Mat2a inhibitors

Abstract

This invention provides a compound as a MAT2A inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof. This invention also provides pharmaceutical compositions comprising said compound and their use in the treatment of cancer.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to MAT2A inhibitors. Background Technology

[0002] Protein arginine methyltransferases (PRMTs) can methylate histones and non-histone proteins, thereby participating in the regulation of biological processes such as gene transcription, signal transduction, protein stability, cell proliferation, differentiation, apoptosis, and tumor formation (Nat Rev Drug Discov. 2021 Jul;20(7):509-530). Currently, 11 members of the PRMT family have been identified, which can be divided into types I, II, and III according to their different catalytic arginine methylation methods. PRMT5 belongs to type II, and its catalytic form is symmetrical dimethylation.

[0003] As an epigenetic enzyme, PRMT5 participates in a variety of biological processes, including transcriptional regulation, RNA metabolism, ribosome biosynthesis, and cell cycle regulation. PRMT5 protein is overexpressed in various cancer types, including B- and T-cell lymphoma, metastatic melanoma, neuroblastoma, glioblastoma, ovarian cancer, and breast cancer, and increasing evidence suggests its important role in tumorigenesis and development (Cell Stress. 2020 Aug; 4(8): 199–215). Based on this, PRMT5 inhibitors have become a hot topic in cancer treatment drug development.

[0004] In 2016, a paper published in Science revealed that MTAP deficiency and PRMT5 have synthetic lethal effects (Science. 2016 Mar 11;351(6278):1214-8.). MTAP has a high deficiency rate in various solid tumors, including pancreatic cancer and glioma. MTAP is an intracellular MTA-degrading enzyme. Because MTAP deficiency can lead to the intracellular accumulation of MTA, and MTA can compete with the methylated donor SAM, the functional substrate of PRMT5, for binding to PRMT5, thereby inhibiting part of PRMT5 function. Currently, although new-generation PRMT5 inhibitors (such as MRTX1719 and AMG193) have solved the hematologic side effects of first-generation inhibitors, their clinical efficacy is still less than 50% (2024 AACR, 2024 ESMO). Therefore, further improving their efficacy will be a clinical necessity. Furthermore, based on biological mechanisms, PRMT5 utilizes SAM to methylate arginine protein substrates. Inhibiting MAT2A reduces endogenous SAM synthesis; therefore, inhibiting MAT2A is expected to further inhibit PRMT5, thereby completely suppressing MATP-deficient tumor cells. Moreover, MATP deficiency, like MAT2A, has synthetic lethal effects (Cancer Cell, 2021, 39, 209-224). This invention develops a highly active MAT2A inhibitor that will inhibit MATP-deficient tumor cells while exhibiting low cytotoxicity to normal cells.

[0005] Despite progress in MAT2A research (e.g., in 2024, IDEAYA Biosciences reported the efficacy of its MAT2A inhibitor IDE397 in patients with MATP-deficient urothelial carcinoma and non-small cell lung cancer, with an ORR of 33%), more effective selective MAT2A inhibitors are still lacking. Summary of the Invention

[0006] Compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof:

[0007] (I)

[0008] in,

[0009] X1 is selected from -CH=, -N=, or -CR1;

[0010] X2 is selected from -N= or -CR2;

[0011] X3 is selected from -CR3;

[0012] R4 is independently selected from H, halogen, C 1-6 Alkyl, C 3-6cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a 4-10 member heterocyclic groups or -SR a R4 is optionally replaced by R6, where R6 is selected from H, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0013] R5 is selected from 5-12 heteroaryl groups; R5 is selected from 1-5 R groups. m replace;

[0014] Ring A is selected from 4-12 membered heterocyclic groups, wherein the 4-10 membered heterocyclic group contains one, two, or three additional heteroatoms selected from oxygen, nitrogen, phosphorus, or sulfur, and the 4-10 membered heterocyclic group is optionally surrounded by one, two, three, or four R atoms. n replace;

[0015] R1 is selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a '), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl is optionally surrounded by one, two or three R x replace;

[0016] R2 is selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a '), CN, phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl is optionally surrounded by 1, 2 or 3 R x replace;

[0017] R3 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a 4-10 membered heterocyclic groups, CN, -C(O)N(R) a - or -C(O)ORb The R3 is optionally divided by one or two Rs. x replace;

[0018] R x Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a '), phenyl, 4-6 membered heterocyclic group or 5-10 membered heteroaryl;

[0019] R m Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -C(O)-N(R) a R a '), -OR a -SR a Or 4-10 membered heterocyclic groups;

[0020] R n Selected from H, halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a -SR a 5-12-membered heteroaryl or 4-10-membered heterocyclic group; the 5-12-membered heteroaryl or 4-10-membered heterocyclic group may optionally be further converted by halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl substitution;

[0021] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0022] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, phenyl, 4-12 membered heterocyclic or 5-6 membered heteroaryl;

[0023] R b Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups.

[0024] In another aspect, the present invention provides specific compounds as exemplified in this application.

[0025] In another aspect, the present invention provides pharmaceutical compositions comprising the compounds of the present invention and pharmaceutically acceptable excipients, and further comprising other therapeutic agents.

[0026] In another aspect, the present invention provides compounds or compositions thereof for the treatment and / or prevention of MAT2A-mediated diseases.

[0027] In specific implementation schemes, the diseases treated by this invention include cancers selected from the following: acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, hemangioma), appendiceal cancer, benign monoclonal gamma disease, bile duct cancer, bladder cancer, brain cancer (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchial cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma). Cancers include: sarcoma, multiple idiopathic hemorrhagic sarcomas; endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumors (GIST); head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma, laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); and hematopoietic system cancers (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL)). Acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, lymph node marginal zone B-cell lymphoma, spleen marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphatic Plasma cell lymphoma, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; as well as T-cell non-Hodgkin lymphoma, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (such as cutaneous T-cell lymphoma (such as fungal infection, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); and mixtures of one or more of the above leukemias / lymphomas;Multiple myeloma (MM), heavy chain diseases (such as alpha chain diseases, gamma chain diseases, and μ chain diseases), hemangioblastoma, inflammatory myofibroblastoma, immune-mediated amyloidosis, renal cell carcinoma (such as nephroblastoma and renal cell carcinoma), liver cancer (such as hepatocellular carcinoma and malignant hepatocellular carcinoma), lung cancer (such as bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, leiomyosarcoma (LMS), mastocytosis (such as generalized mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (such as true myeloma) Polycythemia vera (PV), essential thrombocythemia (ET), idiopathic extramedullary metaplasia (AMM), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES), neuroblastoma, neurofibroma (such as neurofibromatosis type 1 or 2, schwannoma), neuroendocrine carcinoma (such as gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (such as cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, or penile cancer.

[0028] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed embodiments, examples and claims.

[0029] definition

[0030] Chemical definition

[0031] The definitions of specific functional groups and chemical terms are described in more detail below.

[0032] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0033] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C1-2 Alkyl groups are preferred. C 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0034] “C 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl groups are preferred. C 2-6 Examples of alkenyl groups include: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0035] “C 2-6 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkyne groups are preferred. C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6"Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0036] “C 1-6 "Alkylene" refers to the removal of C 1-6 The alkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylenes are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0037] “C 2-6 "Alkenyl" refers to the group that has been de-carbonied. 2-6 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 2-4Alkenyl groups are particularly preferred. Exemplary unsubstituted alkenyl groups include, but are not limited to, vinylidene (-CH=CH-) and propenylidene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenyl groups, such as alkenyl groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylidene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylidene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and so on.

[0038] “C 2-6 "Iso-ynyl" refers to the group that has the C group removed. 2-6 The other hydrogen atom of the alkynyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 2-4 The ethynyl group is particularly preferred. Exemplary ethynyl groups include, but are not limited to: ethynyl group (-C≡C-), substituted or unsubstituted propynyl group (-C≡CCH2-), etc.

[0039] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0040] Therefore, "C" 1-6 "Halogenated alkyl" refers to the above "C 1-6 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-4 Haloalkyl groups are particularly preferred, and C4 groups are more preferred. 1-2 Halogenated alkyl groups. Exemplary alkyl halogenated groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The alkyl halogenated group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0041] “C 1-6 "Alkoxy" refers to the -OR group, where R is C as defined above. 1-6 Alkyl group. C 1-4 Alkyl groups are preferred.

[0042] “C 1-6 "Haloalkoxy" refers to "C 1-6"Alkoxy" is substituted with one or more halogen groups. In some embodiments, C 1-4 Halogenated alkoxyalkyl groups are particularly preferred, and C4 is more preferred. 1-2 Halogenated alkoxyalkyl groups.

[0043] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-10 cycloalkyl, C 5-10 cycloalkyl, C 4-7 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl and C 3-4 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6 Cycloalkyl groups. Cycloalkyl groups also include ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the linkage is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), etc. The cycloalkyl group may optionally be substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0044] "3-12 membered heterocyclic groups" refer to groups with a 3- to 12-membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon or nitrogen atom, provided that the valence allows. In some embodiments, a 3-10 membered heterocyclic group is preferred, which is a 3-10 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; in some embodiments, a 4-10 membered heterocyclic group is preferred, which is a 4-10 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; in some embodiments, a 5-10 membered heterocyclic group is preferred, which is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 5-8 membered heterocyclic group is preferred, which is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3-7 membered heterocyclic group is preferred, which is a 3-10 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. The heterocyclic group comprises a 3- to 7-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; preferably a 3- to 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 4- to 7-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 4- to 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; more preferably a 5- to 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; more preferably a 3- to 5-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the cycloalkyl ring, or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl.Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxaheptanyl, and thianyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused with a C6 aryl ring (also referring herein to 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyranopyridyl, etc. The heterocyclic group may be optionally substituted with one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0045] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0046] "5-14 membered heteroaryl" refers to a 4n+2 aromatic ring system of a 5-14 membered monocyclic or bicyclic ring (e.g., having 6, 10, or 14 shared π electrons arranged in a ring) having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 4n+2 aromatic ring system of a 5-10 membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms. In some embodiments, 5-10-membered heteroaryl groups are preferred, which are 4n+2 aromatic ring systems of 6-10-membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. In some embodiments, 5-9-membered heteroaryl groups are preferred, which are 4n+2 aromatic ring systems of 5-9-membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. In other embodiments, 5-6-membered heteroaryl groups are particularly preferred, which are 4n+2 aromatic ring systems of 5-6-membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azirheptatrienyl, oxaheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.The heteroaryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0047] "Cycloalkylene", "heterocyclic", "aryl", or "heteroaryl" refers to a divalent group formed by removing one hydrogen atom from "cycloalkyl", "heterocyclic", "aryl", or "heteroaryl" as defined above, and can be substituted or unsubstituted. For example, "C 5-7 "Cycloalkylene" refers to the removal of C2464. 5-7 The divalent group formed by removing another hydrogen from a cycloalkyl group, "5-8 membered heterocyclic group" refers to the divalent group formed by removing another hydrogen from a 5-8 membered heterocyclic group, "C 6-10 "Aromatic" refers to the removal of C 6-10 A divalent group formed by removing another hydrogen atom from an aryl group; "5-6-membered heteroaryl" refers to a divalent group formed by removing another hydrogen atom from a 5-6-membered heteroaryl group.

[0048] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0049] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(Rcc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0050] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or =NOR cc replace;

[0051] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0052] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0053] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0054] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2, 、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee-C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee )3、-OSi(R ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0055] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0056] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0057] R ggEach of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl group), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3、-C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0058] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SORaa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0059] The term "deuterium (D or 2H)" is a stable isotope of hydrogen, which exists naturally at an abundance of 0.015 mol%. The term "deuteration" refers to the substitution of one or more hydrogen atoms (H) in a group or compound by the replacement of one hydrogen atom (D).

[0060] "Deuterated compound" refers to a compound in which one or more hydrogen atoms bonded to a carbon atom are replaced by one or more deuterium atoms. Similarly, "deuterated" refers to a chemical structure or organic group in which one or more hydrogen atoms bonded to a carbon atom are replaced by one or more deuterium atoms, such as "deuterated alkyl", "deuterated cycloalkyl", "deuterated heterocycloalkyl", "deuterated aryl", etc. For example, "deuterated alkyl" refers to an alkyl group as defined in this application, wherein at least one hydrogen atom bonded to a carbon atom is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to one deuterium atom; one carbon atom may be bonded to multiple deuterium atoms; multiple carbon atoms in an alkyl group may also be bonded to deuterium atoms. For example, deuterated methyl includes methyl-d3, in which three hydrogen atoms are replaced by deuterium atoms; it also includes monodeuterated methyl and dideuterated methyl. In some embodiments, the compounds of the present invention include deuterated compounds.

[0061] Other definitions

[0062] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0063] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0064] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0065] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0066] The term "combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present invention and other therapeutic agents. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. Detailed Implementation

[0067] In this document, “compounds of the present invention” refers to compounds of formula (I) (including sub-formulas, such as formulas ((II), (III), etc.), their pharmaceutically acceptable salts, enantiomers, diastereomers or isotopic variants, and mixtures thereof.

[0068] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0069] (I)

[0070] in,

[0071] X1 is selected from -CH=, -N=, or -CR1;

[0072] X2 is selected from -N= or -CR2;

[0073] X3 is selected from -CR3;

[0074] R4 is independently selected from H, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a 4-10 member heterocyclic groups or -SR a R4 is optionally replaced by R6, where R6 is selected from H, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0075] R5 is selected from 5-12 heteroaryl groups; R5 is selected from 1-5 R groups. m replace;

[0076] Ring A is selected from 4-12 membered heterocyclic groups, wherein the 4-10 membered heterocyclic group contains one, two, or three additional heteroatoms selected from oxygen, nitrogen, phosphorus, or sulfur, and the 4-10 membered heterocyclic group is optionally surrounded by one, two, three, or four R atoms. n replace;

[0077] R1 is selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a '), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl is optionally surrounded by one, two or three R x replace;

[0078] R2 is selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a '), CN, phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl is optionally surrounded by 1, 2 or 3 R x replace;

[0079] R3 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a 4-10 membered heterocyclic groups, CN, -C(O)N(R) a - or -C(O)ORb The R3 is optionally divided by one or two Rs. x replace;

[0080] R x Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a '), phenyl, 4-6 membered heterocyclic group or 5-10 membered heteroaryl;

[0081] R m Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -C(O)-N(R) a R a '), -OR a -SR a Or 4-10 membered heterocyclic groups;

[0082] R n Selected from H, halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a -SR a 5-12-membered heteroaryl or 4-10-membered heterocyclic group; the 5-12-membered heteroaryl or 4-10-membered heterocyclic group may optionally be further converted by halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl substitution;

[0083] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0084] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, phenyl, 4-12 membered heterocyclic or 5-6 membered heteroaryl;

[0085] R b Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups.

[0086] In another, more specific embodiment, formula (I) or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0087] X1 is selected from -CH=, -N=, or -CR1;

[0088] X2 is selected from -N= or -CR2;

[0089] X3 is selected from -CR3;

[0090] R4 is independently selected from H, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a 4-10 member heterocyclic groups or -SR a R4 is optionally replaced by R6, where R6 is selected from H, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0091] R5 is selected from furanyl, thienyl, thiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, or isoquinolinyl; R5 is optionally surrounded by 1-5 R... m replace;

[0092] Ring A is selected from 4-12 membered heterocyclic groups, wherein the 4-10 membered heterocyclic group contains one, two, or three additional heteroatoms selected from oxygen, nitrogen, phosphorus, or sulfur, and the 4-10 membered heterocyclic group is optionally surrounded by one, two, three, or four R atoms. n replace;

[0093] R1 is selected from F, Cl, Br, methyl, trifluoromethyl, OH, OMe or -NMe2;

[0094] R2 is selected from H, F, Cl, Br, methyl, trifluoromethyl, OH, OMe or -NMe2;

[0095] R3 is independently selected from H, F, Cl, Br, methyl, trifluoromethyl, OH, OMe, -NMe2, CN, , -C(O)N(R) a - or -C(O)OR b The R3 is optionally divided by one or two Rs. x replace;

[0096] R x Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a '), phenyl, 4-6 membered heterocyclic group or 5-10 membered heteroaryl;

[0097] R m Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -C(O)-N(R) a R a '), -OR a -SR a Or 4-10 membered heterocyclic groups;

[0098] R n Selected from H, halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a -SR a 5-12-membered heteroaryl or 4-10-membered heterocyclic group; the 5-12-membered heteroaryl or 4-10-membered heterocyclic group may optionally be further converted by halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl substitution;

[0099] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0100] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, phenyl, 4-12 membered heterocyclic or 5-6 membered heteroaryl;

[0101] R b Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups.

[0102] In another, more specific embodiment, the present invention relates to compounds of formula (II) or formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof:

[0103] (II) or (III)

[0104] in,

[0105] X1 is selected from -CH=, -N=, or -CR1;

[0106] X4 is selected from -CH= or N;

[0107] R4 is independently selected from H, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a 4-10 member heterocyclic groups or -SRa R4 is optionally replaced by R6, where R6 is selected from H, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0108] Ring A is selected from 4-12 membered heterocyclic groups, wherein the 4-10 membered heterocyclic group contains one, two, or three additional heteroatoms selected from oxygen, nitrogen, phosphorus, or sulfur, and the 4-10 membered heterocyclic group is optionally surrounded by one, two, three, or four R atoms. n replace;

[0109] R1 is selected from F, Cl, Br, methyl, trifluoromethyl, OH, OMe or -NMe2;

[0110] R x Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a '), phenyl, 4-6 membered heterocyclic group or 5-10 membered heteroaryl;

[0111] R m Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -C(O)-N(R) a R a '), -OR a -SR a Or 4-10 membered heterocyclic groups;

[0112] R n Selected from H, halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a -SR a 5-12-membered heteroaryl or 4-10-membered heterocyclic group; the 5-12-membered heteroaryl or 4-10-membered heterocyclic group may optionally be further converted by halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl substitution;

[0113] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0114] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, phenyl, 4-12 membered heterocyclic or 5-6 membered heteroaryl;

[0115] R b Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0116] n is selected from 0, 1, 2, 3 or 4.

[0117] In another, more specific embodiment, the present invention provides a compound of formula (II-1) or formula (II-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0118] (II-1) or (II-2)

[0119] in,

[0120] X1 is selected from -CH=, -N=, -CF, CCl or CMe;

[0121] X4 is selected from -CH= or N;

[0122] R4 is independently selected from H, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a Ra '), -OR a 4-10 member heterocyclic groups or -SR a R4 is optionally replaced by R6, where R6 is selected from H, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups;

[0123] R m Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -C(O)-N(R) a R a '), -OR a -SR a Or 4-10 membered heterocyclic groups;

[0124] R n Selected from H, halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a -SR a 5-12-membered heteroaryl or 4-10-membered heterocyclic group; the 5-12-membered heteroaryl or 4-10-membered heterocyclic group may optionally be further converted by halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl substitution;

[0125] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0126] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, phenyl, 4-12 membered heterocyclic or 5-6 membered heteroaryl;

[0127] R b Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups;

[0128] n is selected from 0, 1, 2, 3 or 4;

[0129] p is selected from 0, 1, 2 or 3.

[0130] In another, more specific embodiment, the present invention provides a compound, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein said compound is selected from:

[0131] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0132] In another, more specific embodiment, the present invention provides a compound, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein said compound is selected from:

[0133] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0134] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0135] The compounds of this invention may also exist as tautomers. A compound is not limited to any particular tautomer, but is intended to encompass all tautomer forms.

[0136] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (A), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotopically labeled compounds of formula (A) of the present invention and their prodrugs can generally be prepared by using readily available isotopically labeled reagents instead of non-isotopically labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0137] Pharmaceutical Compositions and Kits

[0138] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as the "active component") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the compound of the present invention.

[0139] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0140] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0141] Dosage

[0142] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0143] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0144] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0145] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0146] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) allows for a more rapid delivery, causing the concentration of the active component in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV intravenous infusion, thereby providing a steady-state concentration of the active component in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0147] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, for the purpose of precise dosing, the compositions are provided in unit dose form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0148] Example

[0149] The reagents used in this invention are commercially available reagents that are purchased directly or synthesized using common methods known in the art.

[0150] The specific reaction routes or steps in the following examples are used in this invention, as detailed below:

[0151] Example 1

[0152] Synthesis of intermediate a1

[0153]

[0154] Step 1: Ice bath. Cyclopropyl methyl ketone a1-1 (50 g, 590 mmol) and a1-2 (151 g, 1.03 mmol) were dissolved in 1000 mL of tetrahydrofuran. NaH (47.6 g, 1190 mmol, 60%) was slowly added, and the mixture was heated to 20°C and reacted for 1 hour. The reaction was then stopped. The reaction solution was placed in an ice bath, and 2 L of ice water and 80 mL of acetic acid were slowly added to quench the reaction. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude a1-3 (85 g).

[0155] Step 2: Ice bath. Dissolve intermediate a1-3 (85 g, 461.48 mmol) and cyanoacetamide a1-4 (38.8 g, 461.48 mmol) from the previous step in 850 mL of ethanol. Stir for 10 minutes, then add piperazine (19.9 g, 230.7 mmol). Heat the mixture to 65°C and react for 1 hour, then stop the reaction. Adjust the pH to approximately 6 with dilute hydrochloric acid, remove the solvent under reduced pressure, add 500 mL of ice water, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (PE / EA, 3 / 1) to obtain an oily substance a1-5 (27 g). Two-step yield: 20%. LCMSESI-MS m / z: 233 [M+H] + .

[0156] Step 2: The intermediate a1-4 (27 g, 116.26 mmol) from the previous step was dissolved in 270 mL of phenylphosphonoyl dichloride. The mixture was reacted at 150 °C for 2 hours, and then the reaction was stopped. 300 mL of ice water was added to the system, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by flash column chromatography (PE / EA, 1 / 1) to give a yellow solid a1 (15.9 g), yield: 55%. LCMS ESI-MS m / z: 251 [M+H] + .

[0157] Synthesis of intermediate a2

[0158]

[0159] Step 1: In an ice bath, methyl 2-iodo-4-chloro-6-methylbenzoate a2-1 (500 mg, 1.61 mmol) and NBS (344 mg, 1.93 mmol) were dissolved in 5 mL of carbon tetrachloride. AIBN (66 mg, 0.4 mmol) was slowly added, and the mixture was heated to 80 °C and reacted for 16 hours. The reaction mixture was then stopped. The reaction solution was placed in an ice bath, and 30 mL of ice water was slowly added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated by column chromatography (PE / EA, 20 / 1) to give compound a2-2 (150 mg), yield: 24%.

[0160] Step 2: Ice bath. Dissolve intermediate a2-2 (150 mg, 0.39 mmol) from the previous step in 5 mL of ethanol. Stir for 5 minutes, then add MeONa (104 mg, 1.93 mmol). Heat the mixture to 25°C and react for 16 hours, then stop the reaction. Add 50 mL of ice water to the reaction mixture, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (PE / EA, 20 / 1) to obtain oil a2-3 (100 mg), yield: 75%.

[0161] Step 3: Under nitrogen protection, the intermediate a2-3 (1.0 g, 2.94 mmol), Cs2CO3 (3.73 g, 11.45 mmol), and 2-chloro-3-aminopyridine a2-4 (491 mg, 3.82 mmol) from the previous step were dissolved in 10 mL of 1,4-dioxane. The catalyst Pd2(dba)3 (350 mg, 0.38 mmol) and the ligand xantphos (442 mg, 0.76 mmol) were added. The mixture was reacted at 110 °C for 16 hours, then the reaction was stopped and filtered. 30 mL of ice water was added to the system, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by flash column chromatography (PE / EA, 10 / 1) to obtain a yellow solid a2 (370 mg), yield: 28%. LCMS ESI-MS m / z: 341 [M+H] + .

[0162] Synthesis of intermediate b1

[0163]

[0164] Step 1: Under nitrogen protection in an ice bath, intermediate a1 (15.9 g, 63.43 mmol) was dissolved in 320 mL of anhydrous ethanol. NaBH4 (12.0 g, 317 mmol) was slowly added, and the mixture was heated to 20 °C and stirred for 0.5 hours. The reaction was then stopped. 200 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. Crude product b1-1 (13.5 g) was obtained. LCMS ESI-MS m / z: 209 [M+H] + .

[0165] Step 2: Dissolve the crude product b1-1 (13.5 g, 63 mmol) and TEA (9.8 g, 97.05 mmol) from the previous step in 270 mL of dichloromethane. Add DMAP (400 mg, 3.24 mmol) and TBSCl (12.7 g, 84.11 mmol). React at 20°C for 1 hour, then stop the reaction. Remove the solvent under reduced pressure, add 200 mL of ice water to the reaction solution, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (PE / EA, 3 / 1) to give a yellow solid b1 (7.0 g). Two-step yield: 34%. LCMS ESI-MS m / z: 323 [M+H] + .

[0166] Synthesis of intermediate b2

[0167]

[0168] Step 1: Intermediate a2 (400 mg, 1.17 mmol) was dissolved in 5 mL of a mixture of tetrahydrofuran and water (v / v, 4 / 1), and LiOH (147 mg, 3.52 mmol) was added. The mixture was heated to 60 °C and reacted for 16 hours. The mixture was cooled to 0 °C, and the pH was adjusted to approximately 5 by slowly adding dilute hydrochloric acid. Extraction was performed with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give intermediate b2-1 (340 mg). Yield: 89%. LCMS ESI-MS m / z: 327 [M+H] + .

[0169] Step 2: Under nitrogen protection in an ice bath, dissolve intermediate b2-1 (340 mg, 1.04 mmol) and EDCI (178 mg, 1.56 mmol) from the previous step in 4 mL of anhydrous dichloromethane. Add HOBT (210 mg, 1.56 mmol) and react at room temperature for 2 hours. Stop the reaction. Add 10 mL of ice water to the reaction mixture, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate to obtain mixture S1. Dissolve methyl cyanoacetate b2-2 (124 mg, 1.25 mmol) in 2 mL of anhydrous tetrahydrofuran. Add NaH (63 mg, 1.56 mmol, 60%), stir for 20 minutes, add mixture S1, and react at room temperature for 2 hours. Stop the reaction. Add 10 mL of ice water to the reaction mixture, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate. The crude product was separated by flash column chromatography (DCM / MeOH, 10 / 1) to give intermediate b2 (100 mg), yield: 26%. LCMS ESI-MS m / z: 376 [M+H] +.

[0170] Synthesis of intermediate C1

[0171]

[0172] Step 1: In an ice bath, intermediate b1 (1.5 g, 4.64 mmol), Cs₂CO₃ (4.5 g, 13.94 mmol), and 2-chloroaniline c1-1 (890 mg, 6.97 mmol) were dissolved in 30 mL of 1,4-dioxane. After stirring for 5 minutes, catalyst Pd(OAc)₂ (100 mg, 0.46 mmol) and ligand BINAP (580 mg, 0.93 mmol) were added. The mixture was heated to 85 °C and reacted for 1 hour. The mixture was then filtered. The solvent was removed under reduced pressure. The crude product was separated by flash reversed column chromatography (column: C18; CH₃CN / H₂O (0.1% HCOOH), 4 / 1) to obtain a yellow solid c1-2 (1.8 g). Yield: 94%. LCMS ESI-MS m / z: 414 [M+H] + .

[0173] Step 2: In an ice bath, the intermediate C1-2 (1.8 g, 4.35 mmol) and KOH (1.2 g, 21.74 mmol) from the previous step were dissolved in 45 mL of a mixed solution of ethanol and water (v / v, 4 / 1). The mixture was heated to 100 °C and reacted for 12 hours, then cooled to room temperature. The pH of the reaction solution was adjusted to approximately 6 with dilute hydrochloric acid, and the mixture was extracted with dichloromethane and the solvent was removed under reduced pressure. The mixture was dissolved in 36 mL of DMF, and imidazole (590 mg, 8.7 mmol) and TBSCl (980 mg, 6.52 mmol) were added. The mixture was reacted at room temperature for 1 hour, and then the reaction was stopped. 100 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash column chromatography (DCM / MeOH, 10 / 1) to obtain a yellow oily substance C1-3 (1.2 g), yield: 64%. LCMS ESI-MS m / z: 433 [M+H] + .

[0174] Step 3: Ice bath reaction. Dissolve intermediate C1-3 (1.2 g, 2.77 mmol) and EDCI (530 mg, 2.77 mmol) from the previous step in 24 mL of dichloromethane. Add HOBT (370 mg, 2.77 mmol) and react at room temperature for 1 hour. Stop the reaction. Add 30 mL of ice water to the reaction solution, extract with dichloromethane, and remove the solvent under reduced pressure to obtain mixture S1. Dissolve methyl cyanoacetate (550 mg, 5.54 mmol) and NaH (550 mg, 13.86 mmol) in 24 mL of anhydrous tetrahydrofuran. After stirring for 1 hour, add mixture S1 from the previous step. React the mixture at room temperature for 5 hours. The reaction was quenched by adding 2 mL of glacial acetic acid, and the solvent was removed under reduced pressure. The crude product was separated by flash reversed-phase column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 7 / 3) to give intermediate c1 (760 mg), yield: 57%. LCMS ESI-MS m / z: 482 [M+H] + .

[0175] Synthesis of intermediate C2

[0176]

[0177] Step 1: In an ice bath, intermediate B2 (100 mg, 0.27 mmol) and DIEA (3.9 mg, 0.03 mmol) were dissolved in 2 mL of phosphorus oxychloride. After stirring for 5 minutes, the mixture was heated to 105 °C and reacted for 2 hours. The mixture was then cooled to room temperature. The solvent was removed by vacuum distillation to obtain crude product C2-1 (100 mg). This crude product was used directly in the next reaction step.

[0178] Step 2: The crude product C2-1 (100 mg, 0.25 mmol) from the previous step was dissolved in 2 mL of tetrahydrofuran. A solution of methylamine in isopropanol (2 mL, 1 M) was added, and the reaction was carried out at room temperature for 1 hour. The reaction was then stopped. 10 mL of ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (DCM / MeOH, 10 / 1) to give intermediate C2 (50 mg). Two-step yield: 48%. LCMS ESI-MS m / z: 389 [M+H] + .

[0179] Synthesis of intermediate C3

[0180]

[0181] Step 1: In an ice bath, intermediate C1-2 (600 mg, 1.44 mmol) was dissolved in 12 mL of dichloroethane. Dimethyl malonate C3-1 (1.1 g, 8.69 mmol) and SnCl4 (2.2 g, 8.69 mmol) were added. The mixture was heated to 80 °C and reacted for 48 hours, then the reaction was stopped. 50 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. Intermediate C2 (600 mg) was obtained, yield: 81%. LCMS ESI-MS m / z: 514 [M+H] + .

[0182] Example 2: Synthesis of target molecules P1-P2

[0183]

[0184] Step 1: Under nitrogen protection, intermediate C1 (760 mg, 1.58 mmol) and DIEA (611 mg, 4.73 mmol) were dissolved in 15 mL of 1,4-dioxane, and POCl3 (1.2 g, 7.88 mmol) was added. The mixture was reacted at 100 °C for 1 hour, cooled to room temperature, and the solvent was removed by vacuum evaporation. The mixture was dissolved in 10 mL of isopropanol, and an isopropanol solution of ammonia (38 mL, 2 M) was added. The reaction was stopped at room temperature for 30 minutes. 100 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 2 / 1) to give compound P1-1 (305 mg), yield: 40%. LCMS ESI-MS m / z: 481 [M+H] + .

[0185] Step 2: Under nitrogen protection, compound P1-1 (300 mg, 0.62 mmol) from the previous step was dissolved in 6 mL of tetrahydrofuran. A tetrahydrofuran solution of tetrabutylammonium fluoride (TBAF) (1.25 mL, 1 M) was added. The mixture was reacted at room temperature for 0.5 hours, and then the reaction was stopped. 20 mL of ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 3 / 2) to give compound P1-2 (190 mg), yield: 83%. LCMS ESI-MS m / z: 367 [M+H] + .

[0186] Step 3: Under nitrogen protection, compound P1-2 (190 mg, 0.52 mmol) from the previous step was dissolved in 4 mL of dichloromethane, and SOCl2 (0.38 mL) was added. The mixture was reacted at room temperature for 48 hours, and then the reaction was stopped. 20 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 4 / 1) to give compound P1-3 (145 mg), yield: 73%.

[0187] Step 4: Under nitrogen protection, compound P1-3 (45 mg, 0.12 mmol) from the previous step was dissolved in 1 mL of anhydrous tetrahydrofuran, and NaH (25 mg, 0.63 mmol, 60%) was added. The mixture was reacted at room temperature for 12 hours, and then the reaction was stopped. 5 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xselect CSH Prep Column, 30*150 mm, 5 μm; mobile phase A: H2O (0.1% HCOOH), mobile phase B: CH3CN; flow rate: 60 mL / min, retention time: 7.7 min) to obtain compound P1 (3.3 mg), yield: 6%. LCMS ESI-MS m / z: 349 [M+H] + .

[0188] 1 H NMR (300 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.67 – 7.64 (m, 1H), 7.53 –7.45 (m, 2H), 7.43 – 7.40 (m, 1H), 7.24 (s, 1H), 5.03 (s, 2H), 2.09 – 2.07(m, 1H), 0.89 – 0.87 (m, 2H), 0.61 – 0.59 (m, 2H).

[0189] Step 5: Under nitrogen protection, compound P1 (60 mg, 0.17 mmol) was dissolved in 2 mL of acetone, and K2CO3 (71 mg, 0.52 mmol) and methyl iodide (MeI) (122 mg, 0.52 mmol) were added. The mixture was reacted at room temperature for 24 hours, and then the reaction was stopped. 15 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xselect CSH Prep Column, 30*150 mm, 5 μm; mobile phase A: H2O (0.1% HCOOH), mobile phase B: CH3CN; flow rate: 60 mL / min, retention time: 8.87 min) to obtain compound P2 (6.2 mg), yield: 10%. LCMS ESI-MS m / z: 363 [M+H] + .

[0190] 1 H NMR (300 MHz, DMSO-d6) δ 7.67 – 7.62 (m, 1H), 7.54 – 7.45 (m, 2H), 7.44 – 7.39 (m, 1H), 7.23 (s, 1H), 5.07 (s, 2H), 3.50 (s, 3H), 2.11 – 2.03(m, 1H), 0.88 – 0.81 (m, 2H), 0.65 – 0.58 (m, 2H).

[0191] Example 3: Synthesis of target molecule P3

[0192]

[0193] Step 1: In an ice bath, intermediate C2 (20 mg, 0.051 mmol) was dissolved in 1 mL of dichloromethane. BBr3 (39 mg, 0.154 mmol) was slowly added. The mixture was reacted at 30°C for 1 hour. The reaction was then stopped, and the solvent was removed by vacuum distillation. The crude product was separated by flash column chromatography (DCM / MeOH, 30 / 1) to give compound P3-1 (6 mg), yield: 32%. LCMS ESI-MS m / z: 375 [M+H] + .

[0194] Step 2: Under nitrogen protection, compounds P3-1 (6 mg, 0.016 mmol), NBS (4 mg, 0.019 mmol), and PPh3 (6 mg, 0.024 mmol) from the previous step were dissolved in 1 mL of dichloromethane. TEA (5 mg, 0.048 mmol) and methanesulfonyl chloride MsCl (2 mg, 0.019 mmol) were added. The mixture was reacted at room temperature for 4 hours, and then the reaction was stopped. 20 mL of ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O, 2 / 3) to give compound P3 (4.0 g), yield: 70 L / C. ESI-MS m / z: 357 [M+H] + .

[0195] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 – 8.65 (m, 1H), 8.15 (s, 1H), 7.88(s, 1H), 7.74 – 7.71 (m, 1H), 7.29 – 7.25 (m, 1H), 5.07 (s, 2H), 3.55 (s,3H).

[0196] Example 4: Synthesis of target molecule H1

[0197]

[0198] Step 1: Under nitrogen protection in an ice bath, intermediate C3 (600 mg, 1.17 mmol) was dissolved in 6 mL of tetrahydrofuran. A tetrahydrofuran solution of tetrabutylammonium fluoride (TBAF) (2.4 mL, 1 M) was added. The mixture was reacted at room temperature for 2 hours, then the reaction was stopped. 50 mL of ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 4 / 1) to give compound H1-1 (230 mg), yield: 40%. LCMS ESI-MS m / z: 400 [M+H] + .

[0199] Step 2: The compound H1-1 (230 mg, 0.57 mmol) from the previous step was dissolved in 5 mL of dichloromethane. SOCl2 (274 mg, 2.30 mmol) was added dropwise. The mixture was reacted at room temperature for 1 hour, then the reaction was stopped. 20 mL of ice water was added to the reaction mixture, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration to give compound H1-2 (200 mg), yield: 84%. LCMS ESI-MS m / z: 418 [M+H] + .

[0200] Step 3: Under nitrogen protection, the crude product H1-2 (100 mg, 0.23 mmol) from the previous step was dissolved in 4 mL of anhydrous tetrahydrofuran, and NaH (48 mg, 1.19 mmol, 60%) was added. The mixture was reacted at room temperature for 6 hours, and then the reaction was stopped. 15 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC preparative chromatography (column: XXBridge Prep C18 OBD Column, 30*150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3 + 0.05% NH3·H2O, mobile phase B: CH3CN; flow rate: 60 mL / min, retention time: 7.2 min) to obtain compound H1 (21.1 mg), yield: 24%. LCMS ESI-MS m / z: 382 [M+H] + .

[0201] 1 H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.66 – 7.60 (m, 1H), 7.51 –7.44 (m, 2H), 7.38 – 7.32 (m, 1H), 7.18 (s, 1H), 4.97 (t, J = 1.4 Hz, 2H), 3.71 (s, 3H), 2.12 – 2.01 (m, 1H), 0.92 – 0.79 (m, 2H), 0.66 – 0.56 (m, 2H).

[0202] Example 5: MAT2A Enzyme Activity Level Test

[0203] 5.1 Materials and Instruments

[0204] Protein or Reagent Supplier Cat No. MAT2a Inhibitor Screening Assay Kit BPS 71402 Tris pH 7.5 Invitrogen 15567-027 DTT Sigma 43816 MnCl2 Sigma M1787 MgCl2 Sigma M1028 EDTA Invitrogen 15575020 BSA (%) PE CR84-100 DMSO Sigma D8418 Instrument or Consumables Supplier Cat No. 384 shallow-pore polystyrene white board CORNING 3702 384 polypropylene microplate Labcyte PP-0200 centrifuge Eppendorf 5810R HTS High-Throughput Drug Screening Microplate Reader BMG PHERAstra FSX Echo Labcyte 655

[0205] Operating steps:

[0206] 1. Using an Echo 655, transfer 200 nL of the diluted compound working solution to each well of the reaction plate (3702, Corning).

[0207] 2. Seal the reaction plate with a sealing film and centrifuge at 1000 RPM for 1 minute.

[0208] 3. Prepare a 1x buffer solution.

[0209] Components Stock Conc. (mM) Final Conc. (mM) Tris pH 8.0 1000 100 <![CDATA[MnCl2]]> 1000 2 DTT 1000 2 KCl 2000 50 MgCl2 1000 15 EDTA 500 0.3 BSA (%) 7.5 0.005

[0210] 4. Prepare a 2× enzyme solution using 1× reaction buffer.

[0211] Enzyme Stock Conc. (nM) Working Conc. (nM) Final Conc. (nM) MAT2A 71111.1 178 89

[0212] 5. Add 10 μL of 2× enzyme solution to the reaction plate. Seal the plate with sealing film, centrifuge at 1000 RPM for 1 minute, and incubate at 25°C for 30 minutes in the dark.

[0213] 6. Prepare a mixture of 2× enzyme substrate L-Methionine and ATP using 1× reaction buffer.

[0214] Mix Stock Conc. (uM) Working Conc. (uM) Final Conc. (uM) ATP 10000 50 25 L-Methionine 10000 160 80

[0215] 7. Add 10 μL of 2× enzyme substrate and ATP mixture to the reaction plate, centrifuge at 1000 RPM for 1 minute, and react at 25°C in the dark for 60 minutes.

[0216] 8. Add 20 μL of detection reagent to each well.

[0217] Centrifuge at 1000 for 60 seconds, then incubate at 25°C for 15 minutes in the dark.

[0218] 10. Set up the microplate reader and read the fluorescence change signal at 630 nm.

[0219] Table 5.2: Inhibitory effects of compounds on MAT2A enzyme

[0220] compound <![CDATA[MAT2A / IC 50 / nM]]> compound <![CDATA[MAT2A / IC 50 / nM]]> P1 241 H1 34 P3 >500

[0221] The above methods show that the compound of this invention exhibits approximately 1000 nM-100 nM (IC50) in the MAT2A enzyme activity assay. 50 Biological activity of ); preferably 10 nM to 100 nM (IC50). 50 ) biological activity.

[0222] ND = Untested

[0223] Example 6

[0224] MTAP-deficient cells, due to the accumulation of MTA, partially inhibit PRMT5 methyltransferase, and their proliferation is sensitive to MAT2A inhibitors; while MTAP wild-type (MTAP normal) cells do not have the MTA accumulation effect, and PRMT5 methyltransferase is unaffected. Therefore, these cells are MAT2A-independent. By testing the activities of both, the inhibitory and selective effects of the molecule of the present invention on MAT2A at the cellular level are demonstrated.

[0225] HCT116 wild-type and MTAP-deficient HCT116 cells were cultured in MCCOYS 5A medium containing 10% FBS and 1% penicillin-streptomycin and incubated at 37°C in a 5% CO2 incubator. 40 μL of cell suspension was added to each well of a 384-well microplate. Using an Echo reader, 40 nL of different concentrations of the compound were added to each well, and the plates were incubated at 37°C in a 5% CO2 incubator for 7–10 days. 40 μL of CTG solution (Promega, Cat No. G7573) was added to each well, and the plates were incubated at 37°C in a 5% CO2 incubator in the dark for 30 minutes. The luminescence values ​​were read using an Envision multi-mode microplate reader (Perkin Elmer, catalog number Envision2104). The light signal was directly proportional to the amount of ATP in the system, and the ATP content directly represented the number of viable cells in the system.

[0226] IC 50 Value calculation:

[0227] Y = Lower platform signal + (Upper platform signal - Lower platform signal) / (1 + 10^(LogIC)) 50 -X)× Hill slope))

[0228] X: Log value of compound concentration

[0229] Y: Inhibition rate (%)

[0230] Experimental results show that the superior compounds of this invention have a significant anti-proliferative effect on MTAP-deficient tumor cells by inhibiting MAT2A, while exhibiting weaker inhibition against wild-type cells, potentially leading to higher safety. Some molecules also show superior activity and selectivity compared to the control molecules.

[0231] Table 6.1: Inhibitory effects of compounds on the activity of HCT116 (MTAP-deficient) and HCT116 (MTAPwt).

[0232] compound <![CDATA[HCT116 mtap deletion / IC 50 / nM]]> <![CDATA[HCT116mtap wild type / IC 50 / nM]]> Wild-type / deletion type selectivity fold H1 733 >30000 >41

[0233] Example 7: Liver microsomal stability test of the compound

[0234] The liver microsomal stability of the compounds of this invention was studied. The test compounds were co-incubated with liver microsomes of different species with or without the addition of NADPH. The final concentrations of the test compounds, NADPH, and liver microsomes in the experimental system were 1 μM, 1 mM, and 0.5 mg / mL, respectively. The concentrations of the compounds in the supernatant at different time points within 60 minutes were measured, and pharmacokinetic parameters (e.g., clearance rate Cl) were calculated. int ).

[0235] This result indicates that the molecules of the present invention have good metabolic stability (especially in the human body).

[0236] The results show that the molecules of this invention have good metabolic stability in liver microsomes.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: (I) in, X1 is selected from -CH=, -N=, or -CR1; X2 is selected from -N= or -CR2; X3 is selected from -CR3; R4 is independently selected from H, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a 4-10 member heterocyclic groups or -SR a R4 is optionally replaced by R6, where R6 is selected from H, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups; R5 is selected from 5-12 heteroaryl groups; R5 is selected from 1-5 R groups. m replace; Ring A is selected from 4-12 membered heterocyclic groups, wherein the 4-10 membered heterocyclic group contains one, two, or three additional heteroatoms selected from oxygen, nitrogen, phosphorus, or sulfur, and the 4-10 membered heterocyclic group is optionally surrounded by one, two, three, or four R atoms. n replace; R1 is selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a '), phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl is optionally surrounded by one, two or three R x replace; R2 is selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a '), CN, phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl, wherein the phenyl, 4-6-membered heterocyclic or 5-10-membered heteroaryl is optionally surrounded by 1, 2 or 3 R x replace; R3 is independently selected from H, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a 4-10 membered heterocyclic groups, CN, -C(O)N(R) a - or -C(O)OR b The R3 is optionally divided by one or two Rs. x replace; R x Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a '), phenyl, 4-6 membered heterocyclic group or 5-10 membered heteroaryl; R m Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -C(O)-N(R) a R a '), -OR a -SR a Or 4-10 membered heterocyclic groups; R n Selected from H, halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a -SR a 5-12-membered heteroaryl or 4-10-membered heterocyclic group; the 5-12-membered heteroaryl or 4-10-membered heterocyclic group may optionally be further converted by halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl substitution; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, phenyl, 4-12 membered heterocyclic or 5-6 membered heteroaryl; R b Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof: in, X1 is selected from -CH=, -N=, or -CR1; X2 is selected from -N= or -CR2; X3 is selected from -CR3; R4 is independently selected from H, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a 4-10 member heterocyclic groups or -SR a R4 is optionally replaced by R6, where R6 is selected from H, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups; R5 is selected from furanyl, thienyl, thiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, or isoquinolinyl; R5 is optionally surrounded by 1-5 R... m replace; Ring A is selected from 4-12 membered heterocyclic groups, wherein the 4-10 membered heterocyclic group contains one, two, or three additional heteroatoms selected from oxygen, nitrogen, phosphorus, or sulfur, and the 4-10 membered heterocyclic group is optionally surrounded by one, two, three, or four R atoms. n replace; R1 is selected from F, Cl, Br, methyl, trifluoromethyl, OH, OMe or -NMe2; R2 is selected from H, F, Cl, Br, methyl, trifluoromethyl, OH, OMe or -NMe2; R3 is independently selected from H, F, Cl, Br, methyl, trifluoromethyl, OH, OMe, -NMe2, CN, , -C(O)N(R) a - or -C(O)OR b The R3 is optionally divided by one or two Rs. x replace; R x Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a '), phenyl, 4-6 membered heterocyclic group or 5-10 membered heteroaryl; R m Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -C(O)-N(R) a R a '), -OR a -SR a Or 4-10 membered heterocyclic groups; R n Selected from H, halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a -SR a 5-12-membered heteroaryl or 4-10-membered heterocyclic group; the 5-12-membered heteroaryl or 4-10-membered heterocyclic group may optionally be further converted by halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl substitution; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, phenyl, 4-12 membered heterocyclic or 5-6 membered heteroaryl; R b Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups.

3. The compound of claim 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is a compound of formula (II) or (III): (II) or (III) in, X1 is selected from -CH=, -N=, or -CR1; X4 is selected from -CH= or N; R4 is independently selected from H, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a 4-10 member heterocyclic groups or -SR a R4 is optionally replaced by R6, where R6 is selected from H, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups; Ring A is selected from 4-12 membered heterocyclic groups, wherein the 4-10 membered heterocyclic group contains one, two, or three additional heteroatoms selected from oxygen, nitrogen, phosphorus, or sulfur, and the 4-10 membered heterocyclic group is optionally surrounded by one, two, three, or four R atoms. n replace; R1 is selected from F, Cl, Br, methyl, trifluoromethyl, OH, OMe or -NMe2; R x Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl, OH, OR a -N(R) a R a '), phenyl, 4-6 membered heterocyclic group or 5-10 membered heteroaryl; R m Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -C(O)-N(R) a R a '), -OR a -SR a Or 4-10 membered heterocyclic groups; R n Selected from H, halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a -SR a 5-12-membered heteroaryl or 4-10-membered heterocyclic group; the 5-12-membered heteroaryl or 4-10-membered heterocyclic group may optionally be further converted by halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl substitution; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, phenyl, 4-12 membered heterocyclic or 5-6 membered heteroaryl; R b Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; n is selected from 0, 1, 2, 3 or 4.

4. The compound of claim 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is of formula (II-1) or formula (II-2): (II-1) or (II-2) in, X1 is selected from -CH=, -N=, -CF, CCl or CMe; X4 is selected from -CH= or N; R4 is independently selected from H, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a 4-10 member heterocyclic groups or -SR a R4 is optionally replaced by R6, where R6 is selected from H, CN, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, SF5, OR a Or 5-6 heteroaryl groups; R m Selected from H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -C(O)-N(R) a R a '), -OR a -SR a Or 4-10 membered heterocyclic groups; R n Selected from H, halogens, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(R) a R a '), -OR a -SR a 5-12-membered heteroaryl or 4-10-membered heterocyclic group; the 5-12-membered heteroaryl or 4-10-membered heterocyclic group may optionally be further converted by halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl substitution; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, phenyl, 4-12 membered heterocyclic or 5-6 membered heteroaryl; R b Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkyl hydroxyl or C 1-6 Halogenated alkyl groups; n is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1, 2 or 3.

5. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

6. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

7. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, for the treatment and / or prevention of MAT2A-mediated diseases.

8. The disease mediated as described in claim 7 is cancer.

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