Tricyclic heterocyclic compound as well as preparation method and medical application thereof

Abstract

The invention relates to a tricyclic heterocyclic compound as well as a preparation method and medical application thereof. Specifically, the invention relates to a compound shown in a general formula (I), a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound as an MAT2A inhibitor. The compound and the pharmaceutical composition containing the compound can be used for treating and / or preventing diseases related to MAT2A activity, such as mesothelioma, neuroblastoma, rectal cancer, colon cancer, esophageal cancer and the like. Wherein the definition of each group in the general formula (I) is the same as that in the specification.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to tricyclic heterocyclic compounds, their preparation methods and pharmaceutical compositions containing them, and their use as MAT2A inhibitors in the treatment and / or prevention of diseases related to MAT2A activity. Background Technology

[0002] Methionine adenosine transferase (MAT), also known as S-adenosylmethionine synthase, is a key enzyme catalyzing the synthesis of S-adenosylmethionine (SAM) from methionine and ATP. SAM is the primary methyl donor for glutathione and polyamine synthesis during the methylation of nucleic acids, phospholipids, histones, biogenic amines, and proteins. Therefore, the regulation of SAM biosynthesis plays a crucial role in cell growth, differentiation, and function. SAM metabolism primarily involves its synthesis and regeneration, a process known as the methionine cycle. SAM is converted to decarboxylated SAM (dcSAM) under the catalysis of SAM decarboxylase (SDC), and then used as an aminopropyl donor for polyamine synthesis. The polyamine synthesis byproduct, methionine (MTA), is further regenerated back to methionine via methionine phosphorylase (MTAP) through the methionine recovery pathway.

[0003] MAT exists in three distinct forms in mammals: MAT1A, MAT2A, and MAT2B. MAT1A and MAT2A are catalytic subunits, while MAT2B is a regulatory subunit. MAT1A is primarily expressed in the liver, playing a crucial role in maintaining the differentiation of hepatocytes and bile duct epithelial cells. MAT2A is widely distributed in non-parenchymal cells of the liver and other non-hepatic tissues, and non-hepatic endogenous SAM is mainly synthesized by MAT2A. Hypomethylation of the MAT2A promoter and histone acetylation lead to upregulation of MAT2A expression. Overexpression of MAT2A can promote tumor cell growth, inhibit apoptosis, and accelerate cancer development. Studies have found that MAT1A is mainly expressed in the adult liver, playing a vital role in the metabolism of dietary methionine. However, during malignant transformation of the liver, MAT1A can be reversed to MAT2A. Furthermore, MAT2A is also highly expressed in human epithelial tumors such as gastric and colon cancer.

[0004] The deletion or mutation of tumor suppressor genes is a key driver of tumorigenesis. However, due to the lack of suitable binding pockets, direct targeting of tumor-driving factors is difficult to achieve therapeutic efficacy. Tumor-specific gene alterations not only drive tumor progression but also reveal the inherent vulnerability of tumors, exploiting this vulnerability to trigger synthetic lethality. The deletion of tumor suppressor genes often leads to co-deletion of adjacent genes. MTAP and CDKN2A are within 100 kbp on chromosome 9p21, therefore MTAP is frequently co-deleted with CDKN2A. Homozygous deletion of the MTAP gene occurs in approximately 15% of human malignancies, particularly glioblastoma, melanoma, urothelial carcinoma, pancreatic adenocarcinoma, and non-small cell lung cancer. For example, MTAP deletion occurs in 41% of glioblastoma, 22% of pancreatic cancer, 16% of melanoma, 15% of non-small cell lung cancer, and 14% of head and neck cancers. These are many areas with limited therapeutic approaches and significant unmet clinical needs.

[0005] Studies have shown that MAT2A is a synthetic lethal target in MTAP-deficient tumors. shRNA screening revealed that MAT2A knockout inhibits the activity of MTAP-deficient tumor cells, making it a susceptibility gene for MTAP-deficient tumors. Since MTAP is the only known enzyme catalyzing the degradation of MTA, its deficiency leads to the accumulation of MTA in cancer cells. MTA can competitively inhibit protein arginine methyltransferase 5 (PRMT5) with SAM; therefore, increased MTA inhibits PRMT5 activity and is sensitive to further inhibition of SAM levels. Furthermore, inhibiting MAT2A reduces PRMT5-dependent mRNA splicing and induces DNA damage. This can produce a synergistic effect in MTAP-deficient tumor cells by inhibiting PRMT5 activity, potentially offering benefits for the treatment of various cancers.

[0006] Given that MAT2A is abnormally overexpressed in various tumor types, and that selective inhibition of MAT2A can reduce the proliferative activity of MTAP-deficient tumor cells, selective inhibition of MAT2A could be an effective cancer treatment. While MAT2A inhibitors have made some progress in cancer treatment, no MAT2A inhibitors have yet been marketed. Researchers still need to develop more MAT2A inhibitor molecules to select better compounds for the treatment of related cancer diseases. Summary of the Invention

[0007] This invention relates to tricyclic heterocyclic MAT2A inhibitor compounds, their preparation methods, and their pharmaceutical uses.

[0008] Therefore, this invention relates, in one aspect, to a compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

[0009]

[0010] in:

[0011] X 1 For CR 4 Or N, X 2 For CR 5 Or N, X 3 For CR 6 Or N, X 4 For CR 7 Or N; and X 1 X 2 X 3 X 4 At most two values ​​are N at the same time;

[0012] R 4 R 5 R 6 R 7 Each group is independently selected from hydrogen, deuterium, halogen, ester group, oxo group, alkyl group, heteroalkyl group, alkoxy group, alkathio group, alkenyl group, alkynyl group, cycloalkyl group, and heterocyclic group, wherein the alkyl group, heteroalkyl group, alkoxy group, alkathio group, alkenyl group, alkynyl group, cycloalkyl group, and heterocyclic group are optionally substituted by one or more groups selected from halogen, amino group, nitro group, cyano group, hydroxy group, mercapto group, carboxyl group, ester group, oxo group, alkyl group, alkoxy group, haloalkyl group, hydroxyalkyl group, aminoalkyl group, haloalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, and heterocyclic group;

[0013] Q is selected from O, S, NR 8 CR 8 R 9 ;

[0014] R 8 and R 9 Each group is independently selected from hydrogen, deuterium, alkyl, and cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted by one or more groups selected from deuterium, halogen, and hydroxyl;

[0015] R 1 For NR a R b ;

[0016] R a and R bEach group is independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkenyl, ynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, ynyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, carboxyl, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0017] R 2 The group is selected from aryl, heteroaryl, and heterocyclic groups; said aryl, heteroaryl, and heterocyclic groups are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0018] R 3 Selected from aryl, heteroaryl, heterocyclic, -C(O)OR 0 Halogen, oxo, and cyano; the aryl, heteroaryl, and heterocyclic groups are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0019] R 0 The group is selected from alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0020] In a preferred embodiment, the compound of general formula (I) according to the present invention, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein X 1 Selected from CH or N, X 2 Selected from CR 5 Or N, X 3 Selected from CH or N, X 4 Selected from CH or N; and X 1 X 2 X 3 X 4 At most two values ​​are N; R 5 As defined above.

[0021] In another preferred embodiment, the compound represented by general formula (I) according to the present invention, or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein Q is selected from O, S, NR. 8 The R 8 As defined above; preferably, Q is 0.

[0022] In another preferred embodiment, the compound represented by general formula (I) according to the present invention, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C 6-10 aryl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic; preferably phenyl or 5- to 6-membered heteroaryl; the C 6-10 The aryl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic groups are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0023] In another preferred embodiment, the compound represented by general formula (I) according to the present invention, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from C 6-10 Aryl, 5- to 13-membered heteroaryl, 5- to 13-membered heterocyclic, -C(O)OR 0 , halogens and cyano groups; the C 6-10 The aryl, 5- to 13-membered heteroaryl and 5- to 13-membered heterocycle are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0024] Preferably, R 3 Selected from -C(O)OR 0 Cyanoyl, halogen, phenyl, pyridyl, indazole, benzimidazolyl, benzotriazolyl, benzothiazolyl, benziisothiazolyl, benzooxazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridyl, pyrazolylpyridyl, triazolylpyridyl, benzopyridinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxyvinyl and tetrahydrobenzodioxyvinyl The phenyl, pyridyl, indazole, benzimidazolyl, benzotriazolyl, benzothiazolyl, benziisothiazolyl, benzoxazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridyl, pyrazolylpyridyl, triazolylpyridyl, benzopyridinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxyvinyl and tetrahydrobenzodioxyvinyl Optional selection from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Replaced by one or more groups of cycloalkyl, 3- to 6-membered heterocyclic groups;

[0025] More preferably, R 3 Selected from -C(O)OR 0 cyano, halogen, in Optional selection from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Replaced by one or more groups of cycloalkyl, 3- to 6-membered heterocyclic groups;

[0026] Optimal choice, R 3 Selected from -C(O)OR 0 , in Optional selection from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Replaced by one or more groups of cycloalkyl, 3- to 6-membered heterocyclic groups;

[0027] R 0 As defined above.

[0028] In another preferred embodiment, the compound represented by general formula (I) according to the present invention, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 For NR a R b ;R a and R bEach is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl group may optionally be replaced by one or more groups selected from deuterium, halogen, and hydroxyl, preferably hydrogen or C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups.

[0029] In another preferred embodiment, the compound of general formula (I) according to the present invention, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, is a compound of general formula (II), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof.

[0030]

[0031] in,

[0032] X is CR 4 Or N;

[0033] Q, R a R b R 2 R 3 R 4 R 5 R 6 R 7 As defined above.

[0034] In another preferred embodiment, the compound of general formula (I) according to the present invention, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, is a compound of general formula (III), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof.

[0035]

[0036] in:

[0037] X is CR 4 Or N;

[0038] A is CH or N;

[0039] Each R 10 Each group is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, and C. 1-6 Alkyl, C 1-10 Heteroalkyl, C1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl;

[0040] m can be 0, 1, 2, 3, or 4;

[0041] R a R b R 3 ~R 7 As defined above.

[0042] In another preferred embodiment, the compound of general formula (I) according to the present invention, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, is a compound of general formula (IV), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof.

[0043]

[0044] in:

[0045] X is CR 4 Or N;

[0046] Y1, Y2, and Y3 are each independently selected from CH or N;

[0047] Y4, Y5, and Y6 are each independently selected from CH, N, O, and S;

[0048] Y7 and Y8 are each independently selected from C or N;

[0049] A is CH or N;

[0050] Each R 10 Each group is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, and C. 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl;

[0051] Each R 11a Each group is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, and C. 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl;

[0052] Each R 11b Each group is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, and C. 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl;

[0053] m can be 0, 1, 2, 3, or 4;

[0054] p is 0, 1, or 2;

[0055] q is 0, 1, 2, or 3;

[0056] R a R b R 4 ~R 7 As defined above.

[0057] In another preferred embodiment, the compound of general formula (I) according to the present invention, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, is a compound of general formula (V), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof.

[0058]

[0059] in:

[0060] X is CR 4 Or N;

[0061] A is CH or N;

[0062] Each R 10 Each group is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, and C. 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl;

[0063] R 0 Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cycloalkyl and 4-6 membered heterocyclic groups are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0064] m can be 0, 1, 2, 3, or 4;

[0065] R a R b R 4 ~R 7 As defined above.

[0066] In another preferred embodiment, the compound represented by general formulas (I), (II), (III), (IV), (V) according to the present invention, or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein Q is O.

[0067] In another preferred embodiment, the compound represented by general formulas (I), (II), (III), (IV), (V) according to the present invention, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl group, preferably hydrogen.

[0068] In another preferred embodiment, the compound represented by general formulas (I), (II), (III), (IV), (V) according to the present invention, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 4 R 5 R 6 R 7 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl; preferably, R 4 R 6 R 7 For hydrogen, R 5 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl.

[0069] In another preferred embodiment, the compound represented by general formulas (III), (IV), and (V) according to the present invention, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein each R 10 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group; m is 1 or 2, preferably 1.

[0070] In another preferred embodiment, the compound represented by general formulas (I), (II), and (III) according to the present invention, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 3 Selected from halogens and cyano groups, with halogens being preferred.

[0071] In another preferred embodiment, the compound of general formula (IV) according to the present invention, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein,

[0072] Selected from

[0073] in,

[0074] R 11a Each is independently selected from hydrogen and C. 1-6 alkyl;

[0075] R 11b Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups;

[0076] p is 1 or 2;

[0077] q is 1 or 2.

[0078] In another preferred embodiment, the compound represented by general formulas (I), (II), (III), (V) according to the present invention, or its tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 0 Selected from C 1-6 alkyl.

[0079] Typical compounds of this invention include, but are not limited to:

[0080]

[0081]

[0082]

[0083]

[0084]

[0085] Its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0086] Another aspect of the present invention provides a method for preparing a compound of general formula (I) according to the present invention, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0087]

[0088] In the presence of a catalyst and a basic reagent, compound I-7 and compound I-8 are coupled to give the compound of general formula (I) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof.

[0089] The catalyst is preferably copper acetate, and the alkaline reagent is preferably pyridine.

[0090] Among them, Q, X1~X4, R 1 ~R 3 As defined by general formula (I).

[0091] Another aspect of the present invention provides a pharmaceutical composition comprising the compound described in the present invention or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0092] The present invention further provides the use of the compound described in the present invention or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing such compounds, in the preparation of MAT2A inhibitors.

[0093] The present invention further provides the use of the compound described in the present invention or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing such compounds, in the preparation of medicaments for the prevention and / or treatment of diseases related to MAT2A activity.

[0094] The present invention further provides compounds according to the present invention or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing such compounds, for use as pharmaceuticals.

[0095] The present invention further provides compounds according to the present invention or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing such compounds, which are used as MAT2A inhibitors.

[0096] The present invention further provides compounds according to the present invention or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing thereof, for the prevention and / or treatment of diseases associated with MAT2A activity.

[0097] The present invention further provides a method for inhibiting MAT2A, comprising administering to a subject in need an effective amount of the compound according to the present invention or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the thereof.

[0098] The present invention further provides a method for preventing and / or treating diseases associated with MAT2A activity, comprising administering to a subject in need a preventive or therapeutically effective amount of the compound according to the invention or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same.

[0099] In a preferred embodiment of the present invention, the disease associated with MAT2A activity according to the present invention can be a solid tumor, such as mesothelioma, neuroblastoma, rectal cancer, colon cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumor, lymphoma, head and neck cancer, etc.

[0100] According to conventional methods in the field to which this invention pertains, the compounds of this invention can react with acids to form pharmaceutically acceptable acid addition salts. The acids include inorganic and organic acids, with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc., being particularly preferred.

[0101] According to conventional methods in the field of this invention, the compounds of this invention can react with a base to form a pharmaceutically acceptable basic addition salt. The base includes inorganic and organic bases; acceptable organic bases include diethanolamine, ethanolamine, N-methylglucosamine, triethanolamine, tromethamine, etc., and acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide, etc.

[0102] Pharmaceutical compositions containing an active ingredient can be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from: sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation. Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation for mixing. These excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginate; binders such as starch, gelatin, polyvinylpyrrolidone, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or coated using known techniques that provide sustained release over a longer period of time by masking the taste of the drug or by delaying disintegration and absorption in the gastrointestinal tract. For example, water-soluble taste-masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose may be used, or time-extending substances such as ethylcellulose or cellulose acetate butyrate may be used.

[0103] Oral formulations can also be provided in hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil solvent such as peanut oil, liquid paraffin or olive oil.

[0104] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic; dispersants or wetting agents, which may be naturally occurring phospholipids such as lecithin, or condensation products of olefinic oxygen and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain fatty alcohols, such as heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides, such as polyoxyethylene dehydrated sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose, saccharin, or aspartame.

[0105] Oil suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oils such as liquid paraffin. Oil suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents mentioned above can be added to provide a palatable formulation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole (BHA) or α-tocopherol.

[0106] By adding water, dispersible powders and granules suitable for preparing aqueous suspensions can provide active ingredients and dispersants or wetting agents, suspending agents, or one or more preservatives for mixing. Suitable dispersants or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.

[0107] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate, and condensation products of said metaesters and ethylene oxide, such as poly(ethylene oxide) sorbitan monooleate. The emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs formulated with sweeteners such as glycerin, propylene glycol, sorbitol, or sucrose may be used. Such formulations may also contain moderating agents, preservatives, coloring agents, and antioxidants.

[0108] The pharmaceutical compositions of the present invention can be in the form of sterile injectable aqueous solutions. Acceptable solvents and media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated with a mixture of water and glycerol to form a microemulsion. The injection solution or microemulsion can be injected into the patient's bloodstream by local large-volume injection. Alternatively, it is preferable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device can be used.

[0109] The pharmaceutical compositions of the present invention can be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations can also be sterile injectable solutions or suspensions prepared in non-toxic, parenteral-acceptable diluents or solvents, such as solutions prepared in 1,3-butanediol. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil, including synthetic mono- or diglycerides of glycerol, can be used. Additionally, fatty acids such as oleic acid can also be used to prepare injectable formulations.

[0110] The compounds of the present invention can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug. Such substances include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycol of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0111] Those skilled in the art will recognize that the dosage of a drug depends on a variety of factors, including, but not limited to, the activity of the specific compound used, the patient's age, weight, health condition, lifestyle, diet, timing of administration, route of administration, rate of excretion, and combination of drugs. Furthermore, optimal treatment modalities, such as treatment patterns, daily dosage of general formula compounds, or types of pharmaceutically acceptable salts, can be validated based on conventional treatment protocols.

[0112] This invention can contain a compound of a general formula, and its pharmaceutically acceptable salts, hydrates, or solvates as active ingredients, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and formulated into a clinically acceptable dosage form. Derivatives of this invention can be used in combination with other active ingredients, provided they do not produce other adverse effects, such as allergic reactions. The compounds of this invention can be used as the sole active ingredient or in combination with other drugs for treating diseases related to MAT2A activity. Combination therapy is achieved by administering the various therapeutic components simultaneously, separately, or sequentially.

[0113] Terminology Definition

[0114] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0115] The carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention all include their isotopes. That is, the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include hydrogen (H), deuterium (D, also known as heavy hydrogen), and tritium (T, also known as superheavy hydrogen), and the isotopes of oxygen include... 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0116] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, an alkyl group containing 1 to 4 carbon atoms, or an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any usable connection point. The substituents can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester.

[0117] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylenes). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C12). 1-12Alkylenes, more preferably alkylenes containing 1 to 6 carbon atoms (i.e., C16-64 ... 1-6 Alkylenes, more preferably alkylenes containing 1 to 4 carbon atoms (i.e., C14-44 carbon atoms). 1-6 Alkylenes. Non-limiting examples of alkylenes include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylene (-CH2CH2CH2CH2-). Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents can be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0118] The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl group containing 2 to 6 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted. When substituted, the substituent can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0119] The term "alkynyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl group containing 2 to 6 carbon atoms or preferably an alkynyl group containing 3 to 4 carbon atoms, such as ethynyl, propynyl, butynyl, etc. The alkynyl group can be substituted or unsubstituted. When substituted, the substituent can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0120] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0121] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (Where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 4 to 12 ring atoms, for example 4 to 6, 4 to 10, 5 to 13, 5 to 10, 6 to 10, or 6 to 12 ring atoms, of which 1 to 4 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl, or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0122] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0123] The term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, such as phenyl and naphthyl. Aryl groups can be substituted or unsubstituted. When substituted, the substituent can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0124] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 13 ring atoms, or 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Examples include benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, benzopyridinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxyvinyl, and tetrahydrobenzodioxyvinyl.

[0125] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0126] The term "heteroalkyl" refers to a straight-chain or branched alkyl group comprising 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms and 1 to 3 heteroatoms selected from O, N, Si and S, wherein the definition of alkyl is as described above, and wherein N and S may optionally be oxidized and N may optionally be quaternized.

[0127] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent can be one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0128] The term "cycloalkoxy" refers to -O- (cycloalkyl), where cycloalkyl is as defined above.

[0129] The term "heterocyclic alkoxy" refers to -O- (heterocyclic group), where the heterocyclic group is as defined above.

[0130] The term "cycloalkylthio" refers to -S-(cycloalkyl), where the cycloalkyl group is as defined above.

[0131] The term "heterocyclic alkylthio" refers to -S- (heterocyclic group), where the heterocyclic group is as defined above.

[0132] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0133] The term "haloalkoxy" refers to an alkoxy group that is substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0134] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, wherein the alkyl group is as defined above.

[0135] The term "hydroxyl group" refers to the -OH group.

[0136] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0137] The term "amino" refers to -NH2.

[0138] The term "cyano" refers to -CN.

[0139] The term "nitro" refers to -NO2.

[0140] The term "oxo" refers to =O.

[0141] The term "carboxyl group" refers to -C(O)OH.

[0142] The term "thiol" refers to -SH.

[0143] The term "ester group" refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0144] The term "acyl" refers to a compound containing a -C(O)R group, where R is an alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group.

[0145] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0146] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0147] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0148] "Pharmaceutical-grade salt" or "pharmaceutically acceptable salt" refers to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0149] "Carrier" refers to a carrier or diluent that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the given compound.

[0150] Method for synthesizing the compounds of the present invention

[0151] To achieve the objectives of this invention, the following technical solution is adopted.

[0152] In some embodiments, the compound represented by general formula (I) of the present invention or its tautomers, mesosomes, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof may be prepared by scheme 1.

[0153]

[0154] Step 1: Compound I-1 is cyclized with methyl bromoacetate under heating and in the presence of an alkaline reagent to obtain compound I-2. The heating condition is preferably 80°C, and the alkaline reagent is preferably potassium carbonate.

[0155] Step 2: Compound I-2 is reacted with iodinated compound R under heating, in the presence of an alkaline reagent and a catalyst. 2 -I undergoes a coupling reaction to yield compound I-3, wherein the preferred heating condition is 80°C, the preferred basic reagent is cesium carbonate, and the preferred catalyst is 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II);

[0156] Step 3: Compound I-3 is subjected to a substitution reaction with methyl 3-chloro-3-oxopropionate under heating and in the presence of an alkaline reagent to obtain compound I-4. Potassium carbonate is preferred as the alkaline reagent.

[0157] Step 4: Compound I-4 is subjected to a cyclization reaction under heating and in the presence of an alkaline reagent to obtain compound I-5, wherein the heating condition is preferably 60°C and the alkaline reagent is preferably potassium tert-butoxide;

[0158] Step 5: Compound I-5 is decarboxylated under heating and in the presence of an alkaline reagent to obtain compound I-6. The heating condition is preferably 100°C, and the alkaline reagent is preferably sodium hydroxide.

[0159] Step 6: At room temperature, in the presence of an alkaline reagent and a condensing agent, react compound I-6 with R. 1 H undergoes a condensation reaction to yield compound I-7, wherein the basic reagent is preferably 1,8-diazabicyclo[5.4.0]undec-7-ene, and the condensing agent is preferably 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate;

[0160] Step 7: In the presence of a halogenating agent, compound I-7 is subjected to a halogenation reaction to obtain compound I-8, wherein the preferred halogenating agent is N-succinimide bromide;

[0161] Step 8: Under heating, in the presence of an alkaline reagent and a catalyst, compound I-8 is coupled with boric acid compound I-9 to obtain the compound of general formula (I) or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein the heating condition is preferably 100°C, the catalyst is preferably (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium methanesulfonate (II), and the alkaline reagent is preferably cesium carbonate;

[0162] Among them, Q, X1~X4, R 1 ~R 3 As defined by general formula (I). Detailed Implementation

[0163] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0164] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Brukerdps 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0165] The LC-MS determination was performed using an Agilent 1100 Series LC / MSD Trap (ESI) mass spectrometer.

[0166] GC-MS measurements were performed using GCMS-QP2010 SE.

[0167] Preparative liquid chromatography was performed using an lc3000 HPLC system and an lc6000 HPLC system (manufacturer: Innovation Tongheng). The chromatographic column was a Daisogel C18 10μm 60A (20mm × 250mm).

[0168] High performance liquid chromatography (HPLC) determination was performed using a Shimadzu LC-20AD HPLC system (Agilent TC-C18 250×4.6mm 5μm column) and a Shimadzu LC-2010AHT HPLC system (Phenomenex C18 250×4.6mm 5μm column).

[0169] The silica gel plates used for thin-layer chromatography are Qingdao Haiyang Chemical GF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0170] Column chromatography generally uses Qingdao marine silica gel of 100-200 mesh or 200-300 mesh as the carrier.

[0171] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as NetEase, Beijing Coupled, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Innocare, Nanjing Yaoshi, and Anaiji Chemical.

[0172] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0173] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0174] The microwave reaction was performed using a CEM Discover SP type microwave reactor.

[0175] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0176] Unless otherwise specified in the examples, the reaction temperature is room temperature, specifically 20°C to 30°C.

[0177] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0178] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: petroleum ether, ethyl acetate and dichloromethane system, C: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and small amounts of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0179] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be used in the methods of this invention.

[0180] Example 1: Preparation of 4-amino-8-chloro-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-2H-indazol-5-yl)benzofurano[3,2-b]pyridine-2(1H)-one (1)

[0181]

[0182]

[0183] Step 1: Preparation of methyl 3-amino-5-chlorobenzofuran-2-carboxylate (1b)

[0184] At room temperature, 10.00 g (6.51 mmol) of 5-chloro-2-hydroxybenzonitrile, 10.00 g (6.51 mmol) of ethyl bromoacetate, 18.00 g (130.2 mmol) of potassium carbonate, and 30 mL of N,N-dimethylformamide solution were added to a reaction flask, and the mixture was stirred at 80 °C for 6 hours. The reaction mixture was then poured into water (400 mL), and a solid precipitated out. After drying, 14.0 g of a white solid, title compound 1b, was obtained, yield: 95.29%.

[0185] LC-MS: m / z 225.6 [M+H] + .

[0186] Step 2: Preparation of methyl 5-chloro-3-((4-(difluoromethoxy)phenyl)amino)benzofuran-2-carboxylic acid (1c)

[0187] Compound 1b (10.00 g, 44.3 mmol), 1-(difluoromethoxy)-4-iodobenzene (23.9 g, 88.6 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (4.76 g, 8.86 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (6.02 g, 6.65 mmol), cesium carbonate (43.3 g, 133.0 mmol), and 1,4-dioxane solution (120 mL) were added to a reaction flask at room temperature and the mixture was stirred at 80 °C for 16 hours. The reaction solution was filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 11.40 g of the yellow oil title compound 1c, with a yield of 65.95%.

[0188] LC-MS: m / z 367.7 [M+H] + .

[0189] Step 3: Preparation of methyl 5-chloro-3-(N-(4-(difluoromethoxy)phenyl)-3-methoxy-3-oxopropamido)benzofuran-2-carboxylate (1d)

[0190] Compound 1c (11.40 g, 31.0 mmol), methyl 3-chloro-3-oxopropionate (27 mL, 0.284 mol), potassium carbonate (8.57 g, 62.0 mmol), and 1,2-dichloroethane (100 mL) were added to a reaction flask at room temperature and stirred for 16 hours. The reaction mixture was filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give 14.0 g of the title compound 1d, a yellow oil, in 96.54% yield.

[0191] LC-MS: m / z 467.8 [M+H] + .

[0192] Step 4: Preparation of methyl 8-chloro-1-(4-(difluoromethoxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrobenzofurano[3,2-b]pyridine-3-carboxylic acid (1e)

[0193] At room temperature, compound 1d (14.5 g, 31.0 mmol), potassium tert-butoxide (10.43 g, 92.99 mmol), and tert-butanol (200 mL) were added to a reaction flask and stirred at 60 °C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, dissolved in dichloromethane (100 mL), filtered, and the filtrate was concentrated under reduced pressure and filtered again with ethyl acetate (100 mL). The filter cake was dried to give 2.0 g of pure yellow solid, title compound 1e, in a yield of 14.81%.

[0194] LC-MS: m / z 435.8 [M+H] + .

[0195] Step 5: Preparation of 8-chloro-1-(4-(difluoromethoxy)phenyl)benzofurano[3,2-b]pyridine-2,4(1H,3H)-dione (1f)

[0196] At room temperature, compound 1e (0.5 g, 1.15 mmol), sodium hydroxide (0.184 g, 4.59 mmol), and water (5 mL) were added to a reaction flask, and the mixture was stirred at 100 °C for 16 hours. The pH of the reaction solution was adjusted to 5 with hydrochloric acid solution, filtered, and the filter cake was dried to obtain 0.40 g of pure yellow solid, title compound 1f, in 92.29% yield.

[0197] LC-MS: m / z 377.7 [M+H] + .

[0198] Step 6: Preparation of 8-chloro-1-(4-(difluoromethoxy)phenyl)-4-((4-methoxybenzyl)amino)benzofurano[3,2-b]pyridine-2(1H)-one (1g)

[0199] At room temperature, compound 1f (0.3 g, 0.794 mmol), 4-methoxybenzylamine (0.436 g, 3.18 mmol), 1H-benzotriazol-1-yloxytripyrrolyl hexafluorophosphate (1.24 g, 2.38 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (725 mg, 4.17 mmol), and acetonitrile (5 mL) were added to a reaction flask and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted in water (20 mL), extracted with ethyl acetate (10 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain a yellow solid pure title compound 1 g (0.36 g), yield 76.02%.

[0200] LC-MS: m / z 496.9 [M+H] + .

[0201] Step 7: Preparation of 4-amino-8-chloro-1-(4-(difluoromethoxy)phenyl)benzofurano[3,2-b]pyridine-2(1H)-one (1h)

[0202] At room temperature, 1 g (0.4 g, 0.794 mmol) of the compound, 5 mL of trifluoroacetic acid, and 5 mL of dichloromethane were added to a reaction flask, and the mixture was stirred at 50 °C for 2 hours. The reaction solution was concentrated under reduced pressure to remove most of the trifluoroacetic acid, diluted in water (20 mL), and the pH was adjusted to 10 with an aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (10 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.21 g of the pure title compound 1 h as a yellow solid, yield 76.94%.

[0203] LC-MS: m / z 376.7 [M+H] + .

[0204] Step 8: Preparation of 4-amino-3-bromo-8-chloro-1-(4-(difluoromethoxy)phenyl)benzofurano[3,2-b]pyridine-2(1H)-one (1i)

[0205] Compound 1h (0.21 g, 0.537 mmol), N-succinimide bromide (99 mg, 0.537 mmol), and acetonitrile (5 mL) were added to a reaction flask at room temperature and stirred for 1 hour. The reaction mixture was diluted in water (20 mL), extracted with ethyl acetate (10 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.23 g of pure title compound 1i as a yellow solid, yield 90.56%.

[0206] LC-MS: m / z 455.6 [M+H] + .

[0207] Step 9: Preparation of 4-amino-8-chloro-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-2H-indazol-5-yl)benzofurano[3,2-b]pyridine-2(1H)-one (1).

[0208] At room temperature, compound 1i (0.10 g, 0.219 mmol), (2-methyl-2H-indazole-5-yl)boronic acid (39.0 mg, 0.219 mmol), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (19.0 mg, 0.0219 mmol), cesium carbonate (143.0 mg, 0.439 mmol), water (0.4 mL), and 1,4-dioxane solution (1.6 mL) were added to a reaction flask, and the mixture was stirred at 100 °C for 2 hours. The reaction solution was filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a white solid, title compound 1, 31 mg, in 61.16% yield.

[0209] LC-MS: m / z 506.9 [M+H] + .

[0210] 1 H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.75(d,J=8.9Hz,1H),7.66–7.57(m,4H),7.5 2–7.41(m,4H),7.26–7.14(m,1H),6.31(s,2H),6.08(d,J=2.3Hz,1H),4.17(s,3H).

[0211] Example 2: Preparation of methyl 4-amino-8-chloro-1-(2-chlorophenyl)-2-oxo-1,2-dihydrobenzofurano[3,2-b]pyridine-3-carboxylic acid (2)

[0212]

[0213] Step 1: Preparation of methyl 5-chloro-3-((2-chlorophenyl)amino)benzofuran-2-carboxylic acid (2a)

[0214] Compound 1b (22.500 g, 0.100 mol), 1-bromo-2-chlorobenzene (18.9 g, 0.100 mol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (5.37 g, 0.01 mol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (4.52 g, 5.00 mmol), cesium carbonate (65.6 g, 0.200 mol), and 1,4-dioxane solution (300 mL) were added to a reaction flask at room temperature, and the mixture was stirred at 80 °C for 16 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give 21.2 g of yellow oily title compound 2a, yield 63.28%.

[0215] LC-MS: m / z 336.01 [M+H] + .

[0216] Step 2: Preparation of methyl 5-chloro-3-(N-(2-chlorophenyl)-3-methoxy-3-oxopropamido)benzofuran-2-carboxylic acid (2b)

[0217] Compound 2a (10.2 g, 30.4 mmol), methyl 3-chloro-3-oxopropionate (32 mL, 0.341 mol), potassium carbonate (9.38 g, 68.0 mmol), and 1,2-dichloroethane (100 mL) were added to a reaction flask at room temperature and stirred for 24 hours at room temperature. The reaction solution was filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to give 11.0 g of the yellow oil title compound 2b, in 84.6% yield.

[0218] LC-MS: m / z 436.1 [M+H] + .

[0219] Step 3: Preparation of methyl 8-chloro-1-(2-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydrobenzofurano[3,2-b]pyridine-3-carboxylic acid (2c)

[0220] At room temperature, compound 2b (10.5 g, 24.1 mmol), potassium tert-butoxide (8.20 g, 73.3 mmol), and tert-butanol (200 mL) were added to a reaction flask and stirred at 60 °C for 8 hours. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane (100 mL), filtered, and the filtrate was concentrated under reduced pressure and filtered again with ethyl acetate (100 mL). The filter cake was dried to give 3.21 g of pure yellow solid, title compound 2c, in a yield of 32.92%.

[0221] LC-MS: m / z 404.2 [M+H] + .

[0222] Step 4: Preparation of methyl 8-chloro-1-(2-chlorophenyl)-4-((4-methoxyphenyl)amino)-2-oxo-1,2-dihydrobenzofurano[3,2-b]pyridine-3-carboxylic acid (2d)

[0223] Compound 2c (400 mg, 0.992 mmol), 4-methoxybenzylamine (323 mg, 2.36 mmol), 1H-benzotriazol-1-yloxytripyrrolyl hexafluorophosphate (1.24 g, 2.38 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (725 mg, 4.17 mmol), and acetonitrile (10 mL) were added to a reaction flask at room temperature and stirred for 4 hours at room temperature. The reaction mixture was diluted in water (20 mL), extracted with ethyl acetate (10 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane:methanol = 15:1) to give a yellow solid pure title compound 2d, 348 mg, yield 67.18%.

[0224] LC-MS: m / z 523.07 [M+H] + .

[0225] Step 5: Preparation of methyl 4-amino-8-chloro-1-(2-chlorophenyl)-2-oxo-1,2-dihydrobenzofurano[3,2-b]pyridine-3-carboxylic acid (2)

[0226] At room temperature, compound 2d (30 mg, 0.057 mmol), trifluoroacetic acid (5 mL), and dichloromethane (5 mL) were added to a reaction flask and stirred at 50 °C for 3 hours. The reaction solution was concentrated under reduced pressure to remove most of the trifluoroacetic acid, diluted in water (20 mL), and the pH was adjusted to 10 with aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (10 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (column type: Daisogei 30 mm * 250 mm, C18, 10 μm, 100 A; mobile phase: acetonitrile / water; gradient: 10%-100%) to give a white solid, 16 mg of title compound 2, yield: 69.56%.

[0227] LC-MS: m / z 403.1 [M+H] + .

[0228] 1 H NMR (400MHz, DMSO-d6) δ8.41 (s, 2H), 7.88–7.77 (m, 2H), 7.75–7.62 (m, 3H), 7.58 (dd, J = 9.0, 2.3Hz, 1H), 5.91 (d, J = 2.2Hz, 1H), 3.74 (s, 3H).

[0229] Example 3: Preparation of 4-amino-8-chloro-1-(4-chlorophenyl)-3-(2-methyl-2H-indazol-5-yl)benzofurano[3,2-b]pyridine-2(1H)-one (3)

[0230]

[0231] The preparation method was the same as in Example 1, except that 1-(difluoromethoxy)-4-iodobenzene was replaced in step 2 with 1-chloro-4-iodobenzene to obtain title compound 3.

[0232] LC-MS: m / z 477.1 [M+H] + .

[0233] 1 H NMR (400MHz, DMSO-d6) δ8.30 (s, 1H), 7.80–7.69 (m, 4H), 7.63 (d, J = 1.5Hz, 1H), 7.60–7.54 ( m, 3H), 7.48 (dd, J = 8.9, 2.3Hz, 1H), 7.17 (dd, J = 8.9, 1.6Hz, 1H), 6.32 (s, 2H), 4.16 (s, 3H).

[0234] Example 4: Preparation of 4-amino-8-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-2H-indazol-5-yl)benzofurano[3,2-b]pyridine-2(1H)-one (4)

[0235]

[0236] The preparation method was the same as in Example 1, except that 5-chloro-2-hydroxybenzonitrile was replaced with 5-cyclopropyl-2-hydroxybenzonitrile in step 1 to obtain title compound 4.

[0237] LC-MS: m / z 512 [M+H] + .

[0238] 1 HNMR(400MHz,DMSO-d6)δ8.29(s,1H),7.64(t,J=1.3Hz,1H),7.61(s,4H),7.46–7.38(m,3H),7.24–7.13(m,2H),6 .17(s,2H),5.74(d,J=1.9Hz,1H),4.16(s,3H),1.76(tt,J=8.3,5.0Hz,1H),0.89–0.80(m,2H),0.37–0.29(m,2H).

[0239] Example 5: Preparation of 4-amino-8-chloro-3-(2-methyl-2H-indazol-5-yl)-1-(2-methylpyridin-3-yl)benzofurano[3,2-b]pyridin-2(1H)-one (5)

[0240]

[0241] The preparation method was the same as in Example 1, except that 1-(difluoromethoxy)-4-iodobenzene in step 2 was replaced with 3-iodo-2-methylpyridine to obtain title compound 5.

[0242] LC-MS: m / z 455.85 [M+H] + .

[0243] 1H NMR(400MHz, DMSO-d6)δ8.71(dd,J=4.9,1.6Hz,1H),8.32(s,1H),7.94(dd,J=7 .9,1.6Hz,1H),7.78(d,J=8.8Hz,1H),7.68(t,J=1.1Hz,1H),7.60(dt,J=8.8,0 .9Hz,1H),7.54(dd,J=7.9,4.8Hz,1H),7.49(dd,J=8.9,2.2Hz,1H),7.19(dd,J =8.9,1.6Hz,1H),6.39(s,2H),5.94(d,J=2.2Hz,1H),4.18(s,3H),2.28(s,3H).

[0244] Example 6: Preparation of 4-amino-8-chloro-1-(2-chloropyridin-3-yl)-3-(2-methyl-2H-indazol-5-yl)benzofurano[3,2-b]pyridin-2(1H)-one (6)

[0245]

[0246] The preparation method was the same as in Example 1, except that 1-(difluoromethoxy)-4-iodobenzene in step 2 was replaced with 2-chloro-3-iodopyridine to obtain title compound 6.

[0247] LC-MS: m / z 475.80 [M+H] + .

[0248] 1 H NMR (400MHz, DMSO-d6) δ8.71(dd,J=4.8,1.8Hz,1H),8.33(s,1H),8.29(dd,J=7.8,1.8Hz,1H),7.82–7.76(m,2H),7.67(s,1H),7 .60(d,J=8.9Hz,1H),7.53(dd,J=8.9,2.2Hz,1H),7.18(dd,J=8.9,1.6Hz,1H),6.50(s,2H),6.05(d,J=2.2Hz,1H),4.18(s,3H).

[0249] Example 7: Preparation of 4-amino-8-chloro-3-(2-methyl-2H-indazol-5-yl)-1-(m-tolyl)benzofurano[3,2-b]pyridin-2(1H)-one (7)

[0250]

[0251] The preparation method was the same as in Example 1, except that 5-chloro-2-hydroxybenzonitrile was replaced with 5-cyclopropyl-2-hydroxybenzonitrile in step 1 to obtain title compound 7.

[0252] LC-MS: m / z 454 [M+H] + .

[0253] 1 H NMR (400MHz, DMSO-d6) δ8.31 (s, 1H), 7.73 (d, J = 8.9Hz, 1H), 7.67 (s, 1H), 7.62–7.53 (m, 3H), 7.48–7. 39(m,3H),7.19(dd,J=8.9,1.6Hz,1H),6.27(s,2H),5.84(d,J=2.3Hz,1H),4.17(s,3H),2.05(s,3H).

[0254] Example 8: Preparation of 4-amino-8-chloro-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-3a,7a-dihydro-1H-benzo[d][1,2,3]triazol-6-yl)benzofurano[3,2-b]pyridine-2(1H)-one (8)

[0255]

[0256] The preparation method was the same as in Example 1, except that (2-methyl-2H-indazole-5-yl)boronic acid in step 9 was replaced with (1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)boronic acid to obtain title compound 8.

[0257] LC-MS: m / z 507 [M+H] + .

[0258] 1 H NMR (400MHz, DMSO-d6) δ7.88(dd,J=8.8,0.9Hz,1H),7.81(t,J=1.1Hz,1H),7.75(d,J=8.9Hz,1H),7.60(d,J= 8.7Hz,1H),7.51–7.40(m,3H),7.36(dd,J=8.9,1.5Hz,1H),6.51(s,2H),6.08(d,J=2.2Hz,1H),4.49(s,2H).

[0259] Example 9: Preparation of 4-amino-8-chloro-1-(4-chlorophenyl)-3-(1-methyl-3a,7a-dihydro-1H-benzo[d][1,2,3]triazol-6-yl)benzofuran[3,2-b]pyridine-2(1H)-one (9)

[0260]

[0261] The preparation method was the same as in Example 1, except that 1-(difluoromethoxy)-4-iodobenzene was replaced in step 2 with 1-chloro-4-iodobenzene, and (2-methyl-2H-indazole-5-yl)boronic acid was replaced in step 9 with β-(1-methyl-1H-benzotriazol-6-yl)boronic acid, to obtain title compound 9.

[0262] LC-MS: m / z 475 [M+H] + .

[0263] 1 H NMR(400MHz, DMSO-d6)δ7.88(dd,J=8.8,0.9Hz,1H),7.81(t,J=1.2Hz,1H),7.78–7.68(m,3H),7.61–7.56(m,2 H), 7.49 (dd, J = 8.9, 2.2Hz, 1H), 7.36 (dd, J = 8.8, 1.5Hz, 1H), 6.53 (s, 2H), 6.13 (d, J = 2.3Hz, 1H), 4.49 (s, 3H).

[0264] Example 10: Preparation of 4-amino-8-chloro-1-(6-methoxypyridin-3-yl)-3-(2-methyl-2H-indazol-5-yl)benzofurano[3,2-b]pyridin-2(1H)-one (10)

[0265]

[0266] The preparation method was the same as in Example 1, except that 1-(difluoromethoxy)-4-iodobenzene in step 2 was replaced with 3-bromo-2-methoxypyridine to obtain title compound 10.

[0267] LC-MS: m / z 471.8 [M+H] + .

[0268] 1 H NMR (400MHz, DMSO-d6) δ8.38–8.29(m,2H),7.92(dd,J=8.7,2.7Hz,1H),7.78(d,J=8.8Hz,1H),7.66(s,1H),7.60(d,J=8.9Hz,1H ),7.51(dd,J=8.9,2.2Hz,1H),7.19(dd,J=8.9,1.6Hz,1H),7.10(d,J=8.7Hz,1H),6.33–6.24(m,3H),4.19(s,3H),3.99(s,3H).

[0269] Example 11: Preparation of 4-amino-8-chloro-3-(2-methyl-2H-indazol-5-yl)-1-(6-methylpyridin-3-yl)benzofurano[3,2-b]pyridin-2(1H)-one (11)

[0270]

[0271] The preparation method was the same as in Example 1, except that 1-(difluoromethoxy)-4-iodobenzene in step 2 was replaced with 3-bromo-2-methylpyridine to obtain title compound 11.

[0272] LC-MS: m / z 455.8 [M+H] + .

[0273] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.5Hz,1H),8.32(s,1H),7.91(dd,J=8.2,2.6Hz,1H),7.78(d,J=8.9Hz,1H),7.66(t,J=1.2Hz,1H),7. 63–7.53(m,2H),7.51(dd,J=8.9,2.2Hz,1H),7.19(dd,J=8.9,1.6Hz,1H),6.36(s,2H),6.16(d,J=2.2Hz,1H),4.18(s,3H),2.65(s,3H).

[0274] Example 12: Preparation of 4-amino-8-chloro-1-(6-difluoromethoxypyridin-3-yl)-3-(2-methyl-2H-indazol-5-yl)benzofurano[3,2-b]pyridin-2(1H)-one (12)

[0275]

[0276] The preparation method was the same as in Example 1, except that 1-(difluoromethoxy)-4-iodobenzene in step 2 was replaced with 2-(difluoromethoxy)-5-iodopyridine to obtain title compound 12.

[0277] LC-MS: m / z 508.0 [M+H] + .

[0278] 1H NMR(400MHz, DMSO-d6)δ8.51(d,J=2.6Hz,1H),8.32(s,1H),8.18(dd,J=8.6, 2.7Hz,1H),7.96(d,J=72.6Hz,1H),7.79(d,J=8.9Hz,1H),7.71–7.64(m,1H) ,7.60(d,J=8.9Hz,1H),7.52(dd,J=8.9,2.3Hz,1H),7.40(d,J=8.7Hz,1H),7 .19(dd,J=9.0,1.6Hz,1H),6.41(s,2H),6.29(d,J=2.2Hz,1H),4.18(s,3H).

[0279] Example 13: Preparation of 4-amino-1-(4-chlorophenyl)-3-(2-methyl-2H-indazol-5-yl)furano[3,2-b:4,5-b']dipyridin-2(1H)-one (13)

[0280]

[0281] The preparation method was the same as in Example 1, except that 1-(difluoromethoxy)-4-iodobenzene was replaced in step 2 with 1-chloro-4-iodobenzene, and 5-chloro-2-hydroxybenzonitrile was replaced in step 1 with 3-hydroxy-2-cyanopyridine, to obtain title compound 13.

[0282] LC-MS: m / z 441.85 [M+H] + .

[0283] 1 H NMR (400MHz, DMSO-d6) δ8.39(dd,J=4.7,1.3Hz,1H),8.32(s,1H),8.14(dd,J=8.5,1.3Hz,1H),7.66(s,1H),7.60( d,J=8.9Hz,1H),7.55(d,J=8.7Hz,2H),7.51–7.42(m,3H),7.19(dd,J=8.9,1.6Hz,1H),6.34(s,2H),4.18(s,3H).

[0284] Example 14: Preparation of methyl 4-amino-8-chloro-1-(4-(1-hydroxyethyl)phenyl)-2-oxo-1,2-dihydrobenzofuran[3,2-b]pyridine-3-carboxylic acid (14)

[0285]

[0286] The preparation method was the same as in Example 2, except that 1-bromo-2-chlorobenzene in step 1 was replaced with 1-(4-iodophenyl)ethyl-1-ol to obtain title compound 14.

[0287] LC-MS: m / z 413.0 [M+H] + .

[0288] 1 H NMR(400MHz, DMSO-d6)δ8.25(s,2H),7.74(d,J=8.9Hz,1H),7.64–7.55(m,2H),7.53(dd,J=9 .0,2.3Hz,1H),7.41–7.33(m,2H),5.89(d,J=2.2Hz,1H),4.90(q,J=6.4Hz,1H),3.72(s,3H).

[0289] Example 15: Preparation of methyl 4-amino-8-chloro-2-oxo-1-(m-tolyl)-1,2-dihydrobenzofurano[3,2-b]pyridine-3-carboxylic acid (15)

[0290]

[0291] The preparation method was the same as in Example 2, except that 1-bromo-2-chlorobenzene was replaced in step 1 with 1-iodo-2-methylbenzene to obtain title compound 15.

[0292] LC-MS: m / z 383.0 [M+H] + .

[0293] 1 H NMR(400MHz, DMSO-d6)δ8.31(s,2H),7.76(d,J=8.9Hz,1H),7.61–7.51(m,3H),7.47(td,J=7 .1,6.6,2.3Hz,1H),7.37(d,J=7.8Hz,1H),5.80(d,J=2.2Hz,1H),3.74(s,3H),2.02(s,3H).

[0294] Example 16: Preparation of methyl 4-amino-8-chloro-1-(4-(difluoromethoxy)phenyl)-2-oxo-1,2-dihydrobenzofurano[3,2-b]pyridine-3-carboxylic acid (16)

[0295]

[0296] The preparation method was the same as in Example 2, except that 1-bromo-2-chlorobenzene in step 1 was replaced with 1-(difluoromethoxy)-4-iodobenzene to obtain title compound 16.

[0297] LC-MS: m / z 434 [M+H] + .

[0298] 1 H NMR (400MHz, DMSO-d6) δ8.31 (s, 2H), 7.77 (d, J = 9.0 Hz, 1H), 7.66–7.54 (m, 3H), 7.49–7.41 (m, 2H), 6.01 (d, J = 2.3 Hz, 1H), 3.71 (s, 3H).

[0299] Example 17: Preparation of methyl 4-amino-8-chloro-2-oxo-1-(3-methylphenyl)-1,2-dihydrobenzofurano[3,2-b]pyridine-3-carboxylic acid (17)

[0300]

[0301] The preparation method was the same as in Example 2, except that 1-bromo-2-chlorobenzene was replaced in step 1 with 1-iodo-3-methylbenzene to obtain title compound 17.

[0302] LC-MS: m / z 383.0 [M+H] + .

[0303] 1 H NMR(400MHz, DMSO-d6)δ8.31(s,2H),7.76(d,J=8.9Hz,1H),7.61–7.51(m,3H),7.47(td,J=7 .1,6.6,2.3Hz,1H),7.37(d,J=7.8Hz,1H),5.80(d,J=2.2Hz,1H),3.74(s,3H),2.02(s,3H).

[0304] Example 18: Preparation of 4-amino-3-bromo-8-chloro-1-(2-methylpyridin-3-yl)benzofurano[3,2-b]pyridin-2(1H)-one (18)

[0305]

[0306] The preparation method was the same as that of compound 1i in Example 1, except that 1-(difluoromethoxy)-4-iodobenzene in step 2 was replaced with 3-iodo-2-methylpyridine to obtain title compound 18.

[0307] LC-MS: m / z 405.70 [M+H] + .

[0308] 1H NMR (400MHz, DMSO-d6) δ8.77(dd,J=4.9,1.6Hz,1H),7.99(dd,J=7.9,1.6Hz,1H),7.77(d,J=8.9Hz,1H),7 .61(dd,J=7.9,4.9Hz,1H),7.52(dd,J=8.9,2.2Hz,1H),7.30(s,2H),5.93(d,J=2.2Hz,1H),2.24(s,3H).

[0309] Example 19: Preparation of 4-amino-3-bromo-8-chloro-1-(2-methylphenyl)benzofuran[3,2-b]pyridine-2(1H)-one (19)

[0310]

[0311] The preparation method was the same as that of compound 1i in Example 1, except that 1-(difluoromethoxy)-4-iodobenzene was replaced in step 2 with 1-iodo-2-methylbenzene to obtain title compound 19.

[0312] LC-MS: m / z 402 [M+H] + .

[0313] 1 H NMR(400MHz,DMSO-d6)δ7.72(d,J=8.9Hz,1H),7.60–7.50(m,2H),7.50–7.41(m,2 H), 7.38 (dd, J = 7.6, 1.2 Hz, 1H), 7.19 (s, 2H), 5.77 (d, J = 2.2 Hz, 1H), 1.98 (s, 3H).

[0314] Biological evaluation

[0315] Experimental Example 1: Inhibition Test of MAT2A Enzyme Activity by the Compounds of the Present Invention

[0316] Objective: To detect the inhibitory level of the compound of this invention on MAT2A enzyme activity.

[0317] Experimental materials: MAT2A inhibitor screening kit (BPS, 71402), Tris pH 7.5 (Invitrogen, 15567-027), DTT (Sigma, 43816), MnCl2 (Sigma, M1787), MgCl2 (Sigma, M1028), EDTA (Invitrogen, 15575020), BSA (petroleum ether, CR84-100), DMSO (Sigma, D8418).

[0318] Experimental steps:

[0319] (I) Reagent Preparation

[0320] The test buffer consisted of 50 mM HEPES (pH 7.8), 100 mM NaCl, 0.5 mM EDTA, 1 mM DTT, 0.01% BSA, and 0.01% Tween-20.

[0321] (II) Experimental Methods

[0322] The compounds were dissolved in DMSO and serially diluted with DMSO to different concentrations. 200 nmL of each diluted compound was transferred to a reaction plate (3702, Corning) using an Echo 655 (Labcyte, 655). 10 μM of the reference compound AG270 (MCE, Cat#HY-112131) was added to the positive control wells. The plate was sealed with a sealing film and centrifuged at 1000g for 1 minute. 2× kinase solution was prepared, and 10 μL of the kinase solution was added to each test well in the reaction plate. 10 μL of the test buffer was added to the negative control wells. The plate was sealed with a sealing film and centrifuged at 1000g for 1 minute, then incubated at room temperature for 30 minutes. A 2× kinase substrate L-methionine and ATP mixture was prepared, and 10 μL of the mixture was added to each well in the reaction plate. The plate was centrifuged at 1000g for 30 seconds and incubated at room temperature for 60 minutes. Add 20 μL of detection reagent to each well, centrifuge at 1000g for 60 seconds, incubate at room temperature in the dark for 15 minutes, and then read the absorbance value at 630 nm using a microplate reader (BMG, PHERAstra FSX).

[0323] The enzyme activity inhibition rate is calculated as follows:

[0324] Inhibition%=100-(Signal cmpd-SignalAve_PC) / (SignalAve_VC-SignalAve_PC)×100

[0325] Wherein, Signal cmpd: chemiluminescence value of each concentration of compound, SignalAve_VC: average absorbance value of positive control wells, and SignalAve_PC: average absorbance value of negative control wells.

[0326] The concentration and inhibition rate were fitted with nonlinear regression curves using Graphpad Prism software to obtain the IC50. 50 value.

[0327] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0328] Where X: the logarithm of the compound concentration; Y: the percentage of inhibition rate; Top and Bottom are the Y values ​​of the highest and lowest plateau periods of the curve; Hillslope is the Hill constant.

[0329] Table 1 provides the in vitro enzymatic activities (IC50) of the compounds of the present invention against MAT2A. 50 ).

[0330] In Table 1, the in vitro enzymatic activity values ​​of the compound MAT2A are listed: A refers to IC50. 50 <100nM; B refers to 100nM <IC 50 <1000nM; C refers to 1000nM <IC 50 <10000nM; D refers to IC 50 >10000nM.

[0331] Table 1. IC50 of the compounds of the present invention inhibiting MAT2A enzyme activity 50

[0332] Example <![CDATA[MAT2A IC 50 ]]> Example <![CDATA[MAT2A IC 50 <!-- 30 -->]]> 1 A 11 A 2 A 12 A 3 A 13 A 4 A 14 A 5 A 15 A 6 A 16 A 7 A 17 A 8 A 18 B 9 A 19 A 10 A

[0333] Results: The compounds of this invention exhibit excellent inhibitory activity against MAT2A.

[0334] Experimental Example 2: Inhibition of HCT-116MTAP Knockout Cell Proliferation Activity by Compounds of the Present Invention

[0335] Objective: To detect the inhibitory level of the compound of this invention on the proliferation activity of HCT-116MTAP knockout cells.

[0336] Experimental materials: test compounds, MCCOYS 5A MED MOD medium (Invitrogen, 16600-082), fetal bovine serum (Gibco, 10099-141), penicillin / streptomycin antibiotics (Gibco, 15140122), HCT-116MTAP knockout cell line (Kanglong Chemical), CTG kit (Promega, G7573).

[0337] Experimental steps:

[0338] The compound was dissolved in DMSO and serially diluted to different concentrations using DMSO. Using an Echo 655 (Labcyte, 655), 40 nmol of the diluted working solution was transferred to each well of a reaction plate (Labcyte, P-05525-BC), and 40 nmol of DMSO was transferred to each negative control well. HCT-116MTAP knockout cells were seeded in white 384-well plates, with 40 μL of cell suspension containing 100 HCT-116MTAP knockout cells added to each well. The plates were incubated at 37°C, 5% CO2 for 10 days. CTG assay reagent was prepared. 40 μL of CTG was added to each well, and the plates were vortexed to mix. The plates were incubated at 37°C, 5% CO2 for 30 minutes in the dark. A microplate reader (Envision, 2105) was used to read the luminescence signal.

[0339] Data Analysis:

[0340] The inhibition rate is calculated as follows:

[0341] Inhibition % = 100 - (Signal) cmpd -Signal Ave_BL ) / (Signal Ave_VC -Signal Ave_BL )×100

[0342] Signal cmpd Chemiluminescence values ​​of compounds at various concentrations

[0343] Signal Ave_BL The average chemiluminescence value of the system on day 0

[0344] Signal Ave_VC Average value of chemiluminescence in negative control

[0345] Computing IC 50 Plot the compound effect-dose curve:

[0346] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0347] X: Logarithm of compound concentration; Y: Percentage of inhibition rate; Top and Bottom are the Y values ​​at the highest and lowest plateau periods of the curve; Hillslope is the Hill constant.

[0348] Table 2 provides the in vitro inhibitory activity (IC50) of the compounds of the present invention against HCT-116MTAP knockout cells. 50 ).

[0349] In Table 2, the in vitro inhibitory activity values ​​of the compounds against HCT-116MTAP knockout cells are shown: A refers to IC50. 50 <100nM; B refers to 100nM <IC 50 <1000nM; C refers to 1000nM <IC 50 <10000nM; D refers to IC 50 >10000nM.

[0350] Table 2. Inhibition IC50 of the compounds of the present invention on the activity of HCT-116MTAP knockout cells 50

[0351]

[0352]

[0353] Results: The compounds of this invention exhibited excellent inhibitory activity against HCT-116MTAP knockout cells.

[0354] Experimental Example 3: Pharmacokinetic Evaluation of the Compounds of the Present Invention in ICR Mice

[0355] The compound of this invention was orally administered to male 6-8 week old ICR mice (Beijing Vital River Laboratory Technology Co., Ltd.). The compound was prepared by reconstitution with 97% 20% hydroxypropyl-β-cyclodextrin solution, and the administration volume was 10 mL / kg. Blood samples were collected from the canthal venous plexus of the mice before administration and at 0.25, 0.50, 1.00, 2.00, 4.00, 6.00, 8.00, and 24.00 hours after administration. The blood was anticoagulated with heparin sodium and centrifuged at 3500 rpm for 10 minutes at 4°C. Plasma was collected and stored at -20°C until testing. 10 μL of the plasma sample was placed in a 96-well plate, and 100 μL of acetonitrile working solution containing 5 ng / mL verapamil hydrochloride (internal standard) (100223-202103, China National Institutes for Food and Drug Control) was added. The mixture was vortexed for 5 minutes to mix thoroughly and centrifuged at 4000 rpm for 10 minutes. Transfer 50 μL of the supernatant, add 150 μL of acetonitrile and mix well. Centrifuge at 4000 rpm for 10 min. Take the supernatant and place it in a 96-well sample tray. Analyze the drug concentration by LC / MS (Waters UPLC I Class / LC 30AD, Waters). Analyze the pharmacokinetic parameters using MassLynx V4.2 SCN977 data processing software. The main pharmacokinetic parameters of the compound of this invention are shown in Table 3 below.

[0356] In Table 3, A* refers to the AUC of the compound. 0-t (μg / L×h)>40000; B* refers to 20000 <AUC 0-t(μg / L×h)<40000; C* refers to 8000 <AUC 0-t (μg / L×h)<20000; D* refers to AUC 0-t (μg / L×h)<8000.

[0357] Table 3. Pharmacokinetic parameters of the compounds of this invention administered orally to male ICR mice after a single oral administration.

[0358]

Claims

1. A compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, in: X 1 For CR 4 Or N, X 2 For CR 5 Or N, X 3 For CR 6 Or N, X 4 For CR 7 Or N; and X 1 X 2 X 3 X 4 At most two values ​​are N at the same time; R 4 R 5 R 6 R 7 Each group is independently selected from hydrogen, deuterium, halogen, ester group, oxo group, alkyl group, heteroalkyl group, alkoxy group, alkathio group, alkenyl group, alkynyl group, cycloalkyl group, and heterocyclic group, wherein the alkyl group, heteroalkyl group, alkoxy group, alkathio group, alkenyl group, alkynyl group, cycloalkyl group, and heterocyclic group are optionally substituted by one or more groups selected from halogen, amino group, nitro group, cyano group, hydroxy group, mercapto group, carboxyl group, ester group, oxo group, alkyl group, alkoxy group, haloalkyl group, hydroxyalkyl group, aminoalkyl group, haloalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, and heterocyclic group; Q is selected from O, S, NR 8 CR 8 R 9 ; R 8 and R 9 Each group is independently selected from hydrogen, deuterium, alkyl, and cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted by one or more groups selected from deuterium, halogen, and hydroxyl; R 1 For NR a R b ; R a and R b Each group is independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkenyl, ynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, ynyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, carboxyl, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 2 The group is selected from aryl, heteroaryl, and heterocyclic groups; said aryl, heteroaryl, and heterocyclic groups are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 3 Selected from aryl, heteroaryl, heterocyclic, -C(O)OR 0 Halogen, oxo, and cyano; the aryl, heteroaryl, and heterocyclic groups are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 0 The group is selected from alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

2. The compound of general formula (I) according to claim 1, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein, X 1 Selected from CH or N, X 2 Selected from CR 5 Or N, X 3 Selected from CH or N, X 4 Selected from CH or N; and X 1 X 2 X 3 X 4 At most two values ​​are N; R 5 As defined in claim 1.

3. The compound of general formula (I) according to claim 1 or 2, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein, Q is selected from O, S, NR 8 The R 8 As defined in claim 1; preferably, Q is 0.

4. The compound of general formula (I) according to any one of claims 1 to 3, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 Selected from C 6-10 aryl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic; preferably phenyl or 5- to 6-membered heteroaryl; the C 6-10 The aryl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic groups are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

5. The compound of general formula (I) according to any one of claims 1 to 4, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R 3 Selected from C 6-10 Aryl, 5- to 13-membered heteroaryl, 5- to 13-membered heterocyclic, -C(O)OR 0 , halogens and cyano groups; the C 6-10 The aryl, 5- to 13-membered heteroaryl and 5- to 13-membered heterocyclic groups are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Preferably, R 3 Selected from -C(O)OR 0 Cyanoyl, halogen, phenyl, pyridyl, indazole, benzimidazolyl, benzotriazolyl, benzothiazolyl, benziisothiazolyl, benzooxazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridyl, pyrazolylpyridyl, triazolylpyridyl, benzopyridinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxyvinyl and tetrahydrobenzodioxyvinyl The phenyl, pyridyl, indazole, benzimidazolyl, benzotriazolyl, benzothiazolyl, benziisothiazolyl, benzoxazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridyl, pyrazolylpyridyl, triazolylpyridyl, benzopyridinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxyvinyl and tetrahydrobenzodioxyvinyl Optional selection from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Replaced by one or more groups of cycloalkyl, 3- to 6-membered heterocyclic groups; More preferably, R 3 Selected from -C(O)OR 0 cyano, halogen, in Optional selection from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Replaced by one or more groups of cycloalkyl, 3- to 6-membered heterocyclic groups; Optimal choice, R 3 Selected from -C(O)OR 0 , in Optional selection from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Replaced by one or more groups of cycloalkyl, 3- to 6-membered heterocyclic groups; R 0 As defined in claim 1.

6. The compound of general formula (I) according to any one of claims 1 to 5, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R 1 For NR a R b ;R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl group may optionally be replaced by one or more groups selected from deuterium, halogen, and hydroxyl, preferably hydrogen or C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups.

7. The compound of general formula (I) according to claim 1, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein the compound is a compound of general formula (II), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof. in, X is CR 4 Or N; Q, R a R b R 2 R 3 R 4 R 5 R 6 R 7 As defined in claim 1.

8. The compound of general formula (I) according to claim 1, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of general formula (III), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. in: X is CR 4 Or N; A is CH or N; Each R 10 Each group is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, and C. 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl; m can be 0, 1, 2, 3, or 4; R a R b R 3 ~R 7 As defined in claim 1.

9. The compound of general formula (I) according to claim 1, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of general formula (IV), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. in: X is CR 4 Or N; Y1, Y2, and Y3 are each independently selected from CH or N; Y4, Y5, and Y6 are each independently selected from CH, N, O, and S; Y7 and Y8 are each independently selected from C or N; A is CH or N; Each R 10 Each group is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, and C. 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl; Each R 11a Each group is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, and C. 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl; Each R 11b Each group is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, and C. 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl; m can be 0, 1, 2, 3, or 4; p is 0, 1, or 2; q is 0, 1, 2, or 3; R a R b R 4 ~R 7 As defined in claim 1.

10. The compound of general formula (I) according to claim 1, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of general formula (V), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. in: X is CR 4 Or N; A is CH or N; Each R 10 Each group is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, and C. 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl; R 0 Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cycloalkyl and 4-6 membered heterocyclic groups are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. m can be 0, 1, 2, 3, or 4; R a R b R 4 ~R 7 As defined in claim 1.

11. The compound of general formula (I) according to any one of claims 1 to 10, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Q is 0.

12. The compound of general formula (I) according to any one of claims 1 to 11, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein, R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl group, preferably hydrogen.

13. The compound of formula (I) according to any one of claims 1 to 11, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R 4 R 5 R 6 R 7 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl; preferably, R 4 R 6 R 7 For hydrogen, R 5 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl.

14. The compound of general formula (I) according to any one of claims 8 to 13, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein, Each R 10 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group; m is 1 or 2, preferably 1.

15. The compound of general formula (I) according to any one of claims 1 to 8, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein, R 3 Selected from halogens and cyano groups, with halogens being preferred.

16. The compound of general formula (I) according to claim 9, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein, Selected from in, R 11a Each is independently selected from hydrogen and C. 1-6 alkyl; R 11b Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Halogenated alkoxy groups; p is 1 or 2; q is 1 or 2.

17. The compound of general formula (I) according to any one of claims 1-8, 10-14, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, wherein, R 0 Selected from C 1-6 alkyl.

18. The compound of general formula (I) according to any one of claims 1 to 17, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, selected from:

19. A method for preparing a compound of general formula (I) according to any one of claims 1 to 18, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, comprising the following steps: In the presence of a catalyst and a basic reagent, compound I-8 and compound I-9 are coupled to give a compound of general formula (I) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof. The catalyst is preferably copper acetate, and the alkaline reagent is preferably pyridine. Among them, Q, X1~X4, R 1 ~R 3 As defined in claim 1.

20. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 18, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. Use of the compound of general formula (I) according to any one of claims 1 to 18, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, in the preparation of a MAT2A inhibitor.

22. Use of the compound of general formula (I) according to any one of claims 1 to 18, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, in the preparation of a medicament for the prevention and / or treatment of diseases associated with MAT2A activity.

23. The use according to claim 22, wherein the disease associated with MAT2A activity is a solid tumor, such as mesothelioma, neuroblastoma, rectal cancer, colon cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumor, lymphoma, and head and neck cancer.

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