Condensed 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 of related applications This application claims priority to international application serial number PCT / CN2018 / 114788, filed on 9 November 2018, which is incorporated herein by reference in its entirety.

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

[0003] Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch in the central proliferation signaling pathway. In response to extracellular signals, Ras is catalyzed by guanine nucleotide exchange factors (GEFs), particularly the SOS1 protein, to GDP binding (Ras GDP ) state to GTP binding (Ras GTP ) is converted to the state of active Ras GTP Ras mediates its diverse growth-stimulating functions through direct interactions with effectors including Raf, PI3K, and the Ral guanine nucleotide dissociation stimulator. Next, Ras's intrinsic GTPase activity hydrolyzes GTP to GDP, terminating Ras signaling. Ras GTPase activity can be further accelerated through interactions with GTPase-activating proteins (gap), including the neurofibromin-1 tumor suppressor.

[0004] Mutant Ras has reduced GTPase activity, which sustains the activated structure of Ras, thereby promoting Ras-dependent signaling and cancer cell survival or proliferation. Mutations in Ras that interact with GAP or affect the ability to convert GTP back to GDP result in sustained activation of the protein, consequently sustained signals that tell cells to continue proliferating and dividing. Because these signals lead to cell proliferation and division, excessively active RAS signaling can ultimately lead to cancer. Mutations in any one of the three main isoforms of the RAS gene (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 of the P-loop, as well as at residue Q61. G12C is a frequently occurring mutation in the K-Ras gene (glycine-12 instead of cysteine). G12D and G13D are other frequently occurring mutations. Mutations in Ras in cancer are associated with poor prognosis. Inactivation of oncogenic Ras in mice results in tumor reduction. Therefore, Ras is widely considered an exceptionally important oncological target. [Overview of the project]

[0006] In one embodiment, the present disclosure relates to a compound of formula (I), Relating to TIFF0007943888000001.tif67170 or its pharmaceutically acceptable salts. [In the formula, R1, R2, R3, R4, R5, X, Y, U, V, W, and n are as defined herein.

[0007] Another aspect of this disclosure relates to a compound of formula (II), Contains TIFF0007943888000002.tif77170 or a pharmaceutically acceptable salt thereof. [In the formula, R2, R3, R4, R5, R7, R8, R9, X, Y, U, V, W, and n are as defined herein.]

[0008] Compound of formula (III), TIFF0007943888000003.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 embodiment, the present disclosure relates to a compound of formula (IV), Relating to TIFF0007943888000004.tif67170 or its pharmaceutically acceptable salts. [In the formula, R1, R 11 X, Y, U, V, W, and n are as defined herein.

[0010] The present invention also provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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

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

[0013] Another embodiment includes a method for treating a disease mediated by the K-Ras G12C mutation in an individual requiring treatment, the method comprising: measuring whether the individual has the mutation; and, if the individual is measured to have the mutation, administering to the individual a therapeutically effective amount of the pharmaceutical composition of the present invention.

[0014] Another aspect includes a method of inhibiting tumor metastasis, comprising administering a therapeutically effective amount of the pharmaceutical composition of the present invention to an individual in need of inhibition of tumor metastasis. [Mode for Carrying Out the Invention]

[0015] Definitions The term "halogen" or "halo" means F, Cl, Br, or I. Furthermore, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl.

[0016] The term "alkyl" means a monovalent saturated linear or branched hydrocarbon group. In one example, the 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), and 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(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH(CH 3) Examples include 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" refers to -NH2.

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

[0019] The term "dialkylamino" means -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" means -C(=O)-alkyl.

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

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

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

[0027] The term "alkoxyalkyl" refers to an alkyl group substituted with one alkoxy substituent.

[0028] The term "dialkylaminocyclopropyl" refers to a cyclopropyl compound substituted with one dialkylamino substituent.

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

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

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

[0032] The term "alkylthio" means -S-alkyl.

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

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

[0035] The term "carbamoylalkyl" refers to an alkyl group substituted with one carbamoyl substituent.

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

[0037] The terms "cyano" or "nitrile" refer to -C≡N or -CN.

[0038] The term "cyanoalkyl" refers to an alkyl group substituted with one cyano substituent.

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

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

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

[0042] The term "hydroxyalkyl" refers to an alkyl group substituted with one hydroxyl substituent.

[0043] The term "alkenyl" refers to a monovalent hydrocarbon, either linear or branched, having at least one carbon-carbon double bond, and includes groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. For 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=CH2), prop-1-enyl (-CH=CHCH3), prop-2-enyl (-CH2CH=CH2), 2-methylprop-1-enyl, buta-1-enyl, buta-2-enyl, buta-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl.

[0044] The term "alkynyl" refers to a monovalent hydrocarbon group, either linear or branched, that has at least one carbon-carbon triple bond. For 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, ethinyl (-C≡CH), prop-1-inyl (-C≡CCH3), prop-2-inyl (propargyl, -CH2C≡CH), buta-1-inyl, buta-2-inyl, and buta-3-inyl.

[0045] The term "alkylene" refers to a saturated, branched, or straight-chain hydrocarbon group having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For 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 1~3Examples of alkylene groups include methylene(-CH2-), 1,1-ethyl(-CH(CH3)-), 1,2-ethyl(-CH2CH2-), 1,1-propyl(-CH(CH2CH3)-), 2,2-propyl(-(C(CH3)2-), 1,2-propyl(-CH(CH3)CH2-), 1,3-propyl(-CH2CH2CH2-), 1,1-dimethylethanol-1,2-yl(-(C(CH3)2CH2-), and 1,4-butyl(-CH2CH2CH2CH2-).

[0046] The term "aryl" refers to a carbocyclic aromatic group having a specified number of carbon atoms, or up to 14 carbon atoms if no number is specified, regardless of whether it is condensed with one or more other groups. Examples include aryl groups having 6 to 14 carbon atoms, and aryl groups having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenantrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, and 2,3-dihydro-1H-indenyl (see, for example, Lang's Handbook of Chemistry (Dean, JA, ed.)13). th See ed.Table 7-2

[1985] ). The specific aryl is phenyl.

[0047] The term "cycloalkyl" refers to a saturated hydrocarbon ring group. Cycloalkyls include monocyclic, dicyclic, tricyclic, spirocyclic, and bridging saturated ring systems. For example, a cycloalkyl group has 3 to 12 carbon atoms (C 3~12 ) is. In other examples, cycloalkyl is C 3~7 , C 3~8 , C 3~10 , or C 5~10 In other examples, a cycloalkyl group as a monocycle is C 3~8 , C3 ~6 , or C 5~6 In another example, the cycloalkyl group as a biring 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, the [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary cross-linked 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. Cycloalkenyls include monocyclic, dicyclic, tricyclic, spirocyclic, 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, the [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Examples of cross-linked 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 formula,” “heterocyclic,” “heterocyclic,” or “heterocyclo” are used interchangeably and refer to any monocyclic, dicyclic, tricyclic, spirocyclic, or bridging saturated, partially saturated, or unsaturated non-aromatic cyclic system having 3 to 20 ring atoms, where the ring atoms are carbon and at least one atom in the ring or cyclic system is a heteroatom selected from nitrogen, sulfur, or oxygen. If any of the ring atoms in the cyclic system is a heteroatom, the system is heterocyclic regardless of the bond points of the cyclic system to the rest of the molecule. In one example, a heterocyclil includes monocyclic, dicyclic, tricyclic, spirocyclic, and bridging cyclic systems containing 3 to 11 ring atoms ("members"), where the ring atoms are carbon and at least one atom in the ring or cyclic system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, a heterocyclil contains 4 to 10 or 5 to 10 ring atoms. In one example, a heterocyclil contains 1 to 4 heteroatoms. In one example, the heterocyclyl contains 1 to 3 heteroatoms. In another example, the heterocyclyl contains a 3 to 7-membered monoring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In yet another example, the heterocyclyl contains a 4 to 6-membered monoring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In yet another example, the heterocyclyl contains a 3-membered monoring. In yet another example, the heterocyclyl contains a 4-membered monoring. In yet another example, the heterocyclyl contains a 5 to 6-membered monoring. In some embodiments, the heterocycloalkyl contains at least one nitrogen. In one example, the heterocyclyl group contains 0 to 3 double bonds. Any nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatoms may optionally be quaternized (e.g., [NR4]). + Cl - [NR4] + OH -Exemplary heterocycles include oxyranil, azilidinil, thiranil, azetidinil, oxetanil, thietanil, 1,2-dithietanil, 1,3-dithietanil, pyrrolidinil, dihydro-1H-pyrrolyl, dihydrofuranil, tetrahydrofuranil, dihydrothienyl, tetrahydrothienyl, imidazolidinil, piperidinil, piperazinil, isoquinolinil, tetrahydroisoquinolinil, morpholinil, thiomorpholinil, 1,1-dioxo-thiomorpholinil, dihydropyranil, tetrahydropyranil, hexahydrothiopyranil, hexa Dropyrimidinil, oxazinanil, thiadinil, thioxanil, homopiperazinil, homopiperidinil, azepanil, oxepanil, thiepanil, oxazepinil, oxazepanil, diazepanil, 1,4-diazepanil, diazepinil, thiazepinil, thiazepanil, tetrahydrothiopyranil, oxazolidinil, thiazolidinil, isothiazolidinil, 1,1-dioxoiisothiazolidinonil, 1,1-dioxoiisothiazolyl, oxazolidinonil, imidazolidinonil, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydro Benzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiadinyl, oxazinyl, thiadiadinyl, oxadiadinyl, dithiadinyl, dioxazinyl, oxathiadinyl, thiatriazinyl, oxatriazinyl, dithiadiadinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranil, 2H-pyranil, 4H-pyranil, dioxanil, 1,3-dioxolanil, pyrazolinyl, pyrazolidinyl, dithianil, dithiolanil , pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperadinonyl, 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.These are [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-azapiro[4.5]decane-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranyl.

[0050] The term "methyl heterocyclyl" refers to a heterocyclyl molecule that has been substituted with a methyl group.

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

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

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

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

[0054] "Condensed" means any cyclic structure described herein that shares one or more atoms (e.g., carbon or nitrogen atoms) with a cyclic structure present in the compound of the present invention.

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

[0056] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogen atoms are substituted by halogens. Examples of haloalkyls include trifluoromethyl, difluoromethyl, and fluoromethyl.

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

[0058] Unless otherwise specified, the term "optionally substituted" means that a group may not be substituted, or it may be substituted with one or more substituents (e.g., 0, 1, 2, 3, 4, or 5, or any range variable thereof) listed with respect to that group (the substituents may 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] When used herein, a wavy line intersects a bond in a chemical structure. TIFF0007943888000005.tif7170 represents an atomic bond site in a chemical structure where a wave-like bond is attached to the remainder of a molecule or the remainder of a molecular fragment.

[0060] In certain embodiments, divalent groups are generally described without specific bonding structures. Unless otherwise specified, the general description is understood to include both bonding structures. For example, group R 1 -R 2 -R 3 In this case, base R 2 When written as -CH2C(O)-, unless otherwise specified, this group is R 1 -CH2C(O)-R 3 and R 1 -C(O)CH2-R 3 It is understood that they can be combined as both.

[0061] The term "pharmaceutically acceptable" means molecular elements and compositions that, when administered appropriately to animals, such as humans, do not produce adverse reactions, allergic reactions, or other side effects.

[0062] The compounds of the present invention may be in the form of salts, such as pharmaceutically acceptable salts. "pharmaceutically acceptable salts" include both acid addition salts and base addition salts. "Pharmacologically acceptable acid addition salts" refer to salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid, which retain the biological efficacy and properties of the free base and are biologically or otherwise desirable. Organic acids can be selected from the aliphatic, alicyclic, aromatic, aromaticaliphatic, heterocyclic, carboxylic acid, and sulfonic acid categories 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, and salicylic acid.

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

[0064] In some embodiments, the salt is 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, saccharinate, adipine, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, phloate (e.g., 2-phloate or 3-phloate), 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-hydroxyethyl sulfonate), 2-mesitylene sulfonate, 2-naphthalene sulfonate, 2,5-dichlorobenzene sulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipine, esylate, malonate, mesicylate (2-mesitylene sulfonate), napsylate (2-na Selected from phthalene sulfonates, cansylates (camphor 10-sulfonates, e.g., (1S)-(+)-10-camphor-sulfonates), glutamates, glutarates, hippuric acid (2-(benzoylamino)acetate), orotinates, xylates (p-xylene-2-sulfonates), and pamoates (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylates).

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

[0066] The term "stereoisomer" refers to a compound that has the same chemical structure but differs in the arrangement of atoms or groups in space. Examples of stereoisomers include diastereomers, enantiomers, and conformational isomers.

[0067] The term "chiral" refers to molecules that have the property of not being able to be superimposed on their mirror image partners, while the term "achiral" refers to molecules that can be superimposed on those mirror image partners.

[0068] The term "diastereomer" refers to stereoisomers that possess two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, 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 "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other but cannot be superimposed.

[0070] The definitions and conventions of stereochemistry used herein generally follow those of SP. 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, that is, they have the ability to rotate the plane of polarized light. When describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around its chiral center(s). The prefixes d and l, or (+) and (-), are used to indicate the 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. Certain stereoisomers are also called enantiomers, and mixtures of such isomers are sometimes called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and these can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to equimolar mixtures of two enantiomer species that are not optically active.

[0071] The term "tautomer" or "tautomer" refers to structural isomers with different energies that can be interconverted via a low-energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversion via proton rearrangement, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversion via rearrangement of some bonding electrons.

[0072] Atropisomers are stereoisomers that arise from sterically hindered rotation around a single bond, where the energy difference due to steric strain or other factors creates a rotational barrier that is high enough to allow for the isolation of individual conformational isomers.

[0073] Certain compounds of the present invention can exist in solvated forms, including non-solvated and hydrated forms. “Solvate” means 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. In general, all physical forms are intended to be within the scope of the present invention. The term “hydrate” refers to a complex in which the solvent molecule is water.

[0074] "Metabolites" refer to products produced in the body through the metabolism of the specified compound or its salt. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, amidation, esterification, deesterification, or enzymatic cleavage of the administered compound.

[0075] Metabolites are typically radiolabeled compounds of the present invention (e.g., 14 C or 3H) The isotope is prepared and administered to animals such as rats, mice, guinea pigs, monkeys, or humans at a detectable dose (e.g., greater than approximately 0.5 mg / kg), allowing metabolism to occur for a sufficient time (typically about 30 seconds to 30 hours), and identified by isolating the conversion product 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 to the epitope surviving in the metabolite). The structure of the metabolite is determined by conventional methods, e.g., MS, LC / MS, or NMR analysis. Generally, the analysis of the metabolite is carried out in the same manner as conventional drug metabolism studies well known to those skilled in the art. The metabolite products are useful in diagnostic assays for therapeutic dosing of the compounds of the present invention unless otherwise found in vivo.

[0076] The inventions described herein also encompass isotope-labeled compounds of the present invention that are identical to those cited herein in respect of the fact that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those normally found in nature. All isotopes of any specific atom or element designated are intended to be within the scope of the compounds of the present invention and their uses. Exemplary isotopes that can be incorporated into the compounds of the present invention include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example. 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 I is an example of the present invention, which includes specific isotope-labeled compounds (for example, 3 H and 14Compounds labeled with 1C are useful in compound and / or substrate tissue partitioning assays. Tritium labeling ( 3 H) and carbon-14 ( 14 C) Isotopes are useful due to their ease of preparation and detection. Furthermore, deuterium (i.e., 2 Substitution with heavier isotopes, such as H), may offer certain therapeutic benefits derived from greater metabolic stability (e.g., extended in vivo half-life or reduced required dose), and may therefore be preferable in some environments. 15 O, 13 N, 11 C, and 18 Positron-emitting isotopes such as 14F are useful for positron emission tomography (PET) studies to investigate substrate receptor occupancy. The isotope-labeled compounds of the present invention can generally be prepared by replacing unlabeled reagents with isotope-labeled reagents and following procedures similar to those described in the examples below.

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

[0078] As used herein, the term “carboxyprotecting group” means a group at another position on the molecule that is stable under the conditions of the subsequent reaction and can be removed at the appropriate location without destroying the remainder of the molecule to obtain an unprotected carboxyl group. Examples of carboxyprotecting groups include ester groups and heterocyclyl groups. Carboxylic acid groups can be blocked or protected using ester derivatives of carboxylic acid groups. Alternatively, the reaction can proceed at another functional group of the compound. Examples of such ester groups include substituted arylalkyls, including substituted benzyls, e.g., 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, e.g., methyl, ethyl, t-butylallyl or t-amyl, triphenylmethyl(trityl), 4- Examples of carboxy protecting groups include methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4''-trimethoxytrityl, 2-phenylpropa-2-yl, thioesters, e.g., t-butylthioester, silyl esters, e.g., trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, β-(trimethylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)propa-1-en-3-yl, and similar moieties. Another example of carboxy protecting groups is heterocyclyl groups such as 1,3-oxazole. Further examples of these groups can be found in TWGreene and PGMWuts, “Protecting Groups in Organic Synthesis, 3 rd This is found in ed., John Wiley & Sons, Inc., 1999. The term "protected carboxyl" refers to a carboxyl group substituted with one of the above carboxyl protecting groups.

[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. Racemic compounds, diastereomers, or enantiomers can be used as starting materials or intermediates in the synthesis of the compounds. A mixture of specific diastereomer compounds can be separated or concentrated into one or more specific diastereomers by chromatography or crystallization. Similarly, enantiomixtures can be separated or enantiomerically concentrated using the same technique or other techniques known in the art. Each of the asymmetric carbon or nitrogen atoms can be present in the R or S configuration, and both of these configurations are within the scope of the present invention.

[0080] In the structures shown herein, if the stereochemistry of any specific chiral atom is not specified, all stereoisomers are conceived and included as compounds of the present invention. Where stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, the stereoisomers are indicated and defined in that way. Unless otherwise stated, where solid wedges or dashed lines are used, relative stereochemistry is intended.

[0081] Another embodiment includes a prodrug of the compound of the present invention comprising known amino-protecting groups and carboxy-protecting groups, which are released and, for example, hydrolyzed to obtain the compound of the present invention under physiological conditions.

[0082] The term "prodrug" refers to a precursor or derivative form of a pharmaceutically active substance that is less effective to the patient than the parent drug and can be activated by enzymes or hydrolysis, or converted to a more active parent form. 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). Examples of 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] Specific prodrugs include compounds in which the nitrogen atom of an amino, amidino, aminoalkyleneamino, iminoalkyleneamino, or guanidino group is substituted with a group having a hydroxyl group, -CO-R, -CO-OR, or -CO-ORO-CO-R (wherein R is a monovalent or divalent group, e.g., alkyl, alkylene, or aryl), or a group having the formula -C(O)-O-CP1P2-haloalkyl (wherein 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 compound of the present invention. Prodrugs can be prepared by reacting the compound of the present invention with an activated group, e.g., an acyl group, to bond, for example, a nitrogen atom in the compound to an exemplary carbonyl of the activated acyl group. Examples of activated carbonyl compounds are compounds containing a leaving group bonded to a carbonyl group, such as acyl halides, acylamines, acylpyridinium salts, acyl alkoxides, and acylphenoxides (e.g., p-nitrophenoxyacyl, dinitrophenoxyacyl, fluorophenoxyacyl, and difluorophenoxyacyl). The reaction is usually carried out in an inert solvent at a temperature of 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, or triethanolamine.

[0084] Further types of prodrugs are also encompassed. For example, a free carboxyl group of the compound of the present invention can be derivatized as an amide or an alkyl ester. As another example, the compound of the present invention containing a free hydroxy group can be derivatized as a prodrug by converting the hydroxy group to a group including, but not limited to, a phosphate ester, a hemisuccinate, a dimethylaminoacetate, or a phosphoryloxymethyloxycarbonyl group, 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, wherein the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functional groups, or wherein the acyl group is an amino acid ester as described above, is also encompassed. Prodrugs of this type are described in J. Med. Chem., (1996), 39:10. As a more specific example, the hydrogen atom of the alcohol group is replaced by (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 1~6This may involve substitution with a group such as an alkyl group, or a glycosyl group (selected independently from the groups resulting from the removal of the hydroxyl group from the hemiacetal form of a carbohydrate).

[0085] The term "leaving group" refers to a part of a first reactant that is replaced in a chemical reaction. Examples of leaving groups include, but are not limited to, halogen atoms, alkoxys, 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] "Subject," "individual," or "patient" is a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, livestock (such as cattle), sports 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 comprising administering the compounds described herein to a patient, the patient typically requires the administration of the compounds.

[0087] The terms “inhibit” and “reduce,” or any variation thereof, include any measurable reduction or complete inhibition to achieve the desired result. For example, there may be a reduction in the variable, a decrease in activity compared to normal, by about, at most 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 range of these variables.

[0088] "A therapeutically effective amount" means an amount of the 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) reduces, improves, 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 the agent can reduce the number of cancer cells, reduce tumor size, inhibit (i.e., to a low degree slow, and preferably stop) the infiltration of cancer cells into peripheral organs, inhibit (i.e., to a low degree slow, and preferably stop) tumor metastasis, inhibit (i.e., to a low degree) tumor growth, or reduce (to a low degree) one or more symptoms associated with cancer. The agent may be cell proliferation inhibitory or cytotoxic to the extent that it can prevent the growth of existing cancer cells or kill them. Regarding cancer therapy, effectiveness can be measured, for example, by evaluating the time to disease progression (TTP) or determining the response rate (RR).

[0089] "Treatment" (and variations such as "to treat" or "to treat") means a clinical intervention to alter the natural course of an individual or cell being treated, and can be carried out for the prevention of a clinical condition or in the course of such prevention. Desired effects of treatment include prevention of disease onset or recurrence, relief of symptoms, reduction of any direct or indirect pathological consequences of the disease, a stable (i.e., non-worsening) state of the disease, a decrease in the rate of disease progression, recovery or mitigation of the condition, extended survival compared to the survival expected without treatment, and remission or an improved prognosis. In some embodiments, the compounds of the present invention are used to delay the progression of a disease or condition, or to slow the progression of a disease or condition. Subjects requiring treatment include subjects who already have a condition or disease, subjects who are prone to having a condition or disease (e.g., due to genetic mutation), or subjects who need to prevent a condition or disease.

[0090] When the term “therapeutic effect” is used herein, it includes the therapeutic and / or preventive effects described above. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0091] The terms “simultaneous administration,” “administered in combination with,” and their grammatical equivalents, as used herein, encompass the administration of two or more active ingredients to an animal, including a human, such that both active ingredients and / or their metabolites are present in the subject simultaneously. Simultaneous administration includes the simultaneous administration of different compositions, the administration of different compositions at different times, or the administration of a composition containing both active ingredients.

[0092] The terms “antagonist” and “inhibitor” are used interchangeably and refer to compounds that have the ability to inhibit 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. Therefore, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. Preferred antagonists in this specification interact specifically with the target (e.g., by binding to the target), while compounds that inhibit the biological activity of the target protein by interacting with other elements of the signaling pathway in which the target protein is an element are also specifically included within this definition. Preferred biological activities inhibited by antagonists are those associated with tumor progression, growth, or expansion. As used herein, the term "agonist" means a compound that has the ability to initiate or enhance the biological function of a target protein, by whether or not it inhibits the activity or expression of the target protein.

[0093] Therefore, the term “agonist” is defined in the context of the biological role of the target polypeptide. Preferred agonists in this specification interact specifically with the target (e.g., by binding to the target), while compounds that initiate or enhance the biological activity of the target polypeptide by interacting with other elements of the signaling pathway in which the target polypeptide is an element are also specifically included within this definition.

[0094] The terms “cancer,” “cancerous,” “neoplasm,” and “tumor,” and related terms refer to or describe a physiological condition in mammals typically characterized by the uncontrolled growth of cells. A “tumor” includes one or more cancerous cells. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, gliablastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma) and lung cancer (such as small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinoma, and lung squamous cell carcinoma). Other cancers include skin cancer, keratoacanthoma, follicular carcinoma, pilocytic cell leukemia, oral cancer, pharyngeal 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, large intestine cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, genitourinary cancer, biliary tract cancer, thyroid cancer, papillary cancer, liver cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer 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 cancer, brain cancer, head and neck cancer, Hodgkin's disease, and associated metastases. Examples of neoplastic diseases include myeloproliferative disorders such as polycythemia vera, myelofibrosis such as essential thrombocytosis and primary myelofibrosis, and chronic myeloid leukemia (CML).

[0095] The term "chemotherapeutic agent" refers to an active substance useful for the treatment of a given disease, for example, cancer or an inflammatory disease. Examples of chemotherapeutic agents are known in the art, and examples include those described in U.S. Patent Application Publication No. 2010 / 0048557, which is incorporated herein by reference. Furthermore, chemotherapeutic agents include pharmaceutically acceptable salts, acids, or derivatives of any of the chemotherapeutic agents, and combinations of two or more thereof.

[0096] Unless otherwise stated, the structures shown herein are also intended to include compounds that differ only in the presence of one or more isotope-enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, such as 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 I. Isotope-labeled compounds (for example, 3 H and 14 C labeled compounds) can be useful in assays for compound or substrate tissue distribution. Tritium labeling (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful due to their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium (i.e., 2 H) and the like, can result in higher metabolic stability, which in turn may provide certain therapeutic benefits (for example, an extended in vivo half-life or a reduced required dosage). In some embodiments, in the compounds of the present invention, one or more carbon atoms are 13 C or 14It is replaced by carbon-enriched carbon. 15 O, 13 N, 11 C, and 18 Positron-emitting isotopes such as 14F are useful for positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotope-labeled compounds can generally be prepared by replacing unlabeled reagents with isotope-labeled reagents and following procedures similar to those described in the schemes or examples herein.

[0097] Any limitations discussed in relation to one embodiment of the present invention can be specifically conceived to apply to any other embodiment of the present invention. Furthermore, any compound or composition of the present invention can be used in any manner of the present invention, and any compound or composition of the present invention can be produced or utilized using any manner of the present invention.

[0098] The use of the term “or” means “and / or” unless expressly indicated to mean only substitutes or that the substitutes are mutually exclusive, even though this disclosure supports a definition that means only substitutes and “and / or.”

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

[0100] As used herein, unless otherwise clearly indicated, “a” or “an” means one or more. As used herein, “another” means at least a second or more.

[0101] The titles used herein are intended solely for structural purposes.

[0102] RAS inhibitors In one embodiment, the present invention provides compounds that can selectively bind to and / or control K-Ras, H-Ras, or N-Ras proteins of G12C, G12D, or G13D variants.

[0103] As described above, one aspect of the present invention relates to a compound of formula (I), Contains TIFF0007943888000006.tif67170 or a pharmaceutically acceptable salt thereof. [In the formula, R1 is an electrophilic moiety at position 12 of the K-Ras G12C mutant protein that can form a covalent bond with a cysteine ​​residue. R2 is H, OH, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, cyclopropyl, and -NHR (wherein 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 Alkyrenyl)NH(CH3)-(C 1~6 )alkylenyl)N(CH3)2, and -(C 1~3 )Selected from the group consisting of alkyrenyl (3-7 member heterocyclyl), R3 and R4 are H, NH2, Halo, and C, respectively. 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 A compound independently selected from the group consisting of alkylaminos and cyclopropyls, R5 stands for 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 Selected from the group consisting of cycloalkyl groups, In the formula, at least one of R2, R3, R4, and R5 is not H, or R2 and R3, R3 and R4, or R4 and R5 each have 1 to 4 substituents along with the atom to which they are bonded (where each substituent is independently OH, NH2, halo, C). 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 C is optionally substituted with (selected from the group consisting of haloalkoxys). 3~7 Cycloalkyl, 3-7 member heterocycloalkyl, C 6~14 Forms an aryl or a 5-10 membered heteroaryl, Each X has 1 to 4 substituents (where each substituent can independently be OH, NH2, halo, cyano, carboxy, carbamoyl, or C). 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Selected from the group consisting of hydroxyalkyl and 4- to 7-membered heterocyclyl groups, the two geminal substituents together form C 3~7 NH2, C (which may optionally be substituted with spirocycloalkyl or 4-7 membered spiroheterocyclyl) 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 3~7 Selected from the group consisting of cycloalkyl, 4-7 membered heterocyclyl, and 4-7 membered heterocyclylamino, Y is selected from the group consisting of -L-Y1 or Y1. Y1 is H, NH2, halo, cyano, carbamoyl, C2~6 Alkenil, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4-10 member heterocyclines that are optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 C substituted with alkyl 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, 4-10 membered heterocyclines, methyl, hydroxy, and oxo-substituted 4-10 membered heterocyclines, Each Y 1a They are independent, Hello, C 1~6 Alkyl, C 1~6 Alkoxy, 3-7 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 Selected from the group consisting of haloalkoxys, L is a bond, O, S, and N(L aSelected from the group consisting of, L a is hydrogen and C 1~3 Selected from the group consisting of alkyl groups, 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 of these is independently H, OH, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 C substituted with alkyl or 4-10 member heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, and 4-10 membered heterocyclines, n is selected from the group consisting of 0, 1, and 2.

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

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

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

[0107] R 1 In the above definition, electrophilic moieties capable of forming covalent bonds with cysteine ​​residues are determined by K-Ras G12C alkylation studies and homogeneous time-resolved fluorescence (HTRF) assays. A G12C mutation in the K-Ras gene is an amino acid change from glycine to cysteine ​​at the 12th amino acid. Compounds conforming to this disclosure were discovered using HTRF assays and K-Ras G12C alkylation assays, as further detailed elsewhere in this specification, and subsequently, NMR spectroscopy was used to confirm the specificity of the molecules to bind to G12C.

[0108] In another embodiment, the present invention relates to a compound of formula (II), Contains TIFF0007943888000007.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 (wherein 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 Alkyrenyl)NH(CH3)-(C 1~6 )alkylenyl)N(CH3)2, and -(C 1~3 )Selected from the group consisting of alkyrenyl (3-7 member heterocyclyl), R3 and R4 are H, NH2, Halo, and C, respectively. 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 A compound independently selected from the group consisting of alkylaminos and cyclopropyls, R5 stands for 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 Selected from the group consisting of cycloalkyl groups, In the formula, at least one of R2, R3, R4, and R5 is not H, or R2 and R3, R3 and R4, or R4 and R5 each have 1 to 4 substituents along with the atom to which they are bonded (where each substituent is independently OH, NH2, halo, C). 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 C is optionally substituted with (selected from the group consisting of haloalkoxys). 3~7 Cycloalkyl, 3-7 member heterocycloalkyl, C 6~14 Forms an aryl or a 5-10 membered heteroaryl, R7 is selected from the group consisting of H, cyano, and halo, and R8 and R9 are H and C, respectively. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 A component independently selected from the group consisting of hydroxyalkyl, cyano, and halo (C 1~6 Alkyl refers to methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), alkyl or arylsulfonate leaving groups, C 1~6 Alkanoylamino, C 1~6 Alkoxy, C 1~6Alkylamino, C 1~6 Alkylsulfonylamino, C 6~12 Dialkylamino, and C 1~6 (Optionally substituted with one substituent selected from the group consisting of haloalkoxys), or R7 and R8 both form a triple bond with the carbon they are bonded to, or R7 and R8 are optionally substituted with one or two halo substituents along with the carbon they are bonded to. 3~7 It forms a cycloalkenyl, and 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 Alkylsulfonylamino, C 6~12 Dialkylamino, and C 1~6 (Optionally substituted with one substituent selected from the group consisting of haloalkoxys), Each X has 1 to 4 substituents (where each substituent can independently be OH, NH2, halo, cyano, carboxy, carbamoyl, or C). 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Selected from the group consisting of hydroxyalkyl and 4- to 7-membered heterocyclyl groups, the two geminal substituents together form C 3~7 NH2, C (which may optionally be substituted with spirocycloalkyl or 4-7 membered spiroheterocyclyl) 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 3~7Selected from the group consisting of cycloalkyl, 4-7 membered heterocyclyl, and 4-7 membered heterocyclylamino, Y is selected from the group consisting of -L-Y1 or Y1. Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4-10 member heterocyclines that are optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 C substituted with alkyl 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, 4-10 membered heterocyclines, methyl, hydroxy, and oxo-substituted 4-10 membered heterocyclines, Each Y 1a They are independent, Hello, C 1~6 Alkyl, C 1~6 Alkoxy, 3-7 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 Selected from the group consisting of haloalkoxys, L is a bond, O, S, and N(L a Selected from the group consisting of, L a is hydrogen and C 1~3 Selected from the group consisting of alkyl groups, 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 of these is independently H, OH, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 C substituted with alkyl or 4-10 member heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, and 4-10 membered heterocyclines, n is selected from the group consisting of 0, 1, and 2.

[0109] In another embodiment, the present invention relates to a compound of formula (III), Contains TIFF0007943888000008.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 (wherein 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 Alkyrenyl)NH(CH3)-(C 1~6 )alkylenyl)N(CH3)2, and -(C 1~3 )Selected from the group consisting of alkyrenyl (3-7 member heterocyclyl), R3 and R4 are H, NH2, Halo, and C, respectively. 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 A compound independently selected from the group consisting of alkylaminos and cyclopropyls, R5 stands for 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 Selected from the group consisting of cycloalkyl groups, In the formula, at least one of R2, R3, R4, and R5 is not H, or R2 and R3, R3 and R4, or R4 and R5 each have 1 to 4 substituents along with the atom to which they are bonded (where each substituent is independently OH, NH2, halo, C). 1~3 Alkyl, C 1~3Haloalkyl, C 1~3 Alkoxy, and C 1~3 C is optionally substituted with (selected from the group consisting of haloalkoxys). 3~7 Cycloalkyl, 3-7 member heterocycloalkyl, C 6~14 Forms an aryl or a 5-10 membered heteroaryl, R 10 is R 10a and -C(O)-R 10a Selected from the group consisting of, R 10a It is selected from the group consisting of oxiranil and aziridinil, Each X has 1 to 4 substituents (where each substituent can independently be OH, NH2, halo, cyano, carboxy, carbamoyl, or C). 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Selected from the group consisting of hydroxyalkyl and 4- to 7-membered heterocyclyl groups, the two geminal substituents together form C 3~7 NH2, C (which may optionally be substituted with spirocycloalkyl or 4-7 membered spiroheterocyclyl) 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 3~7 Selected from the group consisting of cycloalkyl, 4-7 membered heterocyclyl, and 4-7 membered heterocyclylamino, Y is selected from the group consisting of -L-Y1 or Y1. Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4-10 member heterocyclines that are optionally substituted with substituents1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 C substituted with alkyl 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, 4-10 membered heterocyclines, methyl, hydroxy, and oxo-substituted 4-10 membered heterocyclines, Each Y 1a They are independent, Hello, C 1~6 Alkyl, C 1~6 Alkoxy, 3-7 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 Selected from the group consisting of haloalkoxys, L is a bond, O, S, and N(L a Selected from the group consisting of, L a is hydrogen and C 1~3 Selected from the group consisting of alkyl groups, 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 of these is independently H, OH, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 C substituted with alkyl or 4-10 member heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, and 4-10 membered heterocyclines, 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 its pharmaceutically acceptable salt, R2 is NH2. In one embodiment of the compound of formula (I), formula (II), or formula (III) or its pharmaceutically acceptable salt, R2 is -NHR, where R is C 1~6 Alkyl or C 1~6It is an alkoxy. In another 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(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 its pharmaceutically acceptable salt, R3 and R4 are independently H, halo, and C. 1~6 Alkyl, C 1~6 Selected from the group consisting of haloalkyl and cyclopropyl. In one embodiment, R3 is C 1~3 Alkyl (e.g., methyl or ethyl), or C 1~3 It is a haloalkyl (e.g., -CF3 or -CH2CF3). In another embodiment of the compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, R3 is hydrogen. In one embodiment of the compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, R4 is hydrogen, halo, C 1~3 Alkyl, C 1~3 It is a haloalkyl or cyclopropyl. In another embodiment of the compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, R4 is hydrogen or halo. In another embodiment of the compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, R4 is C 1~3 It is alkyl (e.g., methyl or ethyl). In another embodiment of the compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, R4 is methyl. In yet another embodiment of the compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, R4 is -CF3. In another embodiment of the 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 its pharmaceutically acceptable salt, R5 is H, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, and C 3~7 Selected from the group consisting of cycloalkyls. In one embodiment, R5 is C 1~6 It is a haloalkyl. 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 It is a haloalkyl. 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 It is alkyl. 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 It is a haloalkoxy. In yet another embodiment of the 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 the 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 It is an alkyl group, and R5 is CF3.

[0116] According to some embodiments of the compounds of formula (I), formula (II), or formula (III) or their pharmaceutically acceptable salts, R5 is cyclopropyl.

[0117] According to some embodiments of the compounds of formula (I), formula (II), or formula (III) or their pharmaceutically acceptable salts, at least two of R2, R3, R4, and R5 are other than H.

[0118] According to some embodiments of the compounds of formula (I), formula (II), or formula (III) or their pharmaceutically acceptable salts, at least three of R2, R3, R4, and R5 are other than H.

[0119] According to some embodiments of the compound of formula (I), formula (II), or formula (III) or its pharmaceutically acceptable salt, R4 and R5, together with the atom to which they are bonded, each have 1 to 4 substituents (where each substituent is independently OH, NH2, halo, C). 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 C is optionally substituted with (selected from the group consisting of haloalkoxys). 3~7 Cycloalkyl, 3-7 member heterocycloalkyl, C 6~14 They form aryl or 5-10 membered heteroaryl groups.

[0120] According to some embodiments of the compound of formula (I), formula (II), or formula (III) or its pharmaceutically acceptable salt, R4 and R5, along with the atom to which they are bonded, have 1 to 4 substituents (where each substituent is independently OH, NH2, halo, C). 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 C (selected from the group consisting of haloalkoxys) is optionally substituted 6~14 Form an aryl group.

[0121] According to some embodiments of the compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, R4 and R 5は Each of these atoms, along with the atom to which they are bonded, has 1 to 4 substituents (where each substituent is independently OH, NH2, halo, C). 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 The C6 aryl is optionally substituted with a compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof. 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 unsubstituted.

[0122] According to some embodiments of the compounds of formula (I), formula (II), or formula (III) or their pharmaceutically acceptable salts, the C6 aryl is substituted with 1 to 4 substituents (where each substituent is independently a halo). According to some embodiments of the compound of formula (I), formula (II), or formula (III) or its pharmaceutically acceptable salt, Y is -L-Y1. In one embodiment of the compound of formula (I), formula (II), or formula (III) or its pharmaceutically acceptable salt, L is O or N(L a ) is. 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, Y1 is C 2~6 Alkenil, C 1~6 C substituted with alkyl, or 4-10 member heterocyclyl or methyl heterocyclyl substituents 1~6 It is alkyl. In another embodiment of the compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, Y1 is C 1~6 C substituted with alkyl, or 4-10 member heterocyclyl or methyl heterocyclyl substituents 1~6It is alkyl. In yet another embodiment of the compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, Y1 is C substituted with a 4- to 10-membered heterocyclyl or methyl heterocyclyl substituent. 1~6 It is alkyl. In another embodiment of the compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, Y1 is a C substituted with a 4- to 10-membered heterocyclyl or methyl heterocyclyl substituent (the heterocyclyl or methyl heterocyclyl substituent contains at least one nitrogen heteroatom). 1~6 It is alkyl. In one embodiment, the heterocyclyl or methyl heterocyclyl substituent is the pyrrolidinyl moiety. In one embodiment, the pyrrolidinyl is substituted with F. In one embodiment, the heterocyclyl and methyl heterocyclyl moieties are independently OH, NH2, halo, cyano, and C. 1~6 Alkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, or C 1~6 It is optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyalkyl groups.

[0123] In one embodiment, Y is a compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof. The filename is TIFF0007943888000009.tif22170. In one embodiment, Y is The code is TIFF0007943888000010.tif21170. In another embodiment of a compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, Y is TIFF0007943888000011.tif19170. In yet another embodiment of a compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, Y is TIFF0007943888000012.tif20170. In yet another embodiment of a compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, Y is The filename is TIFF0007943888000013.tif20170.

[0124] According to some embodiments of the compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, R 6a is hydrogen, halo, or C 1~3 It is alkyl. According to some embodiments of the compound of formula (I), formula (II), or formula (III) or its pharmaceutically acceptable salt, R 6b is hydrogen, halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 It is an alkoxy or cyclopropyl. In one embodiment, R is a compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof. 6b is hydrogen, halo, or C 1~3 It is a haloalkyl compound. In another embodiment of the 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 a halo (e.g., Cl or F). In yet another embodiment of the compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt 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 its pharmaceutically acceptable salt, R 6c is hydrogen or a halo. In one embodiment, R is a compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof. 6c is hydrogen. In one embodiment, R 6c is a halo. In one embodiment, R is a compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof. 6b and R 6c In another embodiment, R 6b It is a halo, R 6c It is hydrogen.

[0125] This specification further provides compounds of formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts thereof. [In the formula, Y is TIFF0007943888000014.tif22170, and X is The filename is TIFF0007943888000015.tif29170, where R2 is NH2, R3 is hydrogen, and R4 is hydrogen or C 1~3 It is methyl, and R5 is CF3.

[0126] According to embodiments of formula (I), formula (II), or formula (III), or their pharmaceutically acceptable salts, the compound is selected from the group consisting of the compounds in Table 1 below or their pharmaceutically acceptable salts. Table 1. Exemplary compounds of the present disclosure. Salts of such compounds can also be conceived. For the preparation of such compounds, see the Examples section. Compounds not having the preparation details expressly described in the Examples can be prepared by modifying the preparation details of other compounds provided herein using methods generally known in the art. TIFF0007943888000016.tif230170TIFF0007943888000017.tif218170TIFF0007943888000018.tif189170TIFF0007943888000019.tif204170TIFF0007943888000020.tif214170TIFF0007943888000021.tif237170TIFF0007943888000022.tif248170TIFF0007943888000023.tif211170TIFF0007943888000024.tif215170TIFF0007943888000025.tif214170TIFF0007943888000026.tif237170TIFF0007943888000027.tif230170TIFF0007943888000028.tif249170TIFF0007943888000029.tif215170TIFF0007943888000030.tif218170TIFF0007943888000031.tif226170TIFF0007943888000032.tif227170TIFF0007943888000033.tif206170TIFF0007943888000034.tif237170TIFF0007943888000035.tif249170TIFF0007943888000036.tif206170TIFF0007943888000037.tif219170TIFF0007943888000038.tif224170TIFF0007943888000039.tif220170TIFF0007943888000040.tif233170TIFF0007943888000041.tif227170TIFF0007943888000042.tif229170TIFF0007943888000043.tif225170TIFF0007943888000044.tif234170TIFF0007943888000045.tif246170TIFF0007943888000046.tif213170TIFF0007943888000047.tif248170TIFF0007943888000048.tif240170TIFF0007943888000049.tif234170TIFF0007943888000050.tif225170TIFF0007943888000051.tif241170TIFF0007943888000052.tif149170.

[0127] In another embodiment, according to some embodiments of the 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 (wherein 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 Alkyrenyl)NH(CH3)-(C 1~6 )alkylenyl)N(CH3)2, and -(C 1~3 )Selected from the group consisting of alkyrenyl (3-7 member heterocyclyl), R3 and R4 are H, NH2, Halo, and C, respectively. 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 alkylaminos, R5 consists of H, Cl, Br, I, NH2, and 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 Selected from the group consisting of cycloalkyl groups, At least two of R2, R3, R4, and R5 are not H, or R2 and R3, R3 and R4, or R4 and R5 each have 1 to 4 substituents along with the atom to which they are bonded (where each substituent is independently OH, NH2, halo, C). 1~3 Alkyl, C 1~3 Haloalkyl and C 1~3 C is optionally substituted with (selected from the group consisting of haloalkoxys). 3~7 Cycloalkyl, 3-7 member heterocycloalkyl, or C 6~14 Forming an aryl group, Each X has 1 to 4 substituents (where each substituent can independently be OH, NH2, halo, cyano, carboxy, carbamoyl, or C). 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Selected from the group consisting of hydroxyalkyl and 4- to 7-membered heterocyclyl groups, the two geminal substituents together form C 3~7 NH2, C (which may optionally be substituted with spirocycloalkyl or 4-7 membered spiroheterocyclyl) 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 3~7 Selected from the group consisting of cycloalkyl, 4-7 membered heterocyclyl, and 4-7 membered heterocyclylamino, Y is selected from the group consisting of -L-Y1 or Y1. Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4-10 member heterocyclines that are optionally substituted with substituents 1~6Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 C substituted with alkyl 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, 4-10 membered heterocyclines, methyl, hydroxy, and oxo-substituted 4-10 membered heterocyclines, Each Y 1a They are independent, Hello, C 1~6 Alkyl, C 1~6 Alkoxy, 3-7 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 Selected from the group consisting of haloalkyls, L is a bond, O, S, and N(L a Selected from the group consisting of, L a is hydrogen and C 1~3 Selected from the group consisting of alkyl groups, 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 of these is independently H, OH, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 C substituted with alkyl or 4-10 member heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, and 4-10 membered heterocyclines, n is selected from the group consisting of 0, 1, and 2.

[0128] In embodiments of compounds of formula (I), formula (II), or formula (III) or their pharmaceutically acceptable salts, when R2 and R3, R3 and R4, or R4 and R5 each form a ring with the atom to which they are bonded, the non-ring substituents should be understood to be defined as described above with respect to formula (I).

[0129] In another embodiment, the present invention relates to a compound of formula (IV), Contains TIFF0007943888000053.tif68170 or a pharmaceutically acceptable salt thereof. [In the formula, R1 is an electrophilic moiety at position 12 of the K-Ras G12C mutant protein that can form a covalent bond with a cysteine ​​residue. Each X has 1 to 4 substituents (where each substituent can independently be OH, NH2, halo, cyano, carboxy, carbamoyl, or C). 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Selected from the group consisting of hydroxyalkyl and 4- to 7-membered heterocyclyl groups, the two geminal substituents together form C 3~7 NH2, C (which may optionally be substituted with spirocycloalkyl or 4-7 membered spiroheterocyclyl) 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 3~7 Selected from the group consisting of cycloalkyl, 4-7 membered heterocyclyl, and 4-7 membered heterocyclylamino, Y is selected from the group consisting of -L-Y1 or Y1. Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4-10 member heterocyclines that are optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 2~6 Alkinyl, C 1~6Alkylamino, C 6~14 Ariel, C 1~6 C substituted with alkyl 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, 4-10 membered heterocyclines, methyl, hydroxy, and oxo-substituted 4-10 membered heterocyclines, Each Y 1a They are independent, Hello, C 1~6 Alkyl, C 1~6 Alkoxy, 3-7 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 Selected from the group consisting of haloalkyls, L is a bond, O, S, and N(L a Selected from the group consisting of, L a is hydrogen and C 1~3 Selected from the group consisting of alkyl groups, 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 of these is independently H, OH, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6C substituted with alkyl or 4-10 member heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, and 4-10 membered heterocyclines, n is selected from the group consisting of 0, 1, and 2. R 11 teeth, Selected from the group consisting of TIFF0007943888000054.tif199170 and TIFF0007943888000055.tif222170.

[0130] According to some embodiments of the compound of formula (I), formula (II), formula (III), or formula (IV) or its pharmaceutically acceptable salt, Y is Y1, and Y1 is H, C 1~6 Alkyl and C 1~6 Selected from the group consisting of haloalkyls.

[0131] According to some embodiments of the compounds of formula (I), formula (II), formula (III), or formula (IV) or their pharmaceutically acceptable salts, Y1 is H.

[0132] According to some embodiments of the compound of formula (I), formula (II), formula (III), or formula (IV) or its pharmaceutically acceptable salt, Y is -L-Y1, and L is O and N(L a Selected from the group consisting of L a H is C, and Y1 is C 1~6C substituted with alkyl or 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 compounds of formula (I), formula (II), formula (III), or formula (IV) or their pharmaceutically acceptable salts, Y1 is a monocyclic aryl or monocyclic heteroaryl.

[0134] According to some embodiments of the compound of formula (I), formula (II), formula (III), or formula (IV) or its pharmaceutically acceptable salt, Y is -L-Y1, and L is O and N(L a Selected from the group consisting of L a H is C, and Y1 is C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4-10 member heterocyclines that are optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Dialkylamino-substituted C 3~7 Selected from the group consisting of cycloalkyls and methyl-substituted 4-10 membered heterocyclines, each Y 1a They are independent, Hello, C 1~6 Alkyl, C 1~6 Alkoxy, 3-7 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 Selected from the group consisting of haloalkoxys.

[0135] According to some embodiments of the compound of formula (I), formula (II), formula (III), or formula (IV) or its pharmaceutically acceptable salt, Y is -L-Y1 and L is N(L a ) and L a H is C, 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 its pharmaceutically acceptable salt, Y is -L-Y1, L is O, and Y1 is 1 to 4 Y 1a C substituted with 4-10 member heterocyclines that are optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Dialkylamino-substituted C 3~7 Selected from the group consisting of cycloalkyls and methyl-substituted 4-10 membered heterocyclines, each Y 1a They are independent, Hello, C 1~6 Alkyl, C 1~6 Alkoxy, 3-7 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 Selected from the group consisting of haloalkoxys.

[0137] According to some embodiments of the compound of formula (I), formula (II), formula (III), or formula (IV) or its pharmaceutically acceptable salt, Y is -L-Y1, and L is O and N(L a Selected from the group consisting of L ais H, and Y1 is C substituted with a 4-10 membered methyl heterocyclyl 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 The data is selected from the group consisting of TIFF0007943888000056.tif231170 and TIFF0007943888000057.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 filename is TIFF0007943888000058.tif21170.

[0140] In one embodiment, Y is a compound of formula (I), formula (II), formula (III), or formula (IV) or a pharmaceutically acceptable salt thereof. TIFF0007943888000059.tif20170. In another embodiment of a compound of formula (I), formula (II), formula (III), or formula (IV) or a pharmaceutically acceptable salt thereof, Y is TIFF0007943888000060.tif20170. In yet another embodiment of a compound of formula (I), formula (II), formula (III), or formula (IV) or a pharmaceutically acceptable salt thereof, Y is TIFF0007943888000061.tif19170. In yet another embodiment of a compound of formula (I), formula (II), formula (III), or formula (IV) or a pharmaceutically acceptable salt thereof, Y is The filename is TIFF0007943888000062.tif20170.

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

[0142] According to some embodiments of the compound of formula (I), formula (II), formula (III), or formula (IV) or a pharmaceutically acceptable salt thereof, R 6b H, Haro, C 1~6 Alkoxy, C 1~6 Alkyl sulfonyl, C 1~6 Haloalkyl, C 3~7 Cycloalkyl, C 1~6 The material is selected from the group consisting of haloalkylthios and 4- to 10-membered heterocyclines.

[0143] According to some embodiments of the compound of formula (I), formula (II), formula (III), or formula (IV) or a pharmaceutically acceptable salt thereof, R 6b H, Haro, C 1~3 Selected from the group consisting of haloalkyls.

[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 The group 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 It is a halo.

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

[0147] 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 each optionally 1 to 4 substituents (wherein each substituent is independently OH, NH2, halo, cyano, carboxy, carbamoyl, C 1~6 Alkyl, C 1~6 C is optionally substituted with a group selected from haloalkyls and 4- to 7-membered heterocyclines. 3~7 The compound is a cycloalkyl, a 4-7 membered heterocyclyl, or a 4-7 membered heterocyclylamino. In one embodiment of the compound of formula (I), formula (II), formula (III), or formula (IV) or a pharmaceutically acceptable salt thereof, X is each optionally 1-4 substituents (wherein each substituent is independently OH, NH2, halo, cyano, C 1~6 Alkyl and C 1~6 C (selected from the group consisting of haloalkyls) is optionally substituted. 3~7 It is a cycloalkyl or a 4- to 7-membered heterocycline. In another embodiment of the compound of formula (I), formula (II), formula (III), or formula (IV) or a pharmaceutically acceptable salt thereof, X is each optionally 1 to 4 substituents (wherein each substituent is independently OH, NH2, halo, cyano, C 1~6 Alkyl and C 1~6 The piperazinyl or azetidinyl moiety is optionally substituted with a substituent selected from the group consisting of haloalkyl groups. In yet another embodiment of the compound of formula (I), formula (II), formula (III), or formula (IV) or a pharmaceutically acceptable salt thereof, X is optionally 1 to 4 substituents (where each substituent is independently halo, cyano, C 1~3 Alkyl and C 1~3 This is a piperazinyl moiety that is optionally substituted with a molecule (independently selected from the group consisting of haloalkyl groups).

[0148] According to some embodiments of the compounds of formula (I), formula (II), formula (III), or formula (IV) or their pharmaceutically acceptable salts, X is a 4- to 7-membered heterocycline.

[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 has 1 to 4 substituents (where each substituent is independently cyano, C 1~6 Alkyl, C 1~6 Cyanoalkyl and C 1~6 It is a 4- to 7-membered heterocycline substituted with (selected from the group consisting of haloalkyls).

[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 Selected from the group consisting of TIFF0007943888000063.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 Selected from the group consisting of TIFF0007943888000064.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 Selected from the group consisting of TIFF0007943888000065.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 filename is TIFF0007943888000066.tif29170.

[0154] In another embodiment of a compound of formula (I), formula (II), formula (III), or formula (IV) or a pharmaceutically acceptable salt thereof, X is The filename is TIFF0007943888000067.tif26170.

[0155] In another embodiment of a compound of formula (I), formula (II), formula (III), or formula (IV) or a pharmaceutically acceptable salt thereof, X is The filename is TIFF0007943888000068.tif27170.

[0156] According to some embodiments of the compound of formula (IV) or its pharmaceutically acceptable salt, R 11 teeth The filename is TIFF0007943888000069.tif103170.

[0157] According to some embodiments of the compound of formula (IV) or its pharmaceutically acceptable salt, R 11 teeth The filename is TIFF0007943888000070.tif24170.

[0158] According to some embodiments of the compound of formula (IV) or its pharmaceutically acceptable salt, R 11 teeth The filename is TIFF0007943888000071.tif22170.

[0159] According to some embodiments of the compounds of formula (I), formula (II), formula (III), or formula (IV) or their pharmaceutically acceptable salts, 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 Selected from the group consisting of TIFF0007943888000072.tif82170. [In the formula, R 12 is C 1~6 Alkanoyl, C 1~6 Alkyl and C 1~6 Selected from the group consisting of alkylsulfonyls, R 13 H, C 1~6 Alkyl and C 1~6 Selected from the group consisting of haloalkyls, R 13aIt is a halo, R 14 This 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 Selected from the group consisting of TIFF0007943888000073.tif35170.

[0162] According to some embodiments of the compound of formula (I) or formula (IV) or a pharmaceutically acceptable salt thereof, R1 is The filename is TIFF0007943888000074.tif21170.

[0163] According to some embodiments of the compound of formula (I) or formula (IV) or a pharmaceutically acceptable salt thereof, R1 is The filename is TIFF0007943888000075.tif17170.

[0164] According to some embodiments of the compound of formula (I) or formula (IV) or a pharmaceutically acceptable salt thereof, R1 is The filename is TIFF0007943888000076.tif19170.

[0165] According to some embodiments of the compound of formula (I) or formula (IV) or a pharmaceutically acceptable salt thereof, R1 is The filename is TIFF0007943888000077.tif17170.

[0166] According to some embodiments of the compound of formula (II) or its pharmaceutically acceptable salt, R7 is selected from the group consisting of H, cyano, and halo, and R8 and R9 are H and C, respectively. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 A component independently selected from the group consisting of hydroxyalkyl, cyano, and halo (C 1~6Alkyl refers to methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), alkyl or arylsulfonate leaving groups, C 1~6 Alkanoylamino, C 1~6 Alkoxy, C 1~6 Alkylamino, C 1~6 Alkylsulfonylamino, C 6~12 Dialkylamino, and C 1~6 (Optionally substituted with one substituent selected from the group consisting of haloalkoxys).

[0167] According to some embodiments of the compound of formula (II) or its pharmaceutically acceptable salts, R7 and R8 together form a triple bond with the carbon to which they are bonded, or R7 and R8 together with the carbon to which they are bonded are optionally substituted with one or two halo substituents. 3~7 It forms a cycloalkenyl, and 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 Alkylsulfonylamino, C 6~12 Dialkylamino, and C 1~6 (Optionally substituted with one substituent selected from the group consisting of haloalkoxys).

[0168] According to some embodiments of the compound of formula (II) or its pharmaceutically acceptable salt, R7, R8, and R9 are each H.

[0169] According to some embodiments of the compound of formula (III) or its pharmaceutically acceptable salt, R 10 -C(O)-R 10a And R 10a It is oxyranil.

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

[0171] According to some embodiments of the compound of formula (I), the compound It has a formula selected from the group consisting of TIFF0007943888000078.tif241170 and TIFF0007943888000079.tif124170, or a pharmaceutically acceptable salt thereof.

[0172] In one embodiment, Y is a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik), or (Il) or a pharmaceutically acceptable salt thereof, The code is TIFF0007943888000080.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 This is TIFF0007943888000081.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 The code is TIFF0007943888000082.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 This is TIFF0007943888000083.tif19170. In yet 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 filename is TIFF0007943888000084.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 formula (Ib) or (Il), or a pharmaceutically acceptable salt thereof.

[0175] According to some embodiments of the compound of formula (I), the compound has formula (Ia), or a pharmaceutically acceptable salt thereof.

[0176] According to some embodiments of the compound of formula (I), the compound has formula (Ib), or a pharmaceutically acceptable salt thereof.

[0177] According to some embodiments of the compound of formula (I), the compound has formula (Ic), or a pharmaceutically acceptable salt thereof.

[0178] According to some embodiments of the compound of formula (I), the compound has formula (Il), or a pharmaceutically acceptable salt thereof.

[0179] According to some embodiments of the compound of formula (IV) or its pharmaceutically acceptable salt, the compound It has a formula selected from the group consisting of TIFF0007943888000085.tif242170, or a pharmaceutically acceptable salt thereof.

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

[0181] In one embodiment of a compound of formula (I), (II), (III), or (IV), the compound is one of the compounds described in Table 1 of this specification, or a pharmaceutically acceptable salt thereof.

[0182] In another embodiment of the compounds 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 the 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 pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof. According to other embodiments 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 their pharmaceutically acceptable salts, may contain one or more chiral centers. Thus, enantiomers, diastereomers, and other stereoisomers may arise, defined from the viewpoint of absolute stereochemistry as (R)- or (S)-, or with respect to amino acids as (D)- or (L)-. Accordingly, embodiments include all possible such 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 they can be 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 racemic compounds (or racemic compounds of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). If a compound described herein contains an olefinic double bond or other centers due to geometric asymmetry, and unless otherwise specified, the compound is intended to contain both E and Z geometric isomers. Similarly, all tautomer forms are also intended to be included.

[0186] Embodiments of the present invention include all forms of rotational isomers and structurally restricted states of the compounds of the present invention. This also includes atropisomers, which are stereoisomers resulting from rotational restrictions around a single bond, where the energy difference due to steric strain or other factors is sufficiently high to create a rotational barrier for the separation of individual conformational isomers. For example, certain compounds of the present invention may exist as a mixture of atropisomers, or they may be purified or concentrated to 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 substantially purified atropisomers. In some embodiments, the compound of formula (I) is substantially purified R-atropisomers. In some other embodiments, the compound of formula (I) is substantially purified R-atropisomers.

[0188] Synthesis of RAS inhibitors The compounds of this disclosure can be prepared by various methods shown in the explanatory synthesis reaction schemes illustrated and described below. The starting materials and reagents used to prepare these compounds are generally available from commercial suppliers such as Aldrich Chemical Co., or from publications such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; RC La Rock, 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, ARKatritzky and CWRees (Eds.) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, ARKatritzky and CWRees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New The compounds are prepared either by following the procedures described in reference literature such as York, 1991, vol. 1-40, or by methods known to those skilled in the art. The following synthesis reactions are merely illustrative of some ways in which the compounds of the present invention can be synthesized, and various modifications can be made to these synthesis reaction schemes, as will be suggested to those skilled in the art who refer to the disclosures contained herein.

[0189] For illustrative purposes, the following reaction scheme provides a route for the synthesis of the compounds and key intermediates of the present invention. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will understand that other synthetic routes are available. Several specific starting materials and reagents are described in the scheme and discussed below, but by substituting other starting materials and reagents, a variety of derivatives or reaction conditions can be provided. Furthermore, many of the compounds prepared by the methods described below can be further modified in the interest of this disclosure using conventional chemical phenomena well known to those skilled in the art.

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

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

[0192] In the following scheme, some of the compounds are described with generalized substituents. However, those skilled in the art will quickly understand that by changing the properties of the substituents, a variety of compounds conceivable in this invention can be obtained. Furthermore, the reaction conditions are illustrative, and alternative conditions are well known. The reaction sequence in the following examples is not intended to limit the scope of the invention as described in the claims.

[0193] Those skilled in the art will recognize that other compounds of the present invention can be prepared by promptly adapting the chemical reactions described. For example, the synthesis of non-exemplary compounds according to the present invention can be successfully carried out by modifications obvious to those 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 changes 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 present invention.

[0194] Treatment methods using RAS inhibitors, and methods for using RAS inhibitors. The compounds of this disclosure are useful as Ras inhibitors. In one embodiment, the compounds of this disclosure are useful as K-Ras inhibitors. In another embodiment, the compounds of this disclosure are useful as N-Ras inhibitors. In yet another embodiment, the compounds of this disclosure are useful as H-Ras inhibitors. Accordingly, in one embodiment, a method is provided for inhibiting intracellular Ras activity (e.g., K-Ras, H-Ras, and / or N-Ras activity) by contacting cells such as ex vivo cells with the compounds of the present invention or pharmaceutically acceptable salts thereof. It is understood that the therapeutic methods described herein may, in certain embodiments, further include measuring the presence or absence of a G12 Ras mutation before administering the compounds described herein or pharmaceutically acceptable salts thereof.

[0195] The present invention further provides a method for preventing, treating, or reducing the severity of a disease or condition in a patient that responds to inhibition of Ras (e.g., K-Ras, H-Ras, and / or N-Ras), comprising administering to the patient a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

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

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

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

[0199] The present invention also provides a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0200] The present invention also provides a method for inhibiting Ras (e.g., K-Ras, H-Ras, and / or N-Ras) in patients requiring treatment, comprising administering to the patient a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

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

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

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

[0204] The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The compound of the present invention, comprising such a pharmaceutical composition, can be used in the methods described herein.

[0205] Embodiments of this disclosure provide a method for inhibiting Ras-mediated cellular signaling, comprising contacting cells with one or more of the compounds disclosed herein or pharmaceutically acceptable salts thereof in a therapeutically effective amount. Inhibition of Ras-mediated signaling can be evaluated and demonstrated by various methods known in the art. Non-limiting examples include (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 pMEK levels, a decrease in the amount of signaling molecules downstream of the Ras pathway, and / or (e) a decrease in the binding of the Ras complex to downstream signaling molecules, including but not limited to Raf. Kits and commercially available assays can be used to measure one or more of the above.

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

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

[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). Therefore, certain embodiments relate to administering the disclosed compounds of the present invention or pharmaceutically acceptable salts thereof (e.g., in the form of pharmaceutical compositions) to patients requiring treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the compounds disclosed herein can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In another embodiment, the compounds of the present invention or pharmaceutically acceptable salts thereof are useful in treating lymphomas, such as Hodgkin lymphoma or all subtypes of non-Hodgkin lymphoma.

[0209] Determining whether a tumor or cancer contains a G12C K-Ras, H-Ras, or N-Ras mutation can be done 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 the predicted K-Ras, H-Ras, or N-Ras mutant protein. The sequences of wild-type human K-Ras (e.g., deposit number NP203524), H-Ras (e.g., deposit number NP001123914), and N-Ras (e.g., deposit 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 higher-order structure 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 thawing assays, and microarray analysis. In some embodiments, real-time PCR is used to evaluate G12C K-Ras, H-Ras, or N-Ras mutations in a sample. In real-time PCR, a fluorescent probe specific to K-Ras, H-Ras, or N-Ras G12C mutations is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, K-Ras, H-Ras, or N-Ras G12C mutations are identified using a direct sequencing method of a specific region (e.g., exon 2 and / or exon 3) within the K-Ras, H-Ras, or N-Ras gene. 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, the detection of K-Ras, H-Ras, or N-Ras mutations using a specific binder (e.g., an antibody) 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 G12C K-Ras, H-Ras, or N-Ras mutations. In some embodiments, the sample is taken from a subject having 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 treated with a cell lysate. In some embodiments, the sample is treated with DNA or RNA.

[0212] Embodiments also relate to a method for treating hyperproliferative disorders in mammals, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to 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 malformation / rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, osteosarcoma, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, embryonic tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia Disease (CML), chronic myeloproliferative disorder, colorectal cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, trophoblastic tumor of pregnancy, pilocytic cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, insular sarcoma Cystic 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, median line carcinoma, oral cancer, multiple endocrine neoplastic syndrome, multiple myeloma / plasmacytic neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC) This relates to the treatment of cancers such as 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, trophoblast tumor, childhood abnormal cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.In some embodiments, the above method relates to the treatment of noncancerous hyperproliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or benign prostatic hyperplasia (BPH).

[0213] In certain specific embodiments, the present invention relates to a method for treating lung cancer, the method comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition containing 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, adenomas, carcinoid tumors, and undifferentiated carcinomas. In some embodiments, the present invention provides a method for inhibiting intracellular K-Ras, H-Ras, or N-Ras G12C activity, the method comprising contacting the cells with a sufficient amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to inhibit the intracellular K-Ras, H-Ras, or N-Ras G12C activity. In some embodiments, the present invention provides a method for inhibiting K-Ras, H-Ras, or N-Ras G12C activity in tissue, comprising contacting the tissue with a sufficient amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to inhibit the activity of K-Ras, H-Ras, or N-Ras G12C in the tissue.

[0214] In some embodiments, the present invention provides a method for inhibiting K-Ras, H-Ras, or N-Ras G12C activity in a living organism, comprising contacting the living organism with a sufficient amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to inhibit the activity of K-Ras, H-Ras, or N-Ras G12C in the living organism. In some embodiments, the present invention provides a method for inhibiting K-Ras, H-Ras, or N-Ras G12C activity in an animal, comprising contacting the animal with a sufficient amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to inhibit the activity of K-Ras, H-Ras, or N-Ras G12C 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, comprising contacting the mammal with a sufficient amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to inhibit the activity of K-Ras, H-Ras, or N-Ras G12C 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, comprising contacting the human with a sufficient amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to inhibit the activity of K-Ras, H-Ras, or N-Ras G12C 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 requiring treatment of the disease.

[0215] In some embodiments, the present invention provides a method for treating cancer, comprising administering to an individual in need of cancer a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention. In some embodiments, the individual is a human. In some embodiments, administration is via an oral route. In some embodiments, administration is via injection. In some embodiments, the cancer is mediated by K-Ras G12C, H-Ras G12C, or N-Ras G12C mutations. In some embodiments, the cancer is mediated by K-Ras G12C mutations. 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, appendiceal 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 controlling 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 a method for inhibiting the proliferation of a cell population, comprising contacting the cell population with a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibition of proliferation is measured as a decrease in the 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 requiring treatment of the disease, the method comprising measuring whether the individual has the mutation, and, if the individual has the mutation, administering to the individual a therapeutically effective amount of the 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, appendiceal 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 labeled K-Ras G12C, H-Ras G12C, or N-Ras G12C mutant proteins, 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 requiring inhibition of tumor metastasis a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, to the individual requiring inhibition of tumor metastasis.

[0221] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the manufacture of a drug for the treatment of cancer. In some embodiments, the drug is formulated for oral administration. In some embodiments, the drug is formulated for injection. In some embodiments, the cancer is mediated by K-Ras G12C, H-Ras G12C, or N-Ras G12C mutations. In some embodiments, the cancer is mediated by K-Ras G12C mutations. In some embodiments, the cancer is mediated by H-Ras G12C mutations. In some embodiments, the cancer is mediated by N-Ras G12C mutations. 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, appendiceal 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 the compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a drug for inhibiting tumor metastasis.

[0222] In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, for use in methods of treating the body of a human or animal by therapeutic means. In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, for use in methods of treating cancer. In some embodiments, cancer is mediated by K-Ras G12C, H-Ras G12C, or N-Ras G12C mutations. In some embodiments, cancer is mediated by K-Ras G12C mutations. In some embodiments, cancer is mediated by H-Ras G12C mutations. In some embodiments, cancer is mediated by N-Ras G12C mutations. In some embodiments, cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, cancer is lung cancer, colorectal cancer, appendiceal cancer, or pancreatic cancer. In one embodiment, cancer is colorectal cancer. In another embodiment, cancer is pancreatic cancer. In some embodiments, cancer is lung adenocarcinoma. In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, for use in methods for inhibiting tumor metastasis.

[0223] This specification further provides a method for treating lung cancer in a patient having lung cancer, comprising administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition containing the same). In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC). NSCLC may be, for example, adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In another embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is an adenoma, carcinoid tumor, or undifferentiated carcinoma. The lung cancer may be stage I or II. In one embodiment, the lung cancer may be stage III or IV. The method provided herein includes administering 1 L of the compound as a treatment. In one embodiment, the lung cancer contains a G12C KRas mutation.

[0224] This specification still provides a method for treating pancreatic cancer in a patient having pancreatic cancer, comprising administering to the patient a therapeutically effective amount of one of the compounds 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 contains a G12C KRas mutation.

[0225] This specification still provides a method for treating colorectal cancer in a patient having colorectal cancer, comprising administering to the patient a therapeutically effective amount of one of the compounds described herein or a pharmaceutically acceptable salt thereof. In one embodiment, the colorectal cancer is stage I or II. In another embodiment, the colorectal cancer is stage III or IV. In one embodiment, the colorectal cancer contains a G12C KRas mutation.

[0226] Furthermore, this specification provides a method for treating organ-cross-organ G12C mutation-mediated KRas cancer. In one embodiment of such a method, the method is a. To identify the absence or presence of the KRas G12C mutation in samples taken from patients diagnosed with suspected cancer, b. Administering to the patient a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, Includes.

[0227] In one embodiment of such a method, a patient is diagnosed with the cancer described herein. In another embodiment of such a method, the sample is a tumor sample taken from a subject. In one embodiment of such a method, the sample is taken before the administration of any treatment. In another embodiment of such a method, the sample is taken before the administration of the compound described herein or a pharmaceutically acceptable salt thereof, and after the administration of another chemotherapeutic agent. In another embodiment of such a method, the 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 a pharmaceutical composition or agent comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one therapeutically inactive excipient, as well as a method of using the compound of the present invention to prepare such compositions and agents.

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

[0230] In one example, a therapeutically effective amount of the 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 the recipient at the dose and concentration used in a dosage form at ambient temperature and appropriate pH. The pH of the formulation depends mainly on the specific use and concentration of the compound, but is typically in the range of about 3 to about 8. In one example, the 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, administered, and given in a manner appropriate to 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 individual patient's clinical condition, the cause of the disease, the site of delivery of the active ingredient, the method of administration, the administration schedule, and other factors known to the physician. The “therapeutically effective amount” of the compound of the present invention or a pharmaceutically acceptable salt thereof administered is controlled with such factors in mind and is the minimum amount required 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 to 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, dispensing articles include containers in which the pharmaceutical formulation is placed in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, and metal cylinders. Containers may also include tamper-evident assemblies to prevent unintentional access to the contents of the package. In addition, containers may have labels placed on them that describe the contents of the container. Labels may also include appropriate cautionary notes.

[0233] Sustained-release preparations may be prepared. Preferred examples of sustained-release preparations include semipermeable solid hydrophobic polymer matrices containing a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, where the matrix is ​​a molded product, such as a film 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 ethyl γ-L-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] Doses for treating human patients may vary within a range of approximately 0.01 mg to approximately 1000 mg of the compound of the present invention or its pharmaceutically acceptable salt. For example, in the treatment of adult humans, doses of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 1 to 50 mg, and 5 to 40 mg per day are examples of doses used in some embodiments. Exemplary doses are 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 subject's body weight, and the attending physician's preference and experience. Doses may be administered once daily (QD), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties of the particular compound, including absorption, distribution, metabolism, and excretion. In addition, toxic factors may affect the dose and administration regimen. When administered orally, pills, capsules, or tablets may be taken orally daily or at longer intervals according to the specified time cycle. This regimen can be repeated for a predetermined number of treatment cycles.

[0235] A therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof may be administered by any preferred method, including oral administration, topical administration (including buccal and sublingual), rectal administration, vaginal administration, transdermal administration, parenteral administration, subcutaneous administration, intraperitoneal administration, intrapulmonary administration, intradermal administration, intrathecal administration, epidural and nasal administration, and, if desired for topical treatment, intralesional administration. Parenteral administration may include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0236] A therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components in pharmaceuticals, such as diluents, carriers, pH adjusters, sweeteners, fillers, and further activators.

[0237] A typical formulation is prepared by mixing a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof with an excipient. Suitable excipients include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants 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 flavor and / or odor modifiers, all of which are well known to those skilled in the art, for example, Ansel, HC, 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, RC, Handbook of Pharmaceutical The details are described in Excipients, Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, surfactants, lubricants, suspending agents, preservatives, opacifiers, lubricants, processing aids, sweeteners, flavors, flavoring additives, diluents, and other known additives that impart a refined appearance to the drug (i.e., the compound or its pharmaceutical composition) or assist in the manufacture of the pharmaceutical product (i.e., the drug).

[0238] In certain embodiments, pharmaceuticals for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, optionally polishing the resulting mixture, and processing the granular mixture after adding a suitable auxiliary agent as desired to obtain tablets or sugar-coated kernels. Suitable excipients include fillers such as sugars, particularly lactose, sucrose, mannitol, or sorbitol; cellulose preparations (e.g., corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, etc.); or other excipients (PVP or povidone) or calcium phosphate. In certain embodiments, disintegrants are optionally added. Disintegrants include, but are not limited to, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or salts thereof such as sodium alginate.

[0239] In one embodiment, dosage forms such as sugar-coated kernels and tablets are provided with one or more suitable coating agents. In certain embodiments, a concentrated sugar solution is used to coat the dosage forms. The sugar solution optionally contains additional components such as, simply as examples, gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes and / or pigments are also optionally added to the coating agent for identification. Furthermore, dyes and / or pigments are optionally used to identify different combinations of dosages of active compounds.

[0240] In certain embodiments, at least one of the compounds described herein, in a therapeutically effective amount, is formulated into other oral dosage forms. Examples of 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 capsule contains the active ingredient in a mixture with one or more fillers. Fillers include, simply as examples, binders such as lactose and starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In another embodiment, the soft capsule contains one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, simply as examples, one or more aliphatic oils, liquid paraffins, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0241] In another embodiment, at least one of the compounds described herein in a therapeutically effective amount is formulated for buccal or sublingual administration. Suitable formulations for buccal or sublingual administration include, but are not limited to, tablets, lozenges, or gels. In yet another embodiment, the compounds described herein are formulated for parenteral administration, including formulations suitable for bolus injection or continuous infusion. In certain embodiments, injectable formulations are presented in unit-dose dosage forms (e.g., ampoules) or in multi-dose containers. Preservatives are optionally added to injectable formulations. In yet another embodiment, 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 injectable formulations optionally contain formulation agents such as suspending agents, stabilizers, and / or dispersants. In certain embodiments, a pharmaceutically acceptable formulation for parenteral administration is an aqueous solution of the active compound in a water-soluble form. In further embodiments, a suspension of the compound of the present invention or a pharmaceutically acceptable salt thereof is prepared as a suitable oily injection suspension. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, but are not limited to, fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain embodiments, the aqueous injection suspension contains a substance that increases the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension contains a suitable stabilizer or active agent that increases the solubility of the compound, enabling the preparation of high-concentration solutions. Alternatively, in other embodiments, the active ingredient is in powder form before use for composition with a suitable vehicle, such as sterilized pyrogenically decontaminated water.

[0242] In certain embodiments, the pharmaceutical composition is formulated by any conventional method using one or more pharmaceutically acceptable excipients and adjuvants that facilitate the processing of the active compound into a preparation. The appropriate formulation varies depending on the chosen route of administration. Any pharmaceutically acceptable techniques and excipients may be optionally used. A pharmaceutical composition containing a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof may be produced by conventional methods, such as, simply as an example, conventional mixing, dissolution, granulation, sugar coating, wet grinding, emulsification, encapsulation, or compression processes.

[0243] A pharmaceutical composition comprises at least one pharmaceutically acceptable excipient and, as an active ingredient, an amount effective for the therapeutic purposes described herein or a pharmaceutically acceptable salt thereof. The active ingredient is in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. 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 having the same type of activity. All tautomers of the compounds described herein are included within the range of compounds presented herein. Furthermore, the compounds described herein include non-solvated and solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). The solvated forms of the compounds presented herein are also considered to be disclosed herein. Furthermore, the pharmaceutical composition optionally includes other pharmaceutical or pharmaceutically active substances such as preservatives, stabilizers, wetting agents, or emulsifiers, solution accelerators, salts for controlling osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0244] A method for producing a composition containing an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof for the treatment described herein includes 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. Examples of solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Examples of liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compound disclosed herein. Examples of semi-solid compositions include, but are not limited to, gels, suspensions, and creams. Examples of pharmaceutical compositions described herein include solutions or suspensions, solid states suitable as solutions or suspensions in liquid before use, or emulsions. These compositions may optionally also contain trace amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, etc.

[0245] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof takes the form of a liquid in which the active substance is present in a solution, a suspension, or both. Typically, when the composition is administered as a solution or suspension, a first portion of the active substance is present in the solution, and a second portion of the active substance is present in particulate form, a suspension in 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 anti-precipitation agents. Useful polymers include water-soluble polymers such as cellulosic polymers (e.g., hydroxypropyl methylcellulose) and water-insoluble polymers (e.g., cross-linked carboxyl-containing polymers). Specific pharmaceutical compositions described herein include, for example, mucosal adhesive polymers selected from 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 include solubilizers useful with respect to the solubility of the compounds of the present invention or their pharmaceutically acceptable salts. The term “solubilizer” generally refers to the active substance that results in the formation of a micelle solution or true solution of the active substance. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizers because they are glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers, which are acceptable in the ophthalmic field.

[0248] Furthermore, useful pharmaceutical compositions may optionally include 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] Furthermore, useful compositions may also optionally include one or more salts in amounts necessary to bring the osmotic pressure of the composition within an acceptable range. Such salts may have a sodium, potassium, or ammonium cation and a chlorine, citric acid, ascorbic acid, boric acid, phosphoric acid, bicarbonate, sulfuric acid, thiosulfate, or bisulfite anion. Preferred salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

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

[0251] Further useful compositions include one or more surfactants for improving 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] Further useful compositions include one or more antioxidants to improve chemical stability as needed. Suitable antioxidants include, but are not limited to, ascorbic acid and sodium metabisulfite.

[0253] In certain embodiments, the aqueous suspension composition is packaged in a single-dose, non-resealable container. Alternatively, a multi-dose, resealable container is used, in which case the composition typically contains a preservative.

[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 sustained-release systems, such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. A variety of sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compound for several weeks to over 100 days.

[0255] The present invention further provides a veterinary composition comprising, together with at least one active ingredient as defined above, and a veterinary excipient for the active ingredient. The veterinary excipient is a substance useful for administering the composition and may otherwise be a solid, liquid, or gaseous substance that is inert or acceptable in the art of veterinary medicine 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 pharmaceutically acceptable salts thereof may be used alone or in combination with other therapeutic agents for the treatment of diseases or illnesses described herein. The second compound in a pharmaceutically combined formulation or administration regimen preferably has complementary activity to the compounds of the present invention or pharmaceutically acceptable salts thereof, such that they do not adversely affect each other. Combination therapy provides a “synergistic effect,” meaning that the effect achieved is “synergistic,” i.e., greater than the combined effect of the active ingredients used together than the combined effect of the compounds used separately.

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

[0258] Therefore, combination therapy according to the present invention comprises the administration of the compound of the present invention or a pharmaceutically acceptable salt thereof, and the use of at least one other therapeutic agent. The amounts of the compound of the present invention or a pharmaceutically acceptable salt thereof, and other pharmaceutically active agents, as well as the relative timing of administration, are selected to achieve the desired combined therapeutic effect.

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

[0260] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, such as erlotinib or 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 bipolar 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 (buparlicib). GDC-0941 means 2-(1H-indazole-4-yl)-6-(4-methanesulfonylpiperazine-1-ylmethyl)-4-morpholine-4-ylthieno[3,2-d]pyrimidine, or a salt thereof (e.g., bismesylate salt).

[0261] In further different embodiments, 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 (lincitinib) or BMS-754807. Alternatively, in other embodiments, the additional therapeutic agent is an IGF1R-specific neutralizing monoclonal antibody, such as AMG-479 (ganitumab), CP-751, 871 (physitumumab), IMC-A12 (sixtumumab), MK-0646 (darotuzumab), or R-1507 (lovatumumab).

[0262] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor. In some embodiments, the additional therapeutic agent is CYT387, GLPG0634, baricitinib, restaurtinib, momerotinib, 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 codolituzumab.

[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. In some embodiments, the MDM2 antagonist is idasanuturin.

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

[0267] In some other embodiments, the additional therapeutic agent is a bispecific antibody. In 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 immune cytokine. In some embodiments, the targeted immune cytokine is RG7813 or RG7461.

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

[0270] In some other embodiments, the additional therapeutic agent is a personalized cancer vaccine. In 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 several other embodiments, the additional therapeutic agent is an antibody designed to bind to TIGIT. In 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, additional therapeutic agents are crizotinib, tivantinib, AMG337, cabozantinib, or foretinib. In other embodiments, additional therapeutic agents are neutralizing monoclonal antibodies against methionine, such as onaltubumab.

[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. An exemplary inhibitor of this embodiment is dasatinib. Other examples related to this include ponatinib, salakatinib, and bosutinib.

[0276] In further different 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 further different embodiments, 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 inhibitors include tasericib, ipataseritib, GDC-0575, GDC-5573 (HM95573), RG6114 (GDC-0077), CKI27, afatinib, axitinib, atezolizumab, bevacizumab, vosutinib, cetuximab, crizotinib, dasatinib, and el. These include lotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, ibrutinib, nilotinib, panitumumab, pazopanib, pegaptanib, ranibizumab, ruxolitinib, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib, or 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 described above, other chemotherapy agents currently known in the art can be used in combination with the compounds of the present invention. In some embodiments, the chemotherapy agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, insertive antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, bioresponse 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 hosts for chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocon, metsuredopa, and uredopa; ethyleneimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; and chloram. Bucil, chlornafadine, cyclophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobenbitin, fenesterine, prednimastine, trophosphamide, uracil mustard and other nitrogen mustards; nitrosoureas such as carmastine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; acrasinomycin, actinomycin, anthramycin, azaserine, Bleomycin, kactinomycin, calicheamicin, carabicin, carminomycin, cardinophilin, Casodex (trademark), chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potophyllomycin, puromycin, Antibiotics such as keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, and zolubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur,Pyrimidine analogs such as cytarabine, dideoxyuridinene, doxifluridine, enocitabine, and fulociuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testactone; anti-adrenal agents such as aminoglutethimide, mitothein, and trilostane; folic acid supplements such as folic acid; acegraton; aldofamide glycoside; aminolevulinic acid; amsacrin; bestrabusil; bisantren; edatrexate; defofamine; demecoltin; diaziquan; elfomitin; eriptinium acetate; etogluside; gallium nitrate; hydroxyurea; Lentinan; Ronidamin; Mitoguazone; Mytoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; Polysaccharide K; Lazoxane; Schizophyllan; Spirogermanium; Tenuazonic acid; Triadiquan; 2,2',2''-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacitosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Taxane (e.g., Paclitaxel (TAXOL®, Bristol-Myers) Examples include Squibb Oncology (Princeton, NJ) and docetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicin; capecitabine; and any pharmaceutically acceptable salts, acids, or derivatives of the above. Suitable chemotherapeutic cell modifiers include, for example, tamoxifen (Nolvadex®), raloxifene, aromatase inhibitor 4(5)imidazole, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapristone, and toremifene (Fairstone); flutamide, nilutamide, bicalutamide, leuprolide,Other examples include anti-androgens such as 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); topoisomerase inhibitor RFS 2000; and anti-estrogens including difluoromethylornithine (DMFO), which have the effect of regulating or inhibiting hormonal activity in tumors. If desired, the compounds or pharmaceutical compositions of the present invention may be used under the following names: Herceptin®, Avastin®, Gazyva®, Tecentriq®, Alecensa®, Perjeta®, Venclexta®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, avagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfarazine, arbocidib, 3-aminopyridine-2-carboxyaldehyde thiosemicarbazone, amonafide, anthracendione, anti-CD22 immunotoxin, antitumor drug, tumor-inhibiting herb, apadiquon, atiprimod, azathioprine, berotecan, bendamustine, BIBW 2992, Bilicodal, Brostarisin, Briostatin, Butionine sulfoximine, CBV (chemotherapy), Kalikrin, Cell cycle nonspecific anti-cancer drug, Dichloroacetate, Discodermolide, Elsamitrusine, Enocitabine, Epothiron, Eribulin, Everolimus, Exatecan, Exrind, Ferginol, Forodesine, Phosfestol, ICE chemotherapy regimen, IT-101, Imexone, Imiquimod, Indocarbazole, Ilofluben, Lanikidal, Lalotaxel, Lenalidomide, Lucanson, Lulutotecan, Maphosphamide, 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, reciquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, stanford V, swinesonin, talaporfin, talikidal, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacinib, uramustine, bajimezan, vinflunin, ZD6126, or zoskidal.

[0281] The precise method for administering the compound and additional therapeutic agents will be apparent to those skilled in the art. In some exemplary embodiments, the compound and additional therapeutic agents are administered simultaneously. In other embodiments, the compound and additional therapeutic agents are administered separately.

[0282] In some embodiments, the compound and the additional therapeutic agent are administered simultaneously with the second agent or individually. This combined administration includes simultaneous administration of the two active ingredients in the same dosage form, simultaneous administration of individual dosage forms, and individual administration. That is, the compound and any of the additional therapeutic agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound and any of the additional therapeutic agents described herein can be administered simultaneously, in which case both active ingredients are present in the individual formulations. In another alternative form, 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 individual administration protocol, the compound and any of the additional therapeutic agents described herein are administered at intervals of several minutes, several hours, or several days.

[0283] product In another embodiment of the present invention, a product or “kit” containing a substance useful for treating the above-mentioned diseases and disorders is provided. In one embodiment, the kit comprises a container containing the compound of the present invention or a pharmaceutically acceptable salt thereof. The kit may further include a label or accompanying information on or associated with the container. The term “accompanying information” is used to refer to instructions typically included in the commercial packaging of a therapeutic agent, containing information on the indications, use, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic agent. Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. Containers may be formed from a variety of materials, such as glass or plastic. Containers may hold the compound of the present invention or a pharmaceutically acceptable salt thereof, or a formulation thereof, that is effective in treating the condition, and may have a sterile inspection port (for example, the container may be an intravenous solution bag or a vial with a stopper that can be pierced with a subcutaneous needle). At least one activator in the composition is the compound of the present invention or a pharmaceutically acceptable salt thereof. Alternatively, the product may further include a second container containing a pharmaceutical diluent such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, or dextrose solution. The product may further include other materials desirable from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

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

[0285] Additional Embodiments Additional embodiments are provided below in this specification.

[0286] Embodiment 1: Compound of formula (I): TIFF0007943888000086.tif68170 or its pharmaceutically acceptable salt. [In the formula, R1 is an electrophilic moiety at position 12 of the K-Ras G12C mutant protein that can form a covalent bond with a cysteine ​​residue. R2 is H, OH, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, cyclopropyl, and -NHR (wherein 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 Alkyrenyl)NH(CH3)-(C 1~6 )alkylenyl)N(CH3)2, and -(C 1~3 )Selected from the group consisting of alkyrenyl (3-7 member heterocyclyl), R3 and R4 are H, NH2, Halo, and C, respectively. 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 A compound independently selected from the group consisting of alkylaminos and cyclopropyls, R5 stands for 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 Selected from the group consisting of cycloalkyl groups, In the formula, at least one of R2, R3, R4, and R5 is not H, or R2 and R3, R3 and R4, or R4 and R5, together with the atoms to which they are respectively bonded, are each optionally substituted with 1 to 4 substituents (wherein each substituent is independently selected from the group consisting of OH, NH2, halo, C 1~3 alkyl, C 1~3 haloalkyl, C 1~3 alkoxy, and C 1~3 haloalkoxy), to form C 3~7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6~14 aryl, or 5- to 10-membered heteroaryl, Each X is independently optionally substituted with 1 to 4 substituents (wherein each substituent is independently selected from the group consisting of OH, NH2, 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 hydroxyalkyl, and 4- to 7-membered heterocyclyl, and two geminal substituents may together form C 3~7 spirocycloalkyl or 4- to 7-membered spiroheterocyclyl), and is selected from the group consisting of NH2, 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 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 selected from H, NH2, halo, cyano, carbamoyl, C 2~6 alkenyl, C 1~6 alkoxy, C 1~6 alkyl, C substituted with 4- to 10-membered heterocyclyl optionally substituted with 1 to 4 Y 1a substituents 1~6 alkyl, C1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 C substituted with alkyl 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, 4-10 membered heterocyclines, methyl, hydroxy, and oxo-substituted 4-10 membered heterocyclines, Each Y 1a They are independent, Hello, C 1~6 Alkyl, C 1~6 Alkoxy, 3-7 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 Selected from the group consisting of haloalkoxys, L is a bond, O, S, and N(L a Selected from the group consisting of, L a is hydrogen and C 1~3 Selected from the group consisting of alkyl groups, U is C(R 6a ) and V is C(R6b ), and W is C(R 6c ) or N, and R 6a , R 6b , and R 6c are each independently selected from the group consisting of H, OH, NH2, halo, cyano, carbamoyl, C 2~6 alkenyl, C 1~6 alkoxy, C 1~6 alkyl, C substituted with a 4-10 membered heterocyclyl substituent 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 haloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl, n is selected from the group consisting of 0, 1 and 2.]

[0287] Embodiment 2: The compound according to Embodiment 1, having Formula (II): TIFF0007943888000087.tif77170 or a pharmaceutically acceptable salt thereof. [wherein, R2 is H, OH, NH2, halo, C 1~6 alkyl, C 1~6 haloalkyl, cyclopropyl, and -NHR (wherein 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 Alkyrenyl)NH(CH3)-(C 1~6 )alkylenyl)N(CH3)2, and -(C 1~3 )Selected from the group consisting of alkyrenyl (3-7 member heterocyclyl), R3 and R4 are H, NH2, Halo, and C, respectively. 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 A compound independently selected from the group consisting of alkylaminos and cyclopropyls, R5 stands for 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 Selected from the group consisting of cycloalkyl groups, In the formula, at least one of R2, R3, R4, and R5 is not H, or R2 and R3, R3 and R4, or R4 and R5 each have 1 to 4 substituents along with the atom to which they are bonded (where each substituent is independently OH, NH2, halo, C). 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 C is optionally substituted with (selected from the group consisting of haloalkoxys). 3~7 Cycloalkyl, 3-7 member heterocycloalkyl, C 6~14 Forms an aryl or a 5-10 membered heteroaryl, R7 is selected from the group consisting of H, cyano, and halo, and R8 and R9 are H and C, respectively. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 A component independently selected from the group consisting of hydroxyalkyl, cyano, and halo (C1~6 Alkyl refers to methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), alkyl or arylsulfonate leaving groups, C 1~6 Alkanoylamino, C 1~6 Alkoxy, C 1~6 Alkylamino, C 1~6 Alkylsulfonylamino, C 6~12 Dialkylamino, and C 1~6 (Optionally substituted with one substituent selected from the group consisting of haloalkoxys), or R7 and R8 both form a triple bond with the carbon they are bonded to, or R7 and R8 are optionally substituted with one or two halo substituents along with the carbon they are bonded to. 3~7 It forms a cycloalkenyl, and 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 Alkylsulfonylamino, C 6~12 Dialkylamino, and C 1~6 (Optionally substituted with one substituent selected from the group consisting of haloalkoxys), Each X has 1 to 4 substituents (where each substituent can independently be OH, NH2, halo, cyano, carboxy, carbamoyl, or C). 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Selected from the group consisting of hydroxyalkyl and 4- to 7-membered heterocyclyl groups, the two geminal substituents together form C 3~7 NH2, C (which may optionally be substituted with spirocycloalkyl or 4-7 membered spiroheterocyclyl) 1~6 Alkoxy, C1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 3~7 Selected from the group consisting of cycloalkyl, 4-7 membered heterocyclyl, and 4-7 membered heterocyclylamino, Y is selected from the group consisting of -L-Y1 or Y1. Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4-10 member heterocyclines that are optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 C substituted with alkyl 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, 4-10 membered heterocyclines, methyl, hydroxy, and oxo-substituted 4-10 membered heterocyclines, Each Y 1a They are independent, Hello, C 1~6 Alkyl, C 1~6Alkoxy, 3-7 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 Selected from the group consisting of haloalkoxys, L is a bond, O, S, and N(L a Selected from the group consisting of, L a is hydrogen and C 1~3 Selected from the group consisting of alkyl groups, 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 of these is independently H, OH, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 C substituted with alkyl or 4-10 member heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, and 4-10 membered heterocyclines, n is selected from the group consisting of 0, 1, and 2.

[0288] Embodiment 3: Compound according to Embodiment 1 having formula (III): TIFF0007943888000088.tif68170 or its pharmaceutically acceptable salt. [In the formula, R2 is H, OH, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, cyclopropyl, and -NHR (wherein 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 Alkyrenyl)NH(CH3)-(C 1~6 )alkylenyl)N(CH3)2, and -(C 1~3 )Selected from the group consisting of alkyrenyl (3-7 member heterocyclyl), R3 and R4 are H, NH2, Halo, and C, respectively. 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 A compound independently selected from the group consisting of alkylaminos and cyclopropyls, R5 stands for 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 Selected from the group consisting of cycloalkyl groups, In the formula, at least one of R2, R3, R4, and R5 is not H, or R2 and R3, R3 and R4, or R4 and R5 each have 1 to 4 substituents along with the atom to which they are bonded (where each substituent is independently OH, NH2, halo, C). 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 C is optionally substituted with (selected from the group consisting of haloalkoxys). 3~7 Cycloalkyl, 3-7 member heterocycloalkyl, C 6~14 Forms an aryl or a 5-10 membered heteroaryl, R 10 is R 10a and -C(O)-R 10a Selected from the group consisting of, R 10a It is selected from the group consisting of oxiranil and aziridinil, Each X has 1 to 4 substituents (where each substituent can independently be OH, NH2, halo, cyano, carboxy, carbamoyl, or C). 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Selected from the group consisting of hydroxyalkyl and 4- to 7-membered heterocyclyl groups, the two geminal substituents together form C 3~7 NH2, C (which may optionally be substituted with spirocycloalkyl or 4-7 membered spiroheterocyclyl) 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 3~7 Selected from the group consisting of cycloalkyl, 4-7 membered heterocyclyl, and 4-7 membered heterocyclylamino, Y is selected from the group consisting of -L-Y1 or Y1. Y1 is H, NH2, halo, cyano, carbamoyl, C2~6 Alkenil, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4-10 member heterocyclines that are optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 C substituted with alkyl 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, 4-10 membered heterocyclines, methyl, hydroxy, and oxo-substituted 4-10 membered heterocyclines, Each Y 1a They are independent, Hello, C 1~6 Alkyl, C 1~6 Alkoxy, 3-7 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 Selected from the group consisting of haloalkoxys, L is a bond, O, S, and N(L aSelected from the group consisting of, L a is hydrogen and C 1~3 Selected from the group consisting of alkyl groups, 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 of these is independently H, OH, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 C substituted with alkyl or 4-10 member heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, and 4-10 membered heterocyclines, 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 A compound or a pharmaceutically acceptable salt thereof, which is alkyl, as described in any one of Embodiments 1 to 3.

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

[0291] Embodiment 6: R3 and R4 independently contain H, halo, and C 1~6 Alkyl, C 1~6 A compound according to any one of Embodiments 1 to 5, selected from the group consisting of haloalkyl and cyclopropyl compounds, or a pharmaceutically acceptable salt thereof.

[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 A compound according to any one of Embodiments 1 to 6, selected from the group consisting of cycloalkyls, or a pharmaceutically acceptable salt thereof.

[0293] Embodiment 8: R 5 C 1~3 A compound or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound, as described in any one of Embodiments 1 to 7.

[0294] Embodiment 9: The compound according to 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 according to any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R5 is cyclopropyl.

[0296] Embodiment 11: R4 and R5 each have 1 to 4 substituents along with the atom to which they are bonded (where each substituent is independently OH, NH2, halo, C). 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 C is optionally substituted with (selected from the group consisting of haloalkoxys). 3~7 Cycloalkyl, 3-7 member heterocycloalkyl, C 6~14 A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, that forms an aryl or a 5- to 10-membered heteroaryl.

[0297] Embodiment 12: R4 and R5 each have 1 to 4 substituents along with the atom to which they are bonded (where each substituent is independently OH, NH2, halo, C). 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 C (selected from the group consisting of haloalkoxys) is optionally substituted 6~14 A compound according to Embodiment 11 or a pharmaceutically acceptable salt thereof that forms an aryl group.

[0298] Embodiment 13: R4 and R5 each have 1 to 4 substituents along with the atom to which they are bonded (where each substituent is independently OH, NH2, halo, C). 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 A compound according to Embodiment 12 or a pharmaceutically acceptable salt thereof, forming a C6 aryl which is optionally substituted with a (selected from the group consisting of haloalkoxys).

[0299] Embodiment 14: The compound described in Embodiment 13 or a pharmaceutically acceptable salt thereof, wherein the C6 aryl group is not substituted.

[0300] Embodiment 15: The compound described in Embodiment 13 or a pharmaceutically acceptable salt thereof, wherein the C6 aryl group is substituted with 1 to 4 substituents (where each substituent is independently a halo).

[0301] Embodiment 16: R2 is H, OH, NH2, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, cyclopropyl, and -NHR (wherein 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 Alkyrenyl)NH(CH3)-(C 1~6 )alkylenyl)N(CH3)2, and -(C 1~3 )Selected from the group consisting of alkyrenyl (3-7 member heterocyclyl), R3 and R4 are H, NH2, Halo, and C respectively. 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 alkylaminos, 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 Selected from the group consisting of cycloalkyl groups, At least two of R2, R3, R4, and R5 are not H, or R2 and R3, R3 and R4, or R4 and R5 each have 1 to 4 substituents along with the atom to which they are bonded (where each substituent is independently OH, NH2, halo, C). 1~3 Alkyl, C 1~3 Haloalkyl and C 1~3 C is optionally substituted with (selected from the group consisting of haloalkoxys). 3~7 Cycloalkyl, 3-7 member heterocycloalkyl, or C 6~14 Forming an aryl group, Each X has 1 to 4 substituents (where each substituent can independently be OH, NH2, halo, cyano, carboxy, carbamoyl, or C). 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, C 1~6 Carboxyalkyl, C 1~6Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Selected from the group consisting of hydroxyalkyl and 4- to 7-membered heterocyclyl groups, the two geminal substituents together form C 3~7 NH2, C (which may optionally be substituted with spirocycloalkyl or 4-7 membered spiroheterocyclyl) 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 3~7 Selected from the group consisting of cycloalkyl, 4-7 membered heterocyclyl, and 4-7 membered heterocyclylamino, Y is selected from the group consisting of -L-Y1 or Y1. Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4-10 member heterocyclines that are optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 C substituted with alkyl 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, 4-10 membered heterocyclines, methyl, hydroxy, and oxo-substituted 4-10 membered heterocyclines, Each Y 1a They became independent, Hello, C 1~6 Alkyl, C 1~6 Alkoxy, 3-7 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 Selected from the group consisting of haloalkoxys, L is bonded to O, S, and N(L a Selected from the group consisting of, L a is hydrogen and C 1~3 Selected from the group consisting of alkyl groups, 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 of these independently consists of H, OH, NH2, halo, cyano, carbamoyl, and C. 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 C substituted with alkyl or 4-10 member heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, C1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 3~7 Cycloalkyl, C 1~6 Haloalkoxy, C 1~6 Selected from the group consisting of haloalkyls, 5-10 membered heteroaryls, and 4-10 membered heterocyclines, n is a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of 0, 1, and 2, according to any one of Embodiments 1 to 3.

[0302] Embodiment 17: Compound of formula (I) having formula (IV): TIFF0007943888000089.tif65170 or its pharmaceutically acceptable salt. [In the formula, R1 is an electrophilic moiety at position 12 of the K-Ras G12C mutant protein that can form a covalent bond with a cysteine ​​residue. Each X has 1 to 4 substituents (where each substituent can independently be OH, NH2, halo, cyano, carboxy, carbamoyl, or C). 1~6 Alkyl, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, C 1~6 Carboxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Selected from the group consisting of hydroxyalkyl and 4- to 7-membered heterocyclyl groups, the two geminal substituents together form C 3~7 NH2, C (which may optionally be substituted with spirocycloalkyl or 4-7 membered spiroheterocyclyl) 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 3~7 Selected from the group consisting of cycloalkyl, 4-7 membered heterocyclyl, and 4-7 membered heterocyclylamino, Y is selected from the group consisting of -L-Y1 or Y1. Y1 is H, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4-10 member heterocyclines that are optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 C substituted with alkyl 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, 4-10 membered heterocyclines, methyl, hydroxy, and oxo-substituted 4-10 membered heterocyclines, Each Y 1a They became independent, Hello, C 1~6 Alkyl, C 1~6 Alkoxy, 3-7 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 Selected from the group consisting of haloalkoxys, L is a bond, O, S, and N(L a Selected from the group consisting of, L a is hydrogen and C 1~3 Selected from the group consisting of alkyl groups, 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 of these is independently H, OH, NH2, halo, cyano, carbamoyl, C 2~6 Alkenil, C 1~6 Alkoxy, C 1~6 C substituted with alkyl or 4-10 member heterocyclyl substituents 1~6 Alkyl, C 1~6 Alkyl sulfanyl, C 1~6 Alkyl sulfonyl, C 1~6 Alkylthio, C 1~6 Haloalkylthio, C 2~6 Alkinyl, C 1~6 Alkylamino, C 6~14 Ariel, C 1~6 Aminoalkyl, C 1~6 Carbamoyl alkyl, 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 haloalkyls, 5-10 membered heteroaryls, and 4-10 membered heterocyclines, n is selected from the group consisting of 0, 1, and 2. R 11 teeth, Selected from the group consisting of TIFF0007943888000090.tif239170 and TIFF0007943888000091.tif182170.

[0303] Embodiment 18: Y is Y1, and Y1 is H, C 1~6 Alkyl and C 1~6A compound according to any one of Embodiments 1 to 17, selected from the group consisting of haloalkyls, or a pharmaceutically acceptable salt thereof.

[0304] Embodiment 19: Y is -L-Y1, L is O and N(L a Selected from the group consisting of, L a H is, Y1 is C 1~6 Alkyl, 1 to 4 Y 1a C substituted with 4-10 member heterocyclines that are optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Dialkylamino-substituted C 3~7 Selected from the group consisting of cycloalkyl and methyl-substituted 4- to 10-membered heterocyclines, Each Y 1a They became independent, Hello, C 1~6 Alkyl, C 1~6 Alkoxy, 3-7 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 Selected from the group consisting of haloalkoxys, A compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1 to 17.

[0305] Embodiment 20: L is N(L a ) and L a H is C 1~6 Alkyl, or C 1~6 C substituted with dialkylamino substituents 1~6A compound described in Embodiment 19 or a pharmaceutically acceptable salt thereof, which is alkyl.

[0306] Embodiment 21: L is O, Y1 has 1 to 4 Y 1a C substituted with 4-10 member heterocyclines that are optionally substituted with substituents 1~6 Alkyl, C 1~6 C substituted with dialkylamino substituents 1~6 Alkyl, C 1~6 C substituted with dialkylaminocyclopropyl 1~6 Alkyl, C 1~6 Dialkylamino-substituted C 3~7 Selected from the group consisting of cycloalkyl and methyl-substituted 4- to 10-membered heterocyclines, Each Y 1a They became independent, Hello, C 1~6 Alkyl, C 1~6 Alkoxy, 3-7 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 Selected from the group consisting of haloalkoxys, The compound described in Embodiment 19 or a pharmaceutically acceptable salt thereof.

[0307] Embodiment 22: Y1 is substituted with a 4- to 10-membered methyl heterocyclyl substituent. 1~6 A compound described in Embodiment 19 or a pharmaceutically acceptable salt thereof, which is alkyl.

[0308] Embodiment 23: Y is A compound described in Embodiment 19 or a pharmaceutically acceptable salt thereof, selected from the group consisting of TIFF0007943888000092.tif236170 and TIFF0007943888000093.tif145170.

[0309] Embodiment 24: Y is The compound described in Embodiment 23 or a pharmaceutically acceptable salt thereof, which is TIFF0007943888000094.tif20170.

[0310] Embodiment 25: R 11 but A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 17 to 24, which is TIFF0007943888000095.tif101170.

[0311] Embodiment 26: R 11 but A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 17 to 25, which is TIFF0007943888000096.tif25170.

[0312] Embodiment 27: R 11 but A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 17 to 25, which is TIFF0007943888000097.tif24170.

[0313] Embodiment 28: R 6a A compound according to any one of Embodiments 1 to 27, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0314] Embodiment 29: R 6b H, Haro, C 1~6 Alkoxy, C 1~6 Alkyl sulfonyl, C 1~6 Haloalkyl, C 3~7 Cycloalkyl, C 1~6 A compound according to any one of Embodiments 1 to 28, or a pharmaceutically acceptable salt thereof, selected from the group consisting of haloalkylthios and 4- to 10-membered heterocyclines.

[0315] Embodiment 30:R 6b is hydrogen, halo, or C 1~3A compound or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound, as described in any one of Embodiments 1 to 28.

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

[0317] Embodiment 32: W is C(R 6c ) and R 6c A compound according to any one of Embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, wherein the compound is a halo.

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

[0319] Embodiment 34: X has 1 to 4 substituents (where each substituent is independently cyano, C 1~6 Alkyl, C 1~6 Cyanoalkyl and C 1~6 A compound according to any one of Embodiments 1 to 32, or a pharmaceutically acceptable salt thereof, which is a 4- to 7-membered heterocycline substituted with (selected from the group consisting of haloalkyls).

[0320] Embodiment 35: X is A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of TIFF0007943888000098.tif126170, according to any one of Embodiments 1 to 32.

[0321] Embodiment 36: X is A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of TIFF0007943888000099.tif79170, according to any one of Embodiments 1 to 32.

[0322] Embodiment 37: X is A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of TIFF0007943888000100.tif76170, according to any one of Embodiments 1 to 32.

[0323] Embodiment 38: X is A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 32, which is TIFF0007943888000101.tif29170.

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

[0325] Embodiment 40: R1 is A compound described in Embodiment 1 or 17, or a pharmaceutically acceptable salt thereof, selected from the group consisting of TIFF0007943888000102.tif80170. [In the formula, R 12 is C 1~6 Alkanoyl, C 1~6 Alkyl and C 1~6 Selected from the group consisting of alkylsulfonyls, R 13 H, C 1~6 Alkyl and C 1~6 Selected from the group consisting of haloalkyls, R 13a It is a halo, R 14 This is a halo.

[0326] Embodiment 41: R1 is A compound described in Embodiment 40 or a pharmaceutically acceptable salt thereof, selected from the group consisting of TIFF0007943888000103.tif35170.

[0327] Embodiment 42: R 1 but The compound described in Embodiment 41 or a pharmaceutically acceptable salt thereof, which is TIFF0007943888000104.tif19170.

[0328] Embodiment 43: R7 is selected from the group consisting of H, cyano, and halo, and R8 and R9 are H and C, respectively. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 A component independently selected from the group consisting of hydroxyalkyl, cyano, and halo (C 1~6 Alkyl refers to methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), alkyl or arylsulfonate leaving groups, C 1~6 Alkanoylamino, C 1~6 Alkoxy, C 1~6 Alkylamino, C 1~6 Alkylsulfonylamino, C 6~12 Dialkylamino, and C 1~6 The compound described in Embodiment 2 or a pharmaceutically acceptable salt thereof, which is optionally substituted with one substituent selected from the group consisting of haloalkoxys.

[0329] Embodiment 44: A compound according to Embodiment 1 or 17, or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of TIFF0007943888000105.tif204170, TIFF0007943888000106.tif55170, or a pharmaceutically acceptable salt thereof.

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

[0331] Embodiment 46: The compound of formula (IV) A compound according to any one of Embodiments 17 to 41 or a pharmaceutically acceptable salt thereof, comprising a formula selected from the group consisting of TIFF0007943888000107.tif120170 and TIFF0007943888000108.tif122170.

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

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

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

[0335] Embodiment 50: Both R7 and R8 form a triple bond with the carbon to which they are bonded, or R7 and R8 are optionally substituted with one or two halo substituents along with the carbon to which they are bonded. 3~7 It forms a cycloalkenyl, and 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 Alkylsulfonylamino, C 6~12 Dialkylamino, and C 1~6 The compound described in Embodiment 2 or a pharmaceutically acceptable salt thereof, which is optionally substituted with one substituent selected from the group consisting of haloalkoxys.

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

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

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

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

[0340] Embodiment 55: The pharmaceutical composition according to 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 of cancer an effective amount of 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.

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

[0343] Embodiment 58: The method according to Embodiment 55 or 56, wherein administration is via the oral route.

[0344] Embodiment 59: The method according to Embodiment 55 or 56, wherein administration is by injection.

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

[0346] Embodiment 61: The method according to 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 according to any one of Embodiments 56 to 61, wherein the cancer is lung adenocarcinoma.

[0348] Embodiment 63: A method for controlling 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 for inhibiting the proliferation of a cell population, comprising contacting the cell population with a compound described in any one of Embodiments 1 to 52 or a pharmaceutically acceptable salt thereof.

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

[0351] Embodiment 66: A method for treating a K-Ras G12C mutation-mediated disease in an individual requiring treatment for the disease, To measure whether an individual has a mutation, If an individual is found to have a mutation, the individual is administered a therapeutically effective amount of the compound described in any one of Embodiments 1 to 52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in any one of Embodiments 53 to 55. A method that includes this.

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

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

[0354] Embodiment 69: The method according to Embodiment 66, wherein the cancer is lung cancer, colorectal cancer, appendiceal cancer, or pancreatic cancer.

[0355] Embodiment 70: The method according to 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 described in 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 for inhibiting tumor metastasis, comprising administering to an individual requiring inhibition of tumor metastasis a therapeutically effective amount of a compound described in any one of Embodiments 1 to 52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in any one of Embodiments 53 to 55.

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

[0359] Embodiment 74: The use according to Embodiment 73, wherein the drug is formulated for oral administration.

[0360] Embodiment 75: The use according to Embodiment 73, wherein the drug is formulated for injection.

[0361] Embodiment 76: The use according to any one of Embodiments 73 to 75, wherein 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 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, appendiceal 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 or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 52 in the manufacture of a drug 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 treating the body of a human or animal by therapeutic means.

[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 of treating cancer.

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

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

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

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

[0372] Embodiment 87: 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 inhibiting tumor metastasis. [Examples]

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

[0374] The following abbreviations will be used in this embodiment: ACN-acetonitrile Ac2O - Acetyl acetate BINAP-(+ / -)-2,2'-bis(diphenylphosphin)-1,1'-binaphthyl Boc2O-di-tert-butyldicarbonate BOP-(benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate CH3Ti(O i -Pr)3-methyltitanium(IV)triisopropoxide DBU-1,8-diazabicyclo[5.4.0]undeca-7-en 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 ethyl acetate EtOH - Ethanol HATU-2(7-azabenzothiazole-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 Methoxyde or Sodium Methanelate MTBE - Methyl tert-butyl ether MW Microwave Oven 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 Carbon Pd2(dba)3-Tris(dibenzylideneacetone)dipalladium(0) Pd2(dba)3CHCl3-Tris(dibenzylideneacetone)dipalladium(0)chloroform [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with Pd(dppf)Cl2·CH2Cl2-dichloromethane, or dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) 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-Hexabutyldystin 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 Examples of the compound 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. TIFF0007943888000109.tif38170 Step 1: 7-Bromo-4,6-dichloroquinazoline TIFF0007943888000110.tif25170

[0376] To a solution of thionyl chloride in 7-bromo-6-chloro-3,4-dihydroquinazolin-4-one (330 g, 1.28 mol) (4.0 L), N,N-dimethylformamide (4 mL) was added. The mixture was stirred at 80°C for 12 hours. After completion, the resulting mixture was concentrated under vacuum to obtain 7-bromo-4,6-dichloroquinazolin (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 TIFF0007943888000111.tif39170

[0377] A 1,4-dioxane solution (3.0 L) containing 7-bromo-4,6-dichloroquinazoline (330 g, 1.20 mol), tert-butylpiperazine-1-carboxylate (340 g, 1.80 mol, 1.50 equivalents), and DIPEA (586 mL, 3.60 mol) was stirred at 110°C for 60 minutes. After completion, the solid was collected by filtering, washed with PE (500 mL) and water (500 mL), and then dried to obtain tert-butyl 4-(7-bromo-6-chloroquinazoline-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-methylpiperidine-2-yl)acetonitrile

[0379] The intermediate compound 2((2R)-5-methylpiperidine-2-yl)acetonitrile was prepared according to the following reaction scheme. TIFF0007943888000112.tif62170 Step 1: tert-butyl(2-((4-methoxybenzyl)amino)propyl)carbamate TIFF0007943888000113.tif26170

[0380] To a 175 mL 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, sodium triacetoxyborohydride (15 g, 71.5 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM and washed with saturated Na2CO3. The organic layer was dried over sodium sulfate, filtered, and concentrated using a rotary evaporator. The crude product was purified by silica flash chromatography (eluted with iPrOAc / Hep) to obtain 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 TIFF0007943888000114.tif36170

[0381] A 30 mL ethanol solution of tert-butyl(2-((4-methoxybenzyl)amino)propyl) carbamate (2.9 g, 9.8 mmol), (E)-4-bromobuta-2-ennitrile (1.2 mg, 8.22 mmol), and sodium carbonate (2.8 g, 26.3 mmol) was stirred at 50°C for 18 hours. After concentrating the reaction mixture, it was diluted with ELISA. The organic layer was washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated using a rotary evaporator. The crude product was purified by silica flash chromatography (eluted with iPrOAc / Hep) (then eluted with MeOH / DCM) to obtain 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 TIFF0007943888000115.tif38170

[0382] A 5% trifluoroacetic acid solution of tert-butyl(E)-(2-((3-cyanoallyl)(4-methoxybenzyl)amino)propyl)carbamate (2.3 g, 6.4 mmol) in hexafluoro-2-propanol (75 mL, 49.3 mmol) was stirred at room temperature for 18 hours. After concentrating the reaction mixture, 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 obtain 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 TIFF0007943888000116.tif22170

[0383] Trifluoroacetic acid (17.5 mL, 231.3 mmol) was added to a 10 mL solution of 2-((2R)-4-(4-methoxybenzyl)-5-methylpiperazin-2-yl)acetonitrile (600 mg, 2.313 mmol) in dichloromethane. The reaction mixture was stirred at 50°C for 48 hours. The reaction mixture was concentrated, and the crude product was transferred 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)pyridine-2-yl)-6-chloro-2-fluoroquinazoline-4-yl)piperazine-1-carboxylate

[0384] The compound tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate was prepared according to the following synthetic scheme: TIFF0007943888000117.tif89170 Step 1: 2-amino-4-bromo-5-chlorobenzamide TIFF0007943888000118.tif24170

[0385] A 50 mL 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 was stirred at room temperature for 5 minutes. Next, HATU (18.22 g, 47.91 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After completion, the reaction was quenched with water. The reaction mixture was filtered, the filtrate was collected, and the mixture was dried under vacuum to obtain 2-amino-4-bromo-5-chlorobenzamide (8 g, 32.0 mmol, yield 80.3%) as a yellow solid. LCMS (ESI, m / z): 248.9 [M+H] + . Step 2: 7-Bromo-2,6-dichloroquinazoline-4-ol TIFF0007943888000119.tif26170

[0386] To a 100 mL solution of 2-amino-4-bromo-5-chlorobenzamide (20.0 g, 80.16 mmol) in 1,4-dioxane, thiophosgene (20.3 g, 176.52 mmol) was added dropwise while stirring. The resulting solution was stirred at room temperature for 1 hour, followed by stirring at 105 °C for 1 hour. After completion, the resulting solution was concentrated under vacuum. The organic layer was washed with diethyl ether to obtain 7-bromo-2,6-dichloroquinazolin-4-ol (20 g, 68.043 mmol, yield 84.9%) as a brown solid. LCMS (ESI, m / z): 292.9 [M+H] + . Step 3: tert-butyl 4-(7-bromo-2,6-dichloroquinazolin-4-yl)piperazine-1-carboxylate TIFF0007943888000120.tif39170

[0387] A 200 mL solution of dichloromethane containing 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) was stirred at 25°C for 0.5 hours. Next, tert-butyl-1-piperazine carboxylate (14.2 g, 76.24 mmol) and N,N-diisopropylethylamine (13.2 g, 102.33 mmol) were added, and the mixture was stirred at 25°C for 2 hours. After 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 eluted with ethyl acetate / petroleum ether (1 / 6) to obtain tert-butyl 4-(7-bromo-2,6-dichloroquinazolin-4-yl)piperazine-1-carboxylate (13 g, 28.13 mmol, yield 55.1%) as a yellow solid. LCMS (ESI, m / z): 461.0 [M+H] + . Step 4: tert-butyl 4-(7-bromo-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate TIFF0007943888000121.tif40170

[0388] A solution of tert-butyl 4-(7-bromo-2,6-dichloroquinazolin-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. After completion, the reaction system 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 under vacuum. The residue was purified by silica gel flash chromatography eluted with petroleum ether / ethyl acetate (3 / 1) to obtain tert-butyl 4-(7-bromo-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate (10 g, 22.44 mmol, yield 66.5%) as a yellow solid. LCMS (ESI, m / z): 445.0 [M+H] + . Step 5: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)pyridine-2-yl)-6-chloro-2-fluoroquinazoline-4-yl)piperazine-1-carboxylate TIFF0007943888000122.tif47170

[0389] Under nitrogen, 1.5 L of tetrahydrofuran solution (1.5 L) and 300 mL of aqueous solution (300 mL) of tert-butyl 4-(7-bromo-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate (50.0 g, 104.66 mmol), (6-(bis(4-methoxyphenyl)amino)pyridine-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) were stirred at 65°C for 3 hours. After completion, the resulting solutions were 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 eluted with ethyl acetate / petroleum ether (1 / 6) to obtain tert-butyl, 4-(7-(6-(bis(4-methoxybenzyl)amino)pyridine-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-iodopyridine-2-yl)-6-chloro-2-fluoroquinazoline-4-yl)piperazine-1-carboxylate TIFF0007943888000123.tif50170

[0390] A solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)pyridine-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. After 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 eluted with ethyl acetate / petroleum ether (1 / 7) to obtain tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodopyridine-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate (7.71 g, 8.85 mmol, yield 68.6%) 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)pyridine-2-yl)-6-chloro-2-fluoroquinazoline-4-yl)piperazine-1-carboxylate TIFF0007943888000124.tif47170

[0391] To a 380 mL N,N-dimethylacetamide solution (15.35 g, 17.62 mmol) of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodopyridine-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate and copper(I) iodide (40.17 g, 211.44 mmol), 84.63 g, 440.51 mmol of methyl 2,2-difluoro-2-(fluorosulfonyl) acetate was added, and the mixture was stirred at 90°C for 6 hours. After 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 eluted with ethyl acetate / petroleum ether (1 / 5) to obtain tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate (11.8 g, 14.51 mmol, yield 82.3%) as a yellow solid. LCMS (ESI, m / z): 781.3 [M+H] + . Intermediate 4: tert-butyl 4-(7-bromo-2,6-dichloroquinazolin-4-yl)piperazine-1-carboxylate

[0392] The compound tert-butyl 4-(7-bromo-2,6-dichloroquinazolin-4-yl)piperazine-1-carboxylate was prepared according to the following synthetic scheme. TIFF0007943888000125.tif33170 Step 1: 7-Bromo-6-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione TIFF0007943888000126.tif29170

[0393] 2-amino-4-bromo-5-chlorobenzoic acid (200 g, 0.8 mol) and urea (720 g, 12 mol) were placed in a 3000 mL round-bottom flask. The resulting solution was stirred at 160 °C for 12 hours. The mixture was cooled to 80 °C, quenched with water, and refluxed for 5-10 minutes. The mixture was cooled to room temperature to allow a precipitate to form. The solid was collected by filtering, washed with H2O, and dried under oven to obtain 200 g (90%) of crude 7-bromo-6-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione as a yellow solid. The crude was proceeded to the next step without further purification. Step 2: 7-Bromo-2,4,6-trichloroquinazoline TIFF0007943888000127.tif26170

[0394] A POCl3 solution (750 mL) 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) was stirred at 120°C for 8 hours, concentrated under vacuum, and proceeded to the next step without further purification. Step 3: tert-butyl 4-(7-bromo-2,6-dichloroquinazolin-4-yl)piperazine-1-carboxylate (intermediate 4) TIFF0007943888000128.tif40170

[0395] A 1,4-dioxane solution (2000 mL) containing 7-bromo-2,4,6-trichloroquinazoline (200 g, 0.64 mol), tert-butylpiperazine-1-carboxylate (178 g, 0.92 mol), and DIEA (3 equivalents) was stirred at 25°C for 8 hours. The resulting solution was diluted with 2000 mL of water and extracted with 3 × 3000 mL of ethyl acetate. The combined organic layer was washed with brine (1 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column elution with ethyl acetate / petroleum ether (1:10) to obtain 126 g (43%) of tert-butyl 4-(7-bromo-2,6-dichloroquinazoline-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 TIFF0007943888000129.tif42170

[0397] The 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-chloroquinazolin-4-yl]piperazine-1-yl]prop-2-en-1-one

[0398] Compound 1-[4-[7-(3-amino-1-isoquinolyl)-6-chloroquinazolin-4-yl]piperazine-1-yl]prop-2-en-1-one was prepared according to the following synthetic scheme. TIFF0007943888000130.tif80170 Step 1: tert-butyl 4-(6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-4-yl)piperazine-1-carboxylate TIFF0007943888000131.tif49170

[0399] 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) were added to a 1,4-dioxane solution (25.0 mL) of tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate (550 mg, 1.29 mmol) and bis(pinacolato)diborone (733 mg, 2.83 mmol). The reaction mixture was degassed and then heated at 85°C for 18 hours. The reaction mixture was filtered through Celite, and the crude product was purified by silica flash chromatography (elution with MeOH / DCM) to obtain 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%). LC-MS shows the mass of boronic acid. LC-MS (ESI, m / z): 393.1 [M+H] + . Step 2: tert-butyl 4-(7-(3-aminoisoquinoline-1-yl)-6-chloroquinazoline-4-yl)piperazine-1-carboxylate TIFF0007943888000132.tif55170

[0400] Solutions of 1-bromoisoquinoline-3-amine (196 mg, 0.85 mmol), tert-butyl 4-[6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-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) were degassed. The reaction mixture was heated at 90°C for 5 hours. The reaction mixture was filtered through Celite, and the crude product was purified by silica flash chromatography (elution with MeOH / DCM) to obtain 235 mg of tert-butyl 4-(7-(3-aminoisoquinoline-1-yl)-6-chloroquinazoline-4-yl)piperazine-1-carboxylate as a yellow solid. LCMS (ESI, m / z): 491.2 [M+H] + . Step 3: 1-(6-chloro-4-(piperazine-1-yl)quinazoline-7-yl)isoquinoline-3-amine TIFF0007943888000133.tif52170

[0401] To a 2.0 mL solution of tert-butyl 4-[7-(3-amino-1-isoquinolyl)-6-chloroquinazolin-4-yl]piperazine-1-carboxylate (235 mg, 0.48 mmol) in 1,4-dioxane, hydrochloric acid (4 mol / L) in 1,4-dioxane (1.2 mL, 4.8 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction product was concentrated to obtain 136 mg of crude 1-(6-chloro-4-(piperazine-1-yl)quinazolin-7-yl)isoquinoline-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-chloroquinazolin-4-yl]piperazine-1-yl]prop-2-en-1-one TIFF0007943888000134.tif58170

[0402] N,N-diisopropylethylamine (0.30 mL, 1.74 mmol) and HATU (203 mg, 0.52 mmol) were added to a 3.5 mL solution of 1-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)isoquinoline-3-amine (136 mg, 0.35 mmol) and acrylic acid (0.026 mL, 0.383 mmol) in N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 15 minutes. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated using a rotary evaporator. The crude product was purified by silica flash chromatography (elution with MeOH / DCM), and then subjected to reverse-phase HPLC to obtain 8 mg of 1-(4-(7-(3-aminoisoquinoline-1-yl)-6-chloroquinazoline-4-yl)piperazine-1-yl)propa-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]piperazine-1-yl]prop-2-en-1-one TIFF0007943888000135.tif53170

[0404] The procedure was the same as in Example 1, except that in Step 2 of Example 2, commercially available 2-bromo-3-methylpyridine was used as a substitute reagent for 1-bromoisoquinoline-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-naphthyridine-8-yl)-6-chloroquinazolin-4-yl]piperazine-1-yl]prop-2-en-1-one TIFF0007943888000136.tif59170

[0406] The procedure is the same as in Example 1, except that in step 2 of Example 3, commercially available 8-bromo-1,7-naphthyrizine-6-amine was used as a substitute reagent in place of 1-bromoisoquinoline-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-naphthidine-1-yl)-6-chloroquinazoline-4-yl]piperazine-1-yl]prop-2-en-1-one TIFF0007943888000137.tif58170

[0408] The procedure was the same as in Example 1, except that in step 2 of Example 4, commercially available 1-bromo-2,6-naphthyrizine-3-amine was used as a substitute reagent in place of 1-bromoisoquinoline-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-chloroquinazolin-4-yl]piperazine-1-yl]prop-2-en-1-one TIFF0007943888000138.tif58170

[0410] The procedure is the same as in Example 1, except that in step 2 of Example 5, commercially available 1-bromo-5-chloro-isoquinoline-3-amine was used as a substitute reagent in place of 1-bromoisoquinoline-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-chloroquinazolin-4-yl]piperazine-1-yl]prop-2-en-1-one TIFF0007943888000139.tif56170

[0412] The procedure is the same as in Example 1, except that in Step 2 of Example 6, commercially available 1-bromo-6-methoxyisoquinoline-3-amine was used as a substitute reagent in place of 1-bromoisoquinoline-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-aminoisoquinoline-1-yl)-6-chloro-8-fluoroquinazoline-4-yl)piperazine-1-yl)prop-2-en-1-one

[0414] The compound (S)-1-(4-(7-(3-aminoisoquinoline-1-yl)-6-chloro-8-fluoroquinazoline-4-yl)piperazine-1-yl)prop-2-en-1-one was prepared according to the following synthetic scheme. TIFF0007943888000140.tif90170 Step 1: 1-(tributylstannyl)isoquinoline-3-amine TIFF0007943888000141.tif26170

[0415] A 1,4-dioxane solution (10 mL) containing 1-bromoisoquinoline-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) was degassed. 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-aminoisoquinoline-1-yl)-6-chloro-8-fluoroquinazoline-4-yl)piperazine-1-carboxylate TIFF0007943888000142.tif54170

[0416] A 14 mL solution (N,N-dimethylformamide) containing 1-tributylstannylisoquinoline-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) was degassed. 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 (elution with MeOH / DCM) to obtain tert-butyl 4-(7-(3-aminoisoquinoline-1-yl)-6-chloro-8-fluoroquinazoline-4-yl)piperazine-1-carboxylate (94 mg, 27%). LC-MS (ESI, m / z): 444.9 [M+H] + . Step 3: 1-(6-chloro-8-fluoro-4-(piperazine-1-yl)quinazoline-7-yl)isoquinoline-3-amine TIFF0007943888000143.tif52170

[0417] To a 3.0 mL solution of tert-butyl 4-[7-(3-amino-1-isoquinolyl)-6-chloro-8-fluoroquinazolin-4-yl]piperazine-1-carboxylate (410 mg, 0.806 mmol) in 1,4-dioxane, hydrochloric acid (4 mol / L) in 1,4-dioxane (2.0 mL, 8.1 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction product was concentrated to obtain 329 mg of crude 1-(6-chloro-8-fluoro-4-(piperazine-1-yl)quinazolin-7-yl)isoquinoline-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-aminoisoquinoline-1-yl)-6-chloro-8-fluoroquinazoline-4-yl)piperazine-1-yl)prop-2-en-1-one TIFF0007943888000144.tif56170

[0418] 1-(6-chloro-8-fluoro-4-piperazine-1-ylquinazolin-7-yl)isoquinoline-3-amine (329 mg, 0.805 mmol) and N,N-diisopropylethylamine (0.70 mL, 4.02 mmol) were dissolved in dichloromethane (8.0 mL). Acrylic acid (0.061 mL, 0.885 mmol) and HATU (468.3 mg, 1.21 mmol) were added at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated using a rotary evaporator. The crude product was purified by silica flash chromatography (elution with MeOH / DCM) to obtain 1-(4-(7-(3-aminoisoquinoline-1-yl)-6-chloro-8-fluoroquinazoline-4-yl)piperazin-1-yl)prop-2-en-1-one, which was then subjected to chiral SFC purification to obtain 30.6 mg of (S)-1-(4-(7-(3-aminoisoquinoline-1-yl)-6-chloro-8-fluoroquinazoline-4-yl)piperazin-1-yl)prop-2-en-1-one as a white solid (yield 8.2%).

[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-aminoisoquinoline-1-yl)-6-chloro-8-fluoroquinazoline-4-yl)piperazine-1-yl)prop-2-en-1-one TIFF0007943888000145.tif56170

[0420] Example 8 was obtained by chiral separation of 1-(4-(7-(3-aminoisoquinoline-1-yl)-6-chloro-8-fluoroquinazoline-4-yl)piperazine-1-yl)prop-2-en-1-one.

[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)pyridine-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-yl)prop-2-en-1-one TIFF0007943888000146.tif56170

[0422] The procedure is the same as in Example 7, except that in Step 1 of Example 9, commercially available 6-chloro-5-(trifluoromethyl)pyridine-2-amine was used as a substitute reagent in place of 1-bromoisoquinoline-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)pyridine-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-yl)prop-2-en-1-one TIFF0007943888000147.tif57170

[0424] The procedure was the same as in Example 7, except that in Step 1 of Example 10, commercially available 6-chloro-5-(trifluoromethyl)pyridine-2-amine was used as a substitute reagent in place of 1-bromoisoquinoline-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-methylpyridine-2-yl)-6-chloroquinazolin-4-yl)piperazine-1-yl)prop-2-en-1-one

[0426] Compound 1-(4-(7-(6-amino-3-fluoro-4-methylpyridine-2-yl)-6-chloroquinazolin-4-yl)piperazine-1-yl)prop-2-en-1-one was prepared according to the following synthetic scheme: TIFF0007943888000148.tif68170 Step 1: 2-(5-fluoro-4-methylpyridine-2-yl)isoindorin-1,3-dione TIFF0007943888000149.tif30170

[0427] A 9.5 mL acetic acid solution (500 mg, 3.77 mmol) of 2-amino-5-fluoro-4-picoline and phthalic anhydride (836 mg, 5.65 mmol) was heated at 90°C for 18 hours. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated using a rotary evaporator. The crude product was purified by silica flash chromatography (eluted with iPrOAc / Hep) to obtain 2-(5-fluoro-4-methylpyridine-2-yl)isoindorin-1,3-dione (834 mg, 86.5%). LCMS (ESI, m / z): 257.1 [M+H] + . Step 2: 2-(6-chloro-5-fluoro-4-methylpyridine-2-yl)isoindorin-1,3-dione TIFF0007943888000150.tif32170

[0428] 3-chloroperoxybenzoic acid (1.30 g, 7.53 mmol) was added to a 37 mL dichloromethane solution of 2-(5-fluoro-4-methylpyridine-2-yl)isoindorin-1,3-dione (964 mg, 3.76 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with a saturated aqueous Na2S2O3 solution and extracted with ethylacetic acid. The organic layer was dried over sodium sulfate, filtered, and concentrated through a rotary evaporator to obtain 2-(1,3-dioxoisoindorin-2-yl)-5-fluoro-4-methylpyridine 1-oxide (945 mg, 92.3%).

[0429] A solution of 2-(1,3-dioxoisoindorin-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 hours. The reaction was quenched with ice water and saturated NaHCO3, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated using a rotary evaporator. The crude product was purified by silica flash chromatography (eluted with iPrOAc / Hep) to obtain 2-(6-chloro-5-fluoro-4-methylpyridine-2-yl)isoindorin-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-methylpyridine-2-amine TIFF0007943888000151.tif25170

[0430] A solution of 2-(6-chloro-5-fluoro-4-methylpyridine-2-yl)isoindorin-1,3-dione (633 mg, 2.18 mmol) in methanol (3.1 mL) with ammonia (7 mol / L) was stirred at 45°C for 5 hours. The solid was filtered to obtain 136 mg of crude 6-chloro-5-fluoro-4-methylpyridine-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 (6.0 mL) of 6-chloro-5-fluoro-4-methylpyridine-2-amine (250 mg, 1.56 mmol) in N,N-dimethylacetamide, sodium hydride (60% by mass) in oil (75.0 mg, 1.87 mmol) was added at 0°C. The reaction mixture 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 ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated using a rotary evaporator. The crude product was purified by silica flash chromatography (eluted by iPrOAc / Hep) to obtain 6-chloro-5-fluoro-N,N-bis(4-methoxybenzyl)-4-methylpyridine-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-methylpyridine-2-yl)-6-chloroquinazoline-4-yl)piperazine-1-carboxylate TIFF0007943888000152.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-methylpyridine-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 (elution with MeOH / DCM) to obtain tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-fluoro-4-methylpyridine-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-(piperazine-1-yl)quinazoline-7-yl)5-fluoro-4-methylpyridine-2-amine TIFF0007943888000153.tif52170

[0433] 200 mg, 0.280 mmol of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-fluoro-4-methylpyridine-2-yl)-6-chloroquinazolin-4-yl)piperazine-1-carboxylate (200 mg, 0.280 mmol) was dissolved in dichloromethane (3.0 mL), to which trifluoroacetic acid (0.106 mL, 1.40 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and diluted with ethyl acetate. The solution was washed with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered, and concentrated through a rotary evaporator to obtain 105 mg of crude 6-(6-chloro-4-(piperazine-1-yl)quinazolin-7-yl)5-fluoro-4-methylpyridine-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-methylpyridine-2-yl)-6-chloroquinazolin-4-yl)piperazine-1-yl)prop-2-en-1-one TIFF0007943888000154.tif56170

[0434] Acrylic acid (0.042 mL, 0.620 mmol) and HATU (328 mg, 0.845 mmol) were added to a 5.5 mL dichloromethane solution of 6-(6-chloro-4-piperazine-1-ylquinazolin-7-yl)-5-fluoro-4-methylpyridine-2-amine (210 mg, 0.563 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.82 mmol) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated using a rotary evaporator. The crude product was purified by silica flash chromatography (elution with MeOH / DCM) and then subjected to reverse-phase HPLC to obtain 1-(4-(7-(6-amino-3-fluoro-4-methylpyridine-2-yl)-6-chloroquinazolin-4-yl)piperazine-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-methylpyridine-2-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-4-yl)piperazine-1-yl)prop-2-en-1-one

[0436] Compound (R)-1-(4-(7-(6-amino-3-fluoro-4-methylpyridine-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. TIFF0007943888000155.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 TIFF0007943888000156.tif43170

[0437] To a 2-propanol solution (10.0 mL) of tert-butyl 4-(7-bromo-2,6-dichloroquinazolin-4-yl)piperazine-1-carboxylate (intermediate 4) (500 mg, 1.08 mmol) and (3R)-4-amino-3-fluoro-2-methylbutan-2-ol hydrochloride (375 mg, 2.38 mmol), N,N-diisopropylethylamine (1.90 mL, 10.8 mmol) was added. The reaction mixture was stirred at 65°C for 18 hours. The reaction product was concentrated, and the crude product was purified by silica flash chromatography (elution with MeOH / DCM) to obtain 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)quinazoline-4-yl)piperazine-1-carboxylate TIFF0007943888000157.tif52170

[0438] 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 to a 1,4-dioxane solution (3.5 mL) of tert-butyl(R)-4-(7-bromo-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazoline-4-yl)piperazine-1-carboxylate (100 mg, 0.183 mmol) and bis(pinacolato)diborone (142 mg, 0.549 mmol). The reaction mixture was then degassed and stirred at 125°C for 1 hour. The reaction mixture was filtered through Celite and concentrated to obtain 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 product 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)quinazoline-7-yl)-5-fluoro-4-methylpyridine-2-yl)carbonyl)benzoic acid TIFF0007943888000158.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 mixture was filtered through Celite. The crude product was purified by silica flash chromatography (elution with MeOH / DCM) to obtain (R)-2-((6-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazoline-7-yl)-5-fluoro-4-methylpyridine-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-methylpyridine-2-yl)-6-chloro-4-(piperazine-1-yl)quinazolin-2-yl)amino)-3-fluoro-2-2-methylbutan-2-ol TIFF0007943888000159.tif51170

[0440] (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-methylpyridine-2-yl)carbonyl)benzoic acid (270 mg, 0.365 mmol) and N,N-diisopropylethylamine (0.32 mL, 1.80 mmol) were mixed in a dichloromethane solution (3.5 mL) to which HATU (212.0 mg, 0.547 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated using a rotary evaporator. The crude product was purified by silica flash chromatography (elution with MeOH / DCM) to obtain 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 at 45°C for 2 hours. The reaction mixture was concentrated, and the crude product was transferred to the next step without further purification.

[0442] To a 1,4-dioxane solution (1.0 mL) 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) 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 product was concentrated to obtain 129 mg of crude (R)-4-((7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-4-(piperazine-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-methylpyridine-2-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazoline-4-yl)piperazine-1-yl)prop-2-en-1-one TIFF0007943888000160.tif56170

[0443] (R)-4-((7-(6-amino-3-fluoro-4-methylpyridine-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) were dissolved in dichloromethane (2.5 mL), to which acrylic acid (0.020 mL, 0.290 mmol) and HATU (153 mg, 0.393 mmol) were added at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated using a rotary evaporator. The crude product was purified by silica flash chromatography (elution with MeOH / DCM) and then subjected to reverse-phase HPLC to obtain (R)-1-(4-(7-(6-amino-3-fluoro-4-methylpyridine-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-dimethylpyridine-2-yl)-6-chloroquinazolin-4-yl)piperidine-1-yl)prop-2-en-1-one TIFF0007943888000161.tif55170

[0445] The procedure is the same as in Example 11, except that in Step 1 of Example 12, commercially available 4,5-dimethylpyridine-2-amine was used as a substitute reagent in place of 2-amino-5-fluoro-4-picoline.

[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-methylpyridine-2-yl)-6-chloroquinazolin-4-yl)piperazine-1-yl)prop-2-en-1-one TIFF0007943888000162.tif56170

[0447] The procedure is the same as in Example 11, except that in Step 1 of Example 13, commercially available 2-amino-5-chloro-4-picoline was used as a substitute reagent in place 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-methylpyridine-2-yl)-6-chloroquinazolin-4-yl)piperazine-1-yl)prop-2-en-1-one TIFF0007943888000163.tif74170 Step 1: tert-butyl 4-(7-(6-amino-3-methylpyridine-2-yl)-6-chloroquinazoline-4-yl)piperazine-1-carboxylate TIFF0007943888000164.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-methylpyridine-2-amine (1 g, 5.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (432 mg, 0.52 mmol), and 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. 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 under vacuum. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10 / 1) to obtain 1.6 g (67%) of tert-butyl 4-[7-(6-amino-3-methylpyridine-2-yl)-6-chloroquinazolin-4-yl]piperazine-1-carboxylate (1.6 g, 3.5 mmol, yield 67%) as a yellow oil. LC-MS (ESI, m / z): 455.2 [M+H] + . Step 2: 6-(6-chloro-4-(piperazine-1-yl)quinazoline-7-yl)-5-methylpyridine-2-amine TIFF0007943888000165.tif44170

[0450] A 20 mL solution of tert-butyl 4-[7-(6-amino-3-methylpyridine-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 was stirred at 25°C for 3 hours. After completion, the resulting mixture was concentrated under vacuum to obtain 1.8 g (crude) of 6-[6-chloro-4-(piperazine-1-yl)quinazolin-7-yl]-5-methylpyridine-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-methylpyridine-2-yl)-6-chloroquinazoline-4-yl]piperazine-1-yl]prop-2-en-1-one TIFF0007943888000166.tif53170

[0451] A 20 mL solution of 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-methylpyridine-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 was stirred at 25°C for 2 hours. After 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 under vacuum. The crude product was further isolated under the following conditions: column: CHIRALPAK IE, 2*25cm, 5um; mobile phase A: MTBE (10mM NH3-methanol)-HPLC, mobile phase B: methanol-HPLC; flow rate: 20 mL / min; gradient: 15B to 15B at 27 min; 220 / 254 nm; RT1: 17.672; RT2: 23.294 to obtain 1-[4-[7-(6-amino-3-methylpyridine-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one (20.2 mg, 0.048 mmol, yield 3%) 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)piperazine-1-yl]quinazolin-7-yl]-5-methylpyridine-2-yl)acetamide TIFF0007943888000167.tif103170 Step 1: N-(6-[6-chloro-4-[4-(prop-2-enoyl)piperazine-1-yl]quinazolin-7-yl]-5-methylpyridine-2-yl)acetamide TIFF0007943888000168.tif52170

[0453] A 20 mL solution of 1-[4-[7-(6-amino-3-methylpyridine-2-yl)-6-chloroquinazolin-4-yl]piperazine-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 was stirred at 25°C for 9 hours. After 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 under vacuum. The crude product was further isolated under the following conditions: column: CHIRALPAK IE, 2*25cm, 5um; mobile phase A: MTBE (10mM NH3-methanol)-HPLC, mobile phase B: methanol-HPLC; flow rate: 20 mL / min; gradient: 15B to 15B at 27 min; 220 / 254 nm; RT1: 17.672; RT2: 23.294 to obtain N-(6-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]-5-methylpyridine-2-yl)acetamide (10.2 mg, 0.023 mmol, yield 3%) 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)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-yl)prop-2-en-1-one (Example 17a) and 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-yl)prop-2-en-1-one (Example 17b) TIFF0007943888000169.tif161170 Step 1: 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine TIFF0007943888000170.tif23170

[0455] To a 500 mL solution of 6-bromo-4-methylpyridine-2-amine (30.0 g, 160 mmol) in N,N-dimethylformamide, sodium hydride (19.0 g, 792 mmol) was slowly added at 0°C, and the mixture was stirred at 25°C for 1 hour. Next, 4-methoxybenzyl chloride (56.0 g, 359 mmol) was added to the reaction system, and the mixture was stirred at 25°C for 2 hours. After completion, the reaction system 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), the organic layers were dried together over Na₂SO₄, and evaporated under vacuum. The residue was applied to a silica gel column while eluting with petroleum ether / ethyl acetate (15%) to obtain 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine (60 g, 140 mmol, yield 87.5%) 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-pyridine-2-amine TIFF0007943888000171.tif23170

[0456] Under nitrogen, a 1,4-dioxane solution (220 mL) containing 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-4-methylpyridine-2-amine (35.0 g, 82 mmol), hexabutyldisin (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) was stirred at 110°C for 5 hours. After completion, the reaction system was concentrated under vacuum. The residue was purified by silica gel flash chromatography eluted with petroleum ether / ethyl acetate (10 / 1) to obtain N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6-tributylstannyl-pyridine-2-amine (45 g, 71 mmol, yield 86.2%) as a red oil. LC-MS:(ESI,m / z):639.3 [M+H] + . Step 3: 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid TIFF0007943888000172.tif29170

[0457] A solution (1 L) 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 was stirred at 80°C for 2 hours. After completion, the system was poured into water (2.0 L) and a large amount of solid precipitated. Next, the solid was collected after being filtered. The solid was washed with warm water (1 L). The solid was then dried under an infrared lamp to obtain 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (100 g, 373 mmol, yield 87.2%) as an off-white solid. LC-MS: (ESI, m / z): 265.9 [MH] + . Step 4: 7-Bromo-6-chloro-8-fluoroquinazoline-2,4(1H,3H)-dione TIFF0007943888000173.tif28170

[0458] A urea solution (806.0 g, 13.4 mol) of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (120.0 g, 447 mmol) was stirred at 200°C for 1.5 hours. After completion, the reaction system was cooled to 80°C, and water (1.5 L) was added to the system while stirring for 20 minutes. After passing through a filter, the solid was collected and washed with warm water (1 L). Next, the solid was dried under an infrared lamp to obtain 7-bromo-6-chloro-8-fluoroquinazoline-2,4(1H,3H)-dione (120 g, 409 mmol, yield 91.5%) as a light brown solid. LC-MS: (ESI, m / z): 290.9 [MH] + . Step 5: tert-butyl(3S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate TIFF0007943888000174.tif43170

[0459] A POCl3 solution (1.0 L) of 7-bromo-6-chloro-8-fluoroquinazoline-2,4-diol (65.0 g, 222 mmol) and DMF (500.0 mg, 6.85 mmol) was stirred at 110°C for 60 hours. After the starting materials were completely dissolved, the resulting mixture was concentrated under vacuum. Next, 1,4-dioxane (1.0 L), N,N-diisopropylethylamine (286.0 g, 2217 mmol), and tert-butyl(3S)-3-methyl-1-piperazine carboxylate (90.0 g, 449 mmol) were added to the reaction system and stirred at 25°C for 1 hour. After completion, the solvent was concentrated under vacuum. The residue was purified by silica gel flash chromatography eluted with petroleum ether / ethyl acetate (20%) to obtain tert-butyl(3S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (65 g, 132 mmol, yield 59.4%) 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 TIFF0007943888000175.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 system was cooled to room temperature. Next, ethyl acetate (1.5 L) was added to the system 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 eluted with petroleum ether / ethyl acetate (20%) to obtain tert-butyl(3S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (23 g, 48 mmol, yield 79.3%) 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-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)-3-methylpiperazine-1-carboxylate TIFF0007943888000176.tif51170

[0461] Under nitrogen, a 1,4-dioxane solution (320 mL) containing 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-tributylstannylpyridine-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) was stirred at 120°C for 16 hours. After completion, the reaction system was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). Next, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluted with petroleum ether / ethyl acetate (30%) to obtain tert-butyl(3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (18.5 g, 25 mmol, yield 51.6%) 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-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)-3-methylpiperazine-1-carboxylate TIFF0007943888000177.tif52170

[0462] A 350 mL solution of tert-butyl(3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridine-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 was stirred at 25°C for 5 hours. After completion, the reaction system 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 eluted with petroleum ether / ethyl acetate (25%) to obtain tert-butyl(3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (16 g, 18.4 mmol, yield 74%) 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)pyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)-3-methylpiperazine-1-carboxylate TIFF0007943888000178.tif51170

[0463] Under nitrogen, a 400 mL solution (N,N-dimethylacetamide) of tert-butyl(3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridine-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) was stirred at 90°C for 18 hours. After completion, the reaction system 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 under vacuum. The residue was purified by silica gel flash chromatography eluted with petroleum ether / ethyl acetate (30%) to obtain tert-butyl(3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (12.2 g, 15 mmol, yield 81.7%) 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)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3-methylpiperazine-1-carboxylate TIFF0007943888000179.tif51170

[0464] To a tetrahydrofuran solution (300 mL) of (S)-(1-methylpyrrolidine-2-yl)methanol (4.32 g, 37.5 mmol), sodium hydride (2.1 g, 87.5 mmol) was slowly added at 0°C, and the mixture was stirred at 25°C for 1 hour. Next, tert-butyl(3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (12.2 g, 15 mmol) was added to the reaction system, and the mixture was stirred at 25°C for 1 hour. After completion, the reaction system was quenched with methanol (50 mL). Next, the mixture was concentrated under vacuum, and the residue was purified by silica gel flash chromatography eluted with dichloromethane / methanol (6 / 94) to obtain tert-butyl(3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (8.6 g, 9.5 mmol, yield 63.1%) as a brown solid. LC-MS:(ESI,m / z):908.4 [M+H] + . Step 11: 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazine-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine TIFF0007943888000180.tif51170

[0465] A trifluoroacetic acid solution (100 mL) of tert-butyl(3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (8.6 g, 9.5 mmol) was stirred at 50°C for 4 hours. After completion, the reaction system was concentrated under vacuum. The residue was dissolved in dichloromethane (50 mL), and the pH was adjusted to 9 with N,N-diisopropylethylamine. After concentration under vacuum, the residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel; mobile phase A: water, B: ACN, ratio of B (5%~40% in 30 minutes); detector: UV 254 nm. 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (3.5 g, 6.17 mmol, yield 65.1%) was obtained 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)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-yl)prop-2-en-1-one (Example 17a), and 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-yl)prop-2-en-1-one (Example 17b) TIFF0007943888000181.tif65170

[0466] Acryloyl chloride (359.0 mg, 3.97 mmol) was added to a 120 mL dichloromethane solution of 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (2.5 g, 4.4 mmol) and N,N-diisopropylethylamine (2.9 g, 22.5 mmol) at -78°C, and the mixture was stirred at -78°C for 25 minutes. The reaction was quenched with water and extracted with dichloromethane. The organic layers were combined. The organic layers were 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, ratio of B (5% to 60% in 30 minutes); detector: UV 254 nm, to obtain 1-[(3S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidine-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazine-1-yl]prop-2-en-1-one (1.3 g, 2.09 mmol, yield 47.5%) as a brown solid.A mixture of diastereoisomers was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IC-3 0.46*5cm 3um; mobile phase: (hexane:dichloromethane=3:1)(0.1%DEA):EtOH=50:50; detector: 254nm; flow rate: 1.0 ml / min; temperature: 25℃. 657.7 mg of 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methyl Lupiperazin-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)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-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)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-yl)-4-fluorobuta-2-en-1-one, and (E)-1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-yl)-4-fluorobuta-2-en-1-one TIFF0007943888000182.tif91170

[0469] (E)-4-fluorobuta-2-enoic acid (100 mg, 3.97 mmol) was added at 25°C to a 25 mL dichloromethane solution of 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidine-2-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridine-2-amine (500 mg, 0.88 mmol), HATU (401 mg, 1.06 mmol), and N,N-diisopropylethylamine (228 mg, 0.96 mmol). 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 layers were 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, ratio of B (5%~60% in 30 minutes); detector: UV 254 nm, and (E)-1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-yl)-4-fluorobuta-2-en-1-one and (E)- A mixture of 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3-methylpiperazine-1-yl)-4-fluorobuta-2-en-1-one (130 mg, 0.20 mmol, yield 23%) was obtained as a white solid.A mixture of diastereoisomers was separated by preparative chiral HPLC under the following conditions: column: CHIRAL Cellulose-SB, column size: 0.46*10cm; mobile phase: 3um; hexane:EtOH=50:50; flow rate: 1.0 mL / min; temperature: 25°C. 32 mg of (E)-1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methyl (E)-1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3-methylpiperazine-1-yl)-4-fluorobuta-2-en-1-one was obtained as a white solid, and 29.9 mg of (E)-1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3-methylpiperazine-1-yl)-4-fluorobuta-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)pyridine-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperazine-1-yl)propa-2-en-1-one TIFF0007943888000183.tif122170 Step 1: tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-2-pyridyl]-6-chloro-8-fluoroquinazoline-4-yl]piperazine-1-carboxylate TIFF0007943888000184.tif50170

[0472] Under nitrogen, a 1,4-dioxane solution (100 mL) containing N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6-tributylstannylpyridine-2-amine (4.0 g, 6.27 mmol), tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-2-pyridyl]-6-chloro-8-fluoroquinazolin-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) was stirred at 120°C for 3 hours. After completion, the solution was diluted with water (200 mL) and extracted (3 × 50 mL). Next, the organic layers were combined and dried over anhydrous sodium sulfate. The organic layers were concentrated under vacuum, and the residue was purified by silica gel flash chromatography eluted with ethyl acetate / petroleum ether (1 / 20) to obtain 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, yield 24.6%) 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-fluoroquinazolin-4-yl]-3-methylpiperazine-1-carboxylate TIFF0007943888000185.tif52170

[0473] A solution of tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-2-pyridyl]-6-chloro-8-fluoroquinazolin-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 under vacuum. The residue was purified by silica gel flash chromatography eluted with ethyl acetate / petroleum ether (1 / 20) to obtain tert-butyl(3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-iodo-4-methyl-2-pyridyl]-6-chloro-8-fluoroquinazolin-4-yl]-3-methyl-piperazine-1-carboxylate (1.3g, 1.55 mmol, yield 656.5%) 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-fluoroquinazoline-4-yl]-3-methylpiperazine-1-carboxylate TIFF0007943888000186.tif51170

[0474] Under nitrogen, a 5 mL solution of tert-butyl(3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluorophenyl)-2-pyridyl]-6-chloro-8-fluoroquinazolin-4-yl]-3-methylpiperazine-1-carboxylate (0.1 g, 0.12 mmol), (1,10-phenantholine)(trifluoromethyl)copper(I) (0.73 g, 2.34 mmol), and cuprous iodide (0.45 g, 2.34 mmol) in N,N-dimethylformamide 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 under vacuum. The residue was purified by silica gel flash chromatography eluted with ethyl acetate / petroleum ether (1 / 5) to obtain tert-butyl(3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoroquinazolin-4-yl]-3-methyl-piperazine-1-carboxylate (60 mg, 0.075 mmol, yield 64.4%) as a yellow solid. LC-MS (ESI, m / z): 781.3 [M+H] + . Step 4: 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazine-1-yl]quinazoline-7-yl]-4-methyl-5-(trifluoromethyl)pyridine-2-amine TIFF0007943888000187.tif49170

[0475] A trifluoroacetic acid solution (5.0 mL) of tert-butyl(3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoroquinazolin-4-yl]-3-methylpiperazine-1-carboxylate (0.1 g, 0.13 mmol) 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 under vacuum. The residue was purified by silica gel flash chromatography eluted with methanol / dichloromethane (1 / 9) to obtain 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridine-2-amine (40 mg, 0.08 mmol, yield 69.9%) 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)pyridine-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperazine-1-yl)propa-2-en-1-one TIFF0007943888000188.tif58170

[0476] 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazine-1-yl]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridine-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) were mixed in a dichloromethane solution (3 mL) at -78 °C for 0.5 hours. Next, acrylic acid (0.01 g, 0.13 mmol) was added and the mixture was mixed at -78 °C for 4 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 under vacuum. The crude product was further isolated by preparative HPLC under the following conditions: column: CHIRALPAK IE, 2*25cm, 5um; mobile phase A: MTBE (10mM NH3-methanol)-HPLC, mobile phase B: methanol-HPLC; flow rate: 20 mL / min; gradient: 15B~15B at 27 min; 220 / 254 nm; RT1: 17.672; RT2: 23.294, yielding 1-[(3S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoroquinazolin-4-yl]-3-methylpiperazine-1-yl]prop-2-en-1-one (10 mg, 0.019 mmol, yield 22.3%) 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-(azetidine-1-yl)quinazoline-4-yl]piperazine-1-yl]prop-2-en-1-one TIFF0007943888000189.tif118170 Step 1: tert-butyl 4-[6-(azetidine-1-yl)-7-bromo-quinazoline-4-yl]piperazine-1-carboxylate TIFF0007943888000190.tif33170

[0478] Under nitrogen, a 20 mL solution of 1,4-dioxane containing tert-butyl 4-(7-bromo-6-iodoquinazolin-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), xanthophos (1.22 g, 2.12 mmol), and cesium carbonate (6.9 g, 21.19 mmol) was stirred at 80°C for 2 hours. After 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 under vacuum. The residue was purified by silica gel flash chromatography eluted with ethyl acetate / petroleum ether (45 / 55) to obtain tert-butyl 4-[6-(azetidine-1-yl)-7-bromo-quinazolin-4-yl]piperazine-1-carboxylate (1.0 g, 2.24 mmol, yield 21.1%) as a yellow solid. LC-MS (ESI, m / z): 448.1 [M+H] + . Step 2: tert-butyl 4-[6-(azetidine-1-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-4-yl]piperazine-1-carboxylate TIFF0007943888000191.tif41170

[0479] Under nitrogen, a 15 mL solution of tert-butyl 4-[6-(azetidine-1-yl)-7-bromo-quinazolin-4-yl]piperazine-1-carboxylate (1.0 g, 2.23 mmol), bis(pinacolato)diborone (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 was stirred at 80°C for 3 hours. After 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 filtrate was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 1) to obtain tert-butyl 4-[6-(azetidine-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, yield 45.3%) 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-(azetidine-1-yl)quinazoline-4-yl]piperazine-1-carboxylate TIFF0007943888000192.tif42170

[0480] Under nitrogen, a solution of tert-butyl 4-[6-(azetidine-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)pyridine-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. After completion, the solution was concentrated under vacuum. The residue was purified by silica gel flash chromatography eluted with methanol / dichloromethane (3 / 97) to obtain tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidine-1-yl)quinazolin-4-yl]piperazine-1-carboxylate (280 mg, 0.53 mmol, yield 52.4%) as a yellow solid. LC-MS (ESI, m / z): 530.2 [M+H] + . Step 4: 6-[6-(azetidine-1-yl)-4-piperazine-1-yl-quinazoline-7-yl]-5-(trifluoromethyl)piperidine-2-amine TIFF0007943888000193.tif39170

[0481] A toluene solution (20 mL) of tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidine-1-yl)quinazolin-4-yl]piperazine-1-carboxylate (200.0 mg, 0.38 mmol) and silica gel (1.0 g) was stirred at 110°C for 12 hours. After completion, the solution was concentrated under vacuum. The residue was purified by silica gel flash chromatography eluted with methanol / dichloromethane (1 / 9) to obtain 6-[6-(azetidine-1-yl)-4-piperazine-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)piperidine-2-amine (150 mg, 0.35 mmol, yield 92.5%) 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-(azetidine-1-yl)quinazoline-4-yl]piperazine-1-yl]prop-2-en-1-one TIFF0007943888000194.tif44170

[0482] A 10 mL solution of 6-[6-(azetidine-1-yl)-4-piperazine-1-ylquinazolin-7-yl]-5-(trifluoromethyl)piperidine-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 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 under vacuum. The residue was purified by reverse-phase column elution with acetonitrile / water (1 / 1) to obtain 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidine-1-yl)quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one (5.9 mg, yield 3.5%) 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...

Claims

1. Compounds having formula (II): or a pharmaceutically acceptable salt thereof. [In the formula, R ２ NH ２ And, R ３ and R ４ are each independently selected from the group consisting of H, NH ２ , 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 cyclopropyl, R ５ H, NH ２ Hello, 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 Selected from the group consisting of cycloalkyl groups, or R ４ and R ５ Each atom is bonded to by one to four substituents (where each substituent is independently OH, NH). ２ Hello, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, and C １～３ C is optionally substituted with (selected from the group consisting of haloalkoxys). ６～１４ Forms an aryl or 5-10 membered heteroaryl, R ７ R is selected from the group consisting of H, cyano, and halo, ８ and R ９ H and C are respectively. １～６ Alkyl, C １～６ Haloalkyl, C １～６ A component independently selected from the group consisting of hydroxyalkyl, cyano, and halo (C １～６ Alkyl refers to methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), alkyl or arylsulfonate leaving groups, 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 haloalkoxys.) or R ７ and R ８ Both form a triple bond with the carbon they are bonded to, or R ７ and R ８ These are C atoms that, along with the carbon atoms to which they are bonded, are optionally substituted with one or two halo substituents. ３～７ Forms a cycloalkenyl, R ９ 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 haloalkoxys.) X is, Selected from the group consisting of, Y is Y １ And, Y １ H is, U is C(R) ６ａ ) and V is C(R ６ｂ ) and W is C(R) ６ｃ ) and R ６ａ , R ６ｂ , and R ６ｃ Each of these is independently H, OH, NH ２ Halo, cyano, carbamoyl, C ２～６ Alkenil, C １～６ Alkoxy, C １～６ C substituted with alkyl or 4-10 member heterocyclyl substituents １～６ Alkyl, C １～６ Alkyl sulfanyl, C １～６ Alkyl sulfonyl, C １～６ Alkylthio, C １～６ Haloalkylthio, C ２～６ Alkinyl, C １～６ Alkylamino, C ６～１４ Ariel, 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 haloalkyls, 5-10 membered heteroaryls, and 4-10 membered heterocyclines, n is selected from the group consisting of 0, 1, and 2.

2. R ３ and R ４ are each independently selected from the group consisting of H, halo, C １～６ alkyl, C １～６ haloalkyl, and cyclopropyl, R ５ is selected from the group consisting of H, halo, C １～６ alkyl, C １～６ haloalkyl, C １～６ haloalkoxy, C １～６ alkylamino, and C ３～７ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R ４ and R ５ together with the atoms to which they are each bonded, form an unsubstituted C ６ aryl or 5- to 10-membered heteroaryl, or R ４ and R ５ together with the atoms to which they are each bonded, form a C １～３ aryl or 5- to 10-membered heteroaryl substituted with one substituent independently selected from the group consisting of halo, C １～３ alkyl, C １～３ haloalkyl, C １～３ alkoxy, and C ６～ haloalkoxy, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. Compounds having formula (IV): or a pharmaceutically acceptable salt thereof. [In the formula, R １ This is an electrophilic moiety at position 12 of the K-Ras G12C mutant protein that can form a covalent bond with a cysteine ​​residue. X is, Selected from the group consisting of, Y is Y １ And, Y １ H is, U is C(R) ６ａ ) and V is C(R ６ｂ ) and W is C(R) ６ｃ ) and R ６ａ , R ６ｂ , and R ６ｃ Each of these is independently H, OH, NH ２ Halo, cyano, carbamoyl, C ２～６ Alkenil, C １～６ Alkoxy, C １～６ C substituted with alkyl or 4-10 member heterocyclyl substituents １～６ Alkyl, C １～６ Alkyl sulfanyl, C １～６ Alkyl sulfonyl, C １～６ Alkylthio, C １～６ Haloalkylthio, C ２～６ Alkinyl, C １～６ Alkylamino, C ６～１４ Ariel, 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 haloalkyls, 5-10 membered heteroaryls, and 4-10 membered heterocyclines, n is selected from the group consisting of 0, 1, and 2. R １１ teeth, Selected from the group consisting of [the specified group].

5. R ６ａ The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein is H.

6. X A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

7. X The compound according to claim 4 or a pharmaceutically acceptable salt thereof.

8. R １ but A compound according to claim 4 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

9. R １ but The compound according to claim 8 or a pharmaceutically acceptable salt thereof.

10. R ７ is H, cyano, or halo, and R ８ and R ９ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each of the elements is H.

11. R ７ , R ８ and R ９ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each of the elements is H.

12. A compound selected from the group or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

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