Combinations and use of methionine adenosyltransferase 2A (MAT2A) inhibitors

Abstract

This specification describes methods for treating cancer using low-molecular-weight methionine adenosyltransferase 2a (MAT2A) inhibitors and additional agents.

Description

[Technical Field]

[0001] [Cross reference] This application claims the interests of International Application PCT / CN2023 / 089330, filed on 19 April 2023, which, by reference, is in whole part of this specification. [Background technology]

[0002] Methionine adenosyltransferase 2a (MAT2A) plays a crucial role in metabolism and epigenetics. Despite its broad cellular role, inhibition of MAT2A has been shown to have a selective antiproliferative effect in cancers with deficiencies in a different metabolic gene, methylthioadenosine phosphorylase (MTAP). MTAP deficiency is frequent in both solid tumors and hematological malignancies. Therefore, compounds that inhibit MAT2A are potential agents for treating MTAP-deficient cancers. [Overview of the Initiative]

[0003] This specification discloses a method for treating cancer in a subject requiring treatment, the method comprising, (a) A compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, [ka] (b) Additional medications, This includes administering, The amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, combined with an additional agent, is a therapeutically effective dose for treating cancer.

[0004] Furthermore, this specification discloses a method for treating cancer in a subject requiring treatment, and this method involves, (a) 5-Methoxy-1-(2-methylpyridine-3-yl)-4-(propa-2-in-1-ylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one: [ka] (Compound 1) or a pharmaceutically acceptable salt thereof, (b) Additional medications, This includes administering [the drug].

[0005] In some embodiments, cancer is primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

[0006] In some embodiments, cancer is liver cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, gastrointestinal stromal tumor, biliary tract cancer, B-cell acute lymphoblastic leukemia (ALL), lymphoma, or T-cell leukemia.

[0007] In some embodiments, additional agents include PARP inhibitors, CHK1 inhibitors, MDM2 inhibitors, hypomethylating agents, mTOR inhibitors, ATM inhibitors, CDK4 / 6 inhibitors, BCL-2 inhibitors, PRMT5 inhibitors, PRMT1 inhibitors, ATR inhibitors, WEE1 inhibitors, APE1 inhibitors, topoisomerase inhibitors, taxanes, immune checkpoint inhibitors, CDK7 inhibitors, CDK9 inhibitors, DNA synthesis inhibitors, antimetabolites, AURORA inhibitors, microtubule stabilizers, DNA crosslinking agents, vinca alkaloids, alkylating agents, PRMT6 inhibitors, PRMT7 inhibitors, PRMT9 inhibitors, KRAS inhibitors, EGFR inhibitors, VEGFR inhibitors, aromatase inhibitors, mitotic inhibitors, radiopharmaceuticals, cytotoxic agents, or any combination thereof.

[0008] The features of the present invention are described in detail in the appended claims. A better understanding of the features of the present invention can be obtained by referring to the following detailed description and accompanying drawings illustrating exemplary embodiments utilizing the principles of the present invention. [Brief explanation of the drawing]

[0009] [Figure 1] This figure shows the efficacy of compound 1 and docetaxel in KP4 MTAP null xenografts. [Figure 2] This figure shows the percentage change in body weight of mice. [Figure 3] This figure shows the efficacy of compound 1 and docetaxel in HCC15 MTAP null xenografts. [Figure 4] This figure shows the percentage change in body weight of mice. [Figure 5] This figure shows the efficacy of compound 1 and MRTX1719 in NCI-H838 MTAP null xenografts. [Figure 6] This figure shows the percentage change in body weight of mice. [Figure 7A] This figure shows the excess bliss synergistic effect of compound 1 combined with the PARP inhibitor olaparib in MTAP-deficient cell lines (RT112-84). [Figure 7B] This figure shows the excess Bliss synergistic effect of compound 1 combined with the PARP inhibitor olaparib in the MTAP-deficient cell line (DOHH-2). [Figure 7C] This figure shows the excess Bliss synergistic effect of compound 1 combined with the PARP inhibitor olaparib in the MTAP-deficient cell line (Jurkat). [Figure 7D] This figure shows the excess Bliss synergistic effect of compound 1 combined with the PARP inhibitor olaparib in the MTAP-deficient cell line (HuP-T4). [Figure 8A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the PARP inhibitor niraparib in an MTAP-deficient cell line (RT112-84). [Figure 8B]This figure shows the excess Bliss synergistic effect of compound 1 combined with the PARP inhibitor niraparib in the MTAP-deficient cell line (DOHH-2). [Figure 8C] This figure shows the excess Bliss synergistic effect of compound 1 combined with the PARP inhibitor niraparib in the MTAP-deficient cell line (HuP-T4). [Figure 9A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the PARP inhibitor talazoparib in the MTAP-deficient cell line (CAPAN-1). [Figure 9B] This figure shows the excess Bliss synergistic effect of compound 1 combined with the PARP inhibitor talazoparib in the MTAP-deficient cell line (Jurkat). [Figure 9C] This figure shows the excess Bliss synergistic effect of compound 1 combined with the PARP inhibitor talazoparib in the MTAP-deficient cell line (SW1573). [Figure 9D] This figure shows the excess Bliss synergistic effect of compound 1 combined with the PARP inhibitor talazoparib in the MTAP-deficient cell line (HuP-T4). [Figure 10A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the PARP inhibitor rucaparib in the MTAP-deficient cell line (DOHH-2). [Figure 10B] This figure shows the excess Bliss synergistic effect of compound 1 combined with the PARP inhibitor lucaparib in the MTAP-deficient cell line (RS4-11). [Figure 11A] This figure shows the excess Bliss synergy effect of compound 1 combined with the BCL-2 inhibitor venetoclax in MTAP-deficient cell lines (RT112-84). [Figure 11B] This figure shows the excess Bliss synergy effect of compound 1 combined with the BCL-2 inhibitor venetoclax in the MTAP-deficient cell line (THP-1). [Figure 11C] This figure shows the excess Bliss synergy effect of compound 1 combined with the BCL-2 inhibitor venetoclax in the MTAP-deficient cell line (DOHH-2). [Figure 11D]This figure shows the excess Bliss synergy effect of compound 1 combined with the BCL-2 inhibitor venetoclax in the MTAP-deficient cell line (Jurkat). [Figure 11E] This figure shows the excess Bliss synergy effect of compound 1 combined with the BCL-2 inhibitor venetoclax in the MTAP-deficient cell line (SW780). [Figure 11F] This figure shows the excess Bliss synergy effect of compound 1 combined with the BCL-2 inhibitor venetoclax in the MTAP-deficient cell line (LN-18). [Figure 12A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor afatinib in the MTAP-deficient cell line (RT112-84). [Figure 12B] This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor afatinib in the MTAP-deficient cell line (DOHH-2). [Figure 12C] This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor afatinib in the MTAP-deficient cell line (HCC1395). [Figure 12D] This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor afatinib in the MTAP-deficient cell line (Jurkat). [Figure 12E] This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor afatinib in an MTAP-deficient cell line (HCT-116 MTAP-null). [Figure 12F] This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor afatinib in the MTAP-deficient cell line (A549). [Figure 13A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor gefitinib in the MTAP-deficient cell line (DOHH-2). [Figure 13B] This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor gefitinib in the MTAP-deficient cell line (HCC1395). [Figure 13C]This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor gefitinib in the MTAP-deficient cell line (Jurkat). [Figure 13D] This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor gefitinib in the MTAP-deficient cell line (LN-18). [Figure 13E] This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor gefitinib in the MTAP-deficient cell line (HuP-T4). [Figure 14A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor erlotinib in the MTAP-deficient cell line (LN-18). [Figure 14B] This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor erlotinib in the MTAP-deficient cell line (SK-HEP-1). [Figure 14C] This figure shows the excess Bliss synergistic effect of compound 1 combined with the EGFR inhibitor erlotinib in the MTAP-deficient cell line (A549). [Figure 15A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the mTOR inhibitor everolimus in the MTAP-deficient cell line (CAPAN-1). [Figure 15B] This figure shows the excess Bliss synergistic effect of compound 1 combined with the mTOR inhibitor everolimus in an MTAP-deficient cell line (HCT-116 MTAP-null). [Figure 15C] This figure shows the excess Bliss synergistic effect of compound 1 combined with the mTOR inhibitor everolimus in the MTAP-deficient cell line (NCI-H1651). [Figure 15D] This figure shows the excess Bliss synergistic effect of compound 1 combined with the mTOR inhibitor everolimus in the MTAP-deficient cell line (BT-474). [Figure 16A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the mTOR inhibitor temsirolimus in the MTAP-deficient cell line (Jurkat). [Figure 16B]This figure shows the excess Bliss synergistic effect of compound 1 combined with the mTOR inhibitor temsirolimus in the MTAP-deficient cell line (MDA-MB-231). [Figure 16C] This figure shows the excess Bliss synergistic effect of compound 1 combined with the mTOR inhibitor temsirolimus in the MTAP-deficient cell line (BT-474). [Figure 17A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the KRAS inhibitor sotrasib in the MTAP-deficient cell line (DOHH-2). [Figure 17B] This figure shows the excess Bliss synergistic effect of compound 1 combined with the KRAS inhibitor sotrasib in the MTAP-deficient cell line (SW1573). [Figure 17C] This figure shows the excess Bliss synergistic effect of compound 1 combined with the KRAS inhibitor sotrasib in the MTAP-deficient cell line (MIA-Paca-2). [Figure 17D] This figure shows the excess Bliss synergistic effect of compound 1 combined with the KRAS inhibitor sotrasib in the MTAP-deficient cell line (RS4-11). [Figure 17E] This figure shows the excess Bliss synergistic effect of compound 1 combined with the KRAS inhibitor sotrasib in the MTAP-deficient cell line (SW1088). [Figure 17F] This figure shows the excess Bliss synergistic effect of compound 1 combined with the KRAS inhibitor sotrasib in an MTAP-deficient cell line (HCT-116-MTAP-null). [Figure 17G] This figure shows the excess Bliss synergistic effect of compound 1 combined with the KRAS inhibitor sotrasib in the MTAP-deficient cell line (A549). [Figure 17H] This figure shows the excess Bliss synergistic effect of compound 1 combined with the KRAS inhibitor sotrasib in the MTAP-deficient cell line (HuP-T4). [Figure 18A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the WEE1 inhibitor bosutinib in the MTAP-deficient cell line (Jurkat). [Figure 18B]This figure shows the excess Bliss synergistic effect of compound 1 combined with the WEE1 inhibitor bosutinib in the MTAP-deficient cell line (LN-18). [Figure 18C] This figure shows the excess Bliss synergistic effect of compound 1 combined with the WEE1 inhibitor bosutinib in the MTAP-deficient cell line (RS4-11). [Figure 18D] This figure shows the excess Bliss synergistic effect of compound 1 combined with the WEE1 inhibitor bosutinib in an MTAP-deficient cell line (HCT-116-MTAP-null). [Figure 18E] This figure shows the excess Bliss synergistic effect of compound 1 combined with the WEE1 inhibitor bosutinib in the MTAP-deficient cell line (A549). [Figure 19A] This figure shows the excess Bliss synergy effect of compound 1 combined with the CDK4 / 6 inhibitor palbociclib in the MTAP-deficient cell line (DOHH-2). [Figure 19B] This figure shows the excess Bliss synergy effect of compound 1 combined with the CDK4 / 6 inhibitor abemaciclib in the MTAP-deficient cell line (UM-UC-3). [Figure 19C] This figure shows the excess Bliss synergy effect of compound 1 combined with the CDK4 / 6 inhibitor abemaciclib in the MTAP-deficient cell line (SW900). [Figure 20A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the topoisomerase inhibitor etoposide in MTAP-deficient cell lines (NCI-H292). [Figure 20B] This figure shows the excess Bliss synergistic effect of compound 1 combined with the topoisomerase inhibitor etoposide in the MTAP-deficient cell line (THP-1). [Figure 20C] This figure shows the excess Bliss synergistic effect of compound 1 combined with the topoisomerase inhibitor etoposide in the MTAP-deficient cell line (LN-18). [Figure 20D] This figure shows the excess Bliss synergy effect of compound 1 combined with the topoisomerase inhibitor etoposide in the MTAP-deficient cell line (HCC1806). [Figure 20E]This figure shows the excess Bliss synergistic effect of compound 1 combined with the topoisomerase inhibitor etoposide in the MTAP-deficient cell line (UM-UC-3). [Figure 20F] This figure shows the excess Bliss synergy effect of compound 1 combined with the topoisomerase inhibitor etoposide in the MTAP-deficient cell line (A172). [Figure 20G] This figure shows the excess Bliss synergistic effect of compound 1 combined with the topoisomerase inhibitor etoposide in the MTAP-deficient cell line (SW900). [Figure 20H] This figure shows the excess Bliss synergistic effect of compound 1 combined with the topoisomerase inhibitor etoposide in the MTAP-deficient cell line (HCC38). [Figure 21A] This figure shows the excess Bliss synergistic effect of compound 1 and the antimetabolite pemetrexed in the MTAP-deficient cell line (DOHH-2). [Figure 21B] This figure shows the excess Bliss synergistic effect of compound 1 combined with the antimetabolite pemetrexed in the MTAP-deficient cell line (Jurkat). [Figure 21C] This figure shows the excess Bliss synergistic effect of compound 1 and the antimetabolite pemetrexed in the MTAP-deficient cell line (SW780). [Figure 21D] This figure shows the excess Bliss synergistic effect of compound 1 combined with the antimetabolite pemetrexed in the MTAP-deficient cell line (LN-18). [Figure 21E] This figure shows the excess Bliss synergistic effect of compound 1 combined with the antimetabolite pemetrexed in the MTAP-deficient cell line (HCC38). [Figure 21F] This figure shows the excess Bliss synergy effect of compound 1 and the antimetabolite pemetrexed in the MTAP-deficient cell line (HCC1806). [Figure 22A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the low-methylating agent decitabine in the MTAP-deficient cell line (CAPAN-1). [Figure 22B]This figure shows the excess Bliss synergy effect of compound 1 combined with the hypomethylating agent decitabine in the MTAP-deficient cell line (HuP-T4). [Figure 23A] This figure shows the excess Bliss synergistic effect of compound 1 in combination with the antimetabolite capecitabine or 5-FU in the MTAP-deficient cell line (NCI-H1651). [Figure 23B] This figure shows the excess Bliss synergistic effect of compound 1 in combination with the antimetabolite capecitabine or 5-FU in the MTAP-deficient cell line (Jurkat). [Figure 23C] This figure shows the excess Bliss synergistic effect of compound 1 in combination with the antimetabolite capecitabine or 5-FU in the MTAP-deficient cell line (K562). [Figure 24A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the microtubule stabilizer docetaxel in the MTAP-deficient cell line (SK-HEP-1). [Figure 24B] This figure shows the excess Bliss synergistic effect of compound 1 combined with the microtubule stabilizer docetaxel in the MTAP-deficient cell line (RT4). [Figure 24C] This figure shows the excess Bliss synergistic effect of compound 1 combined with the microtubule stabilizer docetaxel in the MTAP-deficient cell line (PANC-1). [Figure 25A] This figure shows the excess Bliss synergy effect of the combination of compound 1 and the vinca alkaloid vinorelbine in the MTAP-deficient cell line (RT4). [Figure 25B] This figure shows the excess Bliss synergistic effect of the combination of compound 1 and the vinca alkaloid vinorelbine in the MTAP-deficient cell line (SK-HEP-1). [Figure 26A] This figure shows the excess Bliss synergistic effect of the combination of compound 1 and the alkylating agent oxaliplatin in the MTAP-deficient cell line (Jurkat). [Figure 26B] This figure shows the excess Bliss synergistic effect of the combination of compound 1 and the alkylating agent oxaliplatin in the MTAP-deficient cell line (DOHH-2). [Figure 26C]This figure shows the excess Bliss synergistic effect of compound 1 combined with the alkylating agent oxaliplatin in the MTAP-deficient cell line (HuP-T4). [Figure 27A] This figure shows the excess Bliss synergistic effect of compound 1 and the alkylating agent altoretamine in the MTAP-deficient cell line (DOHH-2). [Figure 27B] This figure shows the excess Bliss synergy effect of the combination of compound 1 and the alkylating agent altoretamine in the MTAP-deficient cell line (SW1573). [Figure 28A] This figure shows the excess Bliss synergistic effect of compound 1 combined with the low-methylating agent procainamide in the MTAP-deficient cell line (DOHH-2). [Figure 28B] This figure shows the excess Bliss synergistic effect of compound 1 combined with the low-methylating agent procainamide in the MTAP-deficient cell line (HCC1395). [Figure 28C] This figure shows the excess Bliss synergistic effect of compound 1 combined with the low-methylating agent procainamide in the MTAP-deficient cell line (HCC38). [Figure 29A] This figure shows the excess Bliss synergy effect of compound 1 combined with the PRMT5 inhibitor MRTX1719 in the MTAP-deficient cell line (NCI-H838). [Figure 29B] This figure shows the excess Bliss synergistic effect of compound 1 and the PRMT5 inhibitor AM-9747 in an MTAP-deficient cell line (NCI-H838). [Modes for carrying out the invention]

[0010] definition The following description includes certain details to provide a complete understanding of the various embodiments. However, those skilled in the art will understand that the invention can be carried out without these details. In other examples, known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments.

[0011] Unless otherwise specified in the context, the word “comprise” and its variations such as “comprises” and “comprising” throughout this specification and the appended claims should be interpreted in an open and comprehensive sense, meaning “including, but not limited to.” Furthermore, the headings presented herein are for convenience only and do not constitute an interpretation of the scope or meaning of the claimed invention.

[0012] Unless otherwise stated, the following terms used in this application have the definitions set forth below. The use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described herein.

[0013] Throughout this specification, any reference to “several embodiments” or “an embodiment” means that any particular feature, structure, or characteristic described in relation to that embodiment is included in at least one embodiment. Therefore, the phrases “in one embodiment” or “in an embodiment” appearing in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, any particular feature, structure, or characteristic can be combined in any suitable way in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms ("a", "an", and "the") include multiple references unless explicitly indicated otherwise. It should also be noted that the term “or” is generally used in its meaning including “and / or” unless explicitly indicated otherwise.

[0014] As used herein, the following terms have the meanings set forth below, unless otherwise indicated.

[0015] "Oxo" refers to =O.

[0016] "Carboxyl" refers to the -COOH group.

[0017] "Cyano" refers to -CN.

[0018] "Alkyl" refers to a linear or branched saturated hydrocarbon monovalent group having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Where applicable in this specification, "C1-C6 alkyl" or "C 1~6 Numerical ranges such as "alkyl" mean that an alkyl group can consist of one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms, but the definition here also includes the appearance of the term "alkyl" without a specified numerical range. In some embodiments, alkyl is C 1~10 It is alkyl. In some embodiments, alkyl is C 1~6 It is alkyl. In some embodiments, alkyl is C 1~5 It is alkyl. In some embodiments, alkyl is C 1~4 It is alkyl. In some embodiments, alkyl is C 1~3It is alkyl. Unless otherwise specified herein, alkyl groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0019] "Alkenyl" refers to a linear or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and containing 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group may be in either a cis or trans configuration with respect to the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Where used herein, "C2-C6 alkenyl" or "C 2~6The numerical ranges for "alkenyl," etc., mean that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition herein also includes the appearance of the term "alkenyl" without a specified numerical range. Unless otherwise specified herein, the alkenyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0020] "Alkynyl" refers to a linear or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and containing 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiinyl. Where used herein, it is referred to as "C2-C6 alkynyl" or "C 2~6The numerical range such as "alkynyl" means that an alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. However, the definition here also includes the appearance of the term "alkynyl" for which no numerical range is specified. Unless otherwise specifically stated herein, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0021] "Alkylene" refers to a straight-chain or branched-chain divalent hydrocarbon chain. Unless otherwise specifically stated herein, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0022] "Alkoxy" refers to a radical of the formula -OR a where R ais an alkyl radical as defined above. Unless otherwise specified herein, the alkoxy group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0023] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, including fused ring systems (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded via an aromatic ring atom) or bridging ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl(phenyl). Examples of aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, aryls may be optionally substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, aryls are optionally substituted with halogens, methyls, ethyls, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryls are optionally substituted with halogens, methyls, ethyls, -CN, -CF3, -OH, or -OMe. In some embodiments, aryls are optionally substituted with halogens.

[0024] "Cycloalkyl" refers to a partially or completely saturated monocyclic or polycyclic carbon ring, which may include fused ring systems (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded via a non-aromatic ring atom), spiro ring systems, or bridging ring systems. In some embodiments, the cycloalkyl is completely saturated. Typical cycloalkyls include cycloalkyls having 3 to 15 carbon atoms (C3-C3). 15 Fully saturated cycloalkyl or C3-C15 Cycloalkenyls, cycloalkyls (C3-C) having 3 to 10 carbon atoms 10 Fully saturated cycloalkyl or C3-C 10Examples include, but are not limited to, cycloalkenyls, cycloalkyls having 3 to 8 carbon atoms (C3-C8 fully saturated cycloalkyls or C3-C8 cycloalkenyls), cycloalkyls having 3 to 6 carbon atoms (C3-C6 fully saturated cycloalkyls or C3-C6 cycloalkenyls), cycloalkyls having 3 to 5 carbon atoms (C3-C5 fully saturated cycloalkyls or C3-C5 cycloalkenyls), or cycloalkyls having 3 or 4 carbon atoms (C3 or C4 fully saturated cycloalkyls or C3 or C4 cycloalkenyls). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- or 6-membered fully saturated cycloalkyl or a 5- or 6-membered cycloalkenyl. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, dekalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified herein, cycloalkyls may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with halogen.

[0025] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodine. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0026] "Haloalkyl" refers to an alkyl radical as defined above, which is substituted with one or more halo radicals as defined above. Examples include trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0027] "Hydroxyalkyl" refers to an alkyl radical as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Examples of hydroxyalkyls include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0028] "Aminoalkyl" refers to an alkyl radical as defined above, which is substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Examples of aminoalkyls include aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0029] A "heteroalkyl" refers to an alkyl group in which one or more of the alkyl backbone atoms are atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. In a heteroalkyl group, the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. In one embodiment, a heteroalkyl group is a C1-C6 heteroalkyl group, which consists of one to six carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, and the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specified herein, heteroalkyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyls are optionally substituted with halogens.

[0030] A "heterocycloalkyl" refers to a 3- to 24-membered, partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1 to 3 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom and 1 oxygen atom. Unless otherwise specified herein, heterocycloalkyl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, including fused ring systems (when fused with an aryl ring or heteroaryl ring, the heterocycloalkyl is bonded via a non-aromatic ring atom), spirocyclic ring systems, or bridging ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may optionally be oxidized, and the nitrogen atom may optionally be quaternized. Typical heterocycloalkyls include heterocycloalkyls having 2 to 15 carbon atoms (C2-C2). 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyls, heterocycloalkyls (C2-C) having 2 to 10 carbon atoms 10 Fully saturated heterocycloalkyl or C2-C 10Examples include, but are not limited to, heterocycloalkenyls, heterocycloalkyls having 2 to 8 carbon atoms (C2-C8 fully saturated heterocycloalkyls or C2-C8 heterocycloalkenyls), heterocycloalkyls having 2 to 7 carbon atoms (C2-C7 fully saturated heterocycloalkyls or C2-C7 heterocycloalkenyls), heterocycloalkyls having 2 to 6 carbon atoms (C2-C6 fully saturated heterocycloalkyls or C2-C6 heterocycloalkenyls), heterocycloalkyls having 2 to 5 carbon atoms (C2-C5 fully saturated heterocycloalkyls or C2-C5 heterocycloalkenyls), or heterocycloalkyls having 2 to 4 carbon atoms (C2-C4 fully saturated heterocycloalkyls or C2-C4 heterocycloalkenyls). Examples of such heterocycloalkyl radicals include azilidinyl, azetidinyl, oxetanyl, dioxolanil, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperadinyl, 4-piperidonyl, and pylori. Examples include, but are not limited to, dinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2 to 10 carbon atoms in the ring.When referring to the number of carbon atoms in a heterocycloalkyl, it should be understood that the number of carbon atoms in a heterocycloalkyl is not the same as the total number of atoms constituting the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring) (including heteroatoms). In some embodiments, the heterocycloalkyl is a 3- to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- or 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-membered or 6-membered heterocycloalkenyl. Unless otherwise specified herein, the heterocycloalkyl may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., as described below. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0031] A "heteroaryl" refers to a 5- to 14-membered cyclic radical comprising 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1 to 3 nitrogen atoms. In some embodiments, the heteroaryl contains 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1 nitrogen atom. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a condensed ring system (when condensed with a cycloalkyl ring or heterocycloalkyl ring, the heteroaryl is bonded via an aromatic ring atom) or a bridging ring system, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may optionally be oxidized, and the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indolyl, in Examples include, but are not limited to, dazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryls may be optionally substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, heteroaryls are optionally substituted with halogens, methyls, ethyls, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the heteroaryl is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.

[0032] The terms “optional” or “optionally” mean that the events or situations described thereafter may or may not occur, and the description includes both cases in which such events or situations occur and cases in which they do not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at a level between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). With respect to any group containing one or more substituents, it will be understood by those skilled in the art that such a group is not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically unrealizable. Therefore, any substituents described should be understood to generally have a maximum molecular weight of up to about 1000 daltons, and more typically up to about 500 daltons.

[0033] As used herein, the terms “effective dose” or “therapeutic effective dose” refer to a sufficient amount of an administered drug or compound, or combination of drugs or compounds, that would, to some extent, alleviate one or more symptoms of the disease or condition being treated. Results include reduction and / or mitigation of the signs, symptoms, or causes of the disease, or other desired changes in the biological system. For example, an “effective dose” for therapeutic use is the amount of a composition containing a compound as disclosed herein that is required to provide a clinically significant reduction in disease symptoms. An appropriate “effective” dose in any individual case may be determined arbitrarily using techniques such as dose escalation studies.

[0034] "Therapy" of an individual (e.g., a mammal such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of that individual or cell. In some embodiments, therapy includes the administration of a pharmaceutical composition after the onset of a pathological event or after contact with a pathogen, and includes stabilization of the condition (e.g., preventing deterioration of the condition) or alleviation of the condition.

[0035] As used herein, the term “acceptable” with respect to a formulation, composition, or component means that it does not cause any lasting adverse effect on the overall health of the subject being treated.

[0036] As used herein, terms such as “administer,” “give delivery,” and “dosage” refer to methods that may be used to enable the delivery of a compound or composition to a desired site of action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those skilled in the art will be familiar with the administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0037] As used herein, the terms “enhance” or “to augment” mean to increase or extend the desired effect in either potency or duration. Therefore, with respect to enhancing the effect of a therapeutic agent, the term “enhance” refers to the ability to increase or extend the effect of another therapeutic agent on a system in either potency or duration. As used herein, “enhancement effective dose” refers to an amount sufficient to enhance the effect of another therapeutic agent on a desired system.

[0038] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia, namely humans, non-human primates such as chimpanzees, and other apes and monkey species; domestic animals such as cattle, horses, sheep, goats, and pigs; companion animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one embodiment, a mammal is a human.

[0039] As used herein, the terms “to treat,” “to treat,” or “to cure” include alleviating, suppressing, or improving at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, for example, preventing the onset of a disease or condition, mitigating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or preventing and / or curatively cessating the symptoms of a disease or condition.

[0040] The term "approximately" means a statistically meaningful range of values ​​such as concentration ranges, timeframes, molecular weights, particle sizes, temperatures, or pH. Such ranges may be within one order of magnitude of the indicated value or range, typically within 10%, more typically within 5%, and even more typically within 3%. In some cases, such ranges may be within the range of typical experimental error of the standard methods used for measuring and / or determining a given value or range. The permissible variation encompassed by the term "approximately" depends on the particular system under study and will be readily apparent to those skilled in the art. Wherever a range is described in this application, all integers within that range are also contemplated as embodiments of the invention.

[0041] As used herein, the term “MTAP-deficient cancer” refers to cancer lacking the activity of the metabolic enzyme methylthioadenosine phosphorylase (MTAP). Therefore, MTAP-deficient cancer is a cancer associated with the non-expression of the MTAP gene, which may result from the absence of the MTAP gene, the lack of MTAP protein expression, or the accumulation of the MTAP substrate MTA. In some embodiments, the term “MTAP-deficient” is referred to as “MTAP deletion” and / or “MTAP-null,” and therefore the three terms may be used interchangeably. For example, in some embodiments, “MTAP deletion” or “MTAP-null” cancer refers to the loss of the MTAP gene chromosome, resulting in the complete or partial loss of MTAP DNA that prevents the expression of a functional full-length MTAP protein. In some embodiments, MTAP-deficient cancer is cancer in which the CDKN2A gene locus is absent or deleted. In some embodiments, MTAP-deficient cancer is cancer in which the MTAP gene is deleted, lost, or otherwise inactivated. In some embodiments, MTAP-deficient cancer is a cancer in which the function of the MTAP protein is reduced or functionally impaired compared to the wild-type MTAP gene. Accordingly, in one embodiment of the present disclosure, a method is provided for treating MTAP-deficient cancer in a subject, wherein the cancer is characterized by at least one of (i) reduced or absent MTAP expression, (ii) absent MTAP gene, and (iii) impaired function of the MTAP protein, compared to a corresponding cancer in which the MTAP gene and / or protein are present and fully functional, or compared to a corresponding cancer having the wild-type MTAP gene.

[0042] As used herein, the terms “wild-type MTAP cancer” or “MTAP wild-type cancer” refer to cancer in which the activity of the metabolic enzyme methylthioadenosine phosphorylase (MTAP) is intact. Therefore, wild-type MTAP cancer is cancer that expresses the MTAP gene and MTAP protein.

[0043] MAT2A inhibitors In some embodiments, this specification refers to MAT2A inhibitors of formula (I), formula (II), or pharmaceutically acceptable salts thereof: [ka] (In the formula, [ka] C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~10 Selected from heteroaryls, Z 1 CR 7 or N, Z 2 CR 9 or N, Z 3 CR 6 or N, Z 4 CR 6a or N, X is -N(R 4 )-, -O-, and -C(R 5 )(R 5a )- Selected from, Y is -N(R 4a )-, -O-, and -C(R 5 )(R 5a )- Selected from, R 1 Hydrogen, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Ariel, C 1~9 Heteroaryl, -OR 10 , -SR 10 -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 ,-OC(O)N(R 10 )(R 11)、 -N(R 12 )C(O)N(R 10 )(R 11 )、 -N(R 12 )C(O)OR 13 、 -N(R 12 )S(O)2R 13 、 -C(O)R 13 、 -S(O)R 13 、 -OC(O)R 13 、 -C(O)N(R 10 )(R 11 )、 -C(O)C(O)N(R 10 )(R 11 )(R 12 )C(O)R 13 、 -S(O)2R 13 、 -S(O)2N(R 10 )(R 11 ) -、 -N=S(=O)(R 13 )2、 -S(=O)(=NH)N(R 10 )(R 11 )、 -S(=O)(=NH)C(R 10 )(R 11 )、 -S(=O)(=NR 13 )R 13 、 -CH2C(O)N(R 10 )(R 11 )、 -CH2N(R 12 )C(O)R 13 、 -CH2S(O)2R 13 、 -CH2S(O)2N(R 10 )(R 11 )、 -Si(C[[ID=6}] 1~6 alkyl)3、 and -P(O)(R 10 )2, selected from, where C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~6 cycloalkyl, C 2~9 heterocycloalkyl, C 6~10 aryl, and C 1~9 heteroaryl are optionally substituted with one, two, or three groups selected from R 15a R 1a and R 1b are hydrogen, halogen, C 1~6 ​Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Selected independently from heteroaryls, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryls are R 15a It is optionally replaced by one, two, or three elements selected from the following: Each R 2 and each R 3 These are hydrogen, halogen, oxo, and C, respectively. 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Ariel, C 1~9 Heteroaryl, -OR 10 , -SR 10 -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 ,-OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 ,-S(O)R 13 ,-OC(O)R 13 ,-C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R 10 )(R 11 )-, -N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)C(R 10 )(R 11 ), -S(=O)(=NR 13 )R 13 -CH2C(O)N(R 10 )(R 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 -CH2S(O)2N(R 10 )(R 11 ), -Si(C 1~6 Alkyl)3, and -P(O)(R 10 ) is independently selected from 2, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryls are R 15b It is optionally substituted with one, two, or three elements selected from, or R 2 and R 3 Together with the carbon atoms to which they are bonded, C 3~6 Cycloalkyl or C 2~9 Forms heterocycloalkyl groups, R 4 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Selected from heteroaryls, where C 1~6Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryls include halogen, -CN, hydroxy, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 It may be optionally substituted with one, two, or three groups selected from heteroaryls, or R 4 and R 3 These are combined as halogen, -CN, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 C optionally substituted with one, two, or three groups selected from heteroaryl groups 2~9 Forms heterocycloalkyl groups, R 4a is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Selected from heteroaryls, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryls include halogen, -CN, hydroxy, and C. 1~6 Alkyl, C1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 It may be optionally substituted with one, two, or three groups selected from heteroaryls, or R 4a and R 3 These are combined as halogen, -CN, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 C optionally substituted with one, two, or three groups selected from heteroaryl groups 2~9 Forms heterocycloalkyl groups, R 5 and R 5a Hydrogen, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Ariel, C 1~9 Heteroaryl, -OR 10 , -SR 10 -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 ,-OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 ,-S(O)R 13 ,-OC(O)R 13 ,-C(O)N(R 10 )(R11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R 10 )(R 11 )-, -N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)C(R 10 )(R 11 ), -S(=O)(=NR 13 )R 13 -CH2C(O)N(R 10 )(R 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 -CH2S(O)2N(R 10 )(R 11 ), -Si(C 1~6 Alkyl)3, and -P(O)(R 10 ) is independently selected from 2, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryls include halogen, -CN, hydroxy, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 It may be optionally substituted with one, two, or three groups selected from heteroaryls, or R 5 and R 3 These are combined into C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, or C 2~9It forms a heteroaryl, and here, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryls include halogen, -CN, hydroxy, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 It is optionally substituted with one, two, or three groups selected from heteroaryls. R 6 , R 7 , R 8 , and R 9 Hydrogen, halogen, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Ariel, C 1~9 Heteroaryl, -OR 10 , -SR 10 -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 ,-OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 ,-S(O)R 13 ,-OC(O)R 13 ,-C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13-S(O)2R 13 -S(O)2N(R 10 )(R 11 )-, -N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)C(R 10 )(R 11 ), -S(=O)(=NR 13 )R 13 -CH2C(O)N(R 10 )(R 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 -CH2S(O)2N(R 10 )(R 11 ), -Si(C 1~6 Alkyl)3, and -P(O)(R 10 ) is independently selected from 2, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryls are R 15c It is optionally replaced by one, two, or three elements selected from the following: R 6a Hydrogen, halogen, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 1~9 Heteroaryl, -OR 10 , -SR 10 -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 ,-OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 ,-S(O)R 13 ,-OC(O)R 13 ,-C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R 10 )(R 11 )-, -N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)C(R 10 )(R 11 ), -S(=O)(=NR 13 )R 13 -CH2C(O)N(R 10 )(R 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 -CH2S(O)2N(R 10 )(R 11 ), -Si(C 1~6 Alkyl)3, and -P(O)(R 10 ) Selected from 2, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, and C 1~9 Heteroaryls are R 15c It is optionally replaced by one, two, or three elements selected from the following: Each R 10 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Selected independently from heteroaryls, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryls include halogen, -CN, hydroxy, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Optionally substituted with one, two, or three groups selected from heteroaryls, Each R 11 is hydrogen, C 1~6 Alkyl and C 1~6 Independently selected from haloalkyls, or R 10 and R 11 Together with the nitrogen to which they are bonded, C 2~9 Forms heterocycloalkyl groups, Each R 12 is hydrogen, C 1~6 Alkyl and C 1~6 Selected independently from haloalkyl groups, Each R 13 C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Selected independently from heteroaryls, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C1~9 Heteroaryls include halogen, -CN, hydroxy, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Optionally substituted with one, two, or three groups selected from heteroaryls, Each R 14 is halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Ariel, C 1~9 Heteroaryl, -OR 10 , -SR 10 -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 ,-OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 ,-S(O)R 13 ,-OC(O)R 13 ,-C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R 10 )(R 11 )-, -N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11), -S(=O)(=NH)C(R 10 )(R 11 ), -S(=O)(=NR 13 )R 13 -CH2C(O)N(R 10 )(R 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 -CH2S(O)2N(R 10 )(R 11 ), -Si(C 1~6 Alkyl)3, and -P(O)(R 10 ) is independently selected from 2, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryls are R 15d It is optionally replaced by one, two, or three elements selected from the following: Each R 15a , R 15b , R 15c , and R 15d These are halogen, oxo, -CN, and C, respectively. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Arial, -CH2-C 6~10 Ariel, C 1~9 Heteroaryl, -CH2-C 1~9 Heteroaryl, -OR 10 , -SR 10 -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 ,-OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 ,-S(O)R 13 ,-OC(O)R 13 ,-C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R 10 )(R 11 )-, -N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)C(R 10 )(R 11 ), -S(=O)(=NR 13 )R 13 -CH2C(O)N(R 10 )(R 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 -CH2S(O)2N(R 10 )(R 11 ), -Si(C 1~6 Alkyl)3, and -P(O)(R 10 ) is independently selected from 2, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, -CH2-C 3~10 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Arial, -CH2-C 6~10 Arial, -CH2-C 1~9 Heteroaryls, and C 1~9 Heteroaryls include halogens, oxo, -CN, and C. 1~6Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 10 , -SR 10 -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 ,-OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 ,-S(O)R 13 ,-OC(O)R 13 ,-C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R 10 )(R 11 )-, -N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)C(R 10 )(R 11 ), -S(=O)(=NR 13 )R 13 -CH2C(O)N(R 10 )(R 11 ), -CH2N(R 12 )C(O)R 13 -CH2S(O)2R 13 -CH2S(O)2N(R 10 )(R 11 ), and -P(O)(R 10 ) Optionally replaced by one, two, or three elements independently selected from 2, m is 0, 1, 2, 3, 4, or 5. n is disclosed as follows: n is 0, 1, 2, 3, 4, 5, or 6.

[0044] In some embodiments, a MAT2A inhibitor of formula (I) or a pharmaceutically acceptable salt thereof is disclosed herein. In some embodiments, a MAT2A inhibitor of formula (II) or a pharmaceutically acceptable salt thereof is disclosed herein.

[0045] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X is -N(R 4 )-. In some embodiments, X is -N(R 4 )- and R 4 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Selected from heteroaryls, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryls include halogen, -CN, hydroxy, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 It is optionally substituted with one, two, or three groups selected from heteroaryl groups. In some embodiments, X is -N(R 4 )- and R 4 is hydrogen or C 1~6 It is alkyl. In some embodiments, X is -N(R 4 )- and R 4is hydrogen. In some embodiments, X is -N(R 4 )- and R 4 is C 1~6 It is alkyl. In some embodiments, X is -N(R 4 )- and R 4 is -CH3. In some embodiments, X is -N(R 4 )- and R 4 and R 3 These are combined as halogen, -CN, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 C optionally substituted with one, two, or three groups selected from heteroaryl groups 2~9 It forms a heterocycloalkyl. In some embodiments, X is -N(R 4 )- and R 4 and R 3 These are combined as halogens, hydroxyls, and C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 C optionally substituted with one, two, or three groups selected from alkoxy groups 2~9 It forms a heterocycloalkyl. In some embodiments, X is -N(R 4 )- and R 4 and R 3 These are combined as halogens, hydroxyls, and C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 A piperidinyl ring, piperazinyl ring, pyrrolidinyl ring, or azetidinyl ring is formed by optionally substituting one, two, or three groups selected from alkoxys. In some embodiments, X is -N(R 4 )- and R 4 and R 3 These combine to form an unsubstituted piperidinyl ring, piperazinyl ring, pyrrolidinyl ring, or azetidinyl ring.

[0046] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X is -O-.

[0047] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X is -C(R 5 )(R 5a )-. In some embodiments, X is -C(R 5 )(R 5a )- and R 5 and R 5a is hydrogen and C 1~6 Selected independently of alkyl. In some embodiments, X is -C(R 5 )(R 5a )- and R 5 and R 5a is hydrogen. In some embodiments, X is -C(R 5 )(R 5a )- and R 5 and R 5a is C 1~6 It is alkyl. In some embodiments, X is -C(R 5 )(R 5a )- and R 5 is hydrogen, R 5a is C 1~6 It is alkyl.

[0048] In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt thereof, Y is -N(R 4a )-. In some embodiments, Y is -N(R 4a )- and R 4a is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Selected from heteroaryls, where C 1~6 Alkyl, C 2~6 Alkenil, C2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryls include halogen, -CN, hydroxy, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 It is optionally substituted with one, two, or three groups selected from heteroaryl groups. In some embodiments, Y is -N(R 4a )- and R 4a is hydrogen or C 1~6 It is alkyl. In some embodiments, Y is -N(R 4a )- and R 4a is hydrogen. In some embodiments, Y is -N(R 4a )- and R 4a is C 1~6 It is alkyl. In some embodiments, Y is -N(R 4a )- and R 4a It is -CH3.

[0049] In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt thereof, Y is -O-.

[0050] In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt thereof, Y is -C(R 5 )(R 5a )-. In some embodiments, Y is -C(R 5 )(R 5a )- and R 5 and R 5a is hydrogen and C 1~6 Selected independently of alkyl. In some embodiments, Y is -C(R 5 )(R 5a )- and R 5 and R 5ais hydrogen. In some embodiments, Y is -C(R 5 )(R 5a )- and R 5 and R 5a is C 1~6 It is alkyl. In some embodiments, Y is -C(R 5 )(R 5a )- and R 5 is hydrogen, R 5a is C 1~6 It is alkyl.

[0051] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, each R 2 is hydrogen and C 1~6 Selected independently of alkyl. In some embodiments, or in pharmaceutically acceptable salts thereof, each R 2 R is hydrogen. In some embodiments, or in pharmaceutically acceptable salts thereof, each R 3 is hydrogen and C 1~6 Selected independently of alkyl. In some embodiments, each R 3 is hydrogen. In some embodiments, each R 2 and R 3 Together with the carbon atoms to which they are bonded, C 3~6 A cycloalkyl group is formed. In some embodiments, each R 2 and R 3 These, together with the carbon atoms to which they are bonded, form a cyclopropyl ring. In some embodiments, each R 2 and R 3 These, together with the carbon atoms to which they are bonded, form a cyclobutyl ring. In some embodiments, each R 2 and R 3 These, together with the carbon atoms to which they are bonded, form a cyclopentyl ring. In some embodiments, each R 2 and R 3 These, together with the carbon atoms to which they are bonded, form a cyclohexyl ring.

[0052] In some embodiments of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, n is 1, 2, or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0053] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, Z 1 CR 7 In some embodiments, Z 1 CR 7 And R 7 Hydrogen, halogen, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 ) is. In some embodiments, Z 1 CR 7 And R 7 Hydrogen, halogen, C 1~6 Alkyl, or C 1~6 It is a haloalkyl. In some embodiments, Z 1 CR 7 And R 7 It is hydrogen.

[0054] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, Z 1 It is N.

[0055] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, Z 2 CR 9 In some embodiments, Z 2 CR 9 And R 9 Hydrogen, halogen, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR10 , or -N(R 10 )(R 11 ) is. In some embodiments, Z 2 CR 9 And R 9 Hydrogen, halogen, C 1~6 Alkyl, or C 1~6 It is a haloalkyl. In some embodiments, Z 2 CR 9 And R 9 It is hydrogen.

[0056] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, Z 2 It is N.

[0057] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Z 3 CR 6 In some embodiments, Z 3 CR 6 And R 6 Halogen, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Ariel, C 1~9 Heteroaryl, -OR 10 , -SR 10 -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 ,-OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 ,-S(O)R 13, -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, -N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)C(R 10 )(R 11 ), -S(=O)(=NR 13 )R 13 , -CH2C(O)N(R 10 )(R 11 ), -CH2N(R 12 )C(O)R 13 , -CH2S(O)2R 13 , -CH2S(O)2N(R 10 )(R 11 ), -Si(C<**********]] 1~6 アルキル)3, and -P(O)(R 10 )2, where C 1~6 アルキル, C 2~6 アルケニル, C 2~6 アルキニル, C 3~6 シクロアルキル, C 2~9 ヘテロシクロアルキル, C 6~10 アリール, and C 1~9 ヘテロアリール are optionally substituted with one, two, or three groups selected from R 15c . In some embodiments of the compounds of formula (I), Z 3 is CR 6 , and R 6 is selected from hydrogen, halogen, -CN, C 1~6 アルキル, C 1~6 ハロアルキル, -OR 10 , and -N(R 10 )(R 11 ). In some embodiments, Z 3 is CR 6 , and R6 is hydrogen and -OR 10 Selected from, R 10 is C 1~6 It is alkyl. In some embodiments, Z 3 CR 6 And R 6 It is hydrogen.

[0058] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Z 3 It is N.

[0059] In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt thereof, Z 4 CR 6a In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt thereof, Z 4 CR 6a And R 6a Hydrogen, halogen, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Selected from ). In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt thereof, Z 4 CR 6a And R 6a is hydrogen and -OR 10 Selected from, R 10 is C 1~6 It is alkyl. In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt thereof, Z 4 CR 6a And R 6a It is hydrogen.

[0060] In some embodiments of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, [ka] C 1~10 It is a heteroaryl compound. In some embodiments, [ka] C is selected from pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl. 1~10 It is a heteroaryl compound. In some embodiments, [ka] It is a 5-membered or 6-membered heteroaryl. In some embodiments, [ka] It is a 5-membered heteroaryl compound. In some embodiments, [ka] It is a 6-membered heteroaryl compound. In some embodiments, [ka] It is pyridyl. In some embodiments, [ka] It is pyrimidyl. In some embodiments, [ka] It is pyrazinyl. In some embodiments, [ka] It is pyridazinyl.

[0061] In some embodiments of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, [ka] C 6~10 It is an arrow. In some embodiments, [ka] is phenyl.

[0062] In some embodiments of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof,

Chemical formula

[0063] In some embodiments of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof,

Chemical formula

[0064] In some embodiments of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, each R 14 is independently selected from halogen, C 1~6 alkyl, C 1~6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ). In some embodiments, each R 14 is independently selected from halogen and C 1~6 alkyl. In some embodiments, each R 14 is independently selected from halogen. In some embodiments, each R 14 is independently selected from C 1~6 alkyl.

[0065] In some embodiments of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0066] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R 8 Halogen, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Ariel, C 1~9 Heteroaryl, -OR 10 , -SR 10 -SF5, -N(R 10 )(R 11 ), -C(O)OR 10 ,-OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 ,-S(O)R 13 ,-OC(O)R 13 ,-C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R 10 )(R 11 )-, -N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)C(R 10 )(R 11 ), -S(=O)(=NR 13 )R 13 -CH2C(O)N(R 10 )(R 11 ), -CH2N(R 12)C(O)R 13 -CH2S(O)2R 13 -CH2S(O)2N(R 10 )(R 11 ), -Si(C 1~6 Alkyl)3, and -P(O)(R 10 ) Selected from 2, where C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryls are R 15c It is optionally replaced by one, two, or three elements selected from the set.

[0067] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R 8 Hydrogen, halogen, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR 10 , or C 3~6 It is cycloalkyl. In some embodiments, R 8 is hydrogen, halogen, or C 1~6 It is a haloalkyl. In some embodiments, R 8 R is hydrogen. In some embodiments, R 8 is a halogen. In some embodiments, R 8 is C 1~6 It is a haloalkyl. In some embodiments, R 8 is -CF3. In some embodiments, R 8 is C 1~6 It is alkyl. In some embodiments, R 8 is -CH3. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 8 is C 3~6 It is cycloalkyl. In some embodiments, R 8 It is cyclopropyl. In some embodiments, R 8 is -CN.

[0068] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, and C 1~9 Selected from heteroaryls, where C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, and C 1~9 Heteroaryls are R 15a It is optionally replaced by one, two, or three elements selected from the set.

[0069] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R 1 It is hydrogen.

[0070] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R 1 R 15a C is optionally substituted with one, two, or three groups selected from the above. 1~6 It is alkyl. In some embodiments, R 1 C 2~9 Heterocycloalkyl, C 1~9 Heteroaryl, -OR 10 , and -N(R 10 )(R 11 C, optionally substituted with one, two, or three groups selected from ) 1~6 It is alkyl. In some embodiments, R 1 C 2~9 Heterocycloalkyl, C 1~9 Heteroaryl, -OR 10 , and -N(R 10 )(R 11 C substituted with one group selected from ) 1~6 It is alkyl. In some embodiments, R 1C 2~9 Heterocycloalkyl, C 1~9 Heteroaryl, -OR 10 , and -N(R 10 )(R 11 C substituted with one group selected from ) 1~6 It is alkyl, R 10 and R 11 is hydrogen and C 1~6 Selected independently of alkyl. In some embodiments, R 1 is a non-substituted C 1~6 It is alkyl.

[0071] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R 1 R 15a C is optionally substituted with one, two, or three groups selected from the above. 3~6 It is cycloalkyl. In some embodiments, R 1 C 1~6 Alkyl, -OR 10 , and -N(R 10 )(R 11 C substituted with one, two, or three groups selected from ) 3~6 It is cycloalkyl. In some embodiments, R 1 is -OR 10 and -N(R 10 )(R 11 C substituted with one group selected from ) 3~6 It is cycloalkyl, R 10 and R 11 is hydrogen and C 1~6 Selected independently of alkyl. In some embodiments, R 1 is a non-substituted C 3~6 It is cycloalkyl. In some embodiments, R 1 R is an unsubstituted cyclopropyl. In some embodiments, R 1 This is unsubstituted cyclobutyl.

[0072] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R1 is C 1~6 It is a haloalkyl group.

[0073] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R 1 R 15a C is optionally substituted with one, two, or three groups selected from the above. 2~9 It is heterocycloalkyl. In some embodiments, R 1 C 1~6 Alkyl, -OR 10 , and -N(R 10 )(R 11 C, optionally substituted with one, two, or three groups selected from ) 2~9 It is heterocycloalkyl. In some embodiments, R 1 is a non-substituted C 2~9 It is heterocycloalkyl.

[0074] In some embodiments of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R 1 R 15a C is optionally substituted with one, two, or three groups selected from the above. 1~9 It is a heteroaryl compound. In some embodiments, R 1 C 1~6 Alkyl, -OR 10 , and -N(R 10 )(R 11 C, optionally substituted with one, two, or three groups selected from ) 1~9 It is a heteroaryl compound. In some embodiments, R 1 is a non-substituted C 1~9 It is a heteroaryl compound.

[0075] In some embodiments, the compound of formula (I) has the structure of formula (Ia) or formula (Ib): [ka]

[0076] In this specification, any combination of the groups described above is considered for various variables. Throughout this specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0077] In some embodiments, the MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, is selected from the compounds found in Table 1.

[0078] [Table 1] TIFF2026514893000021.tif246170TIFF2026514893000022.tif249170TIFF2026514893 000023.tif222170TIFF2026514893000024.tif249170TIFF2026514893000025.tif99170

[0079] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis isomers, trans isomers, syn isomers, anti isomers, entgegen(E) isomers, and zusammen(Z) isomers, as well as their corresponding mixtures. In some situations, the compounds described herein have one or more chiral centers, each center existing in either an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers, as well as their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomer compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these dissimilarity. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by separation / resolving techniques based on differences in solubility. Then, in some embodiments, the optically pure enantiomers are recovered together with the resolving agent by any practical means that do not result in racemization.

[0080] isotopically enriched compounds Unless otherwise stated, the compounds described herein may represent their natural isotopic abundances, or one or more atoms may be artificially enriched in specific isotopes having the same atomic number but different atomic masses or mass numbers from those predominantly found in nature. All isotopic variants of the compounds disclosed herein, whether radioactive or not, are included within the scope of this disclosure. For example, hydrogen, 1 H (light hydrogen), 2 H (deuterium), and 3 It has three naturally occurring isotopes, denoted by H (tritium). Light hydrogen is the most abundant hydrogen isotope in nature. Enriching to deuterium may yield several therapeutic benefits, such as increased in vivo half-life and / or exposure, or may provide compounds useful for investigating the in vivo excretion and metabolic pathways of drugs.

[0081] For example, the compounds described herein may be artificially enriched with one or more specific isotopes. In some embodiments, the compounds described herein may be artificially enriched with one or more isotopes not primarily found in nature. In some embodiments, the compounds described herein are deuterium ( 2 H), tritium ( 3 H), Iodine-125( 125 I), or carbon-14 ( 14 The compounds may be artificially enriched with one or more isotopes selected from C). In some embodiments, the compounds described herein are 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125 It is artificially enriched with one or more isotopes selected from I. In some embodiments, the abundance of the enriched isotopes is, independently, at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% on a molar basis.

[0082] In some embodiments, the compound is deuterated at at least one position. In some embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 It is substituted with a hydrogen atom.

[0083] Methods for synthesizing deuterium-containing compounds are known in the art and are not limited to the present examples, but include the methods described in U.S. Patents No. 5,846,514 and No. 6,334,997, as well as the following synthesis methods. For example, deuterium-substituted compounds can be synthesized using various methods, as described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0084] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0085] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with a number of inorganic or organic bases, as well as either inorganic or organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their stereoisomers, or by reacting the purified compounds separately in their free form with suitable acids or bases and then isolating the salts thus formed.

[0086] Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds described herein with mineral acids, organic acids, or inorganic bases, such as acetates, acrylates, adipicates, alginates, aspartates, benzoates, benzenesulfons, bisulfates, bisulfites, bromides, butyrates, butyn-1,4-dioate, camphorates, camphorsulfons, capronates, caprylates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, diglucons, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyn-1,6-dioate, hydroxybenzoates, γ-hydroxybutyrates, hydrochlorides, and bromine. Examples include hydrochlorides, hydroiodides, 2-hydroxyethanesulfonates, iodides, isobutyrates, lactates, maleates, malons, methanesulfonates, mandelates, metaphosphates, methanesulfonates, methoxybenzoates, methylbenzoates, monohydrogen phosphates, 1-naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, palmoate, pectinates, persulfates, 3-phenylpropionates, phosphates, picrinates, pivalates, propions, pyrosulfates, pyrophosphates, propiolates, phthalates, phenylacetates, phenylbutyrates, propanesulfonates, salicylates, succinates, sulfates, sulfites, succinates, suberinates, sebacinates, sulfonates, tartrates, thiocyanates, tosylates, undecanoates, and xylenesulfonates.

[0087] Furthermore, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, such as inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, as well as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, and manic acid. Examples of organic acids include, but are not limited to, delicates, aryl sulfonic acids, methanesulfonic acids, ethanesulfonic acids, 1,2-ethanedisulfonic acids, 2-hydroxyethanesulfonic acids, benzenesulfonic acids, 2-naphthalenesulfonic acids, 4-methylbicyclo-[2.2.2]octa-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids such as oxalic acid are used in the preparation of salts that are useful as intermediates in obtaining the compounds disclosed herein, or their stereoisomers, and their pharmaceutically acceptable acid addition salts, although they are not pharmaceutically acceptable in themselves.

[0088] In some embodiments, the compounds described herein containing a free acid group react with a suitable base such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, or sulfate, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Typical salts include alkali metal salts or alkaline earth metal salts such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2. + (C 1~4 Examples include alkyl(4) and others.

[0089] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine. It should be understood that the compounds described herein also include those in which any basic nitrogen-containing group contained in the compound has been quaternized. In some embodiments, such quaternization yields water-soluble or oil-soluble or water-dispersible or oil-dispersible products.

[0090] Tautomers In some circumstances, compounds exist as tautomers. The compounds described herein include all possible tautomers in the formulas described herein. A tautomer is a compound that can be interconverted by the movement of hydrogen atoms, involving the switching of a single bond with an adjacent double bond. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomers of the compounds disclosed herein are intended. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0091] compound 1 In some embodiments disclosed herein, the MAT2A inhibitor is compound 1. In some embodiments disclosed herein, the MAT2A inhibitor is compound 1 or a salt thereof.

[0092] Compound 1 is 5-methoxy-1-(2-methylpyridine-3-yl)-4-(propa-2-in-1-ylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one: [ka] Compound 1 is a methionine adenosyltransferase IIα (MAT2A) inhibitor. In some embodiments, Compound 1 is in the form of a free base. In some embodiments, Compound 1 is in the form of its pharmaceutically acceptable salt.

[0093] In some embodiments, compound 1 is in the form of an HCl salt. In some embodiments, compound 1 is in the form of a sulfate. In some embodiments, compound 1 is in the form of a maleate. In some embodiments, compound 1 is in the form of a phosphate. In some embodiments, compound 1 is in the form of a citrate. In some embodiments, compound 1 is in the form of an L-malate. In some embodiments, compound 1 is in the form of a succinate. In some embodiments, compound 1 is in the form of a tosylate. In some embodiments, compound 1 is in the form of a mesylate. In some embodiments, compound 1 is in the form of a besylate. In some embodiments, compound 1 is in the form of an oxalate. In some embodiments, compound 1 is in the form of an esylate.

[0094] In some embodiments disclosed herein, the MAT2A inhibitors are known in the art and suitable for use in the manner disclosed herein. In some embodiments, the MAT2A inhibitors are as described in International Publication Nos. 2019191470, 2020123395, 2020139992, 2020243376, 2021252678, 2021252679, 2021252680, and 2021 International Publication No. 252681, International Publication No. 2020139991, International Publication No. 2021139775, International Publication No. 2021254529, International Publication No. 2021254529, International Publication No. 2022053022, International Publication No. 2022063128, International Publication No. 2022078403, International Publication No. 2022052924, International Publication No. 20 A selection is made from compounds disclosed in International Publication No. 22206730, International Publication No. 2022222911, International Publication No. 2022228515, International Publication No. 2022253242, International Publication No. 2022268180, International Publication No. 2023066283, International Publication No. 2023083210, International Publication No. 2023116390, International Publication No. 2023116696, International Publication No. 2023143356, International Publication No. 2023169554, International Publication No. 2023185811, International Publication No. 2023196985, International Publication No. 2024002024, and International Publication No. 2024012507 (the entire contents of these publications, by reference, constitute part of this specification). In some embodiments, the MAT2A inhibitor is AG-270 or IDE397, or a pharmaceutically acceptable salt thereof.

[0095] Method / Combination This specification discloses a method for treating cancer in a subject requiring treatment, the method comprising, (a) A MAT2A inhibitor or a pharmaceutically acceptable salt thereof, (b) Additional medications, This includes administering, The combined dose of a MAT2A inhibitor or a pharmaceutically acceptable salt thereof with additional drugs constitutes a therapeutically effective dose for treating cancer.

[0096] This specification discloses a method for treating cancer in a subject requiring treatment, the method comprising, (a) A compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, [ka] (b) Additional medications, This includes administering, The amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, combined with an additional agent, is a therapeutically effective dose for treating cancer. In some embodiments, the additional agent is an anticancer agent.

[0097] In some embodiments, the compound is the compound of formula (I). In some embodiments, the compound is a salt of the compound of formula (I).

[0098] In some embodiments, the compound is the compound of formula (II). In some embodiments, the compound is a salt of the compound of formula (II).

[0099] This specification discloses a method for treating cancer in a subject requiring treatment, the method comprising, (a) 5-Methoxy-1-(2-methylpyridine-3-yl)-4-(propa-2-in-1-ylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one: [ka] (Compound 1) or a pharmaceutically acceptable salt thereof, (b) Additional medications, This includes administering [the drug].

[0100] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and an additional agent are administered in a therapeutically effective dose for treating cancer. In some embodiments, the combined amount of compound 1 or a pharmaceutically acceptable salt thereof and an additional agent is a therapeutically effective dose for treating cancer.

[0101] In some embodiments, cancer is gastric cancer, primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

[0102] In some embodiments, the cancer is liver cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, or T-cell leukemia.

[0103] In some embodiments, cancer is liver cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, gastrointestinal stromal tumor, biliary tract cancer, B-cell acute lymphoblastic leukemia (ALL), lymphoma, or T-cell leukemia.

[0104] In some embodiments, the cancer is MTAP-deficient cancer. In some embodiments, MTAP-deficient cancer is primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

[0105] In other embodiments, MTAP-deficient cancer is MTAP-deficient lung cancer, MTAP-deficient pancreatic cancer, MTAP-deficient esophageal cancer, MTAP-deficient colorectal cancer, MTAP-deficient kidney cancer, or MTAP-deficient leukemia such as acute myeloid leukemia (AML).

[0106] In some embodiments, MTAP-deficient cancer is MTAP-deficient lung cancer such as NSCLC.

[0107] In other embodiments, MTAP-deficient cancer is MTAP-deficient pancreatic cancer such as PDAC. In some embodiments, MTAP-deficient cancer is MTAP-deficient esophageal cancer.

[0108] In some embodiments, MTAP-deficient cancer is MTAP-deficient colorectal cancer.

[0109] In some embodiments, MTAP-deficient cancer is MTAP-deficient renal cancer.

[0110] In some embodiments, MTAP-deficient cancer is MTAP-deficient leukemia, such as acute myeloid leukemia (AML).

[0111] In some embodiments, the cancer is MTAP wild-type cancer. In some embodiments, MTAP wild-type cancer is primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

[0112] In some embodiments, MTAP wild-type cancer is MTAP wild-type lung cancer, MTAP wild-type pancreatic cancer, MTAP wild-type esophageal cancer, MTAP wild-type colorectal cancer, MTAP wild-type kidney cancer, or MTAP wild-type leukemia such as acute myeloid leukemia (AML).

[0113] In some embodiments, MTAP wild-type cancer is MTAP wild-type lung cancer such as NSCLC.

[0114] In some embodiments, MTAP wild-type cancer is MTAP wild-type pancreatic cancer such as PDAC.

[0115] In some embodiments, MTAP wild-type cancer is MTAP wild-type esophageal cancer.

[0116] In some embodiments, MTAP wild-type cancer is MTAP wild-type colorectal cancer.

[0117] In some embodiments, MTAP wild-type cancer is MTAP wild-type renal cancer.

[0118] In some embodiments, MTAP wild-type cancer is MTAP wild-type leukemia such as acute myeloid leukemia (AML).

[0119] In some embodiments, the cancer is a cancer that responds to a decrease in SAM resulting from the administration of a MAT2A inhibitor. In some embodiments, cancers that respond to a decrease in SAM resulting from the administration of a MAT2A inhibitor include primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

[0120] In some embodiments, cancers that respond to a decrease in SAM resulting from the administration of a MAT2A inhibitor include lung cancer, pancreatic cancer, esophageal cancer, colorectal cancer, kidney cancer, or leukemias such as acute myeloid leukemia (AML).

[0121] In some embodiments, the cancers that respond to the reduction in SAM resulting from the administration of MAT2A inhibitors are lung cancers such as NSCLC.

[0122] In some embodiments, the cancers that respond to the reduction in SAM resulting from the administration of MAT2A inhibitors are pancreatic cancers such as PDAC.

[0123] In some embodiments, the cancer that responds to the reduction in SAM resulting from the administration of a MAT2A inhibitor is esophageal cancer.

[0124] In some embodiments, the cancer that responds to the reduction in SAM resulting from the administration of a MAT2A inhibitor is colorectal cancer.

[0125] In some embodiments, the cancer that responds to the reduction in SAM resulting from the administration of a MAT2A inhibitor is renal cancer.

[0126] In some embodiments, cancers that respond to a decrease in SAM resulting from the administration of MAT2A inhibitors are leukemias such as acute myeloid leukemia (AML).

[0127] In some embodiments of methods for treating cancer, additional agents include PARP inhibitors, CHK1 inhibitors, MDM2 inhibitors, hypomethylating agents, mTOR inhibitors, ATM inhibitors, CDK4 / 6 inhibitors, BCL-2 inhibitors, PRMT5 inhibitors, PRMT1 inhibitors, ATR inhibitors, WEE1 inhibitors, APE1 inhibitors, topoisomerase inhibitors, taxanes, immune checkpoint inhibitors, CDK7 inhibitors, CDK9 inhibitors, DNA synthesis inhibitors, antimetabolites, AURORA inhibitors, microtubule stabilizers, DNA crosslinking agents, vinca alkaloids, alkylating agents, PRMT6 inhibitors, PRMT7 inhibitors, PRMT9 inhibitors, KRAS inhibitors, EGFR inhibitors, VEGFR inhibitors, aromatase inhibitors, mitotic inhibitors, radiopharmaceuticals, cytotoxic agents, or any combination thereof.

[0128] In some embodiments of methods for treating cancer, the additional drug is a PARP inhibitor.

[0129] In some embodiments of methods for treating cancer, the PARP inhibitor is olaparib (AZD2281), veliparib (ABT-888), lucaparib, talazoparib (BMN 673), AG-14361, INO-1001 (3-aminobenzamide), A-966492, PJ34 HC1, niraparib, UPF 1069, ME0328, RK-287107, pamiparib (BGB-290), NMS-P118, E7449, picolinamide, benzamide, NU1025, iniparib (BSI-201), AZD2461, BGP-15 2HC1, XAV-939, 4-hydroxyquinazoline, NVP-TNKS656, MN 64, or G007-LK, or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments of methods for treating cancer, the PARP inhibitor is olaparib (AZD2281), lucaparib, talazoparib (BMN 673), niraparib, or talazoparib (BMN 673), or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments of methods for treating cancer, the PARP inhibitor is olaparib (AZD2281) or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments of methods for treating cancer, the PARP inhibitor is talazoparib (BMN 673) or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments of methods for treating cancer, an additional drug is a CHK1 inhibitor.

[0134] In some embodiments of methods for treating cancer, the CHK1 inhibitor is AZD7762, ravsertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, VX-803 (M4344), GDC-0575 (ARRY-575), SAR-020106, CCT245737, PD0166285, or prexasertib (LY2606368), or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments of methods for treating cancer, the CHK1 inhibitor is AZD7762 or ravsertib (LY2603618), or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments of methods for treating cancer, the CHK1 inhibitor is AZD7762 or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments of methods for treating cancer, the CHK1 inhibitor is ravsertib (LY2603618) or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments of methods for treating cancer, the additional agent is an MDM2 inhibitor.

[0139] In some embodiments of methods for treating cancer, the MDM2 inhibitor is Nutrin-3, NSC 207895, Nutrin-3a, Nutrin-3b, MX69, NVP-CGM097, MI-773 (SAR405838), Idasanutrin (RG-7388), RG-7112, HDM201 (Siremadlin), YH239-EE, (-)-Parthenolide, or Seldemethane (JNJ-26854165), or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments of methods for treating cancer, the MDM2 inhibitor is nutrin-3 or seldemethane (JNJ-26854165), or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments of methods for treating cancer, the MDM2 inhibitor is nutrin-3 or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments of methods for treating cancer, the MDM2 inhibitor is seldemethane (JNJ-26854165) or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments of methods for treating cancer, an additional agent is a hypomethylating agent.

[0144] In some embodiments of methods for treating cancer, the hypomethylating agent is decitabine, azacitidine (5-azacitidine), RG108, thioguanine, zebralin, SGI-1027, CM272, 2'-deoxy-5-fluorocytidine, procainamide, bobcat339, γ-oryzanol, thujapridine, or (-)-epigallocatechin gallate, or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments of methods for treating cancer, the hypomethylating agent is decitabine or azacitidine (5-azacitidine), or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments of methods for treating cancer, the demethylating agent is procainamide or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments of methods for treating cancer, the demethylating agent is decitabine or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments of methods for treating cancer, the hypomethylating agent is azacitidine (5-azacitidine) or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments of methods for treating cancer, the additional drug is an mTOR inhibitor.

[0150] In some embodiments of methods for treating cancer, mTOR inhibitors include dactricib (BEZ235), rapamycin (sirolimus), everolimus (RAD001), AZD8055, temsirolimus (CCI-779), PI-103, KU-0063794, tolkinib (PP242), ridafololimus (defololimus, MK-8669), sapanicertib (MLN0128), voxtalisib (XL765), trin-1, trin-2, omiparisib (GSK2126458), and OSI- 027, PF-04691502, Apitricib (GDC-0980), GSK1059615, Gedatricib (PKI-587), WYE-354, Bisutseltive (AZD2014), WYE-125132 (WYE-132), PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, GNE-477, Vimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onataseltive (CC 223) Boxtalisib (XL765), Zotarolimus (ABT-578), Tacrolimus (FK506), BGT226 maleate (NVP-BGT226 maleate), Paromide 529 (P529), LY3023414 (samotricib), Biolimus-7, Biolimus-9, Azathioprine, Cansam 1H, or chrysophanic acid, or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments of methods for treating cancer, the mTOR inhibitor is everolimus (RAD001) or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments of methods for treating cancer, the additional drug is an ATM inhibitor.

[0153] In some embodiments of methods for treating cancer, the ATM inhibitor is KU-55933, KU-60019, Waltomanin, Trin 2, CP-466722, ETP-46464, CGK 733, AZ32, AZD1390, AZ31, or AZD0156, or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments of methods for treating cancer, the ATM inhibitor is KU-60019 or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments of methods for treating cancer, the additional agent is a CDK4 / 6 inhibitor.

[0156] In some embodiments of methods for treating cancer, the CDK4 / 6 inhibitor is palbociclib (PD-0332991), arbocidib, AT7519, JNJ-7706621, PHA-793887, BMS-265246, milcilib (PHA-848125), R547, ribiciclib (P276-00), MC180295, G1T38, abemaciclib, ON123300, AT7519, pruvalanol A, SU9516, ribociclib (LEE011), or BSJ-03-123, or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments of methods for treating cancer, the CDK4 / 6 inhibitor is palbociclib (PD-0332991) or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments of methods for treating cancer, the additional agent is a BCL-2 inhibitor.

[0159] In some embodiments of methods for treating cancer, the BCL-2 inhibitor is ABT-737, Navitoclax (ABT-263), Obatoclax (GX15-070), TW-37, Venetoclax (ABT-199), AT101, HA14-1, Subtoclax, S55746, or Gumboginate, or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments of methods for treating cancer, the BCL-2 inhibitor is venetoclax (ABT-199) or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments of methods for treating cancer, the additional drug is a type I PRMT inhibitor.

[0162] In some embodiments of methods for treating cancer, the type I PRMT inhibitor is selected from compounds disclosed in International Publication No. 2014153226, International Publication No. 2021023609, or International Publication No. 2022256808 (the entire contents of these publications, by reference, constitute part of this specification).

[0163] In some embodiments of methods for treating cancer, type I PRMT inhibitors are used. [ka] or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments of methods for treating cancer, type I PRMT inhibitors are protein arginine methyltransferase 1 (PRMT1) inhibitors or protein arginine methyltransferase 6 (PRMT6) inhibitors.

[0165] In some embodiments of methods for treating cancer, an additional drug is a PRMT1 inhibitor.

[0166] In some embodiments of methods for treating cancer, the PRMT1 inhibitor is GSK3368715 (EPZ019997), C7280948, EPZ020411 2HCl, MSO23, Flamidine, C21, or TC-E 5003, or a pharmaceutically acceptable salt of the listed compounds.

[0167] In some embodiments of methods for treating cancer, the PRMT1 inhibitor is GSK3368715 (EPZ019997) or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments of methods for treating cancer, an additional drug is a PRMT6 inhibitor.

[0169] In some embodiments of methods for treating cancer, the PRMT6 inhibitor is SGC 6870 or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments of methods for treating cancer, the additional drug is a type II PRMT inhibitor.

[0171] In some embodiments of methods for treating cancer, type II PRMT inhibitors are protein arginine methyltransferase 5 (PRMT5) inhibitors, protein arginine methyltransferase 7 (PRMT7) inhibitors, or protein arginine methyltransferase 9 (PRMT9) inhibitors.

[0172] In some embodiments of methods for treating cancer, an additional drug is a PRMT5 inhibitor.

[0173] In some embodiments of methods for treating cancer, the PRMT5 inhibitor is JNJ-64619178 (AGI-931), HLCL-61, GSK591, EPZ015666 (GSK3235025), GSK3326595 (EPZ015938; AGI-219), TNG908, TNG462, AMG193, AMG9747, MRTX1719, P305-05313, CTS3157, PH-020-803, or AZ-PRMT5i-1, or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments of methods for treating cancer, the PRMT5 inhibitor is TNG908, TNG462, AMG193, AMG9747, MRTX1719, or P305-05313, or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments of methods for treating cancer, the PRMT5 inhibitor is GSK3326595 (EPZ015938; AGI-219) or JNJ-64619178 (AGI-931), or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments of methods for treating cancer, the PRMT5 inhibitor is GSK3326595 or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments of methods for treating cancer, the PRMT5 inhibitor is JNJ-64619178 (AGI-931) or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments of methods for treating cancer, PRMT5 inhibitors are used. [ka] or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments of methods for treating cancer, PRMT5 inhibitors are used. [ka] or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments of methods for treating cancer, PRMT5 inhibitors are used. [ka] or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments of methods for treating cancer, PRMT5 inhibitors are used in International Publication Nos. 2021050915, 2021086879, 2021 / 163344, 2022 / 026892, 2022 / 256806, 2023036974, and 2021050915. A selection is made from compounds disclosed in International Publication No. 2022192745, International Publication No. 2023278564, International Publication No. 2022132914, International Publication No. 2022169948, International Publication No. 2022115377, International Publication No. 2021163344, International Publication No. 2021086879, International Publication No. 2022026892, U.S. Patent No. 11077101, Malik, R., et al. AACR Annual Meeting, 2021, Abstract Number 1140, or Bondy, ZQ, et al., ACS Med. Chem. Lett. 2018, 9, 612-617 (the entire contents of these publications, by reference, constitute part of this specification).

[0182] In some embodiments of methods for treating cancer, an additional drug is a PRMT7 inhibitor.

[0183] In some embodiments of methods for treating cancer, the PRMT7 inhibitor is SGC 3027 or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments of methods for treating cancer, the additional agent is a PRMT9 inhibitor.

[0185] In some embodiments of methods for treating cancer, the additional drug is an ATR inhibitor.

[0186] In some embodiments of methods for treating cancer, the ATR inhibitor is RP-3500, M-6620, belzocertib (M-6620, VX-970; VE-822), AZD-6738, AZ-20, M-4344 (VX-803), BAY-1895344, M-1774, IMP-9064, nLs-BG-129, SC-0245, BKT-300, ART-0380, ATRN-119, ATRN-212, or NU-6027, or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments of methods for treating cancer, the additional agent is a WEE1 inhibitor.

[0188] In some embodiments of methods for treating cancer, the WEE1 inhibitor is AZD1775 (MK1775), ZN-c3, debio 0123, IMP7068, SDR-7995, SDR-7778, NUV-569, PD0166285, PD0407824, SC-0191, DC-859 / A, bosutinib, or Bos-I, or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments of methods for treating cancer, an additional agent is a topoisomerase inhibitor.

[0190] In some embodiments of methods for treating cancer, the topoisomerase inhibitor is epipodophyllotoxin, SN-38, ARC, NPC, camptothecin, topotecan, 9-nitrocamptothecin, exatecan, lulutotecan, lamelarin D9-aminocamptothecin, rubifen, gimatecan, diflomotecan, BN80927, DX-8951f, MAG-CPT, thiotepa, cyclosphospamide, amsacrin, etoposide, phosphate etoposide, teniposide, daunorubicin, mitoxantrone, amsacrin, ellipticin, aurintricarboxylic acid, doxorubicin, or HU-331, or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments of a method for treating cancer, the additional agent is a cytotoxic agent. In some embodiments, the cytotoxic agent is an alkylating agent, a cytotoxic antibiotic, an antimetabolite, a vinca alkaloid, a platinum compound, a taxane, or a topoisomerase inhibitor. In some embodiments of a method for treating cancer, the additional agent is a cytotoxic antibiotic. In some embodiments, the cytotoxic antibiotic is an anthracycline (e.g., doxorubicin and barrubicin). In some embodiments, the cytotoxic antibiotic is a non-anthracycline (e.g., bleomycin and dactinomycin). In some embodiments, the additional agent is a drug that is detrimental to cell viability.

[0192] In some embodiments of the method for treating cancer, the additional agent is a platinum-based drug. In some embodiments of the method for treating cancer, the platinum-based drug is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin.

[0193] In some embodiments of methods for treating cancer, the additional drug is a taxane.

[0194] In some embodiments of methods for treating cancer, the taxane is docetaxel, paclitaxel, accatin III, 10-deacetyltaxol, 7-xylosyl-10-deacetyltaxol, chalcomenite, 10-deacetyl-7-epitaxol, 7-epitaxol, 10-deacetylbaccatin III, or 10-deacetylchalcomenite, or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments of methods for treating cancer, the taxane is docetaxel or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments of methods for treating cancer, additional drugs are immune checkpoint inhibitors.

[0197] In some embodiments of methods for treating cancer, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pizilizumab, AMP-224, PF-06801591, MEDI0680, PDR001, REGN2810, SHR-12-1, TSR-042, CA-170, atezolizumab, durvalumab, KN035, and BMS-936559, ipilimumab, tremelimumab, AGEN1884, AGEN2041, BMS-986016, GSK2831781, IMP321, LAG525, MGD013, or TSR-022, or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments of methods for treating cancer, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pizilizumab, or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments of methods for treating cancer, the immune checkpoint inhibitor is nivolumab or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments of methods for treating cancer, the immune checkpoint inhibitor is pembrolizumab or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments of methods for treating cancer, the immune checkpoint inhibitor is pizilizumab or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments of methods for treating cancer, the additional drug is a CDK7 inhibitor.

[0203] In some embodiments of methods for treating cancer, the CDK7 inhibitor is LDC4297, THZ1, THZ2, YKL-5-124, BS-181, samraciclib, LY3405105, PHA-793887, SNS-032 (BMS-387032), PF-562271, or milciclib (PHA-848125), or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments of methods for treating cancer, the additional agent is a CDK9 inhibitor.

[0205] In some embodiments of methods for treating cancer, the CDK9 inhibitor is SNS-032 (BMS-387032), LY2857785, albocidib, or ribiclib hydrochloride (P276-00), or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments of methods for treating cancer, an additional drug is a DNA synthesis inhibitor.

[0207] In some embodiments of methods for treating cancer, the DNA synthesis inhibitor is 5-fluorouracil (5-FE1), 6-mercaptopurine (6-MP), capecitabine, cytarabine, phloxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, or pemetrexed, or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments of methods for treating cancer, the DNA synthesis inhibitor is pemetrexed or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments of methods for treating cancer, the additional agent is an antimetabolite.

[0210] In some embodiments of methods for treating cancer, the antimetabolite is 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine, cytarabine, phloxuridine, fludarabine, gemcitabine, hydroxycarbamide, methotrexate, pemetrexed, or phototrexate, or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments of methods for treating cancer, the antimetabolite is pemetrexed, 5-fluorouracil (5-FU), or pemetrexed, or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments of methods for treating cancer, the antimetabolite is pemetrexed or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments of methods for treating cancer, the additional agent is an AURORA inhibitor.

[0214] In some embodiments of methods for treating cancer, AURORA inhibitors include aricertib (MLN8237), tozacertib (VX-680, MK-0457), valacertib (AZDI 152-HQPA), ZM 447439, MLN8054, danucertib (PHA-739358), AT9283, JNJ-7706621, hesperazine, aurora A inhibitor I (TC-S 7010), KW-2449, SNS-314, ENMD-2076, PHA-680632, MK-5108 (VX-689), CYC116, AMG-900, PF-03814735, and CCT. 129202, GSK1070916, TAK-901, CCT137690, MK-8745, ENMD-2076, Aurora Kinase Inhibitor III, SNS-314 Mesylate, BI-847325, Reversin, or ABT-348, or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments of methods for treating cancer, the additional drug is a KRAS inhibitor.

[0216] In some embodiments of methods for treating cancer, the KRAS inhibitor is a KRAS G12C inhibitor.

[0217] In some embodiments of methods for treating cancer, the KRAS inhibitor is a KRAS G12D inhibitor.

[0218] In some embodiments of methods for treating cancer, the KRAS inhibitor is a KRAS G12S inhibitor.

[0219] In some embodiments of methods for treating cancer, KRAS inhibitors include 6H05, adagrasib, ARS-1323, ARS-1323-alkyne, ARS-1620, ARS-1630, ARS-853, ASP2453, AZD4625, BAY-293, BI-0474, BI-2852, BI-3406, divalasib, G12Si-1, G12Si-5 formate, G12Si-5, galsolacib, K20, KRAS G12C inhibitor 1, KRAS G12C inhibitor 2, KRAS G12C inhibitor 3, KRAS G12C inhibitor 4, KRAS G12C inhibitor 5, KRAS G12C inhibitor 13, KRAS G12C inhibitor 14, KRAS G12C inhibitor 15, KRAS G12C inhibitor 16, KRAS KRAS G12C inhibitor 17, KRAS G12C inhibitor 18, KRAS G12C inhibitor 23, KRAS G12C inhibitor 24, KRAS G12C inhibitor 25, KRAS G12C inhibitor 26, KRAS G12C inhibitor 27, KRAS G12C inhibitor 28, KRAS G12C inhibitor 32, KRAS G12C inhibitor 43, KRAS G12C inhibitor 44, KRAS G12C inhibitor 45, KRAS G12C inhibitor 46, KRAS G12C inhibitor 47, KRAS G12C inhibitor 48, KRAS G12C inhibitor 49, KRAS G12C inhibitor 50, KRAS G12C inhibitor 51, KRAS G12C inhibitor 52, KRAS G12C inhibitor 53, KRAS G12C inhibitor 54, KRAS G12C inhibitor 55, KRAS G12C inhibitors 57, K-Ras G12C-IN-2, KRAS G12D inhibitors 3, KRAS G12D inhibitors 7, KRAS G12D inhibitors 14, KRAS G12D inhibitors 16, KRAS G12D inhibitor 17, KRAS inhibitor-3, KRAS inhibitor-6, KRAS inhibitor-7, KRAS inhibitor-8, KRAS inhibitor-10, KRAS inhibitor-11, KRAS inhibitor-12, KRAS inhibitor-13, KRAS inhibitor-14, KRAS inhibitor-15, KRAS inhibitor-16, KRAS inhibitor-17, KRAS inhibitor-18, KRAS inhibitor-20, K-Ras(G12C) inhibitor 6, KRpep-2d, LC-2, MRTX1133, MRTX-1257, MRTX849 acid type, MRTX-EX185 formate type, opnurasib, Pan KRas-IN-1, PROTACK-Ras Degrader-1, RM-018, SAH-SOS1A, SOS1-IN-4, SOS1-IN-9, sotrasib, or ZG1077, or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments of methods for treating cancer, the KRAS inhibitor is ARS-3248 (JNJ-74699157), AMG510, MRTX849, MRTX1133, ASP245, 3GDC6036, BI-2852, BI 1701963, mRNA-5671, JDQ443, RAS(ON) inhibitor, BBP-454, RM-018, RMC-6291, or RMC-6236, or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments of methods for treating cancer, the KRAS inhibitor is adaglacib, divalacib, galsolacib, opunurasib, or sotrasib, or a pharmaceutically acceptable salt thereof.

[0222] In some embodiments of methods for treating cancer, the KRAS inhibitor is sotrasib or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments of methods for treating cancer, the KRAS inhibitor is adaglacib or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments of methods for treating cancer, KRAS inhibitors are used in International Publication Nos. 2018119183, 2018217651, 2019051291, 2019213526, 2019213516, 2019217691, 2019232419, 2019241157, 2020106640, and International Publication Nos. and International Publication Nos. 2020106640. International Publication No. 2021081212, International Publication No. 2022083569, International Publication No. 2022093856, International Publication No. 2022232332, International Publication No. 2022232331, International Publication No. 2020146613, International Publication No. 2020097537, International Publication No. 2015054572, International Publication No. 2020177629, International Publication No. 2019141250, International Publication No. 2020081282, International Publication No. 2 International Publication No. 020085493, International Publication No. 2018143315, International Publication No. 2018206539, International Publication No. 2019110751, International Publication No. 2019195609, International Publication No. 2021207172, International Publication No. 2021041671, International Publication No. 2021150613, International Publication No. 2021142252, International Publication No. 2021152149, International Publication No. 2021248090, International Publication No. 20 A compound is selected from those disclosed in U.S. Patent No. 21216770, International Publication No. 2022002102, International Publication No. 2022031678, U.S. Patent No. 10662204, U.S. Patent No. 10689377, U.S. Patent No. 10689377, U.S. Patent No. 10689377, or U.S. Patent No. 10519146 (the entire contents of these are, by reference, part of this Specified).

[0225] In some embodiments of methods for treating cancer, the additional drug is an EGFR inhibitor.

[0226] In some embodiments of methods for treating cancer, EGFR inhibitors include erlotinib (OSI-774)HCl, gefitinib (ZD1839), lapatinib (GW-572016) ditosylate, afatinib (BIBW2992), salakatinib (AZD0530), vandetanib (ZD6474), neratinib (HKI-272), canertinib (CI-1033), lapatinib (GW-572016), AG-490 (Tyrphostin B42), CP-724714, dacomitinib (PF-00299804), WZ4002, sapitinib (AZD8931), CUDC-101, and AG-1478 (Tyrphostin B42). AG-1478), PD153035 HCl, Peritinib (EKB-569), AEE788 (NVP-AEE788), AC480 (BMS-599626), AP26113-analog (ALK-IN-1), OSI-420, WZ3146, Alitinib tosylate, Rosiletinib (CO-1686), Vallitinib, Icotinib (BPI-2009H), TAK-285, WHI-P154, Daphnetin, PD168393, CNX-2006, Tyrphostin 9, AG-18, O-Demethyl-Gefitinib, AST-1306, BDTX-189, Epertinib hydrochloride, JND3229, BI-4020, Tyrphostin AG-528, AG 556, canertinib dihydrochloride, EGFR inhibitor, gefitinib-based PROTAC 3, SU5214, RG 13022, TQB3804 (EGFR-IN-7), diparereltinib, pirotinib (SHR-1258) dimaleate, PD153035, AG 494, AG 555, Teriatinib (HMPL-309), Abitinib (AC0010), Lazertinib, Gefitinib Hydrochloride, Cetuximab (Anti-EGFR), Rifilafenib (BGB-283), Nazartinib (EGF816), Brigatinib (AP26113), Tucatinib, Zolifertinib (AZD3759), Afatinib (BIBW2992) Dimaleate, Erlotinib (OSI-774), CL-387785 (EKI-785), Poziotinib (HM781-36B), Osimertinib (AZD9291), AZ5104, AV-412 Free Base, WZ8040, Genistein (NPI031L), farnidamol, BLU-945, sunvozertinib, CH7233163, licochalcone D, alflutinib (AST2818) mesylate, (Rac)-JBJ-04-125-02, mobocertinib (TAK788), typhostin AG30 (AG30), AG-1557, AG99, MTX-211, RG14620, almonertinib (HS-10296), ciaosterone, osimertinib mesylate, norcantharidin, nacotinib (ASP8273), EAI045, lidocaine hydrochloride, olmutinib (BI 1482694), butein, chrysophanic acid, or (-)-epigallocatechin gallate, or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments of methods for treating cancer, the additional drug is a VEGFR inhibitor.

[0228] In some embodiments of methods for treating cancer, VEGFR inhibitors include sorafenib (BAY 43-9006) tosylate, sunitinib (SU11248) malate, cabozantinib (BMS-907351), ponatinib (AP24534), axitinib (AG 013736), foretinib (GSK1363089), vandetanib (ZD6474), nintedanib (BIBF 1120), regorafenib (BAY 73-4506), and pazopanib HCl (GW786034). HCl), cediranib (AZD2171), PD173074, dovitinib (TKI-258), linifanib (ABT-869), batalanib (PTK787) 2HCl, RAF265 (CHIR-265), tivozanib (AV-951), motesanib diphosphate (AMG-706), lenvatinib (E7080), brivanib (BMS-540215), MGCD-265 analog, AEE788 (NVP-AEE788), ENMD-2076, OSI-930, CYC116, Ki8751, teratinib, PP121, pazopanib, KRN 633, SAR131675, Apatinib (YN968D1) mesylate, BMS-794833, Sorafenib (BAY 43-9006), Cabozantinib malate, Brivanib alaninate (BMS-582664), Golbatinib (E7050), Semaxanib (SU5416), ZM 323881 HCl, ZM 306416, ENMD-2076 L-(+)-Tartaric Acid, R1530, Chiauranib, Emvododstat (PTC299), XL092, Regorafenib hydrochloride, Lusitanib (E3810) hydrochloride, Ningetinib, Donafenib (Sorafenib D3), Ki20227, TyrphostinAG1433, SU14813, sulfatinib, CS-2660 (JNJ-38158471), SU5204, SU5214, SU5205, SU5408, pamfetinib (TAS-115), ODM-203, WHI-P180, artiratinib, motesanib (AMG-706), fluquintinib (HMPL-013), lenvatinib (E7080) mesylate, nintedanib ethanesulfonate, apatinib, cediranib maleate, toceranibrinate, anlotinib (AL3818) dihydrochloride, regorafenib (BAY-734506) monohydrate, citrava Tinib (MGCD516), Ramucirumab, BFH772, BAW2881 (NVP-BAW2881), SU5402, Sunitinib (SU11248), Dovitinib (TKI258) Lactate Monohydrate, LY2874455, SKLB1002, AZD2932, Lenalidomide (CC-5013), WAY-340935, Oglufanide, hVEGF-IN-1, 4SC-203, Kebrinic Acid, Nastorazepide, X-82 (Borolanib), MAZ51, TMTD (Tetramethylthiuram Disulfide), SU5208, SU5614, AG-13958, SKLB 610, SU1498, ZD-4190, PDGFR inhibitor 1, bevacizumab, erdafitinib (JNJ-42756493), vitamin E, or taxifolin (dihydroquercetin), or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments of methods for treating cancer, an additional agent is an aromatase inhibitor.

[0230] In some embodiments of methods for treating cancer, the aromatase inhibitor is letrozole (CGS 20267), anastrozole (ZD-1033), exemestane (FCE 24304), formestane, fadrozole (CGS16949A), alpha-naphthoflavone, or ovakunone (AI3-37934), or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments of methods for treating cancer, additional agents are mitotic inhibitors.

[0232] In some embodiments of methods for treating cancer, the mitotic inhibitor is a taxane (e.g., paclitaxel and docetaxel), a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, and vinorelbine), colchicine, podophyllotoxin, griseofulvin, or glaziovianin A, or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments of methods for treating cancer, an additional agent is a microtubule stabilizer.

[0234] In some embodiments of methods for treating cancer, the microtubule stabilizer is paclitaxel, nab-paclitaxel, docetaxel, colchicine, podophyllin, epotilon A, or epotilon B, or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments of methods for treating cancer, an additional agent is a DNA crosslinking agent.

[0236] In some embodiments of methods for treating cancer, the DNA crosslinking agent is oxaliplatin, cisplatin, or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments of methods for treating cancer, the additional agent is a vinca alkaloid.

[0238] In some embodiments of methods for treating cancer, the vinca alkaloid is vinorelbine, vincristine, vinblastine, vinblastine N-oxide, vindesine, vinflunin, vincamine, vintafolide, or deacetoxybinzolidine, or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments of methods for treating cancer, an additional agent is an alkylating agent.

[0240] In some embodiments of methods for treating cancer, the alkylating agent is altoretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechloretamine, melphalan, oxaliplatin, temozolomide, thiotepa, trabectedin, platinum-coordinated complex, or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments of the method for treating cancer, additional agents include folate analogs, pyrimidine analogs, purine analogs, antibiotics, L-asparaginase, interferon, anthracendione-substituted ureas, methylhydrazine derivatives, corticosteroids, progestins, estrogens, anti-estrogen receptor inhibitors, androgens, anti-androgen receptor inhibitors, endocrine / hormone agents, or gonadotropin-releasing hormone analogs, or pharmaceutically acceptable salts thereof.

[0242] In some embodiments of methods for treating cancer, anti-estrogen receptor inhibitors include fulvestrant (ICI-182780), raloxifene HCl, bazedoxifene (WAY-140424) HCl, G-1, amsenestrant (SAR439859), estrogen receptor modulator 1, rasofoxifene tartrate, H3B-5942, raloxifene, brillanestrant (GDC-0810), tamoxifen (ICI 46474) citrate, and toremifene citrate (NK 622) Clomiphene citrate, estriol, estrone, bazedoxifene (TSE-424) acetate, SPP-86, enclomiphene citrate, phenol red sodium salt, camizestrant (AZD9833), G15 (GRB-G15), cyclophenyl, PHTPP, AZD9496, chlorotrianicene, endoxifene HCl, ospemifene, or tamoxifen (ICI 46474), or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments of methods for treating cancer, anti-androgen receptor inhibitors include enzalutamide (MDV3100), bicalutamide (ICI-176334), ostarine, apalutamide (ARN-509), galeterone, flutamide, cyproterone acetate, AZD3514, spironolactone, ORM-15341, CLP-3094, proxalutamide (GT0918), JNJ-63576253 (TRC-253), bubdegalutamide (ARV-110), AC P-105, Ilanton, UT-34, tryptophenolide, 4,4'-DDE, EPI-001, darolutamide (ODM-201), megestrol acetate, clascoterone, inobrodib (CCS-1477), GSK-2881078, (S,R,S)-AHPC (MDK7526), ​​dimethylcurcumin (ASC-J9), RU58841, nilutamide, 3,3'-diindolylmethane, or chlormadinone acetate, or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments of methods for treating cancer, the additional agent is a chemotherapeutic agent.

[0245] Furthermore, this specification discloses a method for treating cancer in a subject requiring treatment, and this method is provided to the subject requiring treatment. (a) 5-Methoxy-1-(2-methylpyridine-3-yl)-4-(propa-2-in-1-ylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one: [ka] (Compound 1) or a pharmaceutically acceptable salt thereof, (b) Docetaxel and, This includes administering [the drug].

[0246] Furthermore, this specification discloses a method for treating cancer in a subject requiring treatment, and this method is provided to the subject requiring treatment. (a) 5-Methoxy-1-(2-methylpyridine-3-yl)-4-(propa-2-in-1-ylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one: [ka] (Compound 1) or a pharmaceutically acceptable salt thereof, (b) Radiation and, This includes applying [the treatment / measure].

[0247] Administration Appropriate routes of administration include, but are not limited to, oral administration, intravenous administration, rectal administration, aerosol administration, parenteral administration, ocular administration, pulmonary administration, transmucosal administration, transdermal administration, transvaginal administration, transaural administration, transnasal administration, and local administration. Furthermore, parenteral delivery, for example, includes intramuscular injection, subcutaneous injection, intravenous injection, intrathecal injection, as well as intrathecal injection, direct intraventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.

[0248] In some embodiments, the compound of formula (I) or formula (II) (e.g., compound 1) is administered in a range of 0.01 mg to 5000 mg per day. In some embodiments, the compound of formula (I) or formula (II) (e.g., compound 1) is administered in a range of about 1 mg to about 1000 mg per day. In some embodiments, the desired dose is conveniently presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, two, three, four or more times per day. In some embodiments, an appropriate daily dose of the compounds described herein, or pharmaceutically acceptable salts thereof, is about 0.01 mg to about 50 mg per kg of body weight.

[0249] Pharmaceutical composition / formulation The compounds described herein are administered to subjects requiring them, in accordance with standard pharmacopoeias, either alone or in combination with pharmaceutically acceptable carriers, additives, or diluents, in a pharmaceutical composition. In some embodiments, the compounds described herein are administered to animals.

[0250] In another embodiment, a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient is provided herein. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E. Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999) (such disclosures are incorporated herein by reference). [Examples]

[0251] All compounds can be synthesized according to the methods disclosed in International Application No. PCT / CN2022 / 126096 (which, by reference, forms an entirety of this Specified Publication).

[0252] The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

[0253] Intermediate C: [ka]

[0254] Step 1: 2,6-difluoro-4-(trifluoromethyl)benzoic acid (500.0 mg, 2.21 mmol) was added to a solution of sodium methanolate (358.0 mg, 6.63 mmol) in MeOH (5 mL), and the reaction mixture was stirred at 80°C for 2 hours. The mixture was then cooled to room temperature and concentrated. The residue was diluted with water (10 mL), the pH was adjusted to 2-3 with 6.0 M aqueous HCl solution, the mixture was extracted with DCM (15.0 mL x 3), the organic layer was washed with brine, dried, and concentrated to obtain compound INTC-1 (215.0 mg, 40.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J = 8.8 Hz, 1H), 7.28 (s, 1H), 3.92 (s, 3H).

[0255] Step 2: Compound INTC-1 (380.0 mg, 1.59 mmol) was mixed with SOCl2 (6.0 mL), and the resulting solution was heated at 80°C for 2 hours. The solution was then cooled to room temperature and concentrated to remove excess SOCl2. The residue was taken in dioxane (6.0 mL) and treated with NH4OH (40% w / w, 6.0 mL). The resulting solution was stirred at 0°C to room temperature for 1 hour. The mixture was concentrated under reduced pressure and diluted with water. The resulting solid product was then collected, washed with water, and dried to obtain compound INTC-2 (230 mg, yield 60.8%). 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.71 (s, 1H), 7.31 (dd, J = 8.8 Hz, 0.4 Hz, 1H), 7.23 (s, 1H), 3.89 (s, 3H).

[0256] Step 3: To a stirred suspension of compound INTC-2 (230 mg, 0.97 mmol) in dichloroethane (5 mL) at room temperature, oxalyl dichloride (135 mg, 1.07 mmol) was added. The resulting suspension was heated at 80°C for 1 hour. The mixture was cooled to room temperature, and 2-methylpyridine-3-amine (209.8 mg, 1.94 mmol) was added. The mixture was stirred at room temperature for 16 hours. The precipitate was collected, washed with water, and dried to obtain compound INTC-3 (120 mg, yield 33.3%). LCMS: 372.0 [M+H] + .

[0257] Step 4: To a mixture of compound INTC-3 (80.0 mg, 0.21 mmol) in THF (3.0 mL) at -20°C, KHMDS (0.47 mL, 0.47 mmol, 1.0 M in THF) was added, and the resulting mixture was heated to room temperature over 1 hour. The mixture was concentrated, diluted with water, and the pH was adjusted to 6-7 with a 4.0 M aqueous HCl solution. The precipitate was collected, washed with water, and dried to obtain compound intermediate C (60.0 mg, yield 79.2%). 1 H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.66 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 7.88 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.52 (dd, J = 7.6 Hz, 4.8 Hz, 1H), 7.15 (s, 1H), 5.98 (s, 1H), 3.98 (s, 3H), 2.25 (s, 3H).

[0258] Example 36: Synthesis of 5-Methoxy-1-(2-methylpyridine-3-yl)-4-(propa-2-in-1-ylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one (Compound 1) [ka] To a stirred suspension of compound intermediate C (70.0 mg, 0.20 mmol) in toluene (1 mL) at 0°C, DIPEA (257.0 mg, 1.99 mmol) and POCl3 (153.0 mg, 1.00 mmol) were added. The resulting suspension was heated at 100°C for 2 hours. After cooling to room temperature, a solution of DIPEA (257.0 g, 1.99 mmol) and propa-2-in-1-amine (109.6 mg, 1.99 mmol) in NMP (0.5 mL) was added. The mixture was stirred at 50°C for 1 hour. Water (10 mL) was added, and the mixture was extracted with dichloromethane (5 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to obtain Example 36 (29.0 mg, yield 37.9%). LCMS: 389.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (t, J = 5.2 Hz, 1H), 8.61 (dd, J = 4.8, 1.6 Hz, 1H), 7.75 (dd, J = 8.0, 1.6 Hz, 1H), 7.47 (dd, J = 7.6, 4.8 Hz, 1H), 7.15 (s, 1H), 6.03 (s, 1H), 4.39 - 4.26 (m, 2H), 4.13 (s, 3H), 3.16 (t, J = 2.4 Hz, 1H), 2.16 (s, 3H)

[0259] Example A: MAT2A Biochemical Assay The compounds described herein were tested as follows:

[0260] Enzyme reaction (1) A 1× assay buffer was prepared. (2) Preparation of compound concentration gradients: The test conditions for the compounds were 1 μM starting, 3-fold dilution, 10 doses, single-test or duplicate-test. Compounds at 100-fold concentrations were prepared in 384-well plates. Then, 250 nl was transferred to a 384-reaction plate using an Echo 550 for later use. 250 nl of 100% DMSO was added to the negative and positive control wells. (3) A 1.67-fold final concentration enzyme solution was prepared using 1× assay buffer. (4) 15 μl of 1.67x enzyme solution was added to the compound wells and positive control wells, and 15 μl of 1× assay buffer was added to the negative control wells. (5) Centrifuged at 1000 rpm for 30 seconds and incubated for 15 minutes. (6) A 2.5-fold final concentration substrate mixture solution was prepared using 1× assay buffer. (7) 10 μl of 2.5x final concentration substrate mixture was added to initiate the reaction. (8) Centrifuged at 1000 rpm for 30 seconds and incubated for 150 minutes. (9) To stop the reaction, 50 μl of Biomol Green was added, the mixture was centrifuged at 1000 rpm for 30 seconds, and incubated for 15 minutes. The OD620 was read and the data was processed.

[0261] Data Analysis (1) Use GraphPad Prism 5. (2) Inhibition rate (%) (%Inh) = (Maximum signal - Compound signal) / (Maximum signal - Minimum signal) × 100. (3) The maximum signal was obtained from the positive control well. (4) The minimum signal was obtained from the negative control well.

[0262] The data from Example A is shown in Table 6.

[0263] [Table 2] TIFF2026514893000038.tif166170

[0264] Example B: In vivo efficacy of MAT2A inhibitors in combination with chemotherapy Efficacy study of a KP-4 human pancreatic cancer xenograft model in NOD SCID mice method: cell culture The KP-4 tumor cell line was maintained in vitro as a monolayer culture in RPMI 1640 medium supplemented with 10% fetal bovine serum, under a 5% CO2 atmosphere in air, at 37°C. Tumor cells were regularly subcultured weekly by trypsin-EDTA treatment, not exceeding 4-5 passages. Cells in the exponential growth phase were collected and counted for tumor inoculation.

[0265] Tumor inoculation and randomization methods In the center of the right flank of each mouse, KP-4 tumor cells (1 × 10⁶) in 0.1 mL of serum-free RPMI-1640 were placed to induce tumor development. 7 The drug was administered subcutaneously. The average tumor size was approximately 100 mm. 3 Treatment was initiated when the target was reached. Mice were assigned to groups so that the average tumor volume at each treatment group and at each time point was the same.

[0266] Measurement parameters As part of routine monitoring, all test animals were monitored not only for tumor growth but also for behavioral changes such as motility, food and water intake (observed only from the side of the cage), body weight (BW), eye / coat matting, and other abnormal effects. All deaths and / or abnormal clinical signs were recorded.

[0267] body weight The weight of all animals was measured twice a week during the study period. Weight change, expressed as a percentage, was calculated using the following formula. Weight change (%) = (BW Day X / BW Day 0 ) × 100 Here, BW Day X This is the weight on a specific day, BW Day 0 This is the weight on day 0 (at the start of treatment).

[0268] Tumor measurement Tumor size is measured twice a week using calipers, and tumor volume (mm³) is measured. 3 ) is the formula: TV = a × b 2The calculation was performed using / 2. Here, a and b are the longest and shortest diameters of the tumor, respectively. TV is calculated only during the administration period (day 0 to day n), using the formula: TGI(%)=[1-(T n -T0) / (C n -C0) × 100% was used to calculate the tumor growth inhibition (TGI, an indicator of antitumor efficacy) value. Here, T n T0 is the mean tumor volume on each day "n" after administration during the treatment period, and C is the mean tumor volume of the treatment group on day 0 immediately before treatment. n C0 is the mean tumor volume of the control group on each day "n" after administration during the treatment period, and C0 is the mean tumor volume of the control group on day 0, immediately before treatment. The mean tumor volume is 2000 mm³. 3 The experiment was terminated when the weight exceeded a certain threshold or when severe weight loss was observed.

[0269] statistical analysis The difference in tumor volume between the treatment group and the solvent control group was analyzed using the statistical software GraphPad Prism (version number: 8). Two-way ANOVA and Bonferroni multiple comparison tests were used to compare whether there was a significant difference in tumor volume between the vehicle control group and each treatment group during the administration period. One-way ANOVA and Dunnett's multiple comparison tests were used to analyze whether there was a significant difference in tumor volume between the vehicle control group and each treatment group on day 21 after administration, and whether there was a difference in tumor weight between the vehicle control group and each treatment group at the end of the experiment. * P<0.05, ** P<0.01, *** We considered the data to be statistically significant if P < 0.001.

[0270] result The average tumor volume at the start of treatment was approximately 102 mm². 3Ten mice were randomly assigned to each treatment group. In the KP4 MTAP null tumor model, mice were orally administered vehicle once daily (QD), compound 1 at 1 mg / kg or 3 mg / kg once daily (QD), AG270 at 100 mg / kg once daily (QD), docetaxel at 2.5 mg / kg once weekly, or compound 1 in combination with docetaxel at each dose level.

[0271] In a KP-4 human pancreatic cancer xenograft model, administration of compound 1 at 1 mg / kg or 3 mg / kg QD resulted in TGI of 36.8% and 53.4%, respectively. Administration of AG270 at 100 mg / kg resulted in a TGI of 55.7%. Administration of docetaxel at 2.5 mg / kg resulted in a TGI of 51.6%. The combination of 2.5 mg / kg of docetaxel once a week with compound 1 at 1 mg / kg or 3 mg / kg resulted in TGI of 69.6% and 73.2%, respectively (Table 7 and Figure 1). The combination of compound 1 and docetaxel significantly inhibited tumor growth in a dose-dependent manner. All mice were well-tolerated, and the changes in mouse body weight are shown in Figure 2.

[0272] [Table 3]

[0273] Example C: In vivo efficacy of MAT2A inhibitors in combination with chemotherapy Efficacy study of an HCC15 human lung cancer xenograft model in NOD SCID mice method: Cell culture: HCC15 cells were maintained in vitro as monolayer cultures at 37°C in 90% 1640 + 10% FBS, 100 U / ml penicillin, and 100 μg / ml streptomycin under a 5% CO2 atmosphere in air. Tumor cells were regularly subcultured every 3-4 days at a ratio of 1:2 to 1:3. Alternatively, the culture was maintained by adding or replacing fresh medium. Cultures were 5 × 10⁶ 5 Start with cells / mL, then 0.5 × 10 5 cells / ml~2×106 The cell count was maintained at cells / ml.

[0274] Animal: NOD SCID mouse, female, 6-8 weeks old, weighing approximately 20-22g.

[0275] Tumor vaccination: In the right flank of each mouse, HCC15 cells (5 × 10) in a 0.2 mL mixture of 1640 medium were placed to induce tumor development. 6 Cells (or mice) were subcutaneously inoculated. In tumor efficacy studies using tool compounds and medicinal chemistry molecules to investigate efficacy against vehicle tumor growth, the average tumor size was approximately 100 mm. 3 ~200mm 3 Administration was started when the target level was reached.

[0276] result The average tumor volume at the start of treatment was approximately 133.09 mm². 3 Ten mice were randomly assigned to each treatment group. In the HCC15 MTAP null tumor model, mice were orally administered vehicle once daily (QD), compound 1 at 3 mg / kg once daily (QD), AG270 at 100 mg / kg once daily (QD), docetaxel at 2.5 mg / kg once weekly, or compound 1 in combination with docetaxel at each dose level.

[0277] In a xenograft model of HCC15 human lung cancer, administration of compound 1 at 3 mg / kg QD resulted in a TGI of 44.6%. Administration of AG270 at 100 mg / kg resulted in a TGI of 51.5%. Administration of docetaxel at 2.5 mg / kg resulted in a TGI of 51.8%. The combination of 2.5 mg / kg of docetaxel once a week and 3 mg / kg of compound 1 resulted in a TGI of 64.2% (Table 8 and Figure 3). The combination of compound 1 and docetaxel significantly inhibited tumor growth.

[0278] All mice were well-tolerated, and the changes in mouse body weight are shown in Figure 4.

[0279] [Table 4]

[0280] Example D: In vivo efficacy of MAT2A inhibitor in combination with PRMT5 inhibitor Efficacy study of the NCI-H838 human lung cancer xenograft model in NOD SCID mice method: Cell culture: NCI-H838 cancer cells were maintained in vitro at 37°C in an air-air, 5% CO2 atmosphere using RPMI-1640 medium supplemented with 10% fetal bovine serum. Cells in the exponential growth phase were collected and quantified using a cell counter before tumor inoculation.

[0281] Animals: NOD SCID mice, female, 6-8 weeks old, weighing approximately 20-22g. All mice were purchased from Shanghai Lingchang Bio-Tech Co., Ltd.

[0282] Tumor vaccination: In the right flank of each mouse, NCI-H838 cells (5 × 10¹³) were placed in 0.1 mL of PBS (1:1) mixed with Matrigel to induce tumor development. 6 Cells (or mice) were subcutaneously inoculated. In tumor efficacy studies using tool compounds and medicinal chemistry molecules to investigate efficacy against vehicle tumor growth, the average tumor size was approximately 150 mm. 3 Administration was started when the target level was reached.

[0283] result The average tumor volume at the start of treatment was approximately 146.51 mm². 3 Six mice were randomly assigned to each treatment group. In the NCI-H838 MTAP null tumor model, mice were orally administered a vehicle once daily (QD), compound 1 at 3 mg / kg or 10 mg / kg once daily (QD), the PRMT5 inhibitor MRTX1719 at 50 mg / kg once daily (QD), or compound 1 in combination with MRTX1719 at each dose level.

[0284] In an NCI-H838 human lung cancer xenograft model, administration of compound 1 at 3 mg / kg or 10 mg / kg QD resulted in TGIs of 1.6% and 19.9%, respectively. Administration of MRTX1719 at 50 mg / kg resulted in a TGI of 81.5%. Combinations of 50 mg / kg of MRTX1719 with 3 mg / kg or 10 mg / kg of compound 1 resulted in TGIs of 83.2% and 103.1%, respectively (Table 9 and Figure 5). The combination of compound 1 and MRTX1719 significantly inhibited tumor growth, showing significant additive or synergistic effects with synergistic effects of 1.02 and 1.21, respectively. Administration was well tolerated. Changes in mouse body weight are shown in Figure 6.

[0285] [Table 5]

[0286] Example E: Synergistic effect screen of MAT2A inhibitor and cancer drug A synergy screening was conducted to evaluate the potential synergistic effects of combining a MAT2A inhibitor (compound 1) for cancer treatment with other therapeutic agents. These drugs included PARP inhibitors (e.g., olaparib, talazoparib), mTOR inhibitors (e.g., everolimus, temsirolimus), antimetabolites (e.g., decitabine, pemetrexed), CDK4 / 6 inhibitors (e.g., abemaciclib, palbociclib), BCL-2 inhibitors (e.g., venetoclax), alkylating agents (e.g., oxaliplatin, altretamine), microtubule stabilizers (e.g., docetaxel), vinca alkaloids (e.g., vinorelbine), KRAS inhibitors (e.g., sotrasib), EGFR inhibitors (e.g., afatinib, gefitinib), topoisomerase inhibitors (e.g., etoposide), PRMT5 inhibitors (e.g., MRTX1719, AM-9747), WEE1 inhibitors (e.g., bosutinib), and hypomethylating agents (e.g., procainamide). A series of dilutions of the MAT2A inhibitor (compound 1) and the concomitant drug were prepared in a dose matrix. A panel of 43 cancer cell lines (Table 10) was then treated to evaluate the potential synergistic effects on cell proliferation inhibition.

[0287] Drug combination therapy and cell viability assays Cells were placed in 384-well plates at an optimal seeding density per well. After seeding, compound 1 and other cancer therapeutics were added in a 6x6 matrix in a sequentially diluted (1:3 dilution, maximum concentration 10 μM) form. The assay plates were then incubated for 7 or 10 days, after which 25 μl of CellTiter-Glo (Promega Corp.) was added at room temperature. The plates were read using Envision (PerkinElmer Inc.) with an enhanced luminescence protocol.

[0288] Excess bliss as an indicator of synergistic effects The synergistic effect of the combinations was evaluated using the Bliss independence model. For compounds A and B, where the experimentally measured inhibitory rates EA and EB are at specified doses of their constituent drugs, the expected inhibitory rate EAB induced by their combination is calculated as EA + EB - EA × EB. The excess Bliss (EOB) score was determined by calculating the difference between the inhibitory rate EZ induced by the compound combination and the expected inhibitory rate EAB, i.e., EOB = EZ - EAB. In our study, the excess Bliss score was calculated only for combinations that induced growth inhibition of more than 20%. Scores between 0 and 10 were considered additive, and scores above 10 were considered synergistic.

[0289] [Table 6]

[0290] result Synergistic inhibition of cell proliferation between compound 1 and several cancer therapeutics (PARP inhibitors, BCL2 inhibitors, EGFR inhibitors, mTOR inhibitors, KRAS inhibitors, PRMT5 inhibitors, protein kinase inhibitors, dual SRC and ABL tyrosine kinase inhibitors, CDK4 / 6 inhibitors, topoisomerase inhibitors, antimetabolites, microtubule stabilizers, microtubule destabilizers, and DNA cross-linking agents) was observed in multiple MTAP-deficient and MTAP knockout cell lines (Figures 7A-7D, 8A-8C, 9A-9D, 10A and 10B, 11A-11F, 12A-12F, 13A-13E, 14A-14C, 15A-15D, 16A). (Figures 16C, 17A-17H, 18A-18E, 19A-19C, 20A-20H, 21A-21F, 22A and 22B, 23A-23C, 24A-24C, 25A and 25B, 26A-26C, 27A and 27B, 28A-28C, and 29A and 29B). Synergistic effects were determined across all dose levels using excess bliss. Additive growth inhibition (score 0-10) is highlighted in light gray, and synergistic growth inhibition (score greater than 10) is highlighted in black. Beyond combined synergistic effects, additive growth inhibition was observed in MTAP-deficient and MTAP knockout cell lines.

Claims

1. A method for treating cancer in a subject requiring treatment, wherein the method involves, (a) Compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula, 【Chemistry 2】 C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～１０ Selected from heteroaryls, Z １ CR ７ or N, Z ２ CR ９ or N, Z ３ is either CR ６ or N, and Z ４ CR ６ａ or N, X is -N(R ４ )-, -O-, and -C(R ５ ) (Caution ５ａ ) - Selected from, Y is -N(R ４ａ )-, -O-, and -C(R ５ ) (Caution ５ａ ) - Selected from, R １ is hydrogen, halogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Ariel, C １～９ heteroaryl, -OR １０ , -SR １０ , -SF ５ , -N(R １０ ) (Caution １１ ), -C(O)OR １０ , -OC(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)OR １３ , -N(R １２ ) S(O) ２ R １３ , -C(O)R １３ , -S(O)R １３ , -OC(O)R １３ , -C(O)N(R １０ ) (Caution １１ ), -C(O)C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)R １３ , -S(O) ２ R １３ , -S(O) ２ N(R) １０ ) (Caution １１ )-, -N=S(=O)(R １３ ) ２ , -S(=O)(=NH)N(R １０ ) (Caution １１ ), -S(=O)(=NH)C(R １０ ) (Caution １１ ), -S(=O)(=NR １３ ) R １３ ien-CH ２ C(O)N(R) １０ ) (Caution １１ ), -CH ２ N(R) １２ ), C(O)R １３ , -CH ２ S(O) ２ R １３ , -CH ２ S(O) ２ N(R １０ )(R １１ ), -Si(C １～６ alkyl) ３ , and -P(O)(R １０ ), ２ selected from, where C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ cycloalkyl, C ２～９ heterocycloalkyl, C ６～１０ aryl, and C １～９ heteroaryl are optionally substituted with one, two, or three groups selected from R １５ａ , R １ａ and R １ｂ are each independently selected from hydrogen, halogen, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ cycloalkyl, C ２～９ heterocycloalkyl, C ６～１０ aryl, and C １～９ heteroaryl, where C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ cycloalkyl, C ２～９ heterocycloalkyl, C ６～１０ aryl, and C １～９ heteroaryl are each optionally substituted with one, two, or three groups selected from R １５ａ ​ Each R ２ and each R ３ These are hydrogen, halogen, oxo, and C, respectively. １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Ariel, C １～９ heteroaryl, -OR １０ , -SR １０ , -SF ５ , -N(R １０ ) (Caution １１ ), -C(O)OR １０ , -OC(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)OR １３ , -N(R １２ ) S(O) ２ R １３ , -C(O)R １３ , -S(O)R １３ , -OC(O)R １３ , -C(O)N(R １０ ) (Caution １１ ), -C(O)C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)R １３ , -S(O) ２ R １３ , -S(O) ２ N(R) １０ ) (Caution １１ )-, -N=S(=O)(R １３ ) ２ , -S(=O)(=NH)N(R １０ ) (Caution １１ ), -S(=O)(=NH)C(R １０ ) (Caution １１ ), -S(=O)(=NR １３ ) R １３ ien-CH ２ C(O)N(R) １０ ) (Caution １１ ), -CH ２ N(R) １２ ) C(O)R １３ ien-CH ２ S(O) ２ R １３ ien-CH ２ S(O) ２ N(R) １０ ) (Caution １１ ), -Si(C １～６ Alkyl) ３ , and -P(O)(R １０ ) ２ Selected independently from, where C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Heteroaryls are R １５ｂ It is arbitrarily substituted with one, two, or three groups selected from, or R ２ and R ３ Together with the carbon atoms to which they are bonded, C ３～６ Cycloalkyl or C ２～９ Forms heterocycloalkyl groups, R ４ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Selected from heteroaryls, where C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Heteroaryls are halogens, -CN, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ It may be optionally substituted with one, two, or three groups selected from heteroaryls, or R ４ and R ３ These are combined as halogen, -CN, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ C optionally substituted with one, two, or three groups selected from heteroaryl groups ２～９ Forms heterocycloalkyl groups, R ４ａ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Selected from heteroaryls, where C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Heteroaryls are halogens, -CN, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ It may be optionally substituted with one, two, or three groups selected from heteroaryls, or R ４ａ and R ３ These are combined as halogen, -CN, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ C optionally substituted with one, two, or three groups selected from heteroaryl groups ２～９ Forms heterocycloalkyl groups, R ５ and R ５ａ is hydrogen, halogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Ariel, C １～９ heteroaryl, -OR １０ , -SR １０ , -SF ５ , -N(R １０ ) (Caution １１ ), -C(O)OR １０ , -OC(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)OR １３ , -N(R １２ ) S(O) ２ R １３ , -C(O)R １３ , -S(O)R １３ , -OC(O)R １３ , -C(O)N(R １０ ) (Caution １１ ), -C(O)C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)R １３ , -S(O) ２ R １３ , -S(O) ２ N(R) １０ ) (Caution １１ )-, -N=S(=O)(R １３ ) ２ , -S(=O)(=NH)N(R １０ ) (Caution １１ ), -S(=O)(=NH)C(R １０ ) (Caution １１ ), -S(=O)(=NR １３ ) R １３ ien-CH ２ C(O)N(R) １０ ) (Caution １１ ), -CH ２ N(R) １２ ) C(O)R １３ ien-CH ２ S(O) ２ R １３ ien-CH ２ S(O) ２ N(R) １０ ) (Caution １１ ), -Si(C １～６ Alkyl) ３ , and -P(O)(R １０ ) ２ Selected independently from, where C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Heteroaryls are halogens, -CN, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ It may be optionally substituted with one, two, or three groups selected from heteroaryls, or R ５ and R ３ These are combined into C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, or C ２～９ It forms a heteroaryl, and here, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Heteroaryls are halogens, -CN, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ It is optionally substituted with one, two, or three groups selected from heteroaryls. R ６ , R ７ , R ８ , and R ９ is hydrogen, halogen, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Ariel, C １～９ heteroaryl, -OR １０ , -SR １０ , -SF ５ , -N(R １０ ) (Caution １１ ), -C(O)OR １０ , -OC(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)OR １３ , -N(R １２ ) S(O) ２ R １３ , -C(O)R １３ , -S(O)R １３ , -OC(O)R １３ , -C(O)N(R １０ ) (Caution １１ ), -C(O)C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)R １３ , -S(O) ２ R １３ , -S(O) ２ N(R) １０ ) (Caution １１ )-, -N=S(=O)(R １３ ) ２ , -S(=O)(=NH)N(R １０ ) (Caution １１ ), -S(=O)(=NH)C(R １０ ) (Caution １１ ), -S(=O)(=NR １３ ) R １３ ien-CH ２ C(O)N(R) １０ ) (Caution １１ ), -CH ２ N(R) １２ ) C(O)R １３ ien-CH ２ S(O) ２ R １３ ien-CH ２ S(O) ２ N(R) １０ ) (Caution １１ ), -Si(C １～６ Alkyl) ３ , and -P(O)(R １０ ) ２ Selected independently from, where C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Heteroaryls are R １５ｃ It is optionally replaced by one, two, or three elements selected from the following: R ６ａ is hydrogen, halogen, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C １～９ heteroaryl, -OR １０ , -SR １０ , -SF ５ , -N(R １０ ) (Caution １１ ), -C(O)OR １０ , -OC(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)OR １３ , -N(R １２ ) S(O) ２ R １３ , -C(O)R １３ , -S(O)R １３ , -OC(O)R １３ , -C(O)N(R １０ ) (Caution １１ ), -C(O)C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)R １３ , -S(O) ２ R １３ , -S(O) ２ N(R) １０ ) (Caution １１ )-, -N=S(=O)(R １３ ) ２ , -S(=O)(=NH)N(R １０ ) (Caution １１ ), -S(=O)(=NH)C(R １０ ) (Caution １１ ), -S(=O)(=NR １３ ) R １３ ien-CH ２ C(O)N(R) １０ ) (Caution １１ ), -CH ２ N(R) １２ ) C(O)R １３ ien-CH ２ S(O) ２ R １３ ien-CH ２ S(O) ２ N(R) １０ ) (Caution １１ ), -Si(C １～６ Alkyl) ３ , and -P(O)(R １０ ) ２ Selected from, where C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl and C １～９ Heteroaryls are R １５ｃ It is optionally replaced by one, two, or three elements selected from the following: Each R １０ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Selected independently from heteroaryls, where C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Heteroaryls are halogens, -CN, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Optionally substituted with one, two, or three groups selected from heteroaryls, Each R １１ is hydrogen, C １～６ Alkyl and C １～６ Independently selected from haloalkyls, or R １０ and R １１ Together with the nitrogen to which they are bonded, C ２～９ Forms heterocycloalkyl groups, Each R １２ is hydrogen, C １～６ Alkyl and C １～６ Selected independently from haloalkyl groups, Each R １３ C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Selected independently from heteroaryls, where C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Heteroaryls are halogens, -CN, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Optionally substituted with one, two, or three groups selected from heteroaryls, Each R １４ is halogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Ariel, C １～９ heteroaryl, -OR １０ , -SR １０ , -SF ５ , -N(R １０ ) (Caution １１ ), -C(O)OR １０ , -OC(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)OR １３ , -N(R １２ ) S(O) ２ R １３ , -C(O)R １３ , -S(O)R １３ , -OC(O)R １３ , -C(O)N(R １０ ) (Caution １１ ), -C(O)C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)R １３ , -S(O) ２ R １３ , -S(O) ２ N(R) １０ ) (Caution １１ )-, -N=S(=O)(R １３ ) ２ , -S(=O)(=NH)N(R １０ ) (Caution １１ ), -S(=O)(=NH)C(R １０ ) (Caution １１ ), -S(=O)(=NR １３ ) R １３ ien-CH ２ C(O)N(R) １０ ) (Caution １１ ), -CH ２ N(R) １２ ) C(O)R １３ ien-CH ２ S(O) ２ R １３ ien-CH ２ S(O) ２ N(R) １０ ) (Caution １１ ), -Si(C １～６ Alkyl) ３ , and -P(O)(R １０ ) ２ Selected independently from, where C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, C ６～１０ Aryl, and C １～９ Heteroaryls are R １５ｄ It is optionally replaced by one, two, or three elements selected from the following: Each R １５ａ , R １５ｂ , R １５ｃ , and R １５ｄ These are halogen, oxo, -CN, and C, respectively. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１０ Cycloalkyl, -CH ２ -C ３～６ Cycloalkyl, C ２～９ Heterocycloalkyl, -CH ２ -C ２～９ Heterocycloalkyl, C ６～１０ Ariel, -CH ２ -C ６～１０ Ariel, C １～９ Heteroaryl, -CH ２ -C １～９ heteroaryl, -OR １０ , -SR １０ , -SF ５ , -N(R １０ ) (Caution １１ ), -C(O)OR １０ , -OC(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)OR １３ , -N(R １２ ) S(O) ２ R １３ , -C(O)R １３ , -S(O)R １３ , -OC(O)R １３ , -C(O)N(R １０ ) (Caution １１ ), -C(O)C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)R １３ , -S(O) ２ R １３ , -S(O) ２ N(R) １０ ) (Caution １１ )-, -N=S(=O)(R １３ ) ２ , -S(=O)(=NH)N(R １０ ) (Caution １１ ), -S(=O)(=NH)C(R １０ ) (Caution １１ ), -S(=O)(=NR １３ ) R １３ ien-CH ２ C(O)N(R) １０ ) (Caution １１ ), -CH ２ N(R) １２ ) C(O)R １３ ien-CH ２ S(O) ２ R １３ ien-CH ２ S(O) ２ N(R) １０ ) (Caution １１ ), -Si(C １～６ Alkyl) ３ , and -P(O)(R １０ ) ２ Selected independently from, where C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, -CH ２ -C ３～１０ Cycloalkyl, C ２～９ Heterocycloalkyl, -CH ２ -C ２～９ Heterocycloalkyl, C ６～１０ Ariel, -CH ２ -C ６～１０ Ariel, -CH ２ -C １～９ Heteroaryls, and C １～９ Heteroaryls include halogens, oxo, -CN, and C. １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, -OR １０ , -SR １０ , -SF ５ , -N(R １０ ) (Caution １１ ), -C(O)OR １０ , -OC(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)OR １３ , -N(R １２ ) S(O) ２ R １３ , -C(O)R １３ , -S(O)R １３ , -OC(O)R １３ , -C(O)N(R １０ ) (Caution １１ ), -C(O)C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)R １３ , -S(O) ２ R １３ , -S(O) ２ N(R) １０ ) (Caution １１ )-, -N=S(=O)(R １３ ) ２ , -S(=O)(=NH)N(R １０ ) (Caution １１ ), -S(=O)(=NH)C(R １０ ) (Caution １１ ), -S(=O)(=NR １３ ) R １３ ien-CH ２ C(O)N(R) １０ ) (Caution １１ ), -CH ２ N(R) １２ ) C(O)R １３ ien-CH ２ S(O) ２ R １３ ien-CH ２ S(O) ２ N(R) １０ ) (Caution １１ ), and -P(O)(R １０ ) ２ It is optionally replaced by one, two, or three elements independently selected from it. m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, 4, 5, or 6) (b) Additional medications and This includes administering, A method wherein the amount of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, combined with the additional agent is a therapeutically effective amount for treating the cancer.

2. A method for treating cancer in a subject requiring treatment, wherein the method involves, (a) 5-Methoxy-1-(2-methylpyridine-3-yl)-4-(propa-2-in-1-ylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one: 【Transformation 3】 (Compound 1) or a pharmaceutically acceptable salt thereof, (b) Additional medications and A method including administering [a substance].

3. The method according to claim 2, wherein the amount of compound 1 or a pharmaceutically acceptable salt thereof combined with the additional agent is a therapeutically effective amount.

4. The method according to any one of claims 1 to 3, wherein the cancer is an MTAP-deficient cancer.

5. The method according to any one of claims 1 to 3, wherein the cancer is MTAP wild-type cancer.

6. The method according to any one of claims 1 to 5, wherein the cancer is primary leukemia, hematological malignancy, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

7. The method according to any one of claims 1 to 5, wherein the cancer is liver cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, gastrointestinal stromal tumor, biliary tract cancer, B-cell acute lymphoblastic leukemia (ALL), lymphoma, or T-cell leukemia.

8. The method according to any one of claims 1 to 7, wherein the additional agent is a PARP inhibitor, a CHK1 inhibitor, an MDM2 inhibitor, a hypomethylating agent, an mTOR inhibitor, an ATM inhibitor, a CDK4 / 6 inhibitor, a BCL-2 inhibitor, a PRMT5 inhibitor, a PRMT1 inhibitor, an ATR inhibitor, a WEE1 inhibitor, an APE1 inhibitor, a topoisomerase inhibitor, a taxane, an immune checkpoint inhibitor, a CDK7 inhibitor, a CDK9 inhibitor, a DNA synthesis inhibitor, an antimetabolite, an AURORA inhibitor, a microtubule stabilizer, a DNA crosslinking agent, a vinca alkaloid, an alkylating agent, a PRMT6 inhibitor, a PRMT7 inhibitor, a PRMT9 inhibitor, a KRAS inhibitor, an EGFR inhibitor, a VEGFR inhibitor, an aromatase inhibitor, a mitotic inhibitor, a radiopharmaceutical, a cytotoxic agent, or any combination thereof.

9. The method according to any one of claims 1 to 8, wherein the additional agent is a PARP inhibitor.

10. The PARP inhibitors mentioned above are olaparib (AZD2281), veliparib (ABT-888), lucaparib, talazoparib (BMN 673), AG-14361, INO-1001 (3-aminobenzamide), A-966492, PJ34 HCl, niraparib, UPF 1069, ME0328, RK-287107, pamiparib (BGB-290), NMS-P118, E7449, picolinamide, benzamide, NU1025, iniparib (BSI-201), AZD2461, BGP-15 2HCl, XAV-939, 4-hydroxyquinazoline, NVP-TNKS656, MN The method according to claim 9, wherein the salt is 64, or G007-LK, or a pharmaceutically acceptable salt thereof.

11. The method according to claim 10, wherein the PARP inhibitor is olaparib (AZD2281), lucaparib, talazoparib (BMN 673), niraparib, or talazoparib (BMN 673), or a pharmaceutically acceptable salt thereof.

12. The method according to any one of claims 1 to 8, wherein the additional agent is a hypomethylating agent.

13. The method according to claim 12, wherein the hypomethylating agent is decitabine, azacitidine (5-azacitidine), RG108, thioguanine, zebralin, SGI-1027, CM272, 2'-deoxy-5-fluorocytidine, procainamide, bobcat339, γ-oryzanol, thujaplicin, or (-)-epigallocatechin gallate, or a pharmaceutically acceptable salt thereof.

14. The method according to claim 13, wherein the low-methylating agent is procainamide or a pharmaceutically acceptable salt thereof.

15. The method according to claim 13, wherein the low-methylating agent is decitabine or a pharmaceutically acceptable salt thereof.

16. The method according to any one of claims 1 to 8, wherein the additional agent is an mTOR inhibitor.

17. The aforementioned mTOR inhibitors are dactricib (BEZ235), rapamycin (sirolimus), everolimus (RAD001), AZD8055, temsirolimus (CCI-779), PI-103, KU-0063794, tolkinib (PP242), ridafololimus (defololimus, MK-8669), sapanicertib (MLN0128), voxtalisib (XL765), trin-1, trin-2, omiparisib (GSK2126458), OSI-027, and PF-046. 91502, Apitricib (GDC-0980), GSK1059615, Gedatricib (PKI-587), WYE-354, Bisutsertib (AZD2014), WYE-125132 (WYE-132), PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, GNE-477, Vimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib (CC The method according to claim 16, wherein the salt is 223), boxtalisib (XL765), zotarolimus (ABT-578), tacrolimus (FK506), BGT226 maleate (NVP-BGT226 maleate), paromide 529 (P529), LY3023414 (samotricib), biolimus-7, biolimus-9, azathioprine, canvas 1H, or chrysophanic acid, or a pharmaceutically acceptable salt thereof.

18. The method according to claim 17, wherein the mTOR inhibitor is everolimus (RAD001) or temsirolimus, or a pharmaceutically acceptable salt thereof.

19. The method according to any one of claims 1 to 8, wherein the additional agent is a CDK4 / 6 inhibitor.

20. The method according to claim 19, wherein the CDK4 / 6 inhibitor is palbociclib (PD-0332991), arbocidib, AT7519, JNJ-7706621, PHA-793887, BMS-265246, milcilib (PHA-848125), R547, ribiclib (P276-00), MC180295, G1T38, abemaciclib, ON123300, AT7519, pluvalanol A, SU9516, ribociclib (LEE011), or BSJ-03-123, or a pharmaceutically acceptable salt thereof.

21. The method according to claim 20, wherein the CDK4 / 6 inhibitor is palbociclib (PD-0332991), abemaciclib, or a pharmaceutically acceptable salt thereof.

22. The method according to any one of claims 1 to 8, wherein the additional agent is a BCL-2 inhibitor.

23. The method according to claim 22, wherein the BCL-2 inhibitor is ABT-737, Navitoclax (ABT-263), Ovatoclax (GX15-070), TW-37, Venetoclax (ABT-199), AT101, HA14-1, Subtoclax, S55746, or Gumboginate, or a pharmaceutically acceptable salt thereof.

24. The method according to claim 23, wherein the BCL-2 inhibitor is venetoclax (ABT-199) or a pharmaceutically acceptable salt thereof.

25. The method according to any one of claims 1 to 8, wherein the additional drug is a PRMT5 inhibitor.

26. The method according to claim 25, wherein the PRMT5 inhibitor is JNJ-64619178 (AGI-931), HLCL-61, GSK591, EPZ015666 (GSK3235025), GSK3326595 (EPZ015938; AGI-219), TNG908, TNG462, AMG193, AMG9747, MRTX1719, P305-05313, CTS3157, PH-020-803, or AZ-PRMT5i-1, or a pharmaceutically acceptable salt thereof.

27. The method according to claim 26, wherein the PRMT5 inhibitor is TNG908, TNG462, AMG193, AMG9747, MRTX1719, or P305-05313, or a pharmaceutically acceptable salt thereof.

28. The method according to any one of claims 1 to 8, wherein the additional agent is a WEE1 inhibitor.

29. The method according to claim 28, wherein the WEE1 inhibitor is AZD1775 (MK1775), Zn-c3, debio 0123, IMP7068, SDR-7995, SDR-7778, NUV-569, PD0166285, PD0407824, SC-0191, DC-859 / A, bosutinib, or Bos-I, or a pharmaceutically acceptable salt thereof.

30. The method according to any one of claims 1 to 8, wherein the additional agent is a topoisomerase inhibitor.

31. The method according to claim 30, wherein the topoisomerase inhibitor is epipodophyllotoxin, SN-38, ARC, NPC, camptothecin, topotecan, 9-nitrocamptothecin, exatecan, lulutotecan, lamelarin D9-aminocamptothecin, rubifen, gimatecan, diflomotecan, BN80927, DX-8951f, MAG-CPT, thiotepa, cyclophosphamide, amsacrin, etoposide, phosphate etoposide, teniposide, daunorubicin, mitoxantrone, amsacrin, ellipticin, aurintricarboxylic acid, doxorubicin, or HU-331, or a pharmaceutically acceptable salt thereof.

32. The method according to any one of claims 1 to 8, wherein the additional agent is an antimetabolite.

33. The method according to claim 32, wherein the antimetabolite is 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine, cytarabine, phloxuridine, fludarabine, gemcitabine, hydroxycarbamide, methotrexate, pemetrexed, or phototrexate, or a pharmaceutically acceptable salt thereof.

34. The method according to claim 33, wherein the antimetabolite is pemetrexed, 5-fluorouracil (5-FU), or pemetrexed, or a pharmaceutically acceptable salt thereof.

35. The method according to any one of claims 1 to 8, wherein the additional agent is a microtubule stabilizer.

36. The method according to claim 35, wherein the microtubule stabilizer is paclitaxel, nab-paclitaxel, docetaxel, colchicine, podophyllin, epotilon A, or epotilon B, or a pharmaceutically acceptable salt thereof.

37. The method according to any one of claims 1 to 8, wherein the additional agent is a DNA crosslinking agent.

38. The method according to claim 37, wherein the DNA crosslinking agent is oxaliplatin, cisplatin, or a pharmaceutically acceptable salt thereof.

39. The method according to any one of claims 1 to 8, wherein the additional agent is a vinca alkaloid.

40. The method according to claim 39, wherein the vinca alkaloid is vinorelbine, vincristine, vinblastine, vinblastine N-oxide, vindesine, vinflunin, vincamine, vintafolide, or deacetoxybinzolidine, or a pharmaceutically acceptable salt thereof.

41. The method according to any one of claims 1 to 8, wherein the additional agent is an alkylating agent.

42. The method according to claim 41, wherein the alkylating agent is altoretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechloretamine, melphalan, oxaliplatin, temozolomide, thiotepa, trabectedin, platinum coordination complex, or a pharmaceutically acceptable salt thereof.

43. The method according to any one of claims 1 to 8, wherein the additional agent is a KRAS inhibitor.

44. The KRAS inhibitors mentioned above are 6H05, adagrasib, ARS-1323, ARS-1323-alkyne, ARS-1620, ARS-1630, ARS-853, ASP2453, AZD4625, BAY-293, BI-0474, BI-2852, BI-3406, divalasib, G12Si-1, G12Si-5 formate type, G12Si-5, galsolacib, K20, KRAS G12C inhibitor 1, KRAS G12C inhibitor 2, KRAS G12C inhibitor 3, KRAS G12C inhibitor 4, KRAS G12C inhibitor 5, KRAS G12C inhibitor 13, KRAS G12C inhibitor 14, KRAS G12C inhibitor 15, KRAS G12C inhibitor 16, KRAS G12C inhibitor 17, KRAS G12C inhibitor 18, KRAS G12C inhibitor 23, KRAS G12C inhibitor 24, KRAS G12C inhibitor 25, KRAS G12C inhibitor 26, KRAS G12C inhibitor 27, KRAS G12C inhibitor 28, KRAS G12C inhibitor 32, KRAS G12C inhibitor 43, KRAS G12C inhibitor 44, KRAS G12C inhibitor 45, KRAS G12C inhibitor 46, KRAS G12C inhibitor 47, KRAS G12C inhibitor 48, KRAS G12C inhibitor 49, KRAS G12C inhibitor 50, KRAS G12C inhibitor 51, KRAS G12C inhibitor 52, KRAS G12C inhibitor 53, KRAS G12C inhibitor 54, KRAS G12C inhibitor 55, KRAS G12C inhibitor 57, K-Ras G12C-IN-2, KRAS G12D inhibitor 3, KRAS G12D inhibitor 7, KRAS G12D inhibitor 14, KRAS G12D inhibitor 16, KRAS G12D inhibitor 17, KRAS inhibitor-3, KRAS inhibitor-6, KRAS inhibitor-7, KRAS inhibitor-8, KRAS inhibitor-10, KRAS inhibitor-11, KRAS inhibitor-12, KRAS inhibitor-13, KRAS inhibitor-14, KRAS inhibitor-15, KRAS inhibitor-16, KRAS inhibitor-17, KRAS inhibitor-18, KRAS inhibitor-20, K-Ras (G12C) inhibitor 6, KRpep-2d, LC-2, MRTX1133, MRTX-1257, MRTX849 acid type, MRTX-EX185 formate type, opnurasib, Pan KRas-IN-1, PROTAC K-RasThe method according to claim 43, wherein the salt is Degrader-1, RM-018, SAH-SOS1A, SOS1-IN-4, SOS1-IN-9, sotrasib, or ZG1077, or a pharmaceutically acceptable salt thereof.

45. The method according to claim 44, wherein the KRAS inhibitor is adaglasib, divalasib, galsolasib, opunurasib, or sotrasib, or a pharmaceutically acceptable salt thereof.

46. The method according to claim 45, wherein the KRAS inhibitor is sotrasib or a pharmaceutically acceptable salt thereof.

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