 N, 11 C, and 18 Positron-emitting isotopes such as F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those described in the schemes or examples herein, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0097] It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or utilize any compound or composition of the invention.

[0098] Use of the term "or" means "and / or" even though the present disclosure supports a definition that refers to alternatives only and "and / or" unless expressly indicated to refer to alternatives only or that the alternatives are mutually exclusive.

[0099] Throughout this application, the term "about" is used to indicate that a value includes the standard deviation of error for the device or method being employed to measure the value.

[0100] As used herein, unless expressly stated otherwise, "a" or "an" means one or more. As used herein, "another" means at least a second, or more.

[0101] The headings used herein are intended for organizational purposes only.

[0102] RAS inhibitors In one aspect, the present invention provides compounds capable of selectively binding to and / or regulating G12C, G12D, or G13D mutant K-Ras, H-Ras, or N-Ras proteins.

[0103] As noted above, one aspect of the present invention is a compound of formula (I): TIFF2025026853000006.tif67170 or a pharmaceutically acceptable salt thereof. [In the formula, R1 is an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the K-Ras G12C mutant protein; R2 is H, OH, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, cyclopropyl, and —NHR (where R is C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkanoyl, C 1~6 Hydroxyalkanoyl, C 1~6 Cyanoalkyl, C 1~6 Alkylamino, -(C 1~6 alkylenyl)NH(CH3)-(C 1~6 ) alkylenyl) N(CH3)2, and -(C 1~3 ) alkylenyl(3- to 7-membered heterocyclyl) R3 and R4 are each H, NH2, halo, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 1~6 independently selected from the group consisting of alkylamino, and cyclopropyl; R5 is H, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6Haloalkylthio, C 1~6 Alkylamino, and C 3~7 cycloalkyl; wherein at least one of R2, R3, R4, and R5 is other than H; or R2 and R3, R3 and R4, or R4 and R5, together with the atom to which they are attached, each represent 1 to 4 substituents (wherein each substituent is independently OH, NH2, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 haloalkoxy), C 3~7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6~14 forming an aryl or a 5- to 10-membered heteroaryl; Each X optionally contains 1 to 4 substituents, where each substituent is independently selected from OH, NH, halo, cyano, carboxy, carbamoyl, C 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 and hydroxyalkyl, and 4- to 7-membered heterocyclyl, and two geminal substituents taken together form C 3~7 optionally substituted with NH, C, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~7 selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is selected from the group consisting of -L-Y1 or Y1; Y1 is H, NH2, halo, cyano, carbamoyl, C2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Alkyl-substituted C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Dialkylamino-substituted C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y 1a independently, halo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkoxy; L is a bond, O, S, and N(L a) selected from the group consisting of L a is hydrogen and C 1~3 is selected from the group consisting of alkyl, U is C(R 6a ) and V is C(R 6b ) and W is C(R 6c ) or N, R 6a , R 6b , and R 6c each independently represents H, OH, NH, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 C substituted with alkyl, 4- to 10-membered heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2.

[0104] According to some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 is an electrophilic moiety that can form a covalent bond with the cysteine ​​residue at position 12 of the K-Ras G12C mutant protein.

[0105] According to some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1is an electrophilic moiety that can form a covalent bond with the cysteine ​​residue at position 12 of the H-Ras G12C mutant protein.

[0106] According to some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 is an electrophilic moiety that can form a covalent bond with the cysteine ​​residue at position 12 of the N-Ras G12C mutant protein.

[0107] R 1 In the above definition, the electrophilic moiety capable of forming a covalent bond with a cysteine ​​residue is determined by K-Ras G12C alkylation studies and homogeneous time-resolved fluorescence (HTRF) assays. The G12C mutation in the K-Ras gene is an amino acid change from glycine to cysteine ​​at the 12th amino acid. Compounds according to the present disclosure were discovered using HTRF assays and K-Ras G12C alkylation assays, as further detailed elsewhere herein below, and then NMR spectroscopy was used to confirm the specificity of the molecules binding to G12C.

[0108] In another aspect, the present invention provides a compound of formula (II): TIFF2025026853000007.tif78170 or a pharmaceutically acceptable salt thereof. [In the formula, R2 is H, OH, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, cyclopropyl, and —NHR (where R is C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkanoyl, C 1~6 Hydroxyalkanoyl, C 1~6 Cyanoalkyl, C 1~6 Alkylamino, -(C 1~6 alkylenyl)NH(CH3)-(C 1~6 ) alkylenyl) N(CH3)2, and -(C 1~3 ) alkylenyl(3- to 7-membered heterocyclyl) R3 and R4 are each H, NH2, halo, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 1~6 independently selected from the group consisting of alkylamino, and cyclopropyl; R5 is H, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 1~6 Alkylamino, and C 3~7 cycloalkyl; wherein at least one of R2, R3, R4, and R5 is other than H; or R2 and R3, R3 and R4, or R4 and R5, together with the atom to which they are attached, each represent 1 to 4 substituents (wherein each substituent is independently OH, NH2, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 haloalkoxy), C 3~7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6~14 forming an aryl or a 5- to 10-membered heteroaryl; R7 is selected from the group consisting of H, cyano, and halo; R8 and R9 are each selected from the group consisting of H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 independently selected from the group consisting of hydroxyalkyl, cyano, and halo (C 1~6 Alkyl is methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), alkyl or aryl sulfonate leaving group, C 1~6 Alkanoylamino, C 1~6 Alkoxy, C 1~6Alkylamino, C 1~6 Alkyl sulfonyl amino, C 6~12 Dialkylamino, and C 1~6 optionally substituted with one substituent selected from the group consisting of haloalkoxy; or R7 and R8 together form a triple bond with the carbon to which they are attached, or R7 and R8 together with the carbon to which they are each attached form a C 3~7 Forms a cycloalkenyl, R9 is H, C 1~6 Alkyl, C 1~6 selected from the group consisting of haloalkyl, cyano, and halo (C 1~6 Alkyl is C 1~6 Alkanoylamino, C 1~6 Alkoxy, C 1~6 Alkylamino, C 1~6 Alkyl sulfonyl amino, C 6~12 Dialkylamino, and C 1~6 optionally substituted with one substituent selected from the group consisting of haloalkoxy; Each X optionally contains 1 to 4 substituents, where each substituent is independently selected from OH, NH, halo, cyano, carboxy, carbamoyl, C 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 and hydroxyalkyl, and 4- to 7-membered heterocyclyl, and two geminal substituents taken together form C 3~7 optionally substituted with NH, C, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~7selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is selected from the group consisting of -L-Y1 or Y1; Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Alkyl-substituted C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Dialkylamino-substituted C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y 1a independently, halo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkoxy; L is a bond, O, S, and N(L a ) selected from the group consisting of L a is hydrogen and C 1~3 is selected from the group consisting of alkyl, U is C(R 6a ) and V is C(R 6b ) and W is C(R 6c ) or N, R 6a , R 6b , and R 6c each independently represents H, OH, NH, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 C substituted with alkyl, 4- to 10-membered heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2.

[0109] In another aspect, the present invention provides a compound of formula (III): TIFF2025026853000008.tif68170 or a pharmaceutically acceptable salt thereof. [In the formula, R2 is H, OH, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, cyclopropyl, and —NHR (where R is C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkanoyl, C 1~6 Hydroxyalkanoyl, C 1~6 Cyanoalkyl, C 1~6 Alkylamino, -(C 1~6 alkylenyl)NH(CH3)-(C 1~6 ) alkylenyl) N(CH3)2, and -(C 1~3 ) alkylenyl(3- to 7-membered heterocyclyl) R3 and R4 are each H, NH2, halo, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 1~6 independently selected from the group consisting of alkylamino, and cyclopropyl; R5 is H, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 1~6 Alkylamino, and C 3~7 cycloalkyl; wherein at least one of R2, R3, R4, and R5 is other than H; or R2 and R3, R3 and R4, or R4 and R5, together with the atom to which they are attached, each represent 1 to 4 substituents (wherein each substituent is independently OH, NH2, halo, C 1~3 Alkyl, C 1~3Haloalkyl, C 1~3 Alkoxy, and C 1~3 haloalkoxy), C 3~7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6~14 forming an aryl or a 5- to 10-membered heteroaryl; R 10 is R 10a and -C(O)-R 10a is selected from the group consisting of R 10a is selected from the group consisting of oxiranyl and aziridinyl; Each X optionally contains 1 to 4 substituents, where each substituent is independently selected from OH, NH, halo, cyano, carboxy, carbamoyl, C 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 and hydroxyalkyl, and 4- to 7-membered heterocyclyl, and two geminal substituents taken together form C 3~7 optionally substituted with NH, C, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~7 selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is selected from the group consisting of -L-Y1 or Y1; Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Alkyl-substituted C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Dialkylamino-substituted C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y 1a independently, halo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkoxy; L is a bond, O, S, and N(L a ) selected from the group consisting of L a is hydrogen and C 1~3 is selected from the group consisting of alkyl, U is C(R 6a ) and V is C(R 6b ) and W is C(R 6c ) or N, R 6a , R 6b , and R 6c each independently represents H, OH, NH, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 C substituted with alkyl, 4- to 10-membered heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2.

[0110] According to some embodiments of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R2 is selected from the group consisting of NH2 and -NHR, and R is C 1~6 It is alkyl.

[0111] According to some embodiments of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R2 is NH2. In one embodiment of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R2 is -NHR, where R is C 1~6 Alkyl or C 1~6In another embodiment of a compound of Formula (I), Formula (II), or Formula (III) or a pharmaceutically acceptable salt thereof, R2 is -NHR, where R is C(O)CH3, C(O)CH2OH, CH(CH3)2, CH2CN, or CH3.

[0112] According to some embodiments of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R and R are independently selected from H, halo, C, 1~6 Alkyl, C 1~6 In one embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R3 is selected from the group consisting of C 1~3 alkyl (e.g., methyl or ethyl), or C 1~3 In another embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R is hydrogen. In one embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R is hydrogen, halo, C 1~3 Alkyl, C 1~3 In another embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R4 is hydrogen or halo. In another embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R4 is C 1~3 and alkyl (e.g., methyl or ethyl). In another embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R4 is methyl. In yet another embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R4 is -CF3. In another embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R4 is hydrogen.

[0113] According to some embodiments of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R5 is H, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, and C 3~7 In one embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R5 is selected from the group consisting of C 1~6 In another embodiment of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R5 is C 1~3 In another embodiment of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R5 is C 1~3 In another embodiment of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R5 is C 1~3 and haloalkoxy. In yet another embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R5 is H, CH3, CHF2, CF3, OCF3, CH2CF3, halo, or cyclopropyl. In yet another embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R5 is CF3.

[0114] In another embodiment of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R5 is CF3 and R2 is NH2.

[0115] In another embodiment of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R2 is NH2 and R4 is C 1~3 alkyl and R5 is CF3.

[0116] According to some embodiments of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R5 is cyclopropyl.

[0117] According to some embodiments of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, at least two of R2, R3, R4, and R5 are other than H.

[0118] According to some embodiments of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, at least three of R2, R3, R4, and R5 are other than H.

[0119] According to some embodiments of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R and R, together with the atom to which they are each attached, each represent 1 to 4 substituents, wherein each substituent is independently selected from the group consisting of OH, NH, halo, C, C, C-C ... 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 haloalkoxy), C 3~7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6~14 It forms an aryl or a 5- to 10-membered heteroaryl.

[0120] According to some embodiments of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R and R, together with the atom to which they are each attached, are selected from 1 to 4 substituents, each substituent being independently selected from OH, NH, halo, C, C-C, C-D, C-H ... 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 C optionally substituted with (selected from the group consisting of haloalkoxy) 6~14 Forms an aryl.

[0121] According to some embodiments of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R and R 5は , together with the atom to which each is attached, one to four substituents, each of which independently represents OH, NH, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 haloalkoxy)。 According to some embodiments of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, the C aryl is unsubstituted.

[0122] According to some embodiments of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, the C6 aryl is substituted with 1 to 4 substituents, wherein each substituent is independently halo. According to some embodiments of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, Y is -L-Y. In one embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, L is O or N(L a In another embodiment of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, L is O. In one embodiment of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, Y is C 2~6 Alkenyl, C 1~6 C substituted with alkyl, or 4- to 10-membered heterocyclyl or methylheterocyclyl substituents 1~6 In another embodiment of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, Y is C 1~6 C substituted with alkyl, or 4- to 10-membered heterocyclyl or methylheterocyclyl substituents 1~6In still another embodiment of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, Y is a C substituted with a 4- to 10-membered heterocyclyl or methylheterocyclyl substituent. 1~6 In another embodiment of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, Y is a C substituted with a 4- to 10-membered heterocyclyl or methylheterocyclyl substituent, wherein the heterocyclyl or methylheterocyclyl substituent contains at least one nitrogen heteroatom. 1~6 In one embodiment, the heterocyclyl or methylheterocyclyl substituent is a pyrrolidinyl moiety. In one embodiment, the pyrrolidinyl is substituted with F. In one embodiment, the heterocyclyl and methylheterocyclyl moieties are each independently OH, NH, halo, cyano, C 1~6 Alkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, or C 1~6 and optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyalkyl.

[0123] In one embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, Y is TIFF2025026853000009.tif22170. In one embodiment, Y is TIFF2025026853000010.tif21170. In another embodiment of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, Y is TIFF2025026853000011.tif19170. In still other embodiments of the compound of Formula (I), Formula (II), or Formula (III) or a pharmaceutically acceptable salt thereof, Y is TIFF2025026853000012.tif20170. In still other embodiments of the compound of Formula (I), Formula (II), or Formula (III) or a pharmaceutically acceptable salt thereof, Y is The file is TIFF2025026853000013.tif20170.

[0124] According to some embodiments of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R 6a is hydrogen, halo, or C 1~3 According to some embodiments of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R 6b is hydrogen, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 In one embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R 6b is hydrogen, halo, or C 1~3 In another embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R 6b is halo or C 1~3 In another embodiment, R 6b is halo (e.g., Cl or F). In still other embodiments of the compounds of Formula (I), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof, R 6b is Cl. In another embodiment, R 6b is CF3 or CHF2. According to some embodiments of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R 6c is hydrogen or halo. In one embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R 6c is hydrogen. In one embodiment, R 6c In one embodiment of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, R 6b and R 6c is independently halo. In another embodiment, R 6b is the halo and R 6c is hydrogen.

[0125] Further provided herein are compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof. [In the formula, Y is TIFF2025026853000014.tif22170, and X is TIFF2025026853000015.tif29170, R2 is NH2, R3 is hydrogen, and R4 is hydrogen or C 1~3 methyl and R5 is CF3.

[0126] According to an embodiment of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, the compound is selected from the group consisting of the compounds in Table 1, shown below, or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds of the present disclosure. Salts of such compounds are also contemplated. See the Examples section for the preparation of such compounds. Compounds that do not have preparative details explicitly described in the Examples can be prepared using methods generally known in the art by modifying the preparative details for other compounds provided herein. TIFF2025026853000016.tif230170TIFF2025026853000017.tif218170TIFF2025026853000018.tif189170TIFF2025026853000019.tif204170TIFF2025026853000020.tif214170TIFF2025026853000021.tif237170TIFF2025026853000022.tif248170TIFF2025026853000023.tif211170TIFF2025026853000024.tif215170TIFF2025026853000025.tif214170TIFF2025026853000026.tif237170TIFF2025026853000027.tif230170TIFF2025026853000028.tif249170TIFF2025026853000029.tif215170TIFF2025026853000030.tif218170TIFF2025026853000031.tif226170TIFF2025026853000032.tif227170TIFF2025026853000033.tif206170TIFF2025026853000034.tif237170TIFF2025026853000035.tif249170TIFF2025026853000036.tif206170TIFF2025026853000037.tif219170TIFF2025026853000038.tif224170TIFF2025026853000039.tif220170TIFF2025026853000040.tif233170TIFF2025026853000041.tif227170TIFF2025026853000042.tif229170TIFF2025026853000043.tif225170TIFF2025026853000044.tif234170TIFF2025026853000045.tif246170TIFF2025026853000046.tif213170TIFF2025026853000047.tif248170TIFF2025026853000048.tif240170TIFF2025026853000049.tif234170TIFF2025026853000050.tif225170TIFF2025026853000051.tif241170TIFF2025026853000052.tif149170.

[0127] In another embodiment, according to some embodiments of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof: R2 is H, OH, NH2, halo, C 1~6 Alkyl, C 1~6 haloalkyl, cyclopropyl, and -NHR (where R is a linear C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkanoyl, C 1~6 Hydroxyalkanoyl, C 1~6 Cyanoalkyl, C 1~6 Alkylamino, -(C 1~6 alkylenyl)NH(CH3)-(C 1~6 ) alkylenyl) N(CH3)2, and -(C 1~3 ) alkylenyl(3- to 7-membered heterocyclyl) R3 and R4 are each H, NH2, halo, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, and C 1~6 alkylamino; R5 is H, Cl, Br, I, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 1~6 Alkylamino, and C 3~7 cycloalkyl; At least two of R2, R3, R4, and R5 are other than H, or R2 and R3, R3 and R4, or R4 and R5, together with the atom to which they are attached, each represent 1 to 4 substituents (wherein each substituent is independently OH, NH2, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, and C 1~3 haloalkoxy), C 3~7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or C 6~14 forming an aryl, Each X optionally contains 1 to 4 substituents, where each substituent is independently selected from OH, NH, halo, cyano, carboxy, carbamoyl, C 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 and hydroxyalkyl, and 4- to 7-membered heterocyclyl, and two geminal substituents taken together form C 3~7 optionally substituted with NH, C, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~7 selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is selected from the group consisting of -L-Y1 or Y1; Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents 1~6Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Alkyl-substituted C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Dialkylamino-substituted C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y 1a independently, halo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkyl; L is a bond, O, S, and N(L a ) selected from the group consisting of L a is hydrogen and C 1~3 is selected from the group consisting of alkyl, U is C(R 6a ) and V is C(R6b ) and W is C(R 6c ) or N, R 6a , R 6b , and R 6c each independently represents H, OH, NH, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 C substituted with alkyl, 4- to 10-membered heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2.

[0128] According to the embodiment of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, when R2 and R3, R3 and R4, or R4 and R5, together with the atoms to which they are each attached, form a ring, it is to be understood that the substituents that do not form the ring are defined as described above for Formula (I).

[0129] In another aspect, the present invention provides a compound of formula (IV): TIFF2025026853000053.tif68170 or a pharmaceutically acceptable salt thereof. [In the formula, R1 is an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the K-Ras G12C mutant protein; Each X optionally contains 1 to 4 substituents, where each substituent is independently selected from OH, NH, halo, cyano, carboxy, carbamoyl, C 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 and hydroxyalkyl, and 4- to 7-membered heterocyclyl, and two geminal substituents taken together form C 3~7 optionally substituted with NH, C, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~7 selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is selected from the group consisting of -L-Y1 or Y1; Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 2~6 Alkynyl, C 1~6Alkylamino, C 6~14 Aryl, C 1~6 Alkyl-substituted C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Dialkylamino-substituted C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y 1a independently, halo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkyl; L is a bond, O, S, and N(L a ) selected from the group consisting of L a is hydrogen and C 1~3 is selected from the group consisting of alkyl, U is C(R 6a ) and V is C(R 6b ) and W is C(R 6c ) or N, R 6a , R 6b , and R 6c each independently represents H, OH, NH, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6C substituted with alkyl, 4- to 10-membered heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2; R 11 teeth, TIFF2025026853000054.tif199170 TIFF2025026853000055.tif222170.]

[0130] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, Y is Y1, and Y1 is H, C 1~6 Alkyl, and C 1~6 haloalkyl.

[0131] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, Y 1 is H.

[0132] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, Y is -L-Y1, and L is selected from the group consisting of O and N(L a ), and L a is H and Y1 is C 1~6C substituted with alkyl, methyl, heterocyclyl substituents 1~6 Alkyl, and C 1~6 C substituted with dialkylamino substituents 1~6 It is alkyl.

[0133] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, Y 1 is a monocyclic aryl or a monocyclic heteroaryl.

[0134] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, Y is -L-Y1, and L is selected from the group consisting of O and N(L a ), and L a is H and Y1 is C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Dialkylamino-substituted C 3~7 cycloalkyl, and 4- to 10-membered heterocyclyl substituted with methyl; 1a independently, halo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkoxy.

[0135] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, Y is -L-Y1, and L is N(L a ) and L a is H and Y1 is C 1~6 Alkyl or C 1~6 C substituted with dialkylamino substituents 1~6 It is alkyl.

[0136] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, Y is -L-Y, where L is O and Y is 1 to 4 Y. 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Dialkylamino-substituted C 3~7 cycloalkyl, and 4- to 10-membered heterocyclyl substituted with methyl; 1a independently, halo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkoxy.

[0137] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, Y is -L-Y1, and L is selected from the group consisting of O and N(L a ), and L ais H and Y1 is a C substituted with a 4- to 10-membered methylheterocyclyl substituent. 1~6 It is alkyl.

[0138] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, Y is TIFF2025026853000056.tif231170TIFF2025026853000057.tif145170.

[0139] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, Y is The file is TIFF2025026853000058.tif21170.

[0140] In one embodiment of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, Y is TIFF2025026853000059.tif20170. In another embodiment of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof, Y is TIFF2025026853000060.tif20170. In still other embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof, Y is In still other embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, Y is The file is TIFF2025026853000062.tif20170.

[0141] According to some embodiments of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, R 6a is H.

[0142] According to some embodiments of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, R 6b H, halo, C 1~6 Alkoxy, C 1~6 Alkylsulfonyl, C 1~6 Haloalkyl, C 3~7 Cycloalkyl, C 1~6 It is selected from the group consisting of haloalkylthio and 4- to 10-membered heterocyclyl.

[0143] According to some embodiments of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, R 6b H, halo, C 1~3 haloalkyl.

[0144] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, W is C(R 6c ) and R 6c is selected from the group consisting of H and halo.

[0145] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, W is C(R 6c ) and R 6c is a halo.

[0146] According to some embodiments of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, R 6a , R 6b , and R 6c is independently selected from the group consisting of monocyclic aryl and monocyclic heteroaryl.

[0147] According to some embodiments of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, X is optionally selected from 1 to 4 substituents, each of which is independently selected from OH, NH, halo, cyano, carboxy, carbamoyl, C 1~6 Alkyl, C 1~6 haloalkyl, and 4- to 7-membered heterocyclyl; 3~7 In one embodiment of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof, X is each optionally selected from 1 to 4 substituents (wherein each substituent is independently selected from OH, NH, halo, cyano, C, C, C-C ... 1~6 Alkyl, and C 1~6 haloalkyl), C 3~7 In another embodiment of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, X is each optionally selected from 1 to 4 substituents, wherein each substituent is independently selected from OH, NH, halo, cyano, C 1~6 Alkyl, and C 1~6 In yet another embodiment of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, X is optionally substituted with 1 to 4 substituents, wherein each substituent is independently selected from the group consisting of halo, cyano, C 1~3 Alkyl, and C 1~3 haloalkyl).

[0148] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, X is a 4- to 7-membered heterocyclyl.

[0149] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, X is selected from 1 to 4 substituents, each of which is independently cyano, C 1~6 Alkyl, C 1~6 Cyanoalkyl, and C 1~6 haloalkyl).

[0150] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, X is TIFF2025026853000063.tif128170.

[0151] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, X is TIFF2025026853000064.tif77170.

[0152] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, X is TIFF2025026853000065.tif74170.

[0153] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, X is The file is TIFF2025026853000066.tif29170.

[0154] In another embodiment of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, X is The file is TIFF2025026853000067.tif26170.

[0155] In another embodiment of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, X is The file is TIFF2025026853000068.tif27170.

[0156] According to some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt thereof, R 11 teeth The file is TIFF2025026853000069.tif103170.

[0157] According to some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt thereof, R 11 teeth TIFF2025026853000070.tif24170.

[0158] According to some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt thereof, R 11 teeth The file is TIFF2025026853000071.tif22170.

[0159] According to some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, n is 0.

[0160] According to some embodiments of the compound of Formula (I), or Formula (IV), or a pharmaceutically acceptable salt thereof, R1 is TIFF2025026853000072.tif82170. [In the formula, R 12 is C 1~6 Alkanoyl, C 1~6 Alkyl, and C 1~6 alkylsulfonyl; R 13 is H, C 1~6 Alkyl, and C 1~6 haloalkyl; R 13ais the halo, R 14 is a halo.]

[0161] According to some embodiments of the compound of Formula (I), or Formula (IV), or a pharmaceutically acceptable salt thereof, R1 is TIFF2025026853000073.tif35170.

[0162] According to some embodiments of the compound of Formula (I), or Formula (IV), or a pharmaceutically acceptable salt thereof, R1 is The file is TIFF2025026853000074.tif21170.

[0163] According to some embodiments of the compound of Formula (I), or Formula (IV), or a pharmaceutically acceptable salt thereof, R1 is The file is TIFF2025026853000075.tif17170.

[0164] According to some embodiments of the compound of Formula (I), or Formula (IV), or a pharmaceutically acceptable salt thereof, R1 is The file is TIFF2025026853000076.tif19170.

[0165] According to some embodiments of the compound of Formula (I), or Formula (IV), or a pharmaceutically acceptable salt thereof, R1 is The file is TIFF2025026853000077.tif17170.

[0166] According to some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt thereof, R7 is selected from the group consisting of H, cyano, and halo, and R8 and R9 are each selected from the group consisting of H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 independently selected from the group consisting of hydroxyalkyl, cyano, and halo (C 1~6Alkyl is methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), alkyl or aryl sulfonate leaving group, C 1~6 Alkanoylamino, C 1~6 Alkoxy, C 1~6 Alkylamino, C 1~6 Alkyl sulfonyl amino, C 6~12 Dialkylamino, and C 1~6 optionally substituted with one substituent selected from the group consisting of haloalkoxy).

[0167] According to some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt thereof, R7 and R8 together form a triple bond with the carbon to which they are attached, or R7 and R8 together with the carbon to which they are each attached form a C 3~7 Forms a cycloalkenyl, R9 is H, C 1~6 Alkyl, C 1~6 selected from the group consisting of haloalkyl, cyano, and halo (C 1~6 Alkyl is C 1~6 Alkanoylamino, C 1~6 Alkoxy, C 1~6 Alkylamino, C 1~6 Alkyl sulfonyl amino, C 6~12 Dialkylamino, and C 1~6 optionally substituted with one substituent selected from the group consisting of haloalkoxy).

[0168] According to some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt thereof, R 7 , R 8 , and R 9 are each H.

[0169] According to some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt thereof, R 10 -C(O)-R 10a and R 10a is oxiranyl.

[0170] According to some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt thereof, R10 -C(O)-R 10a and R 10a is aziridinyl.

[0171] According to some embodiments of the compound of formula (I), the compound is TIFF2025026853000078.tif241170TIFF2025026853000079.tif124170, or a pharmaceutically acceptable salt thereof.

[0172] In one embodiment of a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik), or (Il) or a pharmaceutically acceptable salt thereof, Y is TIFF2025026853000080.tif21170. In one embodiment of a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik), or (Il) or a pharmaceutically acceptable salt thereof, Y is TIFF2025026853000081.tif20170. In one embodiment of a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik), or (Il) or a pharmaceutically acceptable salt thereof, Y is TIFF2025026853000082.tif19170. In one embodiment of a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik), or (Il) or a pharmaceutically acceptable salt thereof, Y is TIFF2025026853000083.tif19170. In still another embodiment of a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik), or (Il) or a pharmaceutically acceptable salt thereof, Y is The file is TIFF2025026853000084.tif19170.

[0173] According to some embodiments of the compound of formula (I), the compound has formula (Ia) or (Ic), or a pharmaceutically acceptable salt thereof:

[0174] According to some embodiments of the compound of formula (I), the compound has the formula (Ib) or (Il), or a pharmaceutically acceptable salt thereof:

[0175] According to some embodiments of the compound of formula (I), the compound has the formula (Ia):

[0176] According to some embodiments of the compound of formula (I), the compound has the formula (Ib):

[0177] According to some embodiments of the compound of formula (I), the compound has the formula (Ic):

[0178] According to some embodiments of the compound of formula (I), the compound has the formula (Il):

[0179] According to some embodiments of the compound of formula (IV) or a pharmaceutically acceptable salt thereof, the compound is TIFF2025026853000085.tif242170, or a pharmaceutically acceptable salt thereof.

[0180] According to some embodiments of the compound of formula (IV), the compound comprises a compound of formula (IVa), (IVb), (IVd), or (IVg), or a pharmaceutically acceptable salt thereof. According to some embodiments of the compound of formula (IV), the compound comprises a compound of formula (IVa) or (IVb), or a pharmaceutically acceptable salt thereof. According to some embodiments of the compound of formula (IV), the compound comprises a compound of formula (IVd) or (IVg), or a pharmaceutically acceptable salt thereof.

[0181] In one embodiment of the compound of Formula (I), (II), (III), or (IV), the compound is as set forth in Table 1 herein, or a pharmaceutically acceptable salt thereof.

[0182] In another embodiment of a compound of Formula (I), (II), (III), or (IV), the compound is a compound corresponding to Compound 9, Compound 17a, Compound 17b, Compound 18a, Compound 18b, Compound 19, Compound 44, Compound 83a, Compound 83b, Compound 83c, Compound 83d, or Compound 69, or a pharmaceutically acceptable salt thereof.

[0183] In one embodiment, the compound is Compound 9. In one embodiment, the compound is Compound 17a. In one embodiment, the compound is Compound 17b. In one embodiment, the compound is Compound 18a. In one embodiment, the compound is Compound 18b. In one embodiment, the compound is Compound 19. In one embodiment, the compound is Compound 83a. In one embodiment, the compound is Compound 83b. In one embodiment, the compound is Compound 83c. In one embodiment, the compound is Compound 83d. In one embodiment, the compound is Compound 69.

[0184] According to an embodiment of Formula (I), the compound is selected from the group consisting of compounds 1, 5, 7-10, 13-15, 17a, 17b, 18a, 18b, 19-33, 35, 40-41, 43-45, 46a, 46b, 47-58, 59a, 59b, 60-61, 62a, 62b, 63a, 63b, 64a, 64b, 65, 66, 67a, 67b, 68a, 68b, 69-74, 75a, 75b, 76, 77, 78a, 78b, 79a, 79b, 80, 81a, 81b, 82a, 82b, 83a, 83b, 83c, 83d, 84a, 84b, and 85-97 in Table 1, or a pharmaceutically acceptable salt thereof. According to another embodiment of Formula (I), the compound is selected from the group consisting of compounds 1, 5, 7-10, 13-15, 17a, 17b, 18a, 18b, 19-33, 35, 40-41, 43-45, 46a, 46b, and 47-54 in Table 1, or a pharmaceutically acceptable salt thereof. According to another embodiment of Formula (I), the compound is selected from the group consisting of compounds 55-58, 59a, 59b, 60-61, 62a, 62b, 63a, 63b, 64a, 64b, 65, 66, 67a, 67b, 68a, 68b, 69-74, 75a, 75b, 76, 77, 78a, 78b, 79a, 79b, 80, 81a, 81b, 82a, 82b, 83a, 83b, 83c, 83d, 84a, 84b, and 85-97 in Table 1.

[0185] The compounds of the present invention (e.g., compounds of Formula (I), (II), (III), or (IV)), or pharmaceutically acceptable salts thereof, can contain one or more asymmetric centers. Enantiomers, diastereomers, and other stereoisomeric forms, defined in terms of absolute stereochemistry as (R)- or (S)-, or with respect to amino acids, as (D)- or (L)-, can therefore occur. Accordingly, embodiments include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative), using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0186] Embodiments of the present invention include all modes of rotamers and conformationally restricted states of the compounds of the present invention. Also included are atropisomers, which are stereoisomers resulting from restricted rotation about a single bond where the energy difference due to steric strain or other factors creates a barrier to rotation high enough to allow separation of the individual conformers. By way of example, certain compounds of the present invention may exist as a mixture of atropisomers, or may be purified or enriched for the presence of a single atropisomer.

[0187] In some embodiments, the compound of Formula (I) is a mixture of atropisomers. In other embodiments, the compound of Formula (I) is a substantially purified atropisomer. In some embodiments, the compound of Formula (I) is a substantially purified R-atropisomer. In some other embodiments, the compound of Formula (I) is a substantially purified R-atropisomer.

[0188] Synthesis of RAS inhibitors The compounds of the present disclosure can be made by a variety of methods shown in the illustrative synthetic reaction schemes depicted and described below. The starting materials and reagents used in preparing these compounds are generally available from commercial sources, such as Aldrich Chemical Co., or are generally described in Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R.C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.), vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A.R. Katrittzky and C.W. Rees (Eds.), Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A.R. Katrittzky and C.W. Rees (Eds), Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New The compounds of the present invention may be prepared according to the procedures described in references such as, for example, NIH, NY, 1991, vol. 1-40, or by methods known to those skilled in the art. The following synthetic reactions are merely illustrative of some of the ways in which the compounds of the present invention may be synthesized, and various modifications to these synthetic reaction schemes may be made and will be suggested to those skilled in the art having reference to the disclosure contained herein.

[0189] For illustrative purposes, the following reaction schemes provide routes for the synthesis of compounds of the present invention and key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will recognize that other synthetic routes can be used. While some specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be substituted to provide a variety of derivatives or reaction conditions. Additionally, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0190] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and optionally purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, etc. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0191] Unless otherwise specified, the reactions described herein are preferably carried out under an inert atmosphere at atmospheric pressure, at reaction temperatures ranging from about −78° C. to about 150° C., more preferably from about 0° C. to about 125° C., and most preferably, and conventionally, at about room temperature (or ambient temperature), i.e., about 20° C.

[0192] In the following schemes, some compounds are depicted with generalized substituents. However, one skilled in the art will readily appreciate that the nature of the substituents can be varied to obtain a variety of compounds contemplated by the present invention. Furthermore, the reaction conditions are exemplary, and alternative conditions are well known. The reaction sequences in the following examples are not intended to limit the scope of the invention as set forth in the claims.

[0193] Those skilled in the art will recognize that the chemical reactions described can be readily adapted to prepare other compounds of the invention. For example, the synthesis of non-exemplary compounds according to the invention can be successfully carried out by making modifications apparent to one skilled in the art, such as by appropriately protecting intervening groups, by using other suitable reagents known in the art other than those described, or by making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.

[0194] Methods of treatment with RAS inhibitors and methods of using RAS inhibitors The compounds of the present disclosure are useful as Ras inhibitors. In one aspect, the compounds of the present disclosure are useful as K-Ras inhibitors. In another aspect, the compounds of the present disclosure are useful as N-Ras inhibitors. In another aspect, the compounds of the present disclosure are useful as H-Ras inhibitors. Thus, in one embodiment, a method is provided in which a cell, such as an ex vivo cell, is contacted with a compound of the present invention or a pharmaceutically acceptable salt thereof to inhibit Ras activity (e.g., K-Ras, H-Ras, and / or N-Ras activity) in the cell. It is understood that the treatment methods described herein can, in certain embodiments, further include determining the presence or absence of a G12 Ras mutation before administering a compound described herein or a pharmaceutically acceptable salt thereof.

[0195] Further provided are methods for preventing, treating, or reducing the severity of a disease or condition responsive to the inhibition of Ras (e.g., K-Ras, H-Ras, and / or N-Ras) in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

[0196] In one aspect, the disclosure relates to a method for preventing, treating, or reducing the severity of a disease or condition responsive to the inhibition of K-Ras in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

[0197] In one aspect, the disclosure relates to a method for preventing, treating, or reducing the severity of a disease or condition in a patient that responds to the inhibition of H-Ras, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0198] In one aspect, the disclosure relates to a method for preventing, treating, or reducing the severity of a disease or condition responsive to the inhibition of N-Ras in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

[0199] Also provided is a method of treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0200] Also provided is a method for inhibiting Ras (e.g., K-Ras, H-Ras, and / or N-Ras) in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

[0201] In one aspect, the disclosure relates to a method for inhibiting K-Ras in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0202] In one aspect, the disclosure relates to a method for inhibiting H-Ras in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

[0203] In one aspect, the disclosure relates to a method for inhibiting N-Ras in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

[0204] Also provided are pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The compounds of the invention, including pharmaceutical compositions comprising such compounds, can be used in the methods described herein.

[0205] Embodiments of the present disclosure provide methods for inhibiting Ras-mediated cellular signaling, comprising contacting a cell with a therapeutically effective amount of one or more compounds disclosed herein or pharmaceutically acceptable salts thereof. Inhibition of Ras-mediated signaling can be assessed and demonstrated by various methods known in the art. Non-limiting examples include demonstrating (a) a decrease in Ras GTPase activity, (b) a decrease in GTP binding affinity or an increase in GDP binding affinity, (c) an increase in GTP Koff or a decrease in GDP Koff, (d) a decrease in the amount of pMEK, and / or (e) a decrease in binding of the Ras complex to downstream signaling molecules, including, but not limited to, Raf. Kits and commercially available assays are available for measuring one or more of the above.

[0206] Embodiments also provide methods of treating disease states, including, but not limited to, conditions associated with G12C K-Ras mutations, G12C H-Ras mutations, and / or G12C N-Ras mutations (e.g., cancer), using compounds or pharmaceutical compositions of the invention.

[0207] In some embodiments, the present invention provides methods for treating a disease in a subject in need thereof, comprising determining whether the subject has a K-Ras, H-Ras, or N-Ras G12C mutation, and administering to the subject a therapeutically effective amount of at least one compound of the present invention, or a pharmaceutically acceptable salt thereof, if the subject is determined to have a K-Ras, H-Ras, or N-Ras G12C mutation.

[0208] K-Ras, H-Ras, or N-Ras G12C mutations have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments relate to administering a disclosed compound of the present invention, or a pharmaceutically acceptable salt thereof (e.g., in the form of a pharmaceutical composition), to a patient in need of treatment for a hematological malignancy. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the compounds disclosed herein can be used to treat diseases such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In another embodiment, the compounds of the present invention, or a pharmaceutically acceptable salt thereof, are useful for treating lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0209] Determining whether a tumor or cancer contains a G12C K-Ras, H-Ras, or N-Ras mutation can be performed by evaluating the nucleotide sequence encoding the K-Ras, H-Ras, or N-Ras protein, by evaluating the amino acid sequence of the K-Ras, H-Ras, or N-Ras protein, or by evaluating the characteristics of a predicted K-Ras, H-Ras, or N-Ras mutant protein. The sequences of wild-type human K-Ras (e.g., accession number NP203524), H-Ras (e.g., accession number NP001123914), and N-Ras (e.g., accession number NP002515) are known in the art.

[0210] Methods for detecting mutations in K-Ras, H-Ras, or N-Ras nucleotide sequences are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, a sample is evaluated for a G12C K-Ras, H-Ras, or N-Ras mutation by real-time PCR. A fluorescent probe specific for the K-Ras, H-Ras, or N-Ras G12C mutation is used in real-time PCR. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, direct sequencing of specific regions within the K-Ras, H-Ras, or N-Ras gene (e.g., exon 2 and / or exon 3) is used to identify K-Ras, H-Ras, or N-Ras G12C mutations. This method identifies all possible mutations within the sequenced region.

[0211] Methods for detecting mutations in K-Ras, H-Ras, or N-Ras proteins are known to those skilled in the art. These methods include, but are not limited to, detecting K-Ras, H-Ras, or N-Ras mutations using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing. Various samples can be used to determine whether a tumor or cancer contains a G12C K-Ras, H-Ras, or N-Ras mutation. In some embodiments, the sample is obtained from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0212]

[0013] Embodiments also relate to methods for treating a hyperproliferative disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. In some embodiments, the method is directed to a cancer selected from the group consisting of acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, osteosarcoma, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and the like. CML, chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, uterine cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell carcinoma Alveolar tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, occult primary metastatic squamous neck cancer, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasia, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasia, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC) , oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, abnormal cancer of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.In some embodiments, the methods relate to the treatment of non-cancerous hyperproliferative diseases such as benign hyperplasia of the skin (eg, psoriasis), restenosis, or benign prostatic hyperplasia (BPH).

[0213] In certain embodiments, the present invention relates to a method for treating lung cancer, the method comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same) to a subject in need of treatment. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In another embodiment, the lung cancer is small cell lung cancer. Other lung cancers treatable with the disclosed compounds include, but are not limited to, adenocarcinoma, carcinoid tumor, and undifferentiated carcinoma. In some embodiments, the present invention provides a method for inhibiting K-Ras, H-Ras, or N-Ras G12C activity in a cell by contacting the cell with a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount sufficient to inhibit K-Ras, H-Ras, or N-Ras G12C activity in the cell. In some embodiments, the present invention provides a method of inhibiting K-Ras, H-Ras, or N-Ras G12C activity in a tissue by contacting the tissue with a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit the activity of K-Ras, H-Ras, or N-Ras G12C in the tissue.

[0214] In some embodiments, the present invention provides methods for inhibiting K-Ras, H-Ras, or N-Ras G12C activity in an organism by contacting the organism with a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit K-Ras, H-Ras, or N-Ras G12C activity in the organism. In some embodiments, the present invention provides methods for inhibiting K-Ras, H-Ras, or N-Ras G12C activity in an animal by contacting the animal with a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit K-Ras, H-Ras, or N-Ras G12C activity in the animal. In some embodiments, the present invention provides a method for inhibiting K-Ras, H-Ras, or N-Ras G12C activity in a mammal by contacting the mammal with a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit K-Ras, H-Ras, or N-Ras G12C activity in the mammal. In some embodiments, the present invention provides a method for inhibiting K-Ras, H-Ras, or N-Ras G12C activity in a human by contacting the human with a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit K-Ras, H-Ras, or N-Ras G12C activity in the human. In another embodiment, the present invention provides a method for treating a disease mediated by K-Ras, H-Ras, or N-Ras G12C activity in a subject in need of such treatment.

[0215] In some embodiments, the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention to an individual in need of cancer treatment. In some embodiments, the individual is human. In some embodiments, the administering is via the oral route. In some embodiments, the administering is via injection. In some embodiments, the cancer is mediated by a K-Ras G12C, H-Ras G12C, or N-Ras G12C mutation. In some embodiments, the cancer is mediated by a K-Ras G12C mutation. In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma.

[0216] In some embodiments, the present invention provides a method for regulating the activity of a mutant protein selected from the group consisting of K-Ras G12C, H-Ras G12C, and N-Ras G12C, comprising reacting the mutant protein with a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the present invention provides methods of inhibiting proliferation of a cell population, comprising contacting the cell population with a compound of the present invention, or a pharmaceutically acceptable salt thereof, hi some embodiments, the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0218] In some embodiments, the present invention provides a method for treating a disease mediated by a mutation selected from the group consisting of K-Ras G12C, H-Ras G12C, and N-Ras G12C in a subject in need of such treatment, comprising determining whether the individual has the mutation, and, if the individual has the mutation, administering to the individual a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention. In some embodiments, the disease is mediated by a K-Ras G12C mutation. In some embodiments, the disease is cancer. In some embodiments, the cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma.

[0219] In some embodiments, the present invention provides a method for preparing a labeled K-Ras G12C, H-Ras G12C, or N-Ras G12C mutant protein, comprising reacting a K-Ras G12C, H-Ras G12C, or N-Ras G12C mutant protein with a compound of the present invention or a pharmaceutically acceptable salt thereof to obtain a labeled K-Ras G12C, H-Ras G12C, or N-Ras G12C mutant protein.

[0220] In some embodiments, the present invention provides a method for inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0221] In some embodiments, the invention provides use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer. In some embodiments, the medicament is formulated for oral administration. In some embodiments, the medicament is formulated for injection. In some embodiments, the cancer is mediated by a K-Ras G12C, H-Ras G12C, or N-Ras G12C mutation. In some embodiments, the cancer is mediated by a K-Ras G12C mutation. In some embodiments, the cancer is mediated by an H-Ras G12C mutation. In some embodiments, the cancer is mediated by an N-Ras G12C mutation. In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0222] In some embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, for use in a method of treating the human or animal body by therapy. In some embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, for use in a method of treating cancer. In some embodiments, the cancer is mediated by a K-Ras G12C, H-Ras G12C, or N-Ras G12C mutation. In some embodiments, the cancer is mediated by a K-Ras G12C mutation. In some embodiments, the cancer is mediated by an H-Ras G12C mutation. In some embodiments, the cancer is mediated by an N-Ras G12C mutation. In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, for use in a method for inhibiting tumor metastasis.

[0223] Further provided herein is a method for treating lung cancer in a patient having lung cancer, the method comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same). In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC). The NSCLC can be, for example, an adenocarcinoma, a squamous cell lung cancer, or a large cell lung cancer. In another embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is an adenocarcinoma, a carcinoid tumor, or an undifferentiated carcinoma. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer can be stage III or stage IV lung cancer. The methods provided herein include administering the compound as a first line of therapy. In one embodiment, the lung cancer comprises a G12C KRas mutation.

[0224] Still further provided herein is a method for treating pancreatic cancer in a patient having pancreatic cancer, the method comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In one embodiment, the patient has previously been treated with radiation and one or more chemotherapeutic agents. In one embodiment, the pancreatic cancer is stage 0, stage I, or stage II. In another embodiment, the pancreatic cancer is stage III or stage IV. In one embodiment, the pancreatic cancer comprises a G12C KRas mutation.

[0225] Still further provided herein is a method for treating colon cancer in a patient having colon cancer, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In one embodiment, the colon cancer is stage I or stage II. In another embodiment, the colon cancer is stage III or stage IV. In one embodiment, the colon cancer comprises a G12C KRas mutation.

[0226] Further provided herein are methods for treating G12C mutant KRas-mediated cancer across organ systems. In one embodiment of such a method, the method comprises: a. Identifying the absence or presence of the KRas G12C mutation in a sample taken from a patient diagnosed with suspected cancer; b. administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof; Includes.

[0227] In one embodiment of such a method, the patient is diagnosed with a cancer described herein. In another embodiment of such a method, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is taken before administration of any therapy. In another such embodiment, the sample is taken before administration of a compound described herein or a pharmaceutically acceptable salt thereof and after administration of another chemotherapeutic agent. In another embodiment of such a method, a compound described herein or a pharmaceutically acceptable salt thereof is administered as provided herein (e.g., orally).

[0228] Dosage and Administration The present invention provides pharmaceutical compositions or medicaments containing a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inactive excipient, and methods of using the compounds of the present invention to prepare such compositions and medicaments.

[0229] Thus, one embodiment includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.

[0230] In one example, a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof having the desired purity can be formulated by mixing it with a physiologically acceptable excipient, i.e., an excipient that is non-toxic to recipients at the dosages and concentrations employed in the formulation at ambient temperature and an appropriate pH. The pH of the formulation will depend primarily on the specific use and concentration of the compound, but typically falls somewhere in the range of about 3 to about 8. In one example, a compound of the present invention or a pharmaceutically acceptable salt thereof is formulated in acetate buffer at pH 5. In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is sterilized. The compound of the present invention or a pharmaceutically acceptable salt thereof can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0231] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the specific disease being treated, the severity of the disease, the specific patient being treated, the clinical condition of the individual patient, the cause of the disease, the delivery site of the active substance, the method of administration, the administration schedule, and other factors known to physicians. The "therapeutically effective amount" of the compound of the present invention or its pharmaceutically acceptable salt to be administered is governed by such considerations and is the minimum amount necessary to inhibit K-Ras, H-Ras, and / or N-Ras activity. Typically, such an amount may be below the amount that is toxic to normal cells or the patient as a whole.

[0232] Pharmaceutical compositions (or formulations) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution includes a container having disposed therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident assembly to prevent unintentional access to the contents of the package. In addition, the container may have disposed thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[0233] Sustained-release preparations may also be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt, wherein the matrices are shaped articles, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and γ-L-ethyl glutamate, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0234] Dosages for treating human patients can range from about 0.01 mg to about 1000 mg of a compound of the present invention or a pharmaceutically acceptable salt thereof. For example, in treating adult humans, doses of 0.01 to 1000 mg per day, 0.5 to 100 mg, 1 to 150 mg per day, and 5 to 40 mg per day are exemplary doses used in some embodiments. An exemplary dose is 10 to 30 mg per day. The exact dose will depend on the route of administration, the form in which the compound is administered, the subject being treated, the body weight of the subject being treated, and the preference and experience of the attending physician. Doses can be administered once daily (QD), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion, of the particular compound. In addition, toxicity factors may affect the dosage and administration regimen. When administered orally, pills, capsules, or tablets may be taken orally daily or at more spaced intervals for a specified period of time. This regimen may be repeated for a predetermined number of treatment cycles.

[0235] A therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof can be administered by any suitable method, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, pulmonary, intradermal, intrathecal, epidural, and nasal administration, and, if desired for local treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0236] A therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof can be administered in any convenient dosage form, such as a tablet, powder, capsule, solution, dispersion, suspension, syrup, spray, suppository, gel, emulsion, patch, etc. Such compositions can contain conventional components of pharmaceuticals, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0237] A typical formulation is prepared by mixing a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, with excipients. Suitable excipients include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, e.g., ascorbic acid), colorants (e.g., inorganic pigments, e.g., iron oxide), and taste and / or odor correctors, and are well known to those skilled in the art, see, e.g., Ansel, H.C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, R.C., Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, surfactants, lubricants, suspending agents, preservatives, opacifying agents, glidants, processing aids, sweeteners, flavors, flavoring agents, diluents, and other known additives that impart an elegant appearance to the drug (i.e., the compound of the present invention or a pharmaceutical composition thereof) or aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0238] In certain embodiments, pharmaceutical preparations for oral use are prepared by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the resulting granular mixture, if desired, after adding suitable additives, to obtain tablets or dragees. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations (e.g., corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.); or other excipients (PVP or povidone) or calcium phosphate. In certain embodiments, disintegrants are optionally added. Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

[0239] In one embodiment, dosage forms such as dragees and tablets are provided with one or more suitable coating agents. In certain embodiments, a concentrated sugar solution is used to coat the dosage form. The sugar solution optionally contains additional components such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and suitable organic solvents or solvent mixtures. Dyes and / or pigments are also optionally added to the coating for identification purposes. Furthermore, dyes and / or pigments are optionally used to distinguish different combinations of active compound doses.

[0240] In certain embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer (e.g., glycerol or sorbitol). In certain embodiments, the push-fit capsules contain the active ingredient in admixture with one or more fillers. Fillers include, by way of example only, binders such as lactose or starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In another embodiment, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0241] In another embodiment, a therapeutically effective amount of at least one compound described herein is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In yet other embodiments, the compounds described herein are formulated for parenteral administration, including formulations suitable for bolus injection or continuous infusion. In certain embodiments, the injectable formulations are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. A preservative is optionally added to the injectable formulation. In still other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection, such as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. Parenteral injection formulations optionally contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. In certain embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In further embodiments, suspensions of the compounds of the present invention or their pharmaceutically acceptable salts are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form before use, for constitution with a suitable vehicle, such as sterilized pyrogen-free water.

[0242] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more pharmaceutically acceptable excipients and auxiliaries that facilitate the processing of active compounds into preparations.Suitable formulations vary depending on the selected route of administration.Any pharmaceutically acceptable technology and excipients are optionally used suitably.Pharmaceutical compositions containing a therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salts are prepared in a conventional manner, for example, by means of conventional mixing, dissolving, granulating, sugar-coating, pulverizing, emulsifying, encapsulating, encapsulating, or compressing processes.

[0243] Pharmaceutical compositions comprise at least one pharmaceutically acceptable excipient and, as an active ingredient, a therapeutically effective amount of a compound of the present invention described herein or a pharmaceutically acceptable salt thereof. The active ingredient may be in free acid or free base form, or in pharmaceutically acceptable salt form. Furthermore, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and activated metabolites of these compounds that have the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Furthermore, the compounds described herein encompass unsolvated and solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). Solvated forms of the compounds presented herein are also considered to be disclosed herein. Additionally, pharmaceutical compositions optionally contain other medicinal or pharmaceutical agents, such as preservatives, stabilizers, wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0244] Methods for preparing compositions containing a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof described herein include formulating the compound of the present invention or a pharmaceutically acceptable salt thereof with one or more inert, pharmaceutically acceptable excipients to form a solid, semi-solid, or liquid form. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. Pharmaceutical compositions described herein may take the form of liquid solutions or suspensions, solids suitable for solution or suspension in liquid prior to use, or as emulsions. These compositions may also optionally contain minor amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like.

[0245] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof illustratively takes the form of a liquid in which the active agent is present in solution, suspension, or both. Typically, when the composition is administered as a solution or suspension, a first portion of the active agent is present in solution, and a second portion of the active agent is present in particulate form, in suspension within a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0246] In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers, such as cellulosic polymers (e.g., hydroxypropylmethylcellulose), and water-insoluble polymers (e.g., cross-linked carboxyl-containing polymers). Certain pharmaceutical compositions described herein include a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0247] Useful pharmaceutical compositions also optionally contain solubilizers that are useful for improving the solubility of the compounds of the present invention or their pharmaceutically acceptable salts. The term "solubilizer" generally includes agents that result in the formation of a micellar or true solution of the agent. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizers, as are glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers, which are acceptable in the ophthalmic field.

[0248] In addition, useful pharmaceutical compositions optionally contain one or more pH adjusters or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0249] Additionally, useful compositions also optionally contain one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0250] Other pharmaceutical compositions optionally contain one or more preservatives that inhibit bacterial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0251] Still other useful compositions include one or more surfactants to improve physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as Octoxynol 10 and Octoxynol 40.

[0252] Yet other useful compositions also include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0253] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0254] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery vehicles or excipients useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In further embodiments, the compounds described herein are delivered using a sustained-release system, such as a semipermeable matrix of solid hydrophobic polymers containing a therapeutic agent. A variety of sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compound for several weeks up to more than 100 days.

[0255] The present invention further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary excipient for the active ingredient. The veterinary excipient is a substance useful for the purpose of administering the composition and can be a solid, liquid, or gaseous substance that is otherwise inert or acceptable in the veterinary art and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or by any other desired route.

[0256] Combination therapy The compounds of the present invention or their pharmaceutically acceptable salts can be used alone or in combination with other therapeutic agents to treat the diseases or disorders described herein. The second compound in the pharmaceutical combination formulation or administration regimen preferably has complementary activity to the compounds of the present invention or their pharmaceutically acceptable salts, so as not to adversely affect each other. Combination therapy can provide "synergistic effects" and can be demonstrated to be "synergistic," i.e., an effect achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately.

[0257] The combination therapy can be administered as a simultaneous regimen or a sequential regimen. When administered sequentially, the combination is administered in two or more doses. The combination administration includes co-administration using separate formulations or a single pharmaceutical formulation, and sequential administration in any order, preferably with time for both (or all) active agents to simultaneously exert their biological activity.

[0258] Thus, combination therapy according to the present invention involves the administration of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one other therapeutic modality, wherein the amounts of the compound of the present invention, or a pharmaceutically acceptable salt thereof, and the other pharmaceutically active agent, as well as the relative timings of administration, are selected to achieve the desired combined therapeutic effect.

[0259] In various embodiments of the method, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor (such as irinotecan, or such as etoposide, or such as doxorubicin), a taxane (such as anti-microtubule inhibitors, including paclitaxel and docetaxel), an antimetabolite (such as 5-FU, or such as gemcitabine), or an alkylating agent (such as cisplatin, or such as cyclophosphamide), or a taxane.

[0260] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, such as erlotinib, or such as afatinib. In some embodiments, the additional therapeutic agent is Iressa. In some embodiments, the additional therapeutic agent is a monoclonal antibody, such as cetuximab (Erbitux) or panitumumab (Vectibix). In some embodiments, the GFR inhibitor is a dual or pan-HER inhibitor. In another embodiment, the additional therapeutic agent is a phosphatidylinositol-3-kinase (PI3K) inhibitor, such as GDC-0941, MLN1117, BYL719 (alpelisib), or BKM120 (buparlisib). GDC-0941 refers to 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, or a salt thereof (e.g., the bismesylate salt).

[0261] In yet another embodiment, the additional therapeutic agent is an insulin-like growth factor receptor (IGF1R) inhibitor. For example, in some embodiments, the insulin-like growth factor receptor (IGF1R) inhibitor is NVP-AEW541. In other embodiments, the additional therapeutic agent is IGOSI-906 (linsitinib), BMS-754807, or another embodiment, a neutralizing monoclonal antibody specific for IGF1R, such as AMG-479 (ganitumab), CP-751, 871 (fizitumumab), IMC-A12 (cixutumumab), MK-0646 (dalotuzumab), or R-1507 (lovatumumab).

[0262] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor, hi some embodiments, the additional therapeutic agent is CYT387, GLPG0634, baricitinib, lestaurtinib, momelotinib, pacritinib, ruxolitinib, or TG101348.

[0263] In some other embodiments, the additional therapeutic agent is an anti-glypican 3 antibody. In some embodiments, the anti-glypican 3 antibody is codrituzumab.

[0264] In some other embodiments, the additional therapeutic agent is an antibody-drug conjugate (ADC). In some embodiments, the ADC is polatuzumab vetotin, RG7986, RG7882, RG6109, or RO7172369.

[0265] In some other embodiments, the additional therapeutic agent is an MDM2 antagonist, hi some embodiments, the MDM2 antagonist is idasanutulin.

[0266] In some other embodiments, the additional therapeutic agent is an agonistic antibody against CD40, hi some embodiments, the agonistic antibody against CD40 is cericlerumab (RG7876).

[0267] In some other embodiments, the additional therapeutic agent is a bispecific antibody, hi some embodiments, the bispecific antibody is RG7828 (BTCT4465A), RG7802, RG7386 (FAP-DR5), RG6160, RG6026, ERY974, or anti-HER2 / CD3.

[0268] In some other embodiments, the additional therapeutic agent is a targeted immunocytokine, hi some embodiments, the targeted immunocytokine is RG7813 or RG7461.

[0269] In some other embodiments, the additional therapeutic agent is an antibody that targets colony-stimulating factor 1 receptor (CSF-1R). In some embodiments, the CSF-1R antibody is emactuzumab.

[0270] In some other embodiments, the additional therapeutic agent is a personalized cancer vaccine, hi some embodiments, the personalized cancer vaccine is RG6180.

[0271] In some other embodiments, the additional therapeutic agent is an inhibitor of BET (bromodomain and extraterminal family) proteins (BRD2 / 3 / 4 / T). In some embodiments, the BET inhibitor is RG6146.

[0272] In some other embodiments, the additional therapeutic agent is an antibody designed to bind to TIGIT, hi some embodiments, the anti-TIGIT antibody is RG6058 (MTIG7192A).

[0273] In some other embodiments, the additional therapeutic agent is a selective estrogen receptor degrader (SERD). In some other embodiments, the SERD is RG6047 (GDC-0927) or RG6171 (GDC-9545).

[0274] In some other embodiments, the additional therapeutic agent is crizotinib, tivantinib, AMG337, cabozantinib, or foretinib, hi other embodiments, the additional therapeutic agent is a neutralizing monoclonal antibody against methionine, such as onartuzumab.

[0275] In further embodiments, the additional therapeutic agent is an SRC family non-tyrosine kinase inhibitor. For example, in some embodiments, the additional therapeutic agent is an inhibitor of a subfamily of SRC family non-receptor tyrosine kinases. Exemplary inhibitors of this aspect include dasatinib. Other examples in this regard include ponatinib, saracatinib, and bosutinib.

[0276] In yet other embodiments, the additional therapeutic agent is a mitogen-activated protein kinase (MEK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is trametinib, selumetinib, COTELLIC® (cobimetinib), PD0325901, or RO5126766. In other embodiments, the MEK inhibitor is GSK-1120212, also known as trametinib.

[0277] In yet another embodiment, the additional therapeutic agent is an extracellular signal-regulated kinase (ERK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is SCH722984 or GDC-0994.

[0278] In other embodiments, the protein kinase inhibitor is taselisib, ipataselitib, GDC-0575, GDC-5573 (HM95573), RG6114 (GDC-0077), CKI27, afatinib, axitinib, atezolizumab, bevacizumab, bosutinib, cetuximab, crizotinib, dasatinib, erlotin ... The additional therapeutic agent is selected from the group consisting of rotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, ibrutinib, nilotinib, panitumumab, pazopanib, pegaptanib, ranibizumab, ruxolitinib, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib, and vemurafenib. In still further embodiments, the additional therapeutic agent is a topoisomerase inhibitor. In some of these embodiments, the topoisomerase inhibitor is irinotecan. In some further embodiments, the additional therapeutic agent is a taxane. Exemplary taxanes include taxol and docetaxel.

[0279] In addition to the additional therapeutic agents listed above, other chemotherapeutics are currently known in the art and can be used in combination with the compounds of the present invention. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0280] Non-limiting examples include chemotherapeutic agents, cytotoxic agents, non-peptide small molecules such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin, as well as a host of other chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; chloramphenicol, ... Nitrogen mustards such as bucill, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; aclacinomycin, actinomycin, anthramycin, and azaserine; Bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, Antibiotics such as keramycin, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur,Pyrimidine analogues such as cytarabine, dideoxyuridinene, doxifluridine, enocitabine, and floxiridine; androgens such as calucelone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotein, and trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elfomitine; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; Lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; polysaccharide K; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes (e.g., paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Suitable chemotherapeutic cell modulating agents include, for example, tamoxifen (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); flutamide, nilutamide, bicalutamide, leuprolide,and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; Xeloda™; ibandronate; camptothecin-11 (CPT-11); the topoisomerase inhibitor RFS 2000; and anti-hormonal agents that act to regulate or inhibit hormone action in tumors, such as antiestrogens including difluoromethylornithine (DMFO). If desired, the compounds or pharmaceutical compositions of the present invention can be administered in combination with other drugs such as Herceptin®, Avastin®, Gazyva®, Tecentriq®, Alecensa®, Perjeta®, Venclexta™, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfalazine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antitumor drugs, tumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle non-specific anticancer drugs, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, eclulind, ferruginol, forodesin, fosfestol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucansone, lurtotecan, mafosfamide, mitozolomide, nafoximide, nedaplatin,It can be used in combination with commonly prescribed anticancer drugs such as olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosquidar.

[0281] The exact method of administering the compound and additional therapeutic agent will be apparent to one of ordinary skill in the art. In some exemplary embodiments, the compound and additional therapeutic agent are administered simultaneously. In other embodiments, the compound and additional therapeutic agent are administered separately.

[0282] In some embodiments, the compound and the additional therapeutic agent are administered simultaneously with the second agent or separately. This combined administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compound described herein and any of the additional therapeutic agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound described herein and any of the additional therapeutic agents can be administered simultaneously, where both agents are present in separate formulations. In another alternative, the compound can be administered immediately after any of the additional therapeutic agents described herein, or in the reverse order. In some embodiments of the separate administration protocol, the compound described herein and any of the additional therapeutic agents are administered within minutes, hours, or days of each other.

[0283] product In another embodiment of the present invention, an article of manufacture, or "kit," containing materials useful for treating the above-mentioned diseases and disorders is provided. In one embodiment, the kit includes a container containing a compound of the present invention or a pharmaceutically acceptable salt thereof. The kit may further include a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions typically included in commercial packaging of therapeutic agents, which contain information about the indications, usage, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic agents. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container may hold a compound of the present invention or a pharmaceutically acceptable salt thereof, or a formulation thereof, effective for treating a condition, and may have a sterilization access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound of the present invention or a pharmaceutically acceptable salt thereof. Alternatively, or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutical diluent, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, or dextrose solution. The article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0284] In another embodiment, the kit is suitable for delivery of a solid oral form (e.g., a tablet or capsule) of a compound of the present invention or a pharmaceutically acceptable salt thereof. Such a kit can contain multiple unit doses. An example of such a kit is a "blister pack." Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms.

[0285] Additional Embodiments Additional embodiments are provided herein below.

[0286] Embodiment 1: A compound of formula (I): TIFF2025026853000086.tif68170 or a pharmaceutically acceptable salt thereof. [In the formula, R1 is an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the K-Ras G12C mutant protein; R2 is H, OH, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, cyclopropyl, and —NHR (where R is C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkanoyl, C 1~6 Hydroxyalkanoyl, C 1~6 Cyanoalkyl, C 1~6 Alkylamino, -(C 1~6 alkylenyl)NH(CH3)-(C 1~6 ) alkylenyl) N(CH3)2, and -(C 1~3 ) alkylenyl(3- to 7-membered heterocyclyl) R3 and R4 are each H, NH2, halo, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 1~6 independently selected from the group consisting of alkylamino, and cyclopropyl; R5 is H, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 1~6 Alkylamino, and C 3~7 cycloalkyl; wherein at least one of R2, R3, R4, and R5 is other than H; or R2 and R3, R3 and R4, or R4 and R5, together with the atom to which they are attached, each represent 1 to 4 substituents (wherein each substituent is independently OH, NH2, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 haloalkoxy), C 3~7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6~14 forming an aryl or a 5- to 10-membered heteroaryl; Each X optionally contains 1 to 4 substituents, where each substituent is independently selected from OH, NH, halo, cyano, carboxy, carbamoyl, C 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 and hydroxyalkyl, and 4- to 7-membered heterocyclyl, and two geminal substituents taken together form C 3~7 optionally substituted with NH, C, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~7 selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is selected from the group consisting of -L-Y1 or Y1; Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents 1~6 Alkyl, C1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Alkyl-substituted C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Dialkylamino-substituted C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y 1a independently, halo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkoxy; L is a bond, O, S, and N(L a ) selected from the group consisting of L a is hydrogen and C 1~3 is selected from the group consisting of alkyl, U is C(R 6a ) and V is C(R6b ) and W is C(R 6c ) or N, R 6a , R 6b , and R 6c each independently represents H, OH, NH, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 C substituted with alkyl, 4- to 10-membered heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2.

[0287] Embodiment 2: The compound of embodiment 1 having formula (II): TIFF2025026853000087.tif77170 or a pharmaceutically acceptable salt thereof. [In the formula, R2 is H, OH, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, cyclopropyl, and —NHR (where R is C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkanoyl, C 1~6 Hydroxyalkanoyl, C 1~6 Cyanoalkyl, C 1~6 Alkylamino, -(C1~6 alkylenyl)NH(CH3)-(C 1~6 ) alkylenyl) N(CH3)2, and -(C 1~3 ) alkylenyl(3- to 7-membered heterocyclyl) R3 and R4 are each H, NH2, halo, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 1~6 independently selected from the group consisting of alkylamino, and cyclopropyl; R5 is H, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 1~6 Alkylamino, and C 3~7 cycloalkyl; wherein at least one of R2, R3, R4, and R5 is other than H; or R2 and R3, R3 and R4, or R4 and R5, together with the atom to which they are attached, each represent 1 to 4 substituents (wherein each substituent is independently OH, NH2, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 haloalkoxy), C 3~7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6~14 forming an aryl or a 5- to 10-membered heteroaryl; R7 is selected from the group consisting of H, cyano, and halo; R8 and R9 are each selected from the group consisting of H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 independently selected from the group consisting of hydroxyalkyl, cyano, and halo (C1~6 Alkyl is methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), alkyl or aryl sulfonate leaving group, C 1~6 Alkanoylamino, C 1~6 Alkoxy, C 1~6 Alkylamino, C 1~6 Alkyl sulfonyl amino, C 6~12 Dialkylamino, and C 1~6 optionally substituted with one substituent selected from the group consisting of haloalkoxy; or R7 and R8 together form a triple bond with the carbon to which they are attached, or R7 and R8 together with the carbon to which they are each attached form a C 3~7 Forms a cycloalkenyl, R9 is H, C 1~6 Alkyl, C 1~6 selected from the group consisting of haloalkyl, cyano, and halo (C 1~6 Alkyl is C 1~6 Alkanoylamino, C 1~6 Alkoxy, C 1~6 Alkylamino, C 1~6 Alkyl sulfonyl amino, C 6~12 Dialkylamino, and C 1~6 optionally substituted with one substituent selected from the group consisting of haloalkoxy; Each X optionally contains 1 to 4 substituents, where each substituent is independently selected from OH, NH, halo, cyano, carboxy, carbamoyl, C 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 and hydroxyalkyl, and 4- to 7-membered heterocyclyl, and two geminal substituents taken together form C 3~7 optionally substituted with NH, C, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; 1~6 Alkoxy, C1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~7 selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is selected from the group consisting of -L-Y1 or Y1; Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Alkyl-substituted C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Dialkylamino-substituted C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y 1a independently, halo, C 1~6 Alkyl, C 1~6Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkoxy; L is a bond, O, S, and N(L a ) selected from the group consisting of L a is hydrogen and C 1~3 is selected from the group consisting of alkyl, U is C(R 6a ) and V is C(R 6b ) and W is C(R 6c ) or N, R 6a , R 6b , and R 6c each independently represents H, OH, NH, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 C substituted with alkyl, 4- to 10-membered heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2.

[0288] Embodiment 3: The compound of embodiment 1 having formula (III): TIFF2025026853000088.tif68170 or a pharmaceutically acceptable salt thereof. [In the formula, R2 is H, OH, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, cyclopropyl, and —NHR (where R is C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkanoyl, C 1~6 Hydroxyalkanoyl, C 1~6 Cyanoalkyl, C 1~6 Alkylamino, -(C 1~6 alkylenyl)NH(CH3)-(C 1~6 ) alkylenyl) N(CH3)2, and -(C 1~3 ) alkylenyl(3- to 7-membered heterocyclyl) R3 and R4 are each H, NH2, halo, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 1~6 independently selected from the group consisting of alkylamino, and cyclopropyl; R5 is H, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 1~6 Alkylamino, and C 3~7 cycloalkyl; wherein at least one of R2, R3, R4, and R5 is other than H; or R2 and R3, R3 and R4, or R4 and R5, together with the atom to which they are attached, each represent 1 to 4 substituents (wherein each substituent is independently OH, NH2, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 haloalkoxy), C 3~7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6~14 forming an aryl or a 5- to 10-membered heteroaryl; R 10 is R 10a and -C(O)-R 10a is selected from the group consisting of R 10a is selected from the group consisting of oxiranyl and aziridinyl; Each X optionally contains 1 to 4 substituents, where each substituent is independently selected from OH, NH, halo, cyano, carboxy, carbamoyl, C 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 and hydroxyalkyl, and 4- to 7-membered heterocyclyl, and two geminal substituents taken together form C 3~7 optionally substituted with NH, C, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~7 selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is selected from the group consisting of -L-Y1 or Y1; Y1 is H, NH2, halo, cyano, carbamoyl, C2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Alkyl-substituted C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Dialkylamino-substituted C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y 1a independently, halo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkoxy; L is a bond, O, S, and N(L a) selected from the group consisting of L a is hydrogen and C 1~3 is selected from the group consisting of alkyl, U is C(R 6a ) and V is C(R 6b ) and W is C(R 6c ) or N, R 6a , R 6b , and R 6c each independently represents H, OH, NH, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 C substituted with alkyl, 4- to 10-membered heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2.

[0289] Embodiment 4: R2 is selected from the group consisting of NH2 and -NHR, and R is C 1~6 The compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0290] Embodiment 5: The compound of any one of embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is NH2.

[0291] Embodiment 6: R3 and R4 are independently H, halo, C 1~6 Alkyl, C 1~6 The compound of any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of haloalkyl, and cyclopropyl.

[0292] Embodiment 7: R5 is H, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, and C 3~7 7. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: cycloalkyl.

[0293] Embodiment 8: R 5 C 1~3 The compound of any one of embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein:

[0294] Embodiment 9: A compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R5 is CF3 and R2 is NH2.

[0295] Embodiment 10: A compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R5 is cyclopropyl.

[0296] Embodiment 11: R4 and R5, together with the atom to which they are attached, each represent 1-4 substituents, wherein each substituent is independently selected from OH, NH2, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 haloalkoxy), C 3~7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6~14 aryl, or 5- to 10-membered heteroaryl; or a pharmaceutically acceptable salt thereof.

[0297] Embodiment 12: R4 and R5, together with the atom to which they are attached, each represent 1-4 substituents, wherein each substituent is independently selected from OH, NH2, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 C optionally substituted with (selected from the group consisting of haloalkoxy) 6~14 aryl-forming compound of embodiment 11, or a pharmaceutically acceptable salt thereof.

[0298] Embodiment 13: R4 and R5, together with the atom to which they are attached, each represent 1-4 substituents, wherein each substituent is independently selected from OH, NH2, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 or a pharmaceutically acceptable salt thereof.

[0299] Embodiment 14: The compound of embodiment 13, or a pharmaceutically acceptable salt thereof, wherein C6 aryl is unsubstituted.

[0300] Embodiment 15: The compound of embodiment 13, or a pharmaceutically acceptable salt thereof, wherein C6 aryl is substituted with 1 to 4 substituents, wherein each substituent is independently halo.

[0301] Embodiment 16: R2 is H, OH, NH2, halo, C 1~6 Alkyl, C 1~6 haloalkyl, cyclopropyl, and -NHR (where R is a linear C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkanoyl, C 1~6 Hydroxyalkanoyl, C 1~6 Cyanoalkyl, C 1~6 Alkylamino, -(C1~6 alkylenyl)NH(CH3)-(C 1~6 ) alkylenyl) N(CH3)2, and -(C 1~3 ) alkylenyl(3- to 7-membered heterocyclyl) R3 and R4 are each H, NH2, halo, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, and C 1~6 alkylamino; R5 is H, Cl, Br, I, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 1~6 Alkylamino, and C 3~7 cycloalkyl; At least two of R2, R3, R4, and R5 are other than H, or R2 and R3, R3 and R4, or R4 and R5, together with the atom to which they are attached, each represent 1 to 4 substituents (wherein each substituent is independently OH, NH2, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, and C 1~3 haloalkoxy), C 3~7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or C 6~14 forming an aryl, Each X optionally contains 1 to 4 substituents, where each substituent is independently selected from OH, NH, halo, cyano, carboxy, carbamoyl, C 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 and hydroxyalkyl, and 4- to 7-membered heterocyclyl, and two geminal substituents taken together form C 3~7 optionally substituted with NH, C, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~7 selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is selected from the group consisting of -L-Y1 or Y1; Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Alkyl-substituted C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Dialkylamino-substituted C 3~7 Cycloalkyl, C1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y 1a independently, Halo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkoxy; L is a bond, O, S, and N(L a ) selected from the group consisting of L a is hydrogen and C 1~3 is selected from the group consisting of alkyl, U is C(R 6a ) and V is C(R 6b ) and W is C(R 6c ) or N, R 6a , R 6b , and R 6c each independently represents H, OH, NH2, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 C substituted with alkyl, 4- to 10-membered heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; The compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein n is selected from the group consisting of 0, 1, and 2.

[0302] Embodiment 17: A compound of formula (I) having formula (IV): TIFF2025026853000089.tif65170 or a pharmaceutically acceptable salt thereof. [In the formula, R1 is an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the K-Ras G12C mutant protein; Each X optionally contains 1 to 4 substituents, where each substituent is independently selected from OH, NH, halo, cyano, carboxy, carbamoyl, C 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 and hydroxyalkyl, and 4- to 7-membered heterocyclyl, and two geminal substituents taken together form C 3~7 optionally substituted with NH, C, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 3~7 selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is selected from the group consisting of -L-Y1 or Y1; Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Alkyl-substituted C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Dialkylamino-substituted C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y 1a independently, Halo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, C 1~6 haloalkoxy; L is a bond, O, S, and N(L a ) selected from the group consisting of L a is hydrogen and C 1~3 is selected from the group consisting of alkyl, U is C(R 6a ) and V is C(R 6b ) and W is C(R 6c ) or N, R 6a , R 6b , and R 6c each independently represents H, OH, NH, halo, cyano, carbamoyl, C 2~6 Alkenyl, C 1~6 Alkoxy, C 1~6 C substituted with alkyl, 4- to 10-membered heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkylsulfanyl, C 1~6 Alkylsulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkynyl, C 1~6 Alkylamino, C 6~14 Aryl, C 1~6 Aminoalkyl, C 1~6 Carbamoylalkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2; R 11 teeth, TIFF2025026853000090.tif239170TIFF2025026853000091.tif182170.]

[0303] Embodiment 18: Y is Y1, and Y1 is H, C 1~6 Alkyl, and C 1~618. The compound of any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of haloalkyl.

[0304] Embodiment 19: Y is -L-Y1, L is O and N(L a ) selected from the group consisting of L a is H, Y1 is C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Dialkylamino-substituted C 3~7 selected from the group consisting of cycloalkyl and 4- to 10-membered heterocyclyl substituted with methyl; Each Y 1a independently, Halo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkoxy, 18. A compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof.

[0305] Embodiment 20: L is N(L a ) and L a is H and Y1 is C 1~6 Alkyl or C 1~6 C substituted with dialkylamino substituents 1~620. The compound of embodiment 19, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0306] Embodiment 21: L is O, Y1 is 1 to 4 Y 1a C substituted with 4- to 10-membered heterocyclyl optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 Dialkylaminocyclopropyl-substituted C 1~6 Alkyl, C 1~6 Dialkylamino-substituted C 3~7 selected from the group consisting of cycloalkyl and 4- to 10-membered heterocyclyl substituted with methyl; Each Y 1a independently, Halo, C 1~6 Alkyl, C 1~6 Alkoxy, 3- to 7-membered heterocyclyl, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Haloalkyl, oxo, hydroxy, NH2, cyano, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkoxy, 20. The compound of embodiment 19, or a pharmaceutically acceptable salt thereof.

[0307] Embodiment 22: Y1 is a C substituted with a 4- to 10-membered methylheterocyclyl substituent. 1~6 20. The compound of embodiment 19, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0308] Embodiment 23: Y is 20. The compound of embodiment 19, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: TIFF2025026853000092.tif236170TIFF2025026853000093.tif145170.

[0309] Embodiment 24: Y is TIFF2025026853000094.tif20170 or a pharmaceutically acceptable salt thereof.

[0310] Embodiment 25:R 11 but TIFF2025026853000095.tif101170 or a pharmaceutically acceptable salt thereof.

[0311] Embodiment 26:R 11 but TIFF2025026853000096.tif25170 or a pharmaceutically acceptable salt thereof.

[0312] Embodiment 27:R 11 but TIFF2025026853000097.tif24170 or a pharmaceutically acceptable salt thereof.

[0313] Embodiment 28:R 6a The compound of any one of embodiments 1-27, wherein is H; or a pharmaceutically acceptable salt thereof.

[0314] Embodiment 29:R 6b H, halo, C 1~6 Alkoxy, C 1~6 Alkylsulfonyl, C 1~6 Haloalkyl, C 3~7 Cycloalkyl, C 1~6 The compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of haloalkylthio, and 4- to 10-membered heterocyclyl.

[0315] Embodiment 30:R 6b is hydrogen, halo, or C 1~3The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

[0316] Embodiment 31: W is C(R 6c ) and R 6c 31. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or halo.

[0317] Embodiment 32: W is C(R 6c ) and R 6c 32. The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein is halo.

[0318] Embodiment 33: A compound of any one of embodiments 1 to 32, or a pharmaceutically acceptable salt thereof, wherein X is 4- to 7-membered heterocyclyl.

[0319] Embodiment 34: X is 1 to 4 substituents, each substituent independently being cyano, C 1~6 Alkyl, C 1~6 Cyanoalkyl, and C 1~6 or a pharmaceutically acceptable salt thereof. The compound of any one of embodiments 1-32, wherein R is 4-7 membered heterocyclyl substituted with R, ...

[0320] Embodiment 35: X is TIFF2025026853000098.tif126170, or a pharmaceutically acceptable salt thereof.

[0321] Embodiment 36: X is TIFF2025026853000099.tif79170, or a pharmaceutically acceptable salt thereof.

[0322] Embodiment 37: X is TIFF2025026853000100.tif76170, or a pharmaceutically acceptable salt thereof.

[0323] Embodiment 38: X is TIFF2025026853000101.tif29170 or a pharmaceutically acceptable salt thereof.

[0324] Embodiment 39: A compound of any one of embodiments 1 to 38, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0325] Embodiment 40: R1 is TIFF2025026853000102.tif80170, or a pharmaceutically acceptable salt thereof. [In the formula, R 12 is C 1~6 Alkanoyl, C 1~6 Alkyl, and C 1~6 alkylsulfonyl; R 13 is H, C 1~6 Alkyl, and C 1~6 haloalkyl; R 13a is the halo, R 14 is a halo.]

[0326] Embodiment 41: R1 is TIFF2025026853000103.tif35170 or a pharmaceutically acceptable salt thereof.

[0327] Embodiment 42:R 1 but TIFF2025026853000104.tif19170 or a pharmaceutically acceptable salt thereof.

[0328] Embodiment 43: R7 is selected from the group consisting of H, cyano, and halo; R8 and R9 are each selected from H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 independently selected from the group consisting of hydroxyalkyl, cyano, and halo (C 1~6 Alkyl is methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), alkyl or aryl sulfonate leaving group, C 1~6 Alkanoylamino, C 1~6 Alkoxy, C 1~6 Alkylamino, C 1~6 Alkyl sulfonyl amino, C 6~12 Dialkylamino, and C 1~6 haloalkoxy), or a pharmaceutically acceptable salt thereof.

[0329] Embodiment 44: 20. The compound of embodiment 1 or 17, having a formula selected from the group consisting of: TIFF2025026853000105.tif204170TIFF2025026853000106.tif55170, or a pharmaceutically acceptable salt thereof.

[0330] Embodiment 45: The compound of embodiment 44, having a formula selected from the group consisting of Formula (Ib) or (Il), or a pharmaceutically acceptable salt thereof.

[0331] Embodiment 46: A compound of formula (IV) 42. The compound of any one of embodiments 17-41, or a pharmaceutically acceptable salt thereof, comprising a formula selected from the group consisting of: TIFF2025026853000107.tif120170TIFF2025026853000108.tif122170.

[0332] Embodiment 47: The compound of embodiment 46, wherein the compound of formula (IV) comprises a compound of formula (IVa), (IVb), (IVd), or (IVg) or a pharmaceutically acceptable salt thereof:

[0333] Embodiment 48: The compound of embodiment 46, wherein the compound of formula (IV) comprises a compound of formula (IVa) or (IVb), or a pharmaceutically acceptable salt thereof:

[0334] Embodiment 49: The compound of embodiment 46, wherein the compound of formula (IV) comprises a compound of formula (IVd) or (IVg), or a pharmaceutically acceptable salt thereof:

[0335] Embodiment 50: R7 and R8 together form a triple bond with the carbon to which they are attached, or R7 and R8 together with the carbon to which they are each attached form a C10 group optionally substituted with one or two halo substituents. 3~7 Forms a cycloalkenyl, R9 is H, C 1~6 Alkyl, C 1~6 selected from the group consisting of haloalkyl, cyano, and halo (C 1~6 Alkyl is C 1~6 Alkanoylamino, C 1~6 Alkoxy, C 1~6 Alkylamino, C 1~6 Alkyl sulfonyl amino, C 6~12 Dialkylamino, and C 1~6 haloalkoxy), or a pharmaceutically acceptable salt thereof.

[0336] Embodiment 51: The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein R7, R8, and R9 are each H.

[0337] Embodiment 52: A compound as provided in Table 1, or a pharmaceutically acceptable salt thereof.

[0338] Embodiment 53: A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 52, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0339] Embodiment 54: The pharmaceutical composition of embodiment 53, wherein the pharmaceutical composition is formulated for oral administration.

[0340] Embodiment 55: The pharmaceutical composition of embodiment 53, wherein the pharmaceutical composition is formulated for injection.

[0341] Embodiment 56: A method for treating cancer, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of embodiments 1 to 52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of embodiments 53 to 55.

[0342] Embodiment 57: The method of embodiment 56, wherein the individual is a human.

[0343] Embodiment 58: The method of embodiment 55 or 56, wherein the administering is via the oral route.

[0344] Embodiment 59: The method of embodiment 55 or 56, wherein administering is via injection.

[0345] Embodiment 60: The method of any one of embodiments 56 to 59, wherein the cancer is mediated by a K-Ras G12C mutation.

[0346] Embodiment 61: The method of any one of embodiments 56 to 60, wherein the cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

[0347] Embodiment 62: The method of any one of embodiments 56 to 61, wherein the cancer is lung adenocarcinoma.

[0348] Embodiment 63: A method for regulating the activity of a K-Ras G12C mutant protein, comprising reacting the mutant protein with a compound described in any one of embodiments 1 to 52 or a pharmaceutically acceptable salt thereof.

[0349] Embodiment 64: A method of inhibiting proliferation of a cell population, comprising contacting the cell population with a compound of any one of embodiments 1 to 52, or a pharmaceutically acceptable salt thereof.

[0350] Embodiment 65: The method of Example 64, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0351] Embodiment 66: A method for treating a disease mediated by K-Ras G12C mutation in an individual in need thereof, comprising: determining whether an individual has a mutation; If the individual is determined to have a mutation, administering to the individual a therapeutically effective amount of a compound of any one of embodiments 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of embodiments 53-55; A method comprising:

[0352] Embodiment 67: The method of embodiment 66, wherein the disease is cancer.

[0353] Embodiment 68: The method of embodiment 67, wherein the cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

[0354] Embodiment 69: The method of embodiment 66, wherein the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer.

[0355] Embodiment 70: The method of any one of embodiments 66 to 69, wherein the cancer is lung adenocarcinoma.

[0356] Embodiment 71: A method for preparing a labeled K-Ras G12C mutant protein, comprising reacting a K-Ras G12C mutant protein with a labeled compound according to any one of embodiments 1 to 52 or a pharmaceutically acceptable salt thereof to obtain a labeled K-Ras G12C mutant protein.

[0357] Embodiment 72: A method of inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of embodiments 1 to 52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of embodiments 53 to 55.

[0358] Embodiment 73: Use of a compound of any one of embodiments 1 to 52, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

[0359] Embodiment 74: The use of embodiment 73, wherein the medicament is formulated for oral administration.

[0360] Embodiment 75: The use of embodiment 73, wherein the medicament is formulated for injection.

[0361] Embodiment 76: The use of any one of embodiments 73 to 75, wherein the cancer is mediated by a K-Ras G12C mutation.

[0362] Embodiment 77: The use according to any one of embodiments 73 to 76, wherein the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

[0363] Embodiment 78: The use according to any one of embodiments 73 to 76, wherein the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer.

[0364] Embodiment 79: The use according to any one of embodiments 73 to 78, wherein the cancer is lung adenocarcinoma.

[0365] Embodiment 80: Use of a compound of any one of embodiments 1 to 52, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0366] Embodiment 81: A compound according to any one of embodiments 1 to 52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 53 to 55, for use in a method of treatment of the human or animal body by therapy.

[0367] Embodiment 82: A compound according to any one of embodiments 1 to 52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 53 to 55, for use in a method for treating cancer.

[0368] Embodiment 83: The compound of embodiment 82, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the cancer is mediated by a K-Ras G12C mutation.

[0369] Embodiment 84: The compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 82 or 83, wherein the cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

[0370] Embodiment 85: The compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 82 or 83, wherein the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer.

[0371] Embodiment 86: The compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 82 to 85, wherein the cancer is lung adenocarcinoma.

[0372] Embodiment 87: A compound of any one of embodiments 1 to 52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of embodiments 53 to 55, for use in a method for inhibiting tumor metastasis. [Example]

[0373] The following examples describe the preparation and biological evaluation of compounds within the scope of the present invention. These examples, and the preparations which follow, are provided to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be construed as limiting the scope of the invention, but should be understood as merely illustrative and representative thereof.

[0374] The following abbreviations are used in the examples: ACN - Acetonitrile Ac2O - Acetyl acetate BINAP-(+ / -)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Boc2O-di-tert-butyl dicarbonate BOP-(benzotriazol-1yloxy)tris(dimethylamino)phosphonium hexafluorophosphate CH3Ti(O i -Pr) 3-Methyltitanium(IV) triisopropoxide DBU-1,8-diazabicyclo[5.4.0]undec-7-ene DCE-1,2-dichloroethane DCM - Dichloromethane DIEA or DIPEA-N,N-diisopropylethylamine DMA-N,N-dimethylacetamide DMAc-N,N-dimethylacetamide DMAP-4-dimethylaminopyridine DMF-N,N-dimethylformamide DMSO - Dimethyl sulfoxide EA - Ethyl Acetate EtOAc - Ethyl acetate EtOH - Ethanol HATU-2(7-azabenzothiazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HFIP - Hexafluoroisopropanol HOAc - Acetic acid iPrOAc - Isopropyl acetate KF - Potassium Fluoride KOAc - Potassium Acetate LDA - Lithium Diisopropylamide LiHMDS Lithium bis(trimethylsilyl)amide mCPBA-3-chloroperoxybenzoic acid MeCN-acetonitrile MeI-iodomethane MeOH-methanol MeONa - Sodium Methoxide or Sodium Methanolate MTBE-Methyl tert-butyl ether MW-Microwave NaBH(OAc)3-Sodium triacetoxyborohydride NIS-N-iodosuccinimide P(Cy)3 or PCy3-tricyclohexylphosphine P(t-Bu)3HBF4 - Tri-tert-butylphosphonium tetrafluoroborate Pd / C - Palladium on carbon Pd2(dba)3-tris(dibenzylideneacetone)dipalladium(0) Pd2(dba)3CHCl3-tris(dibenzylideneacetone)dipalladium(0)chloroform [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) or dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) complexed with Pd(dppf)Cl2·CH2Cl2-dichloromethane Pd(PPh3)4-tetrakis(triphenylphosphine)palladium(0) Pd(PPh3)2Cl2 - Bis(triphenylphosphine)palladium(II) dichloride PE-Petroleum Ether PMBCl-4-Methoxybenzyl chloride pTsA-p-toluenesulfonic acid rt - room temperature Sn2(n-Bu)6-hexabutylditin TBSCl-tert-butyldimethylsilyl chloride or tert-butyldimethylchlorosilane [Rh(COD)Cl] 2-chloro(1,5-cyclooctadiene)rhodium(I) dimer TEA - Triethylamine TFA-trifluoroacetic acid or 2,2,2-trifluoroacetic acid THF - Tetrahydrofuran THP-Tetrahydropyran TsOH-p-toluenesulfonic acid Compound Examples Intermediate 1: tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate

[0375] The intermediate, tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate, was prepared according to the following synthetic scheme. TIFF2025026853000109.tif38170Step 1: 7-Bromo-4,6-dichloroquinazoline TIFF2025026853000110.tif25170

[0376] To a solution of 7-bromo-6-chloro-3,4-dihydroquinazolin-4-one (330 g, 1.28 mol) in thionyl chloride (4.0 L) was added N,N-dimethylformamide (4 mL). The mixture was stirred for 12 hours at 80° C. After completion, the resulting mixture was concentrated in vacuo to give 7-bromo-4,6-dichloroquinazoline (350 g, crude) as a yellow solid. LCMS (ESI, m / z): 277.1 [M+H] + . Step 2: tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000111.tif39170

[0377] A solution of 7-bromo-4,6-dichloroquinazoline (330 g, 1.20 mol), tert-butyl piperazine-1-carboxylate (340 g, 1.80 mol, 1.50 equiv.), and DIPEA (586 mL, 3.60 mol) in 1,4-dioxane (3.0 L) was stirred for 60 minutes at 110° C. Upon completion, the solid was collected by filtration, washed with PE (500 mL) and water (500 mL), and then dried to give tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate (446 g, 87.4%) as a pale yellow solid.

[0378] 1H NMR(400 MHz,CDCl3)δ 8.71(s,1H),8.22(s,1H),7.95(s,1H),3.76(dd,J=6.2,3.7 Hz,4H),3.65(dd,J=6.4,3.8 Hz,4H),1.50(s,9H).LCMS(ESI,m / z):429.2 [M+H] + . Intermediate 2: 2((2R)-5-methylpiperidin-2-yl)acetonitrile

[0379] The intermediate compound 2((2R)-5-methylpiperidin-2-yl)acetonitrile was prepared according to the following reaction scheme. TIFF2025026853000112.tif62170Step 1: tert-Butyl (2-((4-methoxybenzyl)amino)propyl)carbamate TIFF2025026853000113.tif26170

[0380] To a solution of tert-butyl N-(2-aminopropyl)carbamate (8.3 g, 47.6 mmol) and p-anisaldehyde (5.8 mL, 47.6 mmol) in 1,2-dichloroethane (175 mL) was added sodium triacetoxyborohydride (15 g, 71.5 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted with DCM and washed with saturated Na2CO3. The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by silica flash chromatography (eluting with iPrOAc / Hep) to give tert-butyl (2-((4-methoxybenzyl)amino)propyl)carbamate (10.2 g, 71%). LCMS (ESI, m / z): 295.5 [M+H] + . Step 2: tert-butyl (E)-(2-((3-cyanoallyl)(4-methoxybenzyl)amino)propyl)carbamate TIFF2025026853000114.tif36170

[0381] A solution of tert-butyl (2-((4-methoxybenzyl)amino)propyl)carbamate (2.9 g, 9.8 mmol), (E)-4-bromobut-2-enenitrile (1.2 mg, 8.22 mmol), and sodium carbonate (2.8 g, 26.3 mmol) in ethanol (30 mL) was stirred at 50° C. for 18 hours. The reaction was concentrated and then diluted with EtOAc. The organic layer was washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by silica flash chromatography (eluting with iPrOAc / Hep) followed by MeOH / DCM to give tert-butyl (E)-(2-((3-cyanoallyl)(4-methoxybenzyl)amino)propyl)carbamate. LCMS (ESI, m / z): 360.6 [M+H] + . Step 3: 2-((2R)-4-(4-methoxybenzyl)-5-methylpiperazin-2-yl)acetonitrile and 2-((2S)-4-(4-methoxybenzyl)-5-methylpiperazin-2-yl)acetonitrile TIFF2025026853000115.tif38170

[0382] A solution of tert-butyl (E)-(2-((3-cyanoallyl)(4-methoxybenzyl)amino)propyl)carbamate (2.3 g, 6.4 mmol) in 5% trifluoroacetic acid in hexafluoro-2-propanol (75 mL, 49.3 mmol) was stirred at room temperature for 18 hours. After the reaction was concentrated, 1,4-dioxane (80 mL) and triethylamine (5.75 mL, 41.1 mmol) were added. The reaction mixture was stirred at room temperature for 60 minutes. The crude product was concentrated and purified by HPLC (NH4OH 5-50%) to give 2-((2R)-4-(4-methoxybenzyl)-5-methylpiperazin-2-yl)acetonitrile (1.05 g, 49%) as HPLC peak 1 and 2-((2S)-4-(4-methoxybenzyl)-5-methylpiperazin-2-yl)acetonitrile (0.76 g, 35%) as HPLC peak 2. Stereochemistry was arbitrarily assigned. LCMS (ESI, m / z): 260.1 [M+H] + . Step 4: 2-((2R)-5-methylpiperazin-2-yl)acetonitrile and 2-((2S)-5-methylpiperazin-2-yl)acetonitrile TIFF2025026853000116.tif22170

[0383] To a solution of 2-((2R)-4-(4-methoxybenzyl)-5-methylpiperazin-2-yl)acetonitrile (600 mg, 2.313 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (17.5 mL, 231.3 mmol). The reaction mixture was stirred at 50° C. for 48 hours. The reaction was concentrated and the crude product was carried on to the next step. LCMS (ESI, m / z): 140.1 [M+H] + . Intermediate 3: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate

[0384] The compound tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate was prepared according to the following synthetic scheme: TIFF2025026853000117.tif89170Step 1: 2-Amino-4-bromo-5-chloro-benzamide TIFF2025026853000118.tif24170

[0385] A solution of 2-amino-4-bromo-5-chlorobenzoic acid (10.0 g, 39.92 mmol), N,N-diisopropylethylamine (15.45 g, 119.77 mmol), and ammonium chloride (6.41 g, 119.77 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 5 minutes. HATU (18.22 g, 47.91 mmol) was then added and stirred at room temperature for 2 hours. Upon completion, the reaction was quenched with water. The reaction mixture was filtered, and the filter cake was collected and dried under vacuum to give 2-amino-4-bromo-5-chlorobenzamide (8 g, 32.0 mmol, 80.3% yield) as a yellow solid. LCMS (ESI, m / z): 248.9 [M+H] + . Step 2: 7-Bromo-2,6-dichloro-quinazolin-4-ol TIFF2025026853000119.tif26170

[0386] To a solution of 2-amino-4-bromo-5-chloro-benzamide (20.0 g, 80.16 mmol) in 1,4-dioxane (100 mL) was added thiophosgene (20.3 g, 176.52 mmol) dropwise with stirring. The resulting solution was stirred for 1 hour at room temperature and then for 1 hour at 105° C. Upon completion, the resulting solution was concentrated under vacuum. The organic layer was washed with diethyl ether to give 7-bromo-2,6-dichloro-quinazolin-4-ol (20 g, 68.043 mmol, 84.9% yield) as a brown solid. LCMS (ESI, m / z): 292.9 [M+H] + . Step 3: tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000120.tif39170

[0387] A solution of 7-bromo-2,6-dichloroquinazolin-4-ol (15.0 g, 51.03 mmol), methanesulfonic anhydride (35.6 g, 204.11 mmol), and N,N-diisopropylethylamine (26.3 g, 203.88 mmol) in dichloromethane (200 mL) was stirred at 25° C. for 0.5 hours. Next, tert-butyl 1-piperazinecarboxylate (14.2 g, 76.24 mmol) and N,N-diisopropylethylamine (13.2 g, 102.33 mmol) were added and stirred at 25° C. for 2 hours. Upon completion, the resulting solution was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 6) to give tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazine-1-carboxylate (13 g, 28.13 mmol, 55.1% yield) as a yellow solid. LCMS (ESI, m / z): 461.0 [M+H] + . Step 4: tert-butyl 4-(7-bromo-6-chloro-2-fluoro-quinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000121.tif40170

[0388] A solution of tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazine-1-carboxylate (15.6 g, 33.75 mmol) and KF (40.0 g, 688.47 mmol) in dimethyl sulfoxide (100 mL) was stirred at 140 °C for 4 hours. Upon completion, the reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (3 / 1) to afford tert-butyl 4-(7-bromo-6-chloro-2-fluoro-quinazolin-4-yl)piperazine-1-carboxylate (10 g, 22.44 mmol, 66.5% yield) as a yellow solid. LCMS (ESI, m / z): 445.0 [M+H] + . Step 5: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000122.tif47170

[0389] Under nitrogen, a solution of tert-butyl 4-(7-bromo-6-chloro-2-fluoro-quinazolin-4-yl)piperazine-1-carboxylate (50.0 g, 104.66 mmol), (6-(bis(4-methoxyphenyl)amino)pyridin-2-yl)boronic acid (90.0 g, 229.44 mmol), potassium phosphate (45.0 g, 212.26 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (11.5 g, 15.73 mmol) in tetrahydrofuran (1.5 L) and water (300 mL) was stirred at 65° C. for 3 hours. Upon completion, the resulting solution was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 6) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate (52 g, 69.77 mmol, 66.7% yield) as a yellow solid. LCMS (ESI, m / z): 713.3 [M+H] + . Step 6: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodopyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000123.tif50170

[0390] A solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate (9.61 g, 12.9 mmol), N-iodosuccinimide (14.45 g, 64.49 mmol), and p-toluenesulfonic acid (0.09 g, 0.52 mmol) in acetonitrile (180 mL) was stirred at 25° C. for 24 hours. Upon completion, the resulting solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 7) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodopyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate (7.71 g, 8.85 mmol, 68.6% yield) as a yellow solid. LCMS (ESI, m / z): 839.2 [M+H] + . Step 7: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000124.tif47170

[0391] To a solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodopyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate (15.35 g, 17.62 mmol) and copper(I) iodide (40.17 g, 211.44 mmol) in N,N-dimethylacetamide (380 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (84.63 g, 440.51 mmol) and stirred at 90° C. for 6 hours. Upon completion, the resulting solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 5) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate (11.8 g, 14.51 mmol, 82.3% yield) as a yellow solid. LCMS (ESI, m / z): 781.3 [M+H] + . Intermediate 4: tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazine-1-carboxylate

[0392] The compound tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazine-1-carboxylate was prepared according to the following synthetic scheme. TIFF2025026853000125.tif33170Step 1: 7-Bromo-6-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione TIFF2025026853000126.tif29170

[0393] A 3000 mL round-bottom flask was charged with 2-amino-4-bromo-5-chlorobenzoic acid (200 g, 0.8 mol) and urea (720 g, 12 mol). The resulting solution was stirred at 160 °C for 12 h. The mixture was cooled to 80 °C, quenched with water, and refluxed for 5–10 min. The mixture was cooled to room temperature, and a precipitate formed. The solid was collected by filtration, washed with HO, and dried in an oven to give 200 g (90%) of crude 7-bromo-6-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione as a yellow solid. The crude material was carried on to the next step without further purification. Step 2: 7-Bromo-2,4,6-trichloroquinazoline TIFF2025026853000127.tif26170

[0394] A solution of 7-bromo-6-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione (200 g, 0.72 mol) and N,N-dimethylaniline (264 g, 2.16 mol) in POCl (750 mL) was stirred at 120 °C for 8 h, concentrated in vacuo, and carried on to the next step without further purification. Step 3: tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazine-1-carboxylate (Intermediate 4) TIFF2025026853000128.tif40170

[0395] A solution of 7-bromo-2,4,6-trichloroquinazoline (200 g, 0.64 mol), tert-butyl piperazine-1-carboxylate (178 g, 0.92 mol), and DIEA (3 equivalents) in 1,4-dioxane (2000 mL) was stirred at 25° C. for 8 hours. The resulting solution was diluted with 2000 mL of water and then extracted with 3×3000 mL of ethyl acetate. The combined organic layers were washed with brine (1×100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified on a silica gel column eluted with ethyl acetate / petroleum ether (1:10) to give 126 g (43%) of tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazine-1-carboxylate as a yellow solid.

[0396] 1H NMR(400 MHz,DMSO-d6)δ 8.20-8.14(m,1H),8.16-8.10(m,1H),3.95-3.87(m,4H),3.60-3.52(m,4H),1.44(s,9H).LCMS(ESI,m / z):461.1 [M+H] + . Intermediate 5: tert-butyl (S)-4-(7-bromo-2,6-dichloroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate TIFF2025026853000129.tif42170

[0397] Compound tert-butyl (S)-4-(7-bromo-2,6-dichloroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (Intermediate 5) was prepared according to the procedure described for Intermediate 4, except that in step 3, tert-butyl (S)-3-methylpiperazine-1-carboxylate was used instead of tert-butylpiperazine-1-carboxylate. Example 1: 1-[4-[7-(3-amino-1-isoquinolyl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0398] The compound 1-[4-[7-(3-amino-1-isoquinolyl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one was prepared according to the following synthetic scheme. TIFF2025026853000130.tif80170 Step 1: tert-Butyl 4-(6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000131.tif49170

[0399] To a solution of tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate (550 mg, 1.29 mmol) and bis(pinacolato)diboron (733 mg, 2.83 mmol) in 1,4-dioxane (25.0 mL) were added potassium acetate (189.3 mg, 0.121 mL, 1.929 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (95.0 mg, 0.129 mmol). The reaction mixture was degassed and then heated at 85°C for 18 hours. The reaction was filtered through Celite and the crude product was purified by silica flash chromatography (eluting with MeOH / DCM) to give tert-butyl 4-(6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperazine-1-carboxylate (514 mg, 84%). LCMS indicates the mass of the boronic acid. LCMS (ESI, m / z): 393.1 [M+H] + . Step 2: tert-butyl 4-(7-(3-aminoisoquinolin-1-yl)-6-chloroquinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000132.tif55170

[0400] A solution of 1-bromoisoquinolin-3-amine (196 mg, 0.85 mmol), tert-butyl 4-[6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate (270 mg, 0.57 mmol), cesium carbonate (371 mg, 1.14 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (47 mg, 0.057 mmol) in acetonitrile (6 mL) and water (3 mL, 157.8 mmol) was degassed. The reaction mixture was heated at 90 °C for 5 h. The reaction was filtered through Celite and the crude product was purified by silica flash chromatography (eluting with MeOH / DCM) to give 235 mg of tert-butyl 4-(7-(3-aminoisoquinolin-1-yl)-6-chloroquinazolin-4-yl)piperazine-1-carboxylate as a yellow solid. LCMS (ESI, m / z): 491.2 [M+H] + . Step 3: 1-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)isoquinolin-3-amine TIFF2025026853000133.tif52170

[0401] To a solution of tert-butyl 4-[7-(3-amino-1-isoquinolyl)-6-chloro-quinazolin-4-yl]piperazine-1-carboxylate (235 mg, 0.48 mmol) in 1,4-dioxane (2.0 mL) was added hydrochloric acid (4 mol / L) in 1,4-dioxane (1.2 mL, 4.8 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was concentrated to give 136 mg of crude 1-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)isoquinolin-3-amine. The crude product was used in the next step without purification. LCMS (ESI, m / z): 391.1 [M+H] + . Step 4: 1-[4-[7-(3-amino-1-isoquinolyl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one TIFF2025026853000134.tif58170

[0402] To a solution of 1-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)isoquinolin-3-amine (136 mg, 0.35 mmol) and acrylic acid (0.026 mL, 0.383 mmol) in N,N-dimethylformamide (3.5 mL) was added N,N-diisopropylethylamine (0.30 mL, 1.74 mmol) and HATU (203 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 15 minutes. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by silica flash chromatography (eluting with MeOH / DCM) and then passed through reverse phase HPLC to give 8 mg of 1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one as a white solid.

[0403] Example 1: 1 H NMR(400 MHz,DMSO-d6)δ 8.70(s,1H),8.21(s,1H),7.84(s,1H),7.63(dd,J=8.5,1.0 Hz,1H),7.47(ddd,J=8.3,6.6,1.2 Hz,1H),7.25(dq,J=8.5,0.9 Hz,1H),7.07(ddd,J=8.5,6.7,1.2 Hz,1H),6.85(dd,J=16.7,10.4 Hz,1H),6.75(d,J=0.9 Hz,1H),6.18(dd,J=16.7,2.4 Hz,1H),6.10(s,2H),5.75(dd,J=10.4,2.4 Hz,1H),4.01-3.73(m,8H).LCMS(ESI,m / z):445.1 [M+H] + . Example 2: 1-[4-[6-chloro-7-(3-methyl-2-pyridyl)quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one TIFF2025026853000135.tif53170

[0404] The same procedure as in Example 1 was carried out, except that in step 2 of Example 2, commercially available 2-bromo-3-methylpyridine was used as an alternative reagent to 1-bromoisoquinolin-3-amine.

[0405] Example 2: 1 H NMR(400 MHz,DMSO-d6)δ 8.69(s,1H),8.51(ddd,J=4.8,1.6,0.7 Hz,1H),8.19(s,1H),7.81(ddd,J=7.8,1.7,0.8 Hz,1H),7.76(s,1H),7.42(dd,J=7.7,4.7 Hz,1H),6.84(dd,J=16.7,10.4 Hz,1H),6.18(dd,J=16.7,2.4 Hz,1H),5.74(dd,J=10.4,2.4 Hz,1H),3.95-3.75(m,8H),2.14(d,J=0.8 Hz,3H).LCMS(ESI,m / z):394.1 [M+H] + . Example 3: 1-[4-[7-(6-amino-1,7-naphthyridin-8-yl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one TIFF2025026853000136.tif59170

[0406] The same procedure as in Example 1, except that in step 2 of Example 3, commercially available 8-bromo-1,7-naphthyridin-6-amine was used as an alternative reagent instead of 1-bromoisoquinolin-3-amine.

[0407] Example 3: 1H NMR(400 MHz,DMSO-d6)δ 8.69(s,1H),8.44(dd,J=4.0,1.6 Hz,1H),8.14(s,1H),8.07(dd,J=8.6,1.6 Hz,1H),7.84(s,1H),7.44(dd,J=8.5,4.0 Hz,1H),6.84(dd,J=16.7,10.5 Hz,1H),6.75(s,1H),6.32(s,2H),6.18(dd,J=16.7,2.4 Hz,1H),5.75(dd,J=10.5,2.3 Hz,1H),3.85(d,J=43.6 Hz,8H).LCMS(ESI,m / z):446.1 [M+H] + . Example 4: 1-[4-[7-(3-amino-2,6-naphthidin-1-yl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one TIFF2025026853000137.tif58170

[0408] The same procedure as in Example 1, except that in step 2 of Example 4, commercially available 1-bromo-2,6-naphthyridin-3-amine was used as an alternative reagent instead of 1-bromoisoquinolin-3-amine.

[0409] Example 4: 1 H NMR(400 MHz,DMSO-d6)δ 9.13(d,J=1.1 Hz,1H),8.71(s,1H),8.23(s,1H),8.09(d,J=5.9 Hz,1H),7.89(s,1H),7.09(dt,J=5.9,1.1 Hz,1H),6.88(t,J=1.1 Hz,1H),6.87-6.79(m,1H),6.49(s,2H),6.18(dd,J=16.7,2.4 Hz,1H),5.75(dd,J=10.4,2.4 Hz,1H),3.99-3.74(m,8H).LCMS(ESI,m / z):446.1 [M+H] + . Example 5: 1-[4-[7-(3-amino-5-chloro-1-isoquinolyl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one TIFF2025026853000138.tif58170

[0410] The same procedure as in Example 1, except that in step 2 of Example 5, commercially available 1-bromo-5-chloro-isoquinolin-3-amine was used as an alternative reagent instead of 1-bromoisoquinolin-3-amine.

[0411] Example 5: 1 H NMR(400 MHz,DMSO-d6)δ 8.70(s,1H),8.22(s,1H),7.88(s,1H),7.67(dd,J=7.4,1.1 Hz,1H),7.25(dt,J=8.5,1.0 Hz,1H),7.03(dd,J=8.5,7.3 Hz,1H),6.98(d,J=1.0 Hz,1H),6.85(dd,J=16.7,10.5 Hz,1H),6.49(s,2H),6.18(dd,J=16.7,2.4 Hz,1H),5.75(dd,J=10.5,2.4 Hz,1H),3.99-3.75(m,8H).LCMS(ESI,m / z):479.1 [M+H] + . Example 6: 1-[4-[7-(3-amino-6-methoxy-1-isoquinolyl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one TIFF2025026853000139.tif56170

[0412] The same procedure as in Example 1, except that in step 2 of Example 6, commercially available 1-bromo-6-methoxyisoquinolin-3-amine was used as an alternative reagent instead of 1-bromoisoquinolin-3-amine.

[0413] Example 6: 1H NMR(400 MHz,DMSO-d6)δ 8.69(s,1H),8.19(s,1H),7.80(s,1H),7.14(d,J=9.2 Hz,1H),6.98(d,J=2.4 Hz,1H),6.84(dd,J=16.7,10.5 Hz,1H),6.74-6.63(m,2H),6.18(dd,J=16.7,2.4 Hz,1H),6.03(s,2H),5.75(dd,J=10.4,2.4 Hz,1H),3.78-3.99(m,11H).LCMS(ESI,m / z):475.1 [M+H] + . Example 7: (S)-1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0414] The compound (S)-1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one was prepared according to the following synthetic scheme. TIFF2025026853000140.tif90170Step 1: 1-(tributylstannyl)isoquinolin-3-amine TIFF2025026853000141.tif26170

[0415] A degassed solution of 1-bromoisoquinolin-3-amine (500 mg, 2.17 mmol), bis(tributyltin) (1.21 mL, 2.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (205 mg, 0.217 mmol), tricyclohexylphosphine (122 mg, 0.435 mmol), and lithium chloride (460 mg, 10.9 mmol) in 1,4-dioxane (10 mL) was added. The reaction mixture was stirred at 115 °C for 18 hours. The reaction mixture was filtered through Celite. The crude product was used in the next step. LCMS (ESI, m / z): 434.1 [M+H] + . Step 2: tert-butyl 4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000142.tif54170

[0416] A degassed solution of 1-tributylstannylisoquinolin-3-amine (300 mg, 0.693 mmol), tert-butyl 4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (617 mg, 1.39 mmol), tetrakis(triphenylphosphine)palladium(0) (80.0 mg, 0.069 mmol), cuprous iodide (39.6 mg, 0.21 mmol), and lithium chloride (124 mg, 2.77 mmol) in N,N-dimethylformamide (14 mL) was added. The reaction mixture was heated in a microwave oven at 150 °C for 15 minutes. The reaction mixture was filtered through Celite and concentrated. The crude product was concentrated and purified by silica flash chromatography (eluting with MeOH / DCM) to give tert-butyl 4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (94 mg, 27%). LCMS (ESI, m / z): 444.9 [M+H] + . Step 3: 1-(6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)isoquinolin-3-amine TIFF2025026853000143.tif52170

[0417] To a solution of tert-butyl 4-[7-(3-amino-1-isoquinolyl)-6-chloro-8-fluoro-quinazolin-4-yl]piperazine-1-carboxylate (410 mg, 0.806 mmol) in 1,4-dioxane (3.0 mL) was added hydrochloric acid (4 mol / L) in 1,4-dioxane (2.0 mL, 8.1 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was concentrated to give 329 mg of crude 1-(6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)isoquinolin-3-amine. The crude product was used in the next step without purification. LCMS (ESI, m / z): 409.1 [M+H] + . Step 4: (S)-1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one TIFF2025026853000144.tif56170

[0418] To a solution of 1-(6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl)isoquinolin-3-amine (329 mg, 0.805 mmol) and N,N-diisopropylethylamine (0.70 mL, 4.02 mmol) in dichloromethane (8.0 mL) was added acrylic acid (0.061 mL, 0.885 mmol) and HATU (468.3 mg, 1.21 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by silica flash chromatography (eluting with MeOH / DCM) to give 1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one, which was passed through chiral SFC purification to give 30.6 mg of (S)-1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one as a white solid (8.2% yield).

[0419] Example 7: 1 H NMR(400 MHz,DMSO-d6)δ 8.73(s,1H),8.08(d,J=1.5 Hz,1H),7.65(dt,J=8.7,0.9 Hz,1H),7.49(ddd,J=8.3,6.7,1.2 Hz,1H),7.25(dt,J=8.6,1.0 Hz,1H),7.09(ddd,J=8.5,6.7,1.1 Hz,1H),6.84(dd,J=16.7,10.4 Hz,1H),6.79(d,J=0.9 Hz,1H),6.24-6.08(m,3H),5.75(dd,J=10.4,2.4 Hz,1H),4.04-3.90(m,4H),3.90-3.74(m,4H).LCMS(ESI,m / z):463.1 [M+H] + . Example 8: (R)-1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one TIFF2025026853000145.tif56170

[0420] Chiral separation of 1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one gave Example 8.

[0421] Example 8: 1H NMR(400 MHz,DMSO-d6)δ 8.73(s,1H),8.08(d,J=1.5 Hz,1H),7.65(dt,J=8.5,0.9 Hz,1H),7.49(ddd,J=8.3,6.7,1.2 Hz,1H),7.25(dt,J=8.6,1.0 Hz,1H),7.09(ddd,J=8.5,6.7,1.2 Hz,1H),6.84(dd,J=16.7,10.5 Hz,1H),6.80-6.76(m,1H),6.23-6.10(m,3H),5.75(dd,J=10.5,2.4 Hz,1H),4.05-3.90(m,4H),3.82(d,J=29.0 Hz,4H).LCMS(ESI,m / z):463.1 [M+H] + . Example 9: (S)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one TIFF2025026853000146.tif56170

[0422] The same procedure as in Example 7, except that in step 1 of Example 9, commercially available 6-chloro-5-(trifluoromethyl)pyridin-2-amine was used as an alternative reagent instead of 1-bromoisoquinolin-3-amine.

[0423] Example 9: 1 H NMR(400 MHz,DMSO-d6)δ 8.70(s,1H),8.01(d,J=1.5 Hz,1H),7.84(d,J=8.9 Hz,1H),7.00(s,2H),6.82(dd,J=16.7,10.4 Hz,1H),6.69-6.61(m,1H),6.17(dd,J=16.7,2.4 Hz,1H),5.74(dd,J=10.4,2.4 Hz,1H),3.92(t,J=5.2 Hz,4H),3.84(s,2H),3.77(s,2H).LCMS(ESI,m / z):481.1 [M+H] + . Example 10: (R)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one TIFF2025026853000147.tif57170

[0424] The same procedure as in Example 7, except that in step 1 of Example 10, commercially available 6-chloro-5-(trifluoromethyl)pyridin-2-amine was used as an alternative reagent instead of 1-bromoisoquinolin-3-amine.

[0425] Example 10: 1 H NMR(400 MHz,DMSO-d6)δ 8.70(s,1H),8.01(d,J=1.6 Hz,1H),7.84(d,J=8.9 Hz,1H),7.00(s,2H),6.82(dd,J=16.7,10.4 Hz,1H),6.69-6.61(m,1H),6.17(dd,J=16.7,2.4 Hz,1H),5.74(dd,J=10.4,2.4 Hz,1H),3.91(dd,J=6.5,4.0 Hz,4H),3.84(s,2H),3.77(s,2H).LCMS(ESI,m / z):481.1 [M+H] + . Example 11: 1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0426] The compound 1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one was prepared according to the following synthetic scheme: TIFF2025026853000148.tif68170Step 1: 2-(5-Fluoro-4-methylpyridin-2-yl)isoindoline-1,3-dione TIFF2025026853000149.tif30170

[0427] A solution of 2-amino-5-fluoro-4-picoline (500 mg, 3.77 mmol) and phthalic anhydride (836 mg, 5.65 mmol) in acetic acid (9.5 mL) was heated at 90° C. for 18 hours. The reaction was quenched with saturated sodium bicarbonate and then extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by silica flash chromatography (eluting with iPrOAc / Hep) to give 2-(5-fluoro-4-methylpyridin-2-yl)isoindoline-1,3-dione (834 mg, 86.5%). LCMS (ESI, m / z): 257.1 [M+H] + . Step 2: 2-(6-chloro-5-fluoro-4-methylpyridin-2-yl)isoindoline-1,3-dione TIFF2025026853000150.tif32170

[0428] To a solution of 2-(5-fluoro-4-methylpyridin-2-yl)isoindoline-1,3-dione (964 mg, 3.76 mmol) in dichloromethane (37 mL) was added 3-chloroperoxybenzoic acid (1.30 g, 7.53 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with saturated aqueous NaSO and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator to give 2-(1,3-dioxoisoindolin-2-yl)-5-fluoro-4-methylpyridine 1-oxide (945 mg, 92.3%).

[0429] A solution of 2-(1,3-dioxoisoindolin-2-yl)-5-fluoro-4-methylpyridine 1-oxide (550 mg, 2.02 mmol) in phosphorus oxychloride (5.0 mL, 50.51 mmol) was heated to 80 °C for 2 h. The reaction was quenched with ice water and saturated NaHCO3, followed by extraction with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by silica flash chromatography (eluting with iPrOAc / Hep) to give 2-(6-chloro-5-fluoro-4-methylpyridin-2-yl)isoindoline-1,3-dione (234 mg, 39.8%). LCMS (ESI, m / z): 290.9 [M+H] + . Step 3: 6-chloro-5-fluoro-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine TIFF2025026853000151.tif25170

[0430] A solution of 2-(6-chloro-5-fluoro-4-methylpyridin-2-yl)isoindoline-1,3-dione (633 mg, 2.18 mmol) in ammonia (7 mol / L) in methanol (3.1 mL) was stirred at 45° C. for 5 hours. The solid was filtered to give 136 mg of crude 6-chloro-5-fluoro-4-methylpyridin-2-amine. The crude product was used in the next step without purification. LCMS (ESI, m / z): 161.1 [M+H] + .

[0431] To a solution of 6-chloro-5-fluoro-4-methyl-pyridin-2-amine (250 mg, 1.56 mmol) in N,N-dimethylacetamide (6.0 mL) was added sodium hydride (60% by weight) in oil (75.0 mg, 1.87 mmol) at 0° C. The reaction was stirred at 0° C. for 30 minutes, after which 4-methoxybenzyl chloride (0.24 mL, 1.71 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by silica flash chromatography (eluted with iPrOAc / Hep) to give 6-chloro-5-fluoro-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (521 mg, 83.4%). LCMS(ESI,m / z):401.9 [M+H] + . Step 4: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-fluoro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000152.tif54170

[0432] A suspension of tert-butyl 4-[6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate (250 mg, 0.527 mmol), 6-chloro-5-fluoro-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (190.0 mg, 0.474 mmol), bis(triphenylphosphine)palladium(II) dichloride (37.3 mg, 0.053 mmol), and potassium fluoride (92 mg, 1.58 mmol) in acetonitrile (5.0 mL) and water (1.0 mL) was degassed. The reaction mixture was heated in a microwave oven at 125 °C for 30 minutes. The reaction mixture was filtered through Celite. The crude product was purified by silica flash chromatography (eluting with MeOH / DCM) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-fluoro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazine-1-carboxylate (145 mg, 38.6%). LCMS (ESI, m / z): 657.1 [M+H] + . Step 5: 6-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)5-fluoro-4-methylpyridin-2-amine TIFF2025026853000153.tif52170

[0433] To a solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-fluoro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazine-1-carboxylate (200 mg, 0.280 mmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (0.106 mL, 1.40 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was concentrated and diluted with EtOAc. The solution was washed with saturated NaHCO. The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator to give 105 mg of crude 6-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)5-fluoro-4-methylpyridin-2-amine. The crude product was used in the next step without purification. LCMS (ESI, m / z): 373.1 [M+H] + . Step 6: 1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one TIFF2025026853000154.tif56170

[0434] To a solution of 6-(6-chloro-4-piperazin-1-yl-quinazolin-7-yl)-5-fluoro-4-methyl-pyridin-2-amine (210 mg, 0.563 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.82 mmol) in dichloromethane (5.5 mL) was added acrylic acid (0.042 mL, 0.620 mmol) and HATU (328 mg, 0.845 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by silica flash chromatography (eluting with MeOH / DCM) and then passed through reverse phase HPLC to give 1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (54.1 mg, 20.7%).

[0435] Example 11: 1 H NMR(400 MHz,DMSO-d6)δ 8.67(s,1H),8.14(s,1H),7.81(s,1H),6.83(dd,J=16.7,10.4 Hz,1H),6.45(dd,J=4.7,1.0 Hz,1H),6.17(dd,J=16.7,2.4 Hz,1H),5.93(s,2H),5.74(dd,J=10.4,2.4 Hz,1H),3.91-3.73(m,8H),2.21(dd,J=1.7,0.9 Hz,3H).LCMS(ESI,m / z):427.1 [M+H] + . Example 12: (R)-1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0436] The compound (R)-1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one was prepared according to the following synthetic scheme. TIFF2025026853000155.tif122170 Step 1: tert-Butyl (R)-4-(7-bromo-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000156.tif43170

[0437] To a solution of tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazine-1-carboxylate (Intermediate 4) (500 mg, 1.08 mmol) and (3R)-4-amino-3-fluoro-2-methyl-butan-2-ol hydrochloride (375 mg, 2.38 mmol) in 2-propanol (10.0 mL) was added N,N-diisopropylethylamine (1.90 mL, 10.8 mmol). The reaction mixture was stirred at 65° C. for 18 hours. The reaction was concentrated, and the crude product was purified by silica flash chromatography (eluting with MeOH / DCM) to give tert-butyl (R)-4-(7-bromo-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-4-yl)piperazine-1-carboxylate (558 mg, 94.3%). LCMS(ESI,m / z):548.1 [M+H] + . Step 2: tert-butyl (R)-4-(6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000157.tif52170

[0438] To a solution of tert-butyl (R)-4-(7-bromo-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-4-yl)piperazine-1-carboxylate (100 mg, 0.183 mmol) and bis(pinacolato)diboron (142 mg, 0.549 mmol) in 1,4-dioxane (3.5 mL), potassium acetate (54 mg, 0.548 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (9.0 mg, 0.0091 mmol) were added. The reaction mixture was degassed and then stirred at 125°C for 1 hour. The reaction was filtered through Celite and concentrated to give 108 mg of crude tert-butyl (R)-4-(6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperazine-1-carboxylate. The crude material was used in the next step without purification. LCMS (ESI, m / z): 595.1 [M+H] + . Step 3: (R)-2-((6-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-7-yl)-5-fluoro-4-methylpyridin-2-yl)carbonyl)benzoic acid TIFF2025026853000158.tif71170

[0439] A solution of tert-butyl (R)-4-(6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperazine-1-carboxylate (108 mg, 0.182 mmol), 2-(6-chloro-5-fluoro-4-methyl-2-pyridyl)isoindoline-1,3-dione (74.0 mg, 0.255 mmol), bis(triphenylphosphine)palladium(II) dichloride (13.0 mg, 0.0182 mmol), and potassium fluoride (42.0 mg, 0.727 mmol) in acetonitrile (2.0 mL) and water (0.5 mL) was degassed. The reaction mixture was heated in a microwave oven at 125 °C for 30 minutes. The reaction was filtered through Celite. The crude product was purified by silica flash chromatography (eluting with MeOH / DCM) to give (R)-2-((6-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-7-yl)-5-fluoro-4-methylpyridin-2-yl)carbonyl)benzoic acid (38 mg, 28.2%). LCMS (ESI, m / z): 741.1 [M+H] + . Step 4: (R)-4-((7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-4-(piperazin-1-yl)quinazolin-2-yl)amino)-3-fluoro-2-2-methylbutan-2-ol TIFF2025026853000159.tif51170

[0440] To a solution of (R)-2-((6-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-7-yl)-5-fluoro-4-methylpyridin-2-yl)carbonyl)benzoic acid (270 mg, 0.365 mmol) and N,N-diisopropylethylamine (0.32 mL, 1.80 mmol) in dichloromethane (3.5 mL) was added HATU (212.0 mg, 0.547 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by silica flash chromatography (eluting with MeOH / DCM) to give tert-butyl 4-[6-chloro-7-[6-(1,3-dioxoisoindolin-2-yl)-3-fluoro-4-methyl-2-pyridyl]-2-[[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]amino]quinazolin-4-yl]piperazine-1-carboxylate (151 mg, 57.3%). LCMS (ESI, m / z): 723.1 [M+H] + .

[0441] A solution of tert-butyl 4-[6-chloro-7-[6-(1,3-dioxoisoindolin-2-yl)-3-fluoro-4-methyl-2-pyridyl]-2-[[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]amino]quinazolin-4-yl]piperazine-1-carboxylate (190 mg, 0.263 mmol) in ammonia (7 mol / L) in methanol (1.90 mL, 13.2 mmol) was stirred for 2 hours at 45° C. The reaction was concentrated, and the crude product was carried on to the next step without further purification.

[0442] To a solution of tert-butyl 4-[7-(6-amino-3-fluoro-4-methyl-2-pyridyl)-6-chloro-2-[[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]amino]quinazolin-4-yl]piperazine-1-carboxylate (156 mg, 0.263 mmol) in 1,4-dioxane (1.0 mL) was added hydrochloric acid (4 mol / L) in 1,4-dioxane (0.65 mL, 2.63 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to give 129 mg of crude (R)-4-((7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-4-(piperazin-1-yl)quinazolin-2-yl)amino)-3-fluoro-2-2-methylbutan-2-ol. The crude product was used in the next step without purification. LCMS (ESI, m / z): 493.1 [M+H] + . Step 5: (R)-1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one TIFF2025026853000160.tif56170

[0443] To a solution of (R)-4-((7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-4-(piperazin-1-yl)quinazolin-2-yl)amino)-3-fluoro-2-2-methylbutan-2-ol (129 mg, 0.262 mmol) and N,N-diisopropylethylamine (0.23 mL, 1.31 mmol) in dichloromethane (2.5 mL) was added acrylic acid (0.020 mL, 0.290 mmol) and HATU (153 mg, 0.393 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was purified by silica flash chromatography (eluting with MeOH / DCM) and then passed through reverse phase HPLC to give (R)-1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (25 mg, 17.3%).

[0444] Example 12: 1 H NMR(400 MHz,DMSO-d6)δ 7.84(s,1H),7.25(d,J=58.3 Hz,2H),6.84(dd,J=16.7,10.5 Hz,1H),6.41(dd,J=4.7,1.0 Hz,1H),6.16(dd,J=16.7,2.4 Hz,1H),5.88(s,2H),5.73(dd,J=10.4,2.4 Hz,1H),4.77(s,1H),4.36(s,1H),3.90-3.59(m,10H),2.19(dd,J=1.7,0.8 Hz,3H),1.20-1.09(m,6H).LCMS(ESI,m / z):526.2 [M+H] + . Example 13: 1-(4-(7-(6-amino-3,4-dimethylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperidin-1-yl)prop-2-en-1-one TIFF2025026853000161.tif55170

[0445] The same procedure as in Example 11, except that in step 1 of Example 12, commercially available 4,5-dimethylpyridin-2-amine was used instead of 2-amino-5-fluoro-4-picoline as an alternative reagent.

[0446] Example 13: 1 H NMR(400 MHz,DMSO-d6)δ 8.66(s,1H),8.12(s,1H),7.64(s,1H),6.83(dd,J=16.7,10.5 Hz,1H),6.40-6.36(m,1H),6.17(dd,J=16.7,2.4 Hz,1H),5.79-5.69(m,3H),3.90-3.74(m,8H),2.18(d,J=0.8 Hz,3H),1.83(s,3H).LCMS(ESI,m / z):423.1 [M+H] + . Example 14: 1-(4-(7-(6-amino-3-chloro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one TIFF2025026853000162.tif56170

[0447] The same procedure as in Example 11, except that in step 1 of Example 13, commercially available 2-amino-5-chloro-4-picoline was used as an alternative reagent instead of 2-amino-5-fluoro-4-picoline.

[0448] Example 14: 1 H NMR(400 MHz,DMSO-d6)δ 8.67(s,1H),8.14(s,1H),7.72(s,1H),6.83(dd,J=16.7,10.5 Hz,1H),6.51(d,J=0.9 Hz,1H),6.23-6.14(m,3H),5.74(dd,J=10.4,2.4 Hz,1H),3.83(dd,J=39.2,5.3 Hz,8H),2.28(d,J=0.7 Hz,3H).LCMS(ESI,m / z):443.1 [M+H] + . Example 15: 1-(4-(7-(6-amino-3-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one TIFF2025026853000163.tif74170 Step 1: tert-Butyl 4-(7-(6-amino-3-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000164.tif40170

[0449] Under nitrogen, a solution of tert-butyl 4-[6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate (2.5 g, 5.2 mmol), 6-bromo-5-methylpyridin-2-amine (1 g, 5.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (432 mg, 0.52 mmol), sodium hydroxide (430 mg, 10.75 mmol) in 1,4-dioxane (15 mL) and water (2 mL) was stirred at 100 °C for 2 hours. Upon completion, the solution was diluted with water (30 mL) and extracted with ethyl acetate (3 × 50 mL), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10 / 1) to give 1.6 g (67%) of tert-butyl 4-[7-(6-amino-3-methylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazine-1-carboxylate (1.6 g, 3.5 mmol, 67% yield) as a yellow oil. LC-MS (ESI, m / z): 455.2 [M+H] + . Step 2: 6-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)-5-methylpyridin-2-amine TIFF2025026853000165.tif44170

[0450] A solution of tert-butyl 4-[7-(6-amino-3-methylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazine-1-carboxylate (1.5 g, 3.29 mmol) and trifluoroacetic acid (1.12 g, 9.82 mmol) in dichloromethane (20 mL) was stirred for 3 hours at 25° C. After completion, the resulting mixture was concentrated in vacuo to afford 1.8 g (crude) of 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-methylpyridin-2-amine as a brown oil, which was used in the next step without further purification. LC-MS (ESI, m / z): 355.1 [M+H] + . Step 3: 1-[4-[7-(6-amino-3-methylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one TIFF2025026853000166.tif53170

[0451] A solution of 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-methylpyridin-2-amine (600 mg, 1.69 mmol), prop-2-enoic acid (140 mg, 1.94 mmol), HATU (1.3 g, 3.41 mmol), and N,N-diisopropylethylamine (877 mg, 6.78 mmol) in dichloromethane (20 mL) was stirred for 2 hours at 25 °C. Upon completion, the solution was quenched with water (5 mL), diluted with dichloromethane (50 mL), and washed with brine (3 × 10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was further isolated by HPLC using the following conditions: column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: MTBE (10 mM NH3-methanol)-HPLC, mobile phase B: methanol-HPLC; flow rate: 20 mL / min; gradient: 15B to 15B in 27 min; 220 / 254 nm; RT1: 17.672; RT2: 23.294 to give 1-[4-[7-(6-amino-3-methylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one (20.2 mg, 0.048 mmol, 3% yield) as a white solid. LC-MS (ESI, m / z): 409.1 [M+H] + .

[0452] Example 15: 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.68(s,1H),8.23(s,1H),7.76(s,1H),7.48(dd,J=8.4,0.4 Hz,1H),6.88-6.81(m,1H),6.66(d,J=8.4 Hz,1H),6.29(dd,J=16.8,2.0 Hz,1H),5.83(dd,J=10.8,2.0 Hz,1H),4.02(s,4H),3.94(s,4H),2.00(s,3H). Example 16: N-(6-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]-5-methylpyridin-2-yl)acetamide TIFF2025026853000167.tif103170 Step 1: N-(6-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]-5-methylpyridin-2-yl)acetamide TIFF2025026853000168.tif52170

[0453] A solution of 1-[4-[7-(6-amino-3-methylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one (300 mg, 0.73 mmol), acetyl acetate (112 mg, 1.09 mmol), and triethylamine (221 mg, 2.18 mmol) in dichloromethane (20 mL) was stirred for 9 hours at 25 °C. Upon completion, the solution was quenched with water (5 mL), diluted with dichloromethane (50 mL), and washed with brine (3 × 10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was further isolated by HPLC using the following conditions: column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: MTBE (10 mM NH3-methanol)-HPLC, mobile phase B: methanol-HPLC; flow rate: 20 mL / min; gradient: 15B to 15B in 27 min; 220 / 254 nm; RT1: 17.672; RT2: 23.294 to give N-(6-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]-5-methylpyridin-2-yl)acetamide (10.2 mg, 0.023 mmol, 3% yield) as a white solid. LC-MS (ESI, m / z): 451.2 [M+H] + .

[0454] Example 16: 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.68(s,1H),8.22(s,1H),8.13-8.08(m,1H),7.76-7.74(m,2H),6.86-6.79(m,1H),6.27(dd,J=16.8,2.0 Hz,1H),5.80(dd,J=14.4,2.0 Hz,1H),4.00(s,4H),3.92(s,4H),2.16(s,3H),2.13(s,3H). Examples 17a and 17b: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 17a) and 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 17b) TIFF2025026853000169.tif161170Step 1: 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine TIFF2025026853000170.tif23170

[0455] To a solution of 6-bromo-4-methylpyridin-2-amine (30.0 g, 160 mmol) in N,N-dimethylformamide (500 mL) was slowly added sodium hydride (19.0 g, 792 mmol) at 0° C. and stirred at 25° C. for 1 hour. Next, 4-methoxybenzyl chloride (56.0 g, 359 mmol) was added to the reaction and stirred at 25° C. for 2 hours. Upon completion, the reaction was quenched with saturated ammonium chloride solution (500 mL) and diluted with ethyl acetate (2.5 L). The mixture was washed with brine (5×500 mL), and the combined organic layers were dried over NaSO and evaporated in vacuo. The residue was applied to a silica gel column eluting with petroleum ether / ethyl acetate (15%) to give 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (60 g, 140 mmol, 87.5% yield) as an off-white solid. LC-MS: (ESI, m / z): 427.1 [M+H] + . Step 2: N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6-tributylstannyl-pyridin-2-amine TIFF2025026853000171.tif23170

[0456] Under nitrogen, a solution of 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (35.0 g, 82 mmol), hexabutylditin (143.0 g, 247 mmol), tris(dibenzylideneacetone)dipalladium (7.53 g, 8.2 mmol), tricyclohexylphosphine (4.6 g, 16.4 mmol), and lithium chloride (17.3 g, 412 mmol) in 1,4-dioxane (220 mL) was stirred at 110° C. for 5 hours. Upon completion, the reaction was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (10 / 1) to give N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6-tributylstannyl-pyridin-2-amine (45 g, 71 mmol, 86.2% yield) as a red oil. LC-MS: (ESI, m / z): 639.3 [M+H] + . Step 3: 2-Amino-4-bromo-5-chloro-3-fluoro-benzoic acid TIFF2025026853000172.tif29170

[0457] A solution of 2-amino-4-bromo-3-fluorobenzoic acid (100.0 g, 427 mmol) and N-chlorosuccinimide (66.0 g, 494 mmol) in N,N-dimethylformamide (1 L) was stirred at 80° C. for 2 hours. After completion, the system was poured into water (2.0 L), causing a large amount of solid to precipitate. The solid was then collected after filtering. The solid was washed with warm water (1 L). The solid was then dried under an infrared lamp to give 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (100 g, 373 mmol, 87.2% yield) as an off-white solid. LC-MS: (ESI, m / z): 265.9 [M−H] + . Step 4: 7-Bromo-6-chloro-8-fluoroquinazoline-2,4(1H,3H)-dione TIFF2025026853000173.tif28170

[0458] A solution of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (120.0 g, 447 mmol) in urea (806.0 g, 13.4 mol) was stirred at 200 °C for 1.5 hours. Upon completion, the reaction was cooled to 80 °C, and water (1.5 L) was added to the system with stirring for 20 minutes. After filtering, the solid was collected and washed with warm water (1 L). The solid was then dried under an infrared lamp to give 7-bromo-6-chloro-8-fluoroquinazoline-2,4(1H,3H)-dione (120 g, 409 mmol, 91.5% yield) as a light brown solid. LC-MS: (ESI, m / z): 290.9 [M−H] + . Step 5: tert-butyl (3S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate TIFF2025026853000174.tif43170

[0459] A solution of 7-bromo-6-chloro-8-fluoroquinazoline-2,4-diol (65.0 g, 222 mmol) and DMF (500.0 mg, 6.85 mmol) in POCl (1.0 L) was stirred at 110 °C for 60 hours. After complete conversion of the starting material, the resulting mixture was concentrated in vacuo. Next, 1,4-dioxane (1.0 L), N,N-diisopropylethylamine (286.0 g, 2217 mmol), and tert-butyl (3S)-3-methyl-1-piperazinecarboxylate (90.0 g, 449 mmol) were added to the reaction mixture and stirred at 25 °C for 1 hour. After completion, the solvent was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (20%) to give tert-butyl (3S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (65 g, 132 mmol, 59.4% yield) as a yellow solid. LC-MS: (ESI, m / z): 493.0 [M+H] + . Step 6: tert-butyl (3S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate TIFF2025026853000175.tif42170

[0460] A solution of tert-butyl (3S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (30.0 g, 61 mmol) and potassium fluoride (71.0 g, 1224 mmol) in N,N-dimethylacetamide (300 mL) was stirred at 120 °C for 18 hours. After completion, the reaction was cooled to room temperature. Ethyl acetate (1.5 L) was then added to the mixture, and the mixture was washed with water (3 × 500 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (20%) to give tert-butyl (3S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (23 g, 48 mmol, 79.3% yield) as a yellow solid. LC-MS: (ESI, m / z): 477.0 [M+H] + . Step 7: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate TIFF2025026853000176.tif51170

[0461] Under nitrogen, a solution of tert-butyl (3S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (23.0 g, 48 mmol), N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6-tributylstannyl-pyridin-2-amine (62.0 g, 97 mmol), tetrakis(triphenylphosphine)palladium (11.2 g, 9.7 mmol), cuprous iodide (2.8 g, 15 mmol), and lithium chloride (5.0 g, 119 mmol) in 1,4-dioxane (320 mL) was stirred at 120 °C for 16 hours. Upon completion, the reaction was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layers were then combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (30%) to give tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (18.5 g, 25 mmol, 51.6% yield) as a yellow solid. LC-MS: (ESI, m / z): 745.3 [M+H] + . Step 8: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate TIFF2025026853000177.tif52170

[0462] A solution of tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (18.5 g, 25 mmol), p-toluenesulfonic acid (171.0 mg, 0.99 mmol), and N-iodosuccinimide (28.0 g, 125 mmol) in N,N-dimethylformamide (350 mL) was stirred at 25° C. for 5 hours. Upon completion, the reaction was diluted with ethyl acetate (1.5 L) and washed with saturated sodium thiosulfate solution (4×350 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (25%) to give tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (16 g, 18.4 mmol, 74% yield) as a yellow solid. LC-MS: (ESI, m / z): 871.2 [M+H] + . Step 9: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate TIFF2025026853000178.tif51170

[0463] Under nitrogen, a solution of tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (16.0 g, 18.4 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (88.3 g, 460 mmol), and cuprous iodide (42.0 g, 221 mmol) in N,N-dimethylacetamide (400 mL) was stirred at 90° C. for 18 hours. Upon completion, the reaction was diluted with ethyl acetate (2.0 L) and washed with brine (4×350 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (30%) to give tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (12.2 g, 15 mmol, 81.7% yield) as a yellow solid. LC-MS: (ESI, m / z): 813.3 [M+H] + . Step 10: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate TIFF2025026853000179.tif51170

[0464] To a solution of (S)-(1-methylpyrrolidin-2-yl)methanol (4.32 g, 37.5 mmol) in tetrahydrofuran (300 mL), sodium hydride (2.1 g, 87.5 mmol) was slowly added at 0° C. and stirred for 1 hour at 25° C. Next, tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (12.2 g, 15 mmol) was added to the reaction mixture and stirred for 1 hour at 25° C. After completion, the reaction mixture was quenched with methanol (50 mL). The mixture was then concentrated in vacuo and the residue was purified by silica gel flash chromatography eluting with dichloromethane / methanol (6 / 94) to give tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (8.6 g, 9.5 mmol, 63.1% yield) as a brown solid. LC-MS: (ESI, m / z): 908.4 [M+H] + . Step 11: 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2025026853000180.tif51170

[0465] A solution of tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (8.6 g, 9.5 mmol) in trifluoroacetic acid (100 mL) was stirred at 50° C. for 4 hours. Upon completion, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and the pH was adjusted to 9 with N,N-diisopropylethylamine. After concentration in vacuo, the residue was purified directly by reverse-phase chromatography under the following conditions: column: C18 silica gel; mobile phase A: water, B: ACN, B ratio (5% to 40% in 30 min); detector: UV 254 nm to give 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (3.5 g, 6.17 mmol, 65.1% yield) as a yellow solid. LC-MS: (ESI, m / z): 568.2 [M+H] + . Step 12: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 17a), and 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 17b) TIFF2025026853000181.tif65170

[0466] To a solution of 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (2.5 g, 4.4 mmol) and N,N-diisopropylethylamine (2.9 g, 22.5 mmol) in dichloromethane (120 mL) was added acryloyl chloride (359.0 mg, 3.97 mmol) at −78° C. and stirred at −78° C. for 25 minutes. The reaction was quenched with water and extracted with dichloromethane. The organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified directly by reverse-phase chromatography under the following conditions: column: C18 silica gel; mobile phase A: water, B: ACN, proportion of B (5% to 60% in 30 min); detector: UV 254 nm to give 1-[(3S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one (1.3 g, 2.09 mmol, 47.5% yield) as a brown solid.The mixture of diastereoisomers was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IC-3 0.46*5 cm 3 um; mobile phase: (hexane:dichloromethane=3:1) (0.1% DEA):EtOH=50:50; detector: 254 nm; flow rate: 1.0 ml / min; temperature: 25°C to obtain 657.7 mg of 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2yl)methoxy)quinazolin-4-yl)-3-methyl 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 17a) was obtained as a white solid, and 352.1 mg of 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 17b) was obtained as a white solid.

[0467] Example 17a: LC-MS: (ESI, m / z): 622.2 [M+H] + , 1 H NMR:(400 MHz,CDCl3,ppm)δ 7.64(s,1H),6.70-6.55(m,1H),6.48(s,1H),6.42-6.35(m,1H),5.82-5.75(m,1H) ,4.90-4.79(m,2H),4.78-4.40(m,3H),4.35-4.28(m,1H),4.18-4.00(m,1H),3.99- 3.76(m,1H),3.72-3.45(m,2H),3.31-2.98(m,2H),2.81-2.70(m,1H),2.55-2.45( m,6H),2.35-2.25(m,1H),2.11-2.01(m,1H),1.95-1.72(m,3H),1.36-1.34(m,3H).

[0468] Example 17b: LC-MS: (ESI, m / z): 622.2 [M+H] + , 1 H NMR:(400 MHz,CDCl3,ppm)δ 7.63(s,1H),6.70-6.55(m,1H),6.50(s,1H),6.42-6.35(m,1H),5.82-5.75(m,1H),4.8 5-4.70(m,2H),4.78-4.68(m,2H),4.65-4.55(m,1H),4.50-4.40(m,1H),4.30-4.10(m,1 H),4.05-3.75(m,1H),3.80-3.76(m,2H),3.25-3.08(m,2H),2.85-2.75(m,1H),2.60-2 .45(m,6H),2.40-2.25(m,1H),2.15-2.05(m,1H),1.95-1.72(m,3H),1.45-1.32(m,3H). Examples 18a and 18b: (E)-1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4-fluorobut-2-en-1-one, and (E)-1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4-fluorobut-2-en-1-one TIFF2025026853000182.tif91170

[0469] To a solution of 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (500 mg, 0.88 mmol), HATU (401 mg, 1.06 mmol), and N,N-diisopropylethylamine (228 mg, 0.96 mmol) in dichloromethane (25 mL), (E)-4-fluorobut-2-enoic acid (100 mg, 3.97 mmol) was added at 25 ° C., and the mixture was stirred for 0.5 hours. After completion, the reaction was quenched with water and extracted with dichloromethane. The organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel; mobile phase A: water, B: ACN, proportion of B (5% to 60% in 30 min); detector: UV 254 nm to obtain (E)-1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4-fluorobut-2-en-1-one and (E)- A mixture of 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4-fluorobut-2-en-1-one (130 mg, 0.20 mmol, 23% yield) was obtained as a white solid.The mixture of diastereoisomers was separated by preparative chiral HPLC under the following conditions: column: CHIRAL Cellulose-SB, column size: 0.46*10cm; 3um: mobile phase; hexane:EtOH=50:50; flow rate: 1.0mL / min; temperature: 25°C to obtain 32mg of (E)-1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpyridin-2-yl (E)-1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4-fluorobut-2-en-1-one was obtained as a white solid.

[0470] Example 18a: LC-MS: (ESI, m / z): 654.2 [M+H] + , 1 HNMR:(400 MHz,DMSO-d6,ppm)δ 7.82(s,1H),6.85(s,2H),6.83-6.68(m,2H),6.50(s,1H),5.20(d,J=2.8 Hz,1H),5.08(d,J=2.8 Hz,1H),4.75(s,1H),4.41-4.23(m,2H),4.19-3.94(m,3H),3.73-3.65(m,1H),3.43-3.0 7(m,2H),2.96-2.93(m,1H),2.60-2.50(m,1H),2.37-2.36(m,6H),2.18(dd,J=16.4,8.0 Hz,1H),1.99-1.90(m,1H),1.72-1.59(m,3H),1.27(t,J=6.8 Hz,3H).

[0471] Example 18b: LC-MS: (ESI, m / z): 654.2 [M+H] + , 1 HNMR:(400 MHz,DMSO-d6,ppm)δ 7.80(s,1H),6.85(s,2H),6.83-6.68(m,2H),6.50(s,1H),5.20(d,J=2.8 Hz,1H),5.08(d,J=2.8 Hz,1H),4.71(s,1H),4.39-4.23(m,2H),4.20-3.93(m,3H),3.70-3.60(m,1H),3.51-3.0 9(m,2H),2.96-2.93(m,1H),2.60-2.52(m,1H),2.37-2.36(m,6H),2.18(dd,J=16.4,8.0 Hz,1H),1.99-1.90(m,1H),1.72-1.59(m,3H),1.30(t,J=8.0 Hz,3H). Example 19: 1-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one TIFF2025026853000183.tif122170 Step 1: tert-Butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]piperazine-1-carboxylate TIFF2025026853000184.tif50170

[0472] Under nitrogen, a solution of N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6-tributylstannyl-pyridin-2-amine (4.0 g, 6.27 mmol) and tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]piperazine-1-carboxylate (2.31 g, 5.02 mmol), tetrakis(triphenylphosphine)palladium (0.72 g, 0.63 mmol), lithium chloride (0.66 g, 15.69 mmol), and cuprous iodide (0.12 g, 0.63 mmol) in 1,4-dioxane (100 mL) was stirred at 120° C. for 3 hours. After completion, the solution was diluted with water (200 mL) and extracted (3 × 50 mL) after completion. The organic layers were then combined and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum, and the residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 20) to give tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]piperazine-1-carboxylate (1.1 g, 1.54 mmol, 24.6% yield) as a yellow oil. LC-MS (ESI, m / z): 713.3 [M+H] + . Step 2: tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-iodo-4-methyl-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate TIFF2025026853000185.tif52170

[0473] A solution of tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]piperazine-1-carboxylate (2 g, 3 mmol) and N-iodosuccinimide (1 g, 3.00 mmol) in acetonitrile (200 mL) was stirred at 50° C. for 4 hours. After completion, the solution was diluted with water (30 mL), extracted with ethyl acetate (4×50 mL), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 20) to give tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-iodo-4-methyl-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate (1.3 g, 1.55 mmol, 656.5% yield) as a yellow oil. LC-MS (ESI, m / z): 839.2 [M+H] +. Step 3: tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate TIFF2025026853000186.tif51170

[0474] Under nitrogen, a solution of tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluorophenyl)-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate (0.1 g, 0.12 mmol), (1,10-phenanthroline)(trifluoromethyl)copper(I) (0.73 g, 2.34 mmol), and cuprous iodide (0.45 g, 2.34 mmol) in N,N-dimethylformamide (5 mL) was stirred at 50 °C for 5 hours. After completion, the solution was diluted with water (30 mL), extracted with ethyl acetate (4 × 350 mL), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 5) to give tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate (60 mg, 0.075 mmol, 64.4% yield) as a yellow solid. LC-MS (ESI, m / z): 781.3 [M+H] + . Step 4: 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2025026853000187.tif49170

[0475] A solution of tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate (0.1 g, 0.13 mmol) in trifluoroacetic acid (5.0 mL) was stirred at 50° C. for 3 hours. After completion, the solution was diluted with water (30 mL), extracted with ethyl acetate (3×50 mL), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with methanol / dichloromethane (1 / 9) to give 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (40 mg, 0.08 mmol, 69.9% yield) as a yellow oil. LC-MS (ESI, m / z): 441.1 [M+H] + . Step 5: 1-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one TIFF2025026853000188.tif58170

[0476] A solution of 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (0.04 g, 0.09 mmol), HATU (0.07 g, 0.18 mmol), and N,N-diisopropylethylamine (0.03 g, 0.26 mmol) in dichloromethane (3 mL) was stirred at −78° C. for 0.5 hours. Acrylic acid (0.01 g, 0.13 mmol) was then added and stirred at −78° C. for 4 hours. Upon completion, the solution was diluted with water (30 mL), extracted with ethyl acetate (3×50 mL), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was further isolated by preparative HPLC under the following conditions: column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: MTBE (10 mM NH3-methanol)-HPLC, mobile phase B: methanol-HPLC; flow rate: 20 mL / min; gradient: 15B to 15B in 27 min; 220 / 254 nm; RT1: 17.672; RT2: 23.294 to give 1-[(3S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one (10 mg, 0.019 mmol, 22.3% yield) as a white solid. LC-MS (ESI, m / z): 509.1 [M+H] + .

[0477] Example 19: 1 H NMR(400 MHz, methanol-d4, ppm)δ 8.67(s,1H),7.92(s,1H),6.89-6.82(m,1H),6.62(s,1H),6.32-6.26(m,1H),5.83-5.80(m,1H),4.56-4.39(m,1H),4.3 8-4.30(m,1H),4.20-4.02(m,1H),3.80-3.52(m,2H),3.33-3.30(m,1H),3.22-3.13(m,1H),2.45(s,3H),1.42(d,J=1.6 Hz,3H). Example 20: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidin-1-yl)quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one TIFF2025026853000189.tif118170 Step 1: tert-Butyl 4-[6-(azetidin-1-yl)-7-bromo-quinazolin-4-yl]piperazine-1-carboxylate TIFF2025026853000190.tif33170

[0478] Under nitrogen, a solution of tert-butyl 4-(7-bromo-6-iodo-quinazolin-4-yl)piperazine-1-carboxylate (5.5 g, 10.59 mmol), azetidine (1.2 g, 21.19 mmol), tris(dibenzylideneacetone)dipalladium (609.15 mg, 1.06 mmol), Xantphos (1.22 g, 2.12 mmol), and cesium carbonate (6.9 g, 21.19 mmol) in 1,4-dioxane (20 mL) was stirred at 80° C. for 2 hours. Upon completion, the solution was diluted with ethyl acetate (200 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (45 / 55) to give tert-butyl 4-[6-(azetidin-1-yl)-7-bromo-quinazolin-4-yl]piperazine-1-carboxylate (1.0 g, 2.24 mmol, 21.1% yield) as a yellow solid. LC-MS (ESI, m / z): 448.1 [M+H] + . Step 2: tert-butyl 4-[6-(azetidin-1-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate TIFF2025026853000191.tif41170

[0479] Under nitrogen, a solution of tert-butyl 4-[6-(azetidin-1-yl)-7-bromo-quinazolin-4-yl]piperazine-1-carboxylate (1.0 g, 2.23 mmol), bis(pinacolato)diboron (5.66 g, 22.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (182.0 mg, 0.22 mmol), and potassium acetate (437.15 mg, 4.46 mmol) in 1,4-dioxane (15 mL) was stirred at 80 °C for 3 hours. Upon completion, the solution was diluted with dichloromethane (100 mL). After filtering, the filtrate was concentrated under reduced pressure. The residue was dissolved in petroleum ether (100 mL). After filtering, the filter cake was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 1) to give tert-butyl 4-[6-(azetidin-1-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate (500 mg, 1.01 mmol, 45.3% yield) as a yellow solid. LC-MS (ESI, m / z): 496.3 [M+H] + . Step 3: tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidin-1-yl)quinazolin-4-yl]piperazine-1-carboxylate TIFF2025026853000192.tif42170

[0480] Under nitrogen, a solution of tert-butyl 4-[6-(azetidin-1-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate (500.0 mg, 1.01 mmol), 6-bromo-5-(trifluoromethyl)pyridin-2-amine (243.24 mg, 1.01 mmol), bis(triphenylphosphine)palladium(II) chloride (70.85 mg, 0.10 mmol), and potassium fluoride (117.07 mg, 2.02 mmol) in acetonitrile (10 mL) and water (2 mL) was stirred at 80° C. for 2 hours. Upon completion, the solution was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with methanol / dichloromethane (3 / 97) to give tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidin-1-yl)quinazolin-4-yl]piperazine-1-carboxylate (280 mg, 0.53 mmol, 52.4% yield) as a yellow solid. LC-MS (ESI, m / z): 530.2 [M+H] + . Step 4: 6-[6-(azetidin-1-yl)-4-piperazin-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)piperidin-2-amine TIFF2025026853000193.tif39170

[0481] A solution of tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidin-1-yl)quinazolin-4-yl]piperazine-1-carboxylate (200.0 mg, 0.38 mmol) and silica gel (1.0 g) in toluene (20 mL) was stirred at 110° C. for 12 hours. After completion, the solution was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with methanol / dichloromethane (1 / 9) to afford 6-[6-(azetidin-1-yl)-4-piperazin-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)piperidin-2-amine (150 mg, 0.35 mmol, 92.5% yield) as a yellow solid. LC-MS (ESI, m / z): 430.2 [M+H] + . Step 5: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidin-1-yl)quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one TIFF2025026853000194.tif44170

[0482] A solution of 6-[6-(azetidin-1-yl)-4-piperazin-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)piperidin-2-amine (150.0 mg, 0.35 mmol), acrylic acid (25.17 mg, 0.35 mmol), HATU (159.37 mg, 0.42 mmol), and N,N-diisopropylethylamine (45 mg, 0.35 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 1 hour. After completion, the solution was diluted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse-phase column chromatography eluting with acetonitrile / water (1 / 1) to give 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidin-1-yl)quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one (5.9 mg, 3.5% yield) as a yellow solid. LC-MS (ESI, m / z): 484.2 [M+H] + .

[0483] Example 20: 1 H NMR(300 MHz,methanol-d4,ppm)δ 8.50(s,1H),7.83(d,J=9.0 Hz,1H),7.54(s,1H),6.91-6.82(m,1H),6.75-6.70(m,2H),6.30(dd,J=16.8,2.0 Hz,1H),5.83(dd,J=10.6,2.0 Hz,1H),3.99-3.81(m,8H),3.78-3.61(m,4H),2.29-2.19(m,2H). Example 21: 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-(1,1-difluoroethyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one TIFF2025026853000195.tif113170 Step 1: tert-Butyl 4-(6-acetyl-7-bromoquinazolin-4-yl)piperazine-1-carboxylate TIFF2025026853000196.tif39170

[0484] Under nitrogen, a solution of tert-butyl 4-(7-bromo-6-iodo-quinazolin-4-yl)piperazine-1-carboxylate (1.8 g, 3.47 mmol), tributyl(1-ethoxyvinyl)tin (2.5 g, 6.93 mmol), and bis(triphenylphosphine)palladium(II) chloride (243.4 mg, 0.35 mmol) in 1,4-dioxane (40 mL) was stirred at 65° C. for 30 hours. Upon completion, hydrochloric acid (40 mL, 2 M) was added to the solution and stirred at 25° C. for 0.5 hours. The solvent was then concentrated under vacuum. The residue was dissolved in water (40 mL), and the pH of the resulting solution was adjusted to 9 with potassium carbonate. Di-tert-butyl dicarbonate (1.67 g, 7.61 mmol) was then added, and the solution was stirred at 25° C. for 2 hours. After completion, the solution was extracted with ethyl acetate (100 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase elution with acetonitrile / water (1:1) to give tert-butyl 4-(6-acetyl-7-bromoquinazolin-4-yl)piperazine-1-carboxylate (1.0 g, 2.30 mmol, 66.3% yield) as a yellow oil. LC-MS: (ESI, m / z): 435.1, 437.1 [M+H] + . Step 2: tert-butyl 4-[7-bromo-6-(1,1-difluoroethyl)quinazolin-4-yl]piperazine-1-carboxylate TIFF2025026853000197.tif39170

[0485] A solution of tert-butyl 4-(6-acetyl-7-bromoquinazolin-4-yl)piperazine-1-carboxylate (1.2 g, 2.8 mmol) in diethylaminosulfur trifluoride (3.6 mL, 27.6 mmol) in chloroform (30 mL) was stirred at 25 °C for 36 hours. After completion, the solution was quenched with water (5 mL) and concentrated in vacuo. The residue was purified by reverse-phase column chromatography with acetonitrile / water (5 / 1) to give tert-butyl 4-[7-bromo-6-(1,1-difluoroethyl)quinazolin-4-yl]piperazine-1-carboxylate (570 mg, 1.2 mmol, 45.2% yield) as a light brown solid. LC-MS: (ESI, m / z): 457.1, 459.1 [M+H] + . Step 3: tert-butyl 4-[6-(1,1-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate TIFF2025026853000198.tif50170

[0486] A solution of tert-butyl 4-[7-bromo-6-(1,1-difluoroethyl)quinazolin-4-yl]piperazine-1-carboxylate (550.0 mg, 1.2 mmol), bis(pinacolato)diboron (1.5 g, 6.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (88.0 mg, 0.1 mmol), and potassium acetate (353.6 mg, 3.6 mmol) in toluene (20.0 mL) was stirred under nitrogen at 95°C for 4 hours. Upon completion, the solution was concentrated in vacuo. The residue was purified by reverse phase elution with acetonitrile / water (4 / 1) to give tert-butyl 4-[6-(1,1-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate (350.0 mg, 0.7 mmol, 57.7% yield) as a pale yellow oil. LC-MS: (ESI, m / z): 505.3 [M+H] + . Step 4: tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(1,1-difluoroethyl)quinazolin-4-yl]piperazine-1-carboxylate TIFF2025026853000199.tif49170

[0487] Under nitrogen, a solution of tert-butyl 4-[6-(1,1-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate (350.0 mg, 0.7 mmol), 6-bromo-5-(trifluoromethyl)pyridin-2-amine (167.2 mg, 0.7 mmol), potassium carbonate (287.3 mg, 2.1 mmol), and bis(triphenylphosphine)palladium(II) chloride (48.7 mg, 0.1 mmol) in acetonitrile (20 mL) and water (2 mL) was stirred at 95° C. for 4 hours. After completion, the solution was concentrated under vacuum. The residue was purified by reverse phase elution with acetonitrile / water (6:1) to give tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(1,1-difluoroethyl)quinazolin-4-yl]piperazine-1-carboxylate (170 mg, 0.3 mmol, 45.5% yield) as a light brown oil. LC-MS: (ESI, m / z): 539.2 [M+H] + . Step 5: 6-[6-(1,1-difluoroethyl)-4-piperazin-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridin-2-amine TIFF2025026853000200.tif47170

[0488] A solution of tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(1,1-difluoroethyl)quinazolin-4-yl]piperazine-1-carboxylate (160.0 mg, 0.3 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (2 mL) was stirred at 25° C. for 3 hours. After completion, the solution was concentrated in vacuo to give 6-[6-(1,1-difluoroethyl)-4-piperazin-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridin-2-amine (170 mg, crude) as a light brown oil, which was used in the next step without purification. LC-MS: (ESI, m / z): 439.2 [M+H] + Step 6: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(1,1-difluoroethyl)quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one TIFF2025026853000201.tif62170

[0489] A solution of 6-[6-(1,1-difluoroethyl)-4-piperazin-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridin-2-amine (160.0 mg, 0.4 mmol), HATU (346.9 mg, 0.9 mmol), acrylic acid (52.6 mg, 0.7 mmol), and N,N-diisopropylethylamine (235.4 mg, 1.8 mmol) in dichloromethane (10 mL) was stirred at −78° C. for 1.0 h. Upon completion, the solution was quenched with water (5 mL). The resulting solution was extracted with dichloromethane (3×20 mL), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase elution with acetonitrile / water (6 / 1) to give 100 mg of crude product. The crude product was then purified by preparative HPLC to give 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-(1,1-difluoroethyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (22.1 mg, 0.04 mmol, 12.3% yield) as an off-white solid. LC-MS: (ESI, m / z): 493.2 [M+H] + .

[0490] Example 21: 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.69(s,1H),8.26(s,1H),7.78(d,J=7.2 Hz,1H),7.67(s,1H),6.84(dd,J=16.8,10.4 Hz,1H),6.67(d,J=8.8 Hz,1H),6.29(dd,J=16.8,2.0 Hz,1H),5.82(dd,J=10.4,2.0 Hz,1H),4.15-4.00(m,4H),3.99-3.86(m,4H),2.02(dd,J=19.2,18.4 Hz,3H). Example 22: 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-1-prop-2-enoyl-piperidine-4-carbonitrile TIFF2025026853000202.tif113170Step 1: 7-Bromo-4,6-dichloroquinazoline TIFF2025026853000203.tif24170

[0491] A solution of 7-bromo-6-chloro-3H-quinazolin-4-one (50 g, 38.5 mmol), N,N-dimethylformamide (1.0 mL) and thionyl chloride (500 mL, 192.7 mmol) was stirred at 80° C. for 3 hours. After completion, the solution was concentrated in vacuo. The residue was then purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 10) to give 7-bromo-4,6-dichloroquinazoline (26 g, 98% yield) as a white solid. Step 2: 7-tert-butyl 4-(7-bromo-6-chloro-quinazolin-4-yl)-4-cyano-piperidine-1-carboxylate TIFF2025026853000204.tif41170

[0492] To a solution of 1-Boc-4-cyanopiperidine (18.9 g, 90.0 mmol) and 7-bromo-4,6-dichloro-quinazoline (5.0 g, 18.0 mmol) in anhydrous toluene (100 mL) was added TMPMgCl under nitrogen. · LiCl (54.0 mL, 54.0 mmol, 1.0 M in THF) was stirred at −78° C. for 0.5 h. Upon completion, the solution was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with ethyl acetate / petroleum ether (1 / 2) to give the crude product. The crude material was then repurified by reverse-phase chromatography eluting with acetonitrile / water (7 / 3) to give tert-butyl 4-(7-bromo-6-chloro-quinazolin-4-yl)-4-cyano-piperidine-1-carboxylate (1.6 g, 3.5 mmol, 19.7% yield). LC-MS: (ESI, m / z): 451.0 [M+H] + Step 3: tert-butyl 4-[6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-2-yl)quinazolin-4-yl]-4-cyano-piperidine-1-carboxylate TIFF2025026853000205.tif51170

[0493] Under nitrogen, a solution of tert-butyl 4-(7-bromo-6-chloro-quinazolin-4-yl)-4-cyano-piperidine-1-carboxylate (1.0 g, 2.2 mmol), bis(pinacolato)diboron (2.8 g, 11.1 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladiu...

Claims

1. Compounds of formula (I): or a pharma- ceutically acceptable salt thereof. [In the formula, R １ is an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the K-Ras G12C mutant protein, R ２ is H, OH, NH ２ , Haro, C １～６ Alkyl, C １～６ Haloalkyl, cyclopropyl, and -NHR, where R is C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkanoyl, C １～６ Hydroxyalkanoyl, C １～６ Cyanoalkyl, C １～６ Alkylamino, -(C １～６ alkylenyl)NH(CH ３ )-(C １～６ ) alkylenyl) N (CH ３ ) ２ , and -(C １～３ ) alkylenyl (3- to 7-membered heterocyclyl); R ３ and R ４ are H and NH, respectively. ２ , Haro, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkylthio, C １～６ Haloalkylthio, C １～６ independently selected from the group consisting of alkylamino, alkylamino, and cyclopropyl; R ５ H, NH ２ , Haro, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkylthio, C １～６ Haloalkylthio, C １～６ Alkylamino, and C ３～７ cycloalkyl; In the formula, R ２ , R ３ , R ４ , and R ５ is other than H, or R ２ and R ３ , R ３ and R ４ , or R ４ and R ５ each, together with the atom to which it is attached, is independently 1 to 4 substituents, ２ , Haro, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, and C １～３ haloalkoxy) ３～７ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６～１４ aryl, or 5- to 10-membered heteroaryl; Each X optionally contains 1 to 4 substituents, each of which is independently OH, NH ２ , halo, cyano, carboxy, carbamoyl, C １～６ Alkyl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ and 4- to 7-membered heterocyclyl, and the two geminal substituents taken together are C ３～７ NH, optionally substituted with NH, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; ２ , C １～６ Alkoxy, C １～６ Alkyl, C １～６ Alkylamino, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C ３～７ selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is -L-Y １ Or Y １ is selected from the group consisting of Y １ H, NH ２ , halo, cyano, carbamoyl, C ２～６ Alkenyl, C １～６ Alkoxy, C １～６ alkyl, 1 to 4 Y １ａ C substituted with 4-10 membered heterocyclyl optionally substituted with substituents １～６ Alkyl, C １～６ C substituted with dialkylamino substituents １～６ Alkyl, C １～６ Dialkylaminocyclopropyl-substituted C １～６ Alkyl, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C ２～６ Alkynyl, C １～６ Alkylamino, C ６～１４ Aryl, C １～６ Alkyl-substituted C ６～１４ Aryl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C ３～７ Cycloalkyl, C １～６ Dialkylamino-substituted C ３～７ Cycloalkyl, C １～６ Haloalkoxy, C １～６ selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y １ａ is independent, halo, C １～６ Alkyl, C １～６ Alkoxy, 3- to 7-membered heterocyclyl, C １～６ Alkoxy C １～６ Alkyl, C １～６ Haloalkyl, oxo, hydroxy, NH ２ , Cyano, C. １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C １～６ Hydroxyalkyl, and C １～６ haloalkoxy; L is a bond, O, S, and N (L ａ ) selected from the group consisting of L ａ is hydrogen and C １～３ is selected from the group consisting of alkyl, U is C(R ６ａ ) and V is C(R ６ｂ ) and W is C(R ６ｃ ) or N, R ６ａ , R ６ｂ , and R ６ｃ each independently represents H, OH, NH ２ , halo, cyano, carbamoyl, C ２～６ Alkenyl, C １～６ Alkoxy, C １～６ C substituted with alkyl, 4-10 membered heterocyclyl substituents １～６ Alkyl, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C １～６ Haloalkylthio, C ２～６ Alkynyl, C １～６ Alkylamino, C ６～１４ Aryl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C ３～７ Cycloalkyl, C １～６ Haloalkoxy, C １～６ selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2.

2. The compound of claim 1 having the formula (II): or a pharma- ceutically acceptable salt thereof. [In the formula, R ２ is H, OH, NH ２ , Haro, C １～６ Alkyl, C １～６ Haloalkyl, cyclopropyl, and -NHR, where R is C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkanoyl, C １～６ Hydroxyalkanoyl, C １～６ Cyanoalkyl, C １～６ Alkylamino, -(C １～６ alkylenyl)NH(CH ３ )-(C １～６ ) alkylenyl) N (CH ３ ) ２ , and -(C １～３ ) alkylenyl (3- to 7-membered heterocyclyl); R ３ and R ４ are H and NH, respectively. ２ , Haro, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkylthio, C １～６ Haloalkylthio, C １～６ independently selected from the group consisting of alkylamino, alkylamino, and cyclopropyl; R ５ H, NH ２ , Haro, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkylthio, C １～６ Haloalkylthio, C １～６ Alkylamino, and C ３～７ cycloalkyl; In the formula, R ２ , R ３ , R ４ , and R ５ is other than H, or R ２ and R ３ , R ３ and R ４ , or R ４ and R ５ each, together with the atom to which it is attached, is independently 1 to 4 substituents, ２ , Haro, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, and C １～３ haloalkoxy) ３～７ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６～１４ aryl, or 5- to 10-membered heteroaryl; R ７ is selected from the group consisting of H, cyano, and halo; R ８ and R ９ are H and C, respectively. １～６ Alkyl, C １～６ Haloalkyl, C １～６ Independently selected from the group consisting of hydroxyalkyl, cyano, and halo (C １～６ Alkyl is methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), alkyl or arylsulfonate leaving group, C １～６ Alkanoylamino, C １～６ Alkoxy, C １～６ Alkylamino, C １～６ Alkylsulfonylamino, C ６～１２ Dialkylamino, and C １～６ haloalkoxy), or R ７ and R ８ together form a triple bond with the carbon to which they are attached, or R ７ and R ８ each of which, together with the carbon to which it is attached, is optionally substituted with one or two halo substituents; ３～７ Form a cycloalkenyl, R ９ is H, C １～６ Alkyl, C １～６ (C) is selected from the group consisting of haloalkyl, cyano, and halo. １～６ Alkyl is C １～６ Alkanoylamino, C １～６ Alkoxy, C １～６ Alkylamino, C １～６ Alkylsulfonylamino, C ６～１２ Dialkylamino, and C １～６ haloalkoxy), Each X optionally contains 1 to 4 substituents, each of which is independently OH, NH ２ , halo, cyano, carboxy, carbamoyl, C １～６ Alkyl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ and 4- to 7-membered heterocyclyl, and the two geminal substituents taken together are C ３～７ NH, optionally substituted with NH, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; ２ , C １～６ Alkoxy, C １～６ Alkyl, C １～６ Alkylamino, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C ３～７ selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is -L-Y １ Or Y １ is selected from the group consisting of Y １ H, NH ２ , halo, cyano, carbamoyl, C ２～６ Alkenyl, C １～６ Alkoxy, C １～６ alkyl, 1 to 4 Y １ａ C substituted with 4-10 membered heterocyclyl optionally substituted with substituents １～６ Alkyl, C １～６ C substituted with dialkylamino substituents １～６ Alkyl, C １～６ Dialkylaminocyclopropyl-substituted C １～６ Alkyl, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C ２～６ Alkynyl, C １～６ Alkylamino, C ６～１４ Aryl, C １～６ Alkyl-substituted C ６～１４ Aryl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C ３～７ Cycloalkyl, C １～６ Dialkylamino-substituted C ３～７ Cycloalkyl, C １～６ Haloalkoxy, C １～６ selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y １ａ is independent, halo, C １～６ Alkyl, C １～６ Alkoxy, 3- to 7-membered heterocyclyl, C １～６ Alkoxy C １～６ Alkyl, C １～６ Haloalkyl, oxo, hydroxy, NH ２ , Cyano, C. １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C １～６ Hydroxyalkyl, and C １～６ haloalkoxy; L is a bond, O, S, and N (L ａ ) selected from the group consisting of L ａ is hydrogen and C １～３ is selected from the group consisting of alkyl, U is C(R ６ａ ) and V is C(R ６ｂ ) and W is C(R ６ｃ ) or N, R ６ａ , R ６ｂ , and R ６ｃ each independently represents H, OH, NH ２ , halo, cyano, carbamoyl, C ２～６ Alkenyl, C １～６ Alkoxy, C １～６ C substituted with alkyl, 4-10 membered heterocyclyl substituents １～６ Alkyl, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C １～６ Haloalkylthio, C ２～６ Alkynyl, C １～６ Alkylamino, C ６～１４ Aryl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C ３～７ Cycloalkyl, C １～６ Haloalkoxy, C １～６ selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2.

3. The compound of claim 1 having the formula (III): or a pharma- ceutically acceptable salt thereof. [In the formula, R ２ is H, OH, NH ２ , Haro, C １～６ Alkyl, C １～６ Haloalkyl, cyclopropyl, and -NHR, where R is C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkanoyl, C １～６ Hydroxyalkanoyl, C １～６ Cyanoalkyl, C １～６ Alkylamino, -(C １～６ alkylenyl)NH(CH ３ )-(C １～６ ) alkylenyl) N (CH ３ ) ２ , and -(C １～３ ) alkylenyl (3- to 7-membered heterocyclyl); R ３ and R ４ are H and NH, respectively. ２ , Haro, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkylthio, C １～６ Haloalkylthio, C １～６ independently selected from the group consisting of alkylamino, alkylamino, and cyclopropyl; R ５ H, NH ２ , Haro, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkylthio, C １～６ Haloalkylthio, C １～６ Alkylamino, and C ３～７ cycloalkyl; In the formula, R ２ , R ３ , R ４ , and R ５ is other than H, or R ２ and R ３ , R ３ and R ４ , or R ４ and R ５ each, together with the atom to which it is attached, is independently 1 to 4 substituents, ２ , Haro, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, and C １～３ haloalkoxy) ３～７ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６～１４ aryl, or 5- to 10-membered heteroaryl; R １０ is R １０ａ and -C(O)-R １０ａ is selected from the group consisting of R １０ａ is selected from the group consisting of oxiranyl and aziridinyl; Each X optionally contains 1 to 4 substituents, each of which is independently OH, NH ２ , halo, cyano, carboxy, carbamoyl, C １～６ Alkyl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ and 4- to 7-membered heterocyclyl, and the two geminal substituents taken together are C ３～７ NH, optionally substituted with NH, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; ２ , C １～６ Alkoxy, C １～６ Alkyl, C １～６ Alkylamino, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C ３～７ selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is -L-Y １ Or Y １ is selected from the group consisting of Y １ H, NH ２ , halo, cyano, carbamoyl, C ２～６ Alkenyl, C １～６ Alkoxy, C １～６ alkyl, 1 to 4 Y １ａ C substituted with 4-10 membered heterocyclyl optionally substituted with substituents １～６ Alkyl, C １～６ C substituted with dialkylamino substituents １～６ Alkyl, C １～６ Dialkylaminocyclopropyl-substituted C １～６ Alkyl, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C ２～６ Alkynyl, C １～６ Alkylamino, C ６～１４ Aryl, C １～６ Alkyl-substituted C ６～１４ Aryl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C ３～７ Cycloalkyl, C １～６ Dialkylamino-substituted C ３～７ Cycloalkyl, C １～６ Haloalkoxy, C １～６ selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y １ａ is independent, halo, C １～６ Alkyl, C １～６ Alkoxy, 3- to 7-membered heterocyclyl, C １～６ Alkoxy C １～６ Alkyl, C １～６ Haloalkyl, oxo, hydroxy, NH ２ , Cyano, C. １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C １～６ Hydroxyalkyl, and C １～６ haloalkoxy; L is a bond, O, S, and N (L ａ ) selected from the group consisting of L ａ is hydrogen and C １～３ is selected from the group consisting of alkyl, U is C(R ６ａ ) and V is C(R ６ｂ ) and W is C(R ６ｃ ) or N, R ６ａ , R ６ｂ , and R ６ｃ each independently represents H, OH, NH ２ , halo, cyano, carbamoyl, C ２～６ Alkenyl, C １～６ Alkoxy, C １～６ C substituted with alkyl, 4-10 membered heterocyclyl substituents １～６ Alkyl, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C １～６ Haloalkylthio, C ２～６ Alkynyl, C １～６ Alkylamino, C ６～１４ Aryl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C ３～７ Cycloalkyl, C １～６ Haloalkoxy, C １～６ selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2.

4. R ２ NH ２ and -NHR, R is C １～６ The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

5. R ２ NH ２ The compound according to any one of claims 1 to 4, wherein:

6. R ３ and R ４ are independent, H, halo, C １～６ Alkyl, C １～６ The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of haloalkyl, and cyclopropyl.

7. R ５ H, halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Haloalkoxy, C １～６ Alkylamino, and C ３～７ 7. The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: cycloalkyl.

8. R ５ C １～３ The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

9. R ５ is CF ３ and R ２ NH ２ The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof.

10. R ５ The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein is cyclopropyl.

11. R ４ and R ５ each, together with the atom to which it is attached, is independently 1 to 4 substituents, ２ , Haro, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, and C １～３ haloalkoxy) ３～７ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６～１４ 6. The compound according to any one of claims 1 to 5, which forms an aryl, or a 5- to 10-membered heteroaryl, or a pharma- ceutically acceptable salt thereof.

12. R ４ and R ５ each, together with the atom to which it is attached, is independently 1 to 4 substituents, ２ , Haro, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, and C １～３ haloalkoxy) ６～１４ 12. The compound of claim 11, or a pharma- ceutically acceptable salt thereof, which forms an aryl.

13. R ４ and R ５ each, together with the atom to which it is attached, is independently 1 to 4 substituents, ２ , Haro, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, and C １～３ haloalkoxy) ６ 13. The compound of claim 12, or a pharma- ceutically acceptable salt thereof, which forms an aryl.

14. C ６ 14. The compound of claim 13, or a pharma- ceutically acceptable salt thereof, wherein aryl is unsubstituted.

15. C ６ 14. The compound of claim 13, or a pharma- ceutically acceptable salt thereof, wherein aryl is substituted with 1 to 4 substituents, each of which is independently halo.

16. R ２ But H, OH, NH ２ , Haro, C １～６ Alkyl, C １～６ Haloalkyl, cyclopropyl, and -NHR, where R is a straight chain C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkanoyl, C １～６ Hydroxyalkanoyl, C １～６ Cyanoalkyl, C １～６ Alkylamino, -(C １～６ alkylenyl)NH(CH ３ )-(C １～６ ) alkylenyl) N (CH ３ ) ２ , and -(C １～３ ) alkylenyl (3- to 7-membered heterocyclyl); R ３ and R ４ are H and NH, respectively. ２ , Haro, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkylthio, C １～６ Haloalkylthio and C １～６ independently selected from the group consisting of alkylamino, R ５ is H, Cl, Br, I, NH ２ , C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkylthio, C １～６ Haloalkylthio, C １～６ Alkylamino, and C ３～７ cycloalkyl; R ２ , R ３ , R ４ , and R ５ are other than H, or R ２ and R ３ , R ３ and R ４ , or R ４ and R ５ each, together with the atom to which it is attached, is independently 1 to 4 substituents, ２ , Haro, C １～３ Alkyl, C １～３ Haloalkyl and C １～３ haloalkoxy) ３～７ cycloalkyl, 3- to 7-membered heterocycloalkyl, or C ６～１４ Forming an aryl Each X optionally contains 1 to 4 substituents, each of which is independently OH, NH ２ , halo, cyano, carboxy, carbamoyl, C １～６ Alkyl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ and 4- to 7-membered heterocyclyl, and the two geminal substituents taken together are C ３～７ NH, optionally substituted with NH, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; ２ , C １～６ Alkoxy, C １～６ Alkyl, C １～６ Alkylamino, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C ３～７ selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is -L-Y １ Or Y １ is selected from the group consisting of Y １ H, NH ２ , halo, cyano, carbamoyl, C ２～６ Alkenyl, C １～６ Alkoxy, C １～６ alkyl, 1 to 4 Y １ａ C substituted with 4-10 membered heterocyclyl optionally substituted with substituents １～６ Alkyl, C １～６ C substituted with dialkylamino substituents １～６ Alkyl, C １～６ Dialkylaminocyclopropyl-substituted C １～６ Alkyl, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C ２～６ Alkynyl, C １～６ Alkylamino, C ６～１４ Aryl, C １～６ Alkyl-substituted C ６～１４ Aryl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C ３～７ Cycloalkyl, C １～６ Dialkylamino-substituted C ３～７ Cycloalkyl, C １～６ Haloalkoxy, C １～６ selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y １ａ became independent, Halo, C １～６ Alkyl, C １～６ Alkoxy, 3- to 7-membered heterocyclyl, C １～６ Alkoxy C １～６ Alkyl, C １～６ Haloalkyl, oxo, hydroxy, NH ２ , Cyano, C. １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C １～６ Hydroxyalkyl, and C １～６ haloalkoxy; L is a bond, O, S, and N (L ａ ) selected from the group consisting of L ａ is hydrogen and C １～３ is selected from the group consisting of alkyl, U is C(R ６ａ ) and V is C(R ６ｂ ) and W is C (R ６ｃ ) or N, R ６ａ , R ６ｂ , and R ６ｃ each independently represents H, OH, NH ２ , halo, cyano, carbamoyl, C ２～６ Alkenyl, C １～６ Alkoxy, C １～６ C substituted with alkyl, 4-10 membered heterocyclyl substituents １～６ Alkyl, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C １～６ Haloalkylthio, C ２～６ Alkynyl, C １～６ Alkylamino, C ６～１４ Aryl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C ３～７ Cycloalkyl, C １～６ Haloalkoxy, C １～６ selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2; The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

17. A compound of formula (I) having the formula (IV): or a pharma- ceutically acceptable salt thereof. [In the formula, R １ is an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the K-Ras G12C mutant protein, Each X optionally contains 1 to 4 substituents, each of which is independently OH, NH ２ , halo, cyano, carboxy, carbamoyl, C １～６ Alkyl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ and 4- to 7-membered heterocyclyl, and the two geminal substituents taken together are C ３～７ NH, optionally substituted with NH, which may form a spirocycloalkyl or a 4- to 7-membered spiroheterocyclyl; ２ , C １～６ Alkoxy, C １～６ Alkyl, C １～６ Alkylamino, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C ３～７ selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 4- to 7-membered heterocyclylamino; Y is -L-Y １ Or Y １ is selected from the group consisting of Y １ H, NH ２ , halo, cyano, carbamoyl, C ２～６ Alkenyl, C １～６ Alkoxy, C １～６ alkyl, 1 to 4 Y １ａ C substituted with 4-10 membered heterocyclyl optionally substituted with substituents １～６ Alkyl, C １～６ C substituted with dialkylamino substituents １～６ Alkyl, C １～６ Dialkylaminocyclopropyl-substituted C １～６ Alkyl, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C ２～６ Alkynyl, C １～６ Alkylamino, C ６～１４ Aryl, C １～６ Alkyl-substituted C ６～１４ Aryl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C ３～７ Cycloalkyl, C １～６ Dialkylamino-substituted C ３～７ Cycloalkyl, C １～６ Haloalkoxy, C １～６ selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, methyl, hydroxy, and 4- to 10-membered heterocyclyl substituted with oxo; Each Y １ａ became independent, Halo, C １～６ Alkyl, C １～６ Alkoxy, 3- to 7-membered heterocyclyl, C １～６ Alkoxy C １～６ Alkyl, C １～６ Haloalkyl, oxo, hydroxy, NH ２ , Cyano, C. １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C １～６ Hydroxyalkyl, C １～６ haloalkoxy; L is a bond, O, S, and N (L ａ ) selected from the group consisting of L ａ is hydrogen and C １～３ is selected from the group consisting of alkyl, U is C(R ６ａ ) and V is C(R ６ｂ ) and W is C(R ６ｃ ) or N, R ６ａ , R ６ｂ , and R ６ｃ each independently represents H, OH, NH ２ , halo, cyano, carbamoyl, C ２～６ Alkenyl, C １～６ Alkoxy, C １～６ C substituted with alkyl, 4-10 membered heterocyclyl substituents １～６ Alkyl, C １～６ Alkylsulfanyl, C １～６ Alkylsulfonyl, C １～６ Alkylthio, C １～６ Haloalkylthio, C ２～６ Alkynyl, C １～６ Alkylamino, C ６～１４ Aryl, C １～６ Aminoalkyl, C １～６ Carbamoylalkyl, C １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C ３～７ Cycloalkyl, C １～６ Haloalkoxy, C １～６ selected from the group consisting of haloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl; n is selected from the group consisting of 0, 1 and 2; R １１ teeth, is selected from the group consisting of

18. Y is Y １ And Y １ H, C １～６ Alkyl, and C １～６ 18. The compound of any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of haloalkyl.

19. Y is -L-Y １ and L is O and N (L ａ ) selected from the group consisting of L ａ is H, Y １ C １～６ alkyl, 1 to 4 Y １ａ C substituted with 4-10 membered heterocyclyl optionally substituted with substituents １～６ Alkyl, C １～６ C substituted with dialkylamino substituents １～６ Alkyl, C １～６ Dialkylaminocyclopropyl-substituted C １～６ Alkyl, C １～６ Dialkylamino-substituted C ３～７ cycloalkyl, and 4- to 10-membered heterocyclyl substituted with methyl; Each Y １ａ became independent, Halo, C １～６ Alkyl, C １～６ Alkoxy, 3- to 7-membered heterocyclyl, C １～６ Alkoxy C １～６ Alkyl, C １～６ Haloalkyl, oxo, hydroxy, NH ２ , Cyano, C. １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C １～６ Hydroxyalkyl, and C １～６ haloalkoxy; 18. The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof.

20. L is N (L ａ ) and L ａ is H, and Y １ C １～６ Alkyl, or C １～６ C substituted with dialkylamino substituents １～６ 20. The compound of claim 19, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

21. L is O; Y １ But 1 to 4 Y １ａ C substituted with 4-10 membered heterocyclyl optionally substituted with substituents １～６ Alkyl, C １～６ C substituted with dialkylamino substituents １～６ Alkyl, C １～６ Dialkylaminocyclopropyl-substituted C １～６ Alkyl, C １～６ Dialkylamino-substituted C ３～７ cycloalkyl, and 4- to 10-membered heterocyclyl substituted with methyl; Each Y １ａ became independent, Halo, C １～６ Alkyl, C １～６ Alkoxy, 3- to 7-membered heterocyclyl, C １～６ Alkoxy C １～６ Alkyl, C １～６ Haloalkyl, oxo, hydroxy, NH ２ , Cyano, C. １～６ Carboxyalkyl, C １～６ Cyanoalkyl, C １～６ Hydroxyalkyl, and C １～６ haloalkoxy; 20. The compound of claim 19, or a pharma- ceutically acceptable salt thereof.

22. Y １ is substituted with a 4-10 membered methylheterocyclyl substituent １～６ 20. The compound of claim 19, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

23. Y Selected from the group consisting of:

20. The compound of claim 19, or a pharma- ceutically acceptable salt thereof.

24. Y 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

25. R １１ but The compound according to any one of claims 17 to 24, or a pharma- ceutically acceptable salt thereof,

26. R １１ but 26. The compound according to any one of claims 17 to 25, wherein:

27. R １１ but 27. The compound according to any one of claims 17 to 26, wherein:

28. R ６ａ or a pharma- ceutically acceptable salt thereof.

29. R ６ｂ H, halo, C １～６ Alkoxy, C １～６ Alkylsulfonyl, C １～６ Haloalkyl, C ３～７ Cycloalkyl, C １～６ 29. The compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of haloalkylthio, and 4- to 10-membered heterocyclyl.

30. R ６ｂ is hydrogen, halo, or C １～３ 29. The compound of any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

31. W is C (R ６ｃ ) and R ６ｃ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 30, wherein is hydrogen or halo.

32. W is C (R ６ｃ ) and R ６ｃ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1 to 31, wherein is halo.

33. 33. The compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, wherein X is 4- to 7-membered heterocyclyl.

34. X is 1 to 4 substituents, each of which is independently cyano, C １～６ Alkyl, C １～６ Cyanoalkyl, and C １～６ 33. The compound according to any one of claims 1 to 32, wherein the heterocyclyl is 4 to 7 membered substituted with (selected from the group consisting of haloalkyl) or a pharma- ceutically acceptable salt thereof.

35. X is 33. The compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

36. X is 33. The compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

37. X is 33. The compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

38. X is 33. The compound according to any one of claims 1 to 32, wherein:

39. The compound according to any one of claims 1 to 38, wherein n is 0, or a pharma- ceutically acceptable salt thereof.

40. R １ but 20. The compound of claim 1 or 17, selected from the group consisting of: [In the formula, R １２ is C １～６ Alkanoyl, C １～６ Alkyl, and C １～６ alkylsulfonyl; R １３ is H, C １～６ Alkyl, and C １～６ haloalkyl; R １３ａ is a halo, R １４ is a halo.]

41. R １ but or a pharma- ceutically acceptable salt thereof.

42. R １ but 42. The compound of claim 41, which is: or a pharma- ceutically acceptable salt thereof.

43. R ７ is selected from the group consisting of H, cyano, and halo; R ８ and R ９ are H and C, respectively. １～６ Alkyl, C １～６ Haloalkyl, C １～６ Independently selected from the group consisting of hydroxyalkyl, cyano, and halo, １～６ Alkyl is methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), alkyl or arylsulfonate leaving group, C １～６ Alkanoylamino, C １～６ Alkoxy, C １～６ Alkylamino, C １～６ Alkylsulfonylamino, C ６～１２ Dialkylamino, and C １～６ 3. The compound of claim 2, or a pharma- ceutically acceptable salt thereof, optionally substituted with one substituent selected from the group consisting of haloalkoxy.

44. The compound of claim 1 or 17, having a formula selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

45. 45. The compound of claim 44 having a formula selected from the group consisting of formula (Ib) or (Il), or a pharma- ceutically acceptable salt thereof.

46. The compound of formula (IV) 42. The compound of any one of claims 17 to 41, comprising a formula selected from the group consisting of:

47. 47. The compound of claim 46, wherein the compound of formula (IV) comprises a compound of formula (IVa), (IVb), (IVd), or (IVg), or a pharma- ceutically acceptable salt thereof.

48. 47. The compound of claim 46, wherein the compound of formula (IV) comprises a compound of formula (IVa) or (IVb), or a pharma- ceutically acceptable salt thereof.

49. 47. The compound of claim 46, wherein the compound of formula (IV) comprises a compound of formula (IVd) or (IVg), or a pharma- ceutically acceptable salt thereof.

50. R ７ and R ８ together form a triple bond with the carbon to which they are attached, or R ７ and R ８ each of which, together with the carbon to which it is attached, is optionally substituted with one or two halo substituents; ３～７ Form a cycloalkenyl, R ９ is H, C １～６ Alkyl, C １～６ haloalkyl, cyano, and halo, １～６ Alkyl is C １～６ Alkanoylamino, C １～６ Alkoxy, C １～６ Alkylamino, C １～６ Alkylsulfonylamino, C ６～１２ Dialkylamino, and C １～６ 3. The compound of claim 2, or a pharma- ceutically acceptable salt thereof, optionally substituted with one substituent selected from the group consisting of haloalkoxy.

51. R ７ , R ８ , and R ９ or a pharma- ceutically acceptable salt thereof.

52. A compound as provided in Table 1 or a pharma- ceutically acceptable salt thereof.

53. 53. A pharmaceutical composition comprising a compound according to any one of claims 1 to 52, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

54. 54. The pharmaceutical composition of claim 53, wherein the pharmaceutical composition is formulated for oral administration.

55. 54. The pharmaceutical composition of claim 53, wherein the pharmaceutical composition is formulated for injection.

56. A method for treating cancer, comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 52, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 53 to 55.

57. 57. The method of claim 56, wherein the individual is a human.

58. 57. The method of claim 55 or 56, wherein the administering is via the oral route.

59. 57. The method of claim 55 or 56, wherein the administering is via injection.

60. 60. The method of any one of claims 56 to 59, wherein the cancer is mediated by a K-Ras G12C mutation.

61. 61. The method of any one of claims 56 to 60, wherein the cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

62. The method of any one of claims 56 to 61, wherein the cancer is lung adenocarcinoma.

63. A method for controlling the activity of K-Ras G12C mutant protein, comprising reacting the mutant protein with a compound according to any one of claims 1 to 52 or a pharma- ceutically acceptable salt thereof.

64. 53. A method of inhibiting proliferation of a cell population, comprising contacting said cell population with a compound according to any one of claims 1 to 52, or a pharma- ceutically acceptable salt thereof.

65. 65. The method of claim 64, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

66. 1. A method for treating a disease mediated by a K-Ras G12C mutation in an individual in need of such treatment, comprising: determining whether the individual has a mutation; If the individual is determined to have a mutation, administering to the individual a therapeutically effective amount of a compound according to any one of claims 1 to 52, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 53 to 55; A method comprising:

67. 67. The method of claim 66, wherein the disease is cancer.

68. 68. The method of claim 67, wherein the cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

69. 67. The method of claim 66, wherein the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer.

70. 70. The method of any one of claims 66 to 69, wherein the cancer is lung adenocarcinoma.

71. A method for preparing a labeled K-Ras G12C mutant protein, comprising reacting a K-Ras G12C mutant protein with a labeled compound according to any one of claims 1 to 52 or a pharma- ceutically acceptable salt thereof to obtain the labeled K-Ras G12C mutant protein.

72. A method for inhibiting tumor metastasis, comprising administering to an individual in need of inhibition of tumor metastasis a therapeutically effective amount of a compound according to any one of claims 1 to 52, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 53 to 55.

73. 53. Use of a compound according to any one of claims 1 to 52, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

74. 74. The use of claim 73, wherein the medicament is formulated for oral administration.

75. 74. The use of claim 73, wherein the medicament is formulated for injection.

76. The use according to any one of claims 73 to 75, wherein the cancer is mediated by a K-Ras G12C mutation.

77. 77. The use according to any one of claims 73 to 76, wherein the cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

78. 77. The use according to any one of claims 73 to 76, wherein the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer.

79. The use according to any one of claims 73 to 78, wherein the cancer is lung adenocarcinoma.

80. 53. Use of a compound according to any one of claims 1 to 52, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

81. A compound according to any one of claims 1 to 52, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 53 to 55, for use in a method of treatment of the human or animal body by therapy.

82. 56. A compound according to any one of claims 1 to 52, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 53 to 55, for use in a method for the treatment of cancer.

83. 83. The compound, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 82, wherein the cancer is mediated by a K-Ras G12C mutation.

84. 84. The compound of claim 82 or 83, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

85. 84. The compound of claim 82 or 83, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer.

86. 86. The compound, pharma- ceutically acceptable salt thereof, or pharmaceutical composition according to any one of claims 82 to 85, wherein the cancer is lung adenocarcinoma.

87. A compound according to any one of claims 1 to 52, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 53 to 55, for use in a method for inhibiting tumour metastasis.

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