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

Abstract

The invention relates to a bicyclic 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. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a bicyclic heterocyclic compound, a preparation method thereof, a pharmaceutical composition containing the same, and its use as a MAT2A inhibitor in the treatment and / or prevention of diseases related to MAT2A activity. Background Art

[0002] Methionine adenosyltransferase (MAT), also known as S-adenosylmethionine synthetase, is a key enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM) from methionine and ATP. During the methylation processes of nucleic acids, phospholipids, histones, biogenic amines, and proteins, SAM is the main methyl donor for the synthesis of glutathione and polyamines. Therefore, the regulation of SAM biosynthesis plays an important role in the processes of cell growth, differentiation, and function. The metabolism of SAM mainly involves its synthesis and regeneration, and the whole process is called the methionine cycle. Among them, SAM is converted into decarboxylated SAM (dcSAM) under the catalysis of SAM decarboxylase (SDC), and then used as an aminopropyl donor for polyamine synthesis. The by-product of polyamine synthesis, methylthioadenosine (MTA), is further regenerated into methionine through the methionine salvage pathway by methionine adenosylphosphorylase (MTAP).

[0003] MAT has three different expression forms in mammals, MAT1A, MAT2A, and MAT2B, where MAT1A and MAT2A are catalytic subunits, and MAT2B is a regulatory subunit. MAT1A is mainly expressed in the liver and is used to maintain the differentiation of hepatocytes and cholangiocyte epithelial cells, while MAT2A is widely distributed in non-parenchymal cells of the liver and non-liver tissues. Endogenous SAM in non-liver tissues 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 and plays an important role in metabolizing dietary methionine. However, during the malignant transformation of the liver, MAT1A can be reversed to MAT2A. In addition, high expression of MAT2A also exists in human epithelial tumors such as gastric cancer and colon cancer.

[0004] The deletion or mutation of tumor suppressor genes is a key driver of tumorigenesis. However, due to the lack of a suitable binding pocket, it is difficult to achieve therapeutic efficacy by directly targeting tumor drivers. Tumor-specific gene alterations not only drive tumor progression but also reveal the vulnerabilities of the tumor itself. Exploiting this vulnerability to develop synthetic lethality is a viable approach. The deletion of tumor suppressor genes often leads to the co-deletion of adjacent genes. MTAP and CDKN2A are located within 100 Kbp on chromosome 9p21, so MTAP is usually co-deleted with CDKN2A. The MTAP gene shows homozygous deletion in approximately 15% of human malignancies, especially glioblastoma, melanoma, urothelial carcinoma, pancreatic adenocarcinoma, and non-small cell lung cancer. For example, MTAP deletion occurs in 41% of glioblastomas, 22% of pancreatic cancers, 16% of melanomas, 15% of non-small cell lung cancers, and 14% of head and neck cancers. Many of these are areas with limited treatment options and a large unmet clinical need.

[0005] Studies have shown that MAT2A is a synthetic lethal target for MTAP-deficient tumors. shRNA screening found that knocking out MAT2A inhibited the activity of MTAP-deficient tumor cells, making it a susceptibility gene for MTAP-deficient tumors. Since MTAP is the only known enzyme that catalyzes the degradation of MTA, the deletion of MTAP leads to the accumulation of MTA in cancer cells. MTA can compete with SAM to selectively inhibit protein arginine methyltransferase 5 (PRMT5). Therefore, the increased MTA inhibits the activity of PRMT5 and is sensitive to further inhibition of SAM levels. Moreover, inhibiting MAT2A can reduce PRMT5-dependent mRNA splicing and induce DNA damage, and can produce a combined effect in MTAP-deficient tumor cells by inhibiting the activity of PRMT5, providing benefits for the treatment of various cancers.

[0006] Given that MAT2A is abnormally highly expressed in multiple tumor types and selective inhibition of MAT2A can reduce the proliferative activity of MTAP-deficient tumor cells, selective inhibition of MAT2A can be used as an effective tumor treatment means. At present, certain research progress has been made in the treatment of cancer with MAT2A inhibitors, but no MAT2A inhibitor has been marketed yet. Researchers still need to develop more MAT2A inhibitor molecules to select better compounds for the treatment of related tumor diseases. Summary of the Invention

[0007] The present invention relates to bicyclic heterocyclic MAT2A inhibitor compounds, their preparation methods, and pharmaceutical uses.

[0008] Accordingly, one aspect of the present invention relates to a compound of the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0009]

[0010] wherein:

[0011] is a single bond or a double bond;

[0012] Y 1 and Y 2 are each independently selected from N, NR 4 CR 4 CR 4 R 5 or C═O;

[0013] L 1 is selected from a single bond, alkylene, O, S or NR 6 ;

[0014] R 1 is selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, heteroalkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0015] R 2 is selected from aryl, heteroaryl and heterocyclic; the aryl, heteroaryl and heterocyclic are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0016] R 3 is selected from aryl, heteroaryl and heterocyclic; the aryl, heteroaryl and heterocyclic are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0017] R4 and R 5 are each independently selected from -L 2 -R 6 ;

[0018] L 2 is selected from a single bond, an alkylene group, O, S or NR 7 ;

[0019] R 6 is selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, alkylthio, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl;

[0020] R 7 is selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; the alkyl, heteroalkyl, alkoxy, alkylthio, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl.

[0021] In a preferred embodiment, the compound of formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y 1 is selected from N or NR 4 , Y 2 is selected from CR 4 or CR 4 R 5 ; R 4 and R 5 are as defined in formula (I).

[0022] In another preferred embodiment, the compound of formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y2 Selected from N or NR 4 , Y 1 Selected from CR 4 or CR 4 R 5 ; R 4 and R 5 As defined by general formula (I).

[0023] In a specific embodiment, the compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, represented by general formula (I) according to the present invention, is a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, represented by general formula (II), general formula (III) or general formula (IV),

[0024]

[0025] Wherein:

[0026] R 4a and R 4b Each independently selected from -L 2 -R 6 ;

[0027] R 1 、R 2 、R 3 、L 1 、L 2 、R 6 As defined by general formula (I).

[0028] In a preferred embodiment, the compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, represented by general formulas (I)-(IV) according to the present invention, wherein R 2 is selected from C 6-10 aryl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic group; preferably phenyl or 5- to 6-membered heteroaryl; the C 6-10 aryl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic group are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester group, oxo group, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl.

[0029] In another preferred embodiment, a compound of the general formula (I)-(IV) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic group; preferably phenyl or 5- to 6-membered heteroaryl; the C 6-10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic group is optionally substituted with one or more groups selected from C 1-6 haloalkoxy.

[0030] In another preferred embodiment, a compound of the general formula (I)-(IV) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 6-10 aryl, 5- to 13-membered heteroaryl, and 5- to 13-membered heterocyclic group; the C 6-10 aryl, 5- to 13-membered heteroaryl, and 5- to 13-membered heterocyclic group is optionally substituted with 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 group, aryl, heteroaryl.

[0031] In another preferred embodiment, a compound of the general formula (I)-(IV) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from phenyl, pyridyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, benzodiazinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxolyl, and tetrahydrobenzodioxolyl, which is optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6 alkyl, C 1-10 heteroalkyl, cyano, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group.

[0032] In another preferred embodiment, a compound represented by the general formula (I) to (IV) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from which is optionally substituted by one or more groups selected from halogen, hydroxyl, C 1-6 alkyl, C 1-10 heteroalkyl, cyano, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group

[0033] In another preferred embodiment, a compound represented by the general formula (I) to (IV) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from which is optionally substituted by one or more groups selected from halogen, hydroxyl, C 1-6 alkyl, C 1-10 heteroalkyl, cyano, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group

[0034] In another preferred embodiment, a compound represented by the general formula (I) to (IV) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from

[0035] In another preferred embodiment, a compound represented by the general formula (II) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from -L 2 -R 6 ;

[0036] L 2 is selected from a single bond, C 1-6 alkylene; preferably a bond or methylene;

[0037] R 6 is selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 heteroalkyl, C1-6 haloalkyl, C 3-6 cycloalkyl;

[0038] Preferably, R 4a is hydrogen.

[0039] In another preferred embodiment, a compound represented by the general formula (III) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b each independently selected from -L 2 -R 6 ;

[0040] L 2 selected from a single bond, C 1-6 alkylene; preferably a bond or methylene;

[0041] R 6 selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0042] Preferably, R 4a is hydrogen; R 4b selected from C 1-6 alkyl, C 3-6 cycloalkyl or -CH 2 -C 3-6 cycloalkyl.

[0043] In another preferred embodiment, a compound represented by the general formula (IV) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4a selected from -L 2 -R 6 ;

[0044] L 2 selected from a single bond, C 1-6 alkylene; preferably a bond or methylene;

[0045] R 6 selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0046] Preferably, R 4a selected from C 1-6 alkyl, C 3-6Cycloalkyl or -CH 2 -C 3-6 Cycloalkyl.

[0047] In another specific embodiment, the compound of formula (I) according to the present invention, or its tautomer, meso form, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II-1), formula (III-1) or formula (IV-1), or its tautomer, meso form, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0048]

[0049]

[0050] wherein X 1 , X 2 , X 3 are each independently selected from N or CH;

[0051] R 8a and R 8b are each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-10 heteroalkyl, cyano, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group;

[0052] R 9 are each independently selected from hydrogen, halogen, amino, cyano, hydroxy, mercapto, carboxy, 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 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group;

[0053] m is an integer from 0 to 3;

[0054] n is an integer from 0 to 4;

[0055] R 4a , R 4b , R 1 , L 1 are as defined above.

[0056] In another specific embodiment, the compound of formula (I) according to the present invention, or its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II-3), formula (III-3) or formula (IV-3), or its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0057]

[0058]

[0059] wherein X 1 、X 2 、X 3 are each independently selected from N or CH;

[0060] R 8a and R 8b are each independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-10 heteroalkyl, cyano, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group;

[0061] R 8c is selected from hydrogen and C 1-6 alkyl;

[0062] R 9 are each independently selected from hydrogen, halogen, amino, cyano, hydroxyl, mercapto, carboxyl, 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 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group;

[0063] m is an integer from 0 to 3;

[0064] n is an integer from 0 to 4;

[0065] R 4a 、R 4b 、R 1 、L 1 are as defined above.

[0066] In a preferred embodiment, a compound represented by general formula (I)-(IV) or general formula (II-1), (III-1), (IV-1), (II-3), (III-3), (IV-3) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 and X 3 are each independently selected from CH.

[0067] In another preferred embodiment, a compound represented by general formula (I)-(IV) or general formula (II-1), (III-1), (IV-1), (II-3), (III-3), (IV-3) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein one of X 1 and X 2 and X 3 is N and the rest are CH.

[0068] In another specific embodiment, a compound represented by general formula (I) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (II-2), general formula (III-2) or general formula (IV-2), or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0069]

[0070] wherein,

[0071] R 8a and R 8b are each independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-10 heteroalkyl, cyano, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group;

[0072] R 9 is selected from hydrogen, halogen, amino, cyano, hydroxyl, mercapto, carboxyl, C 1-6 alkyl, C 1-10 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6Aminoalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group;

[0073] m is an integer from 0 to 3;

[0074] n is an integer from 0 to 4;

[0075] R 4a 、R 4b 、R 1 、L 1 As defined above.

[0076] In another specific embodiment, the compound of formula (I) according to the present invention or its tautomer, meso form, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II-4), formula (III-4) or formula (IV-4) or its tautomer, meso form, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0077]

[0078] wherein,

[0079] R 8a and R 8b are each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-10 heteroalkyl, cyano, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group;

[0080] R 8c is selected from hydrogen and C 1-6 alkyl;

[0081] R 9 is selected from hydrogen, halogen, amino, cyano, hydroxy, mercapto, carboxy, 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, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group;

[0082] m is an integer from 0 to 3;

[0083] n is an integer from 0 to 4;

[0084] R 4a 、R 4b 、R 1 、L 1 as defined above.

[0085] In another preferred embodiment, a compound represented by general formula (II-1), (II-2), (II-3), or (II-4) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from -L 2 -R 6 ;

[0086] L 2 is selected from a single bond, C 1-6 alkylene; preferably a bond or methylene;

[0087] R 6 is selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0088] Preferably, R 4a is hydrogen.

[0089] In another preferred embodiment, a compound represented by general formula (III-1), (III-2), (III-3), or (III-4) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b are each independently selected from -L 2 -R 6 ;

[0090] L 2 is selected from a single bond, C 1-6 alkylene; preferably a bond or methylene;

[0091] R 6 is selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0092] Preferably, R 4a is hydrogen; R 4b is selected from C 1-6 alkyl, C 3-6 cycloalkyl or -CH2 -C 3-6 Cycloalkyl

[0093] In another preferred embodiment, a compound represented by the general formula (IV-1), (IV-2), (IV-3), (IV-4) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from -L 2 -R 6 ;

[0094] L 2 is selected from a single bond, C 1-6 alkylene; preferably a bond or a methylene group;

[0095] R 6 is selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl;

[0096] Preferably, R 4a is selected from C 1-6 alkyl, C 3-6 cycloalkyl or -CH 2 -C 3-6 cycloalkyl.

[0097] In a preferred embodiment, a compound represented by the general formula (I)-(IV) or the general formula (II-1), (III-1), (IV-1), (II-2), (III-2), (IV-2), (II-3), (III-3), (IV-3), (II-4), (III-4), (IV-4) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 or L 2 is selected from a bond or C 1-6 alkylene, preferably a bond or a methylene group.

[0098] In a preferred embodiment, a compound represented by the general formula (I)-(IV) or the general formula (II-1), (III-1), (IV-1), (II-2), (III-2), (IV-2), (II-3), (III-3), (IV-3), (II-4), (III-4), (IV-4) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from a bond or C 1-6Alkylene, preferably a bond, methylene, ethylene.

[0099] In another preferred embodiment, a compound represented by the general formula (I)-(IV) or general formula (II-1), (III-1), (IV-1), (II-2), (III-2), (IV-2), (II-3), (III-3), (IV-3), (II-4), (III-4), (IV-4) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 or R 6 is selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, preferably C 3-6 cycloalkyl.

[0100] In another preferred embodiment, a compound represented by the general formula (I)-(IV) or general formula (II-1), (IV-1), (II-2), (IV-2), (II-3), (IV-3), (II-4), (IV-4) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, the C 1-6 alkyl, C 3-6 cycloalkyl is optionally substituted by halogen; preferably C 3-6 cycloalkyl optionally substituted by halogen.

[0101] In another preferred embodiment, a compound represented by the general formula (I)-(IV) or general formula (III-1), (IV-1), (III-2), (IV-2), (III-3), (IV-3), (III-4), (IV-4) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl.

[0102] In another preferred embodiment, a compound represented by general formula (I)-(IV) or general formula (II-1), (III-1), (IV-1), (II-2), (III-2), (IV-2), (II-3), (III-3), (IV-3), (II-4), (III-4), (IV-4) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 8a is C 1-6 alkyl; R 8b is hydrogen.

[0103] In another preferred embodiment, a compound represented by general formula (I)-(IV) or general formula (II-1), (III-1), (IV-1), (II-2), (III-2), (IV-2), (II-3), (III-3), (IV-3), (II-4), (III-4), (IV-4) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 8c is C 1-6 alkyl.

[0104] In another preferred embodiment, a compound represented by general formula (I)-(IV) or general formula (II-1), (III-1), (IV-1), (II-2), (III-2), (IV-2), (II-3), (III-3), (IV-3), (II-4), (III-4), (IV-4) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 9 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; preferably C 1-6 haloalkoxy; n is 1.

[0105] In another preferred embodiment, a compound represented by general formula (I)-(IV) or general formula (II-1), (III-1), (IV-1), (II-2), (III-2), (IV-2), (II-3), (III-3), (IV-3), (II-4), (III-4), (IV-4) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4a and R4b each independently selected from -L 2 -R 6 ;

[0106] L 2 selected from a single bond, C 1-6 alkylene; preferably a bond or methylene;

[0107] R 6 selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl.

[0108] Typical compounds of the present invention include, but are not limited to:

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0116] Another aspect of the present invention provides a method for preparing a compound of formula (I) according to the present invention or its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0117]

[0118] In the presence of a catalyst and a base reagent, coupling compound I-7 with compound I-8 to obtain a compound of formula (I) or its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0119] wherein, the catalyst is preferably copper acetate, and the base reagent is preferably pyridine;

[0120] wherein, Y 1 、Y 2 、L 1 、R1 、R 2 、R 3 As defined by general formula (I).

[0121] On the other hand, the present invention provides a pharmaceutical composition comprising a compound according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0122] The present invention further provides the use of a compound according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of a MAT2A inhibitor.

[0123] The present invention further provides the use of a compound according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of a drug for preventing and / or treating diseases related to MAT2A activity.

[0124] The present invention further provides a pharmaceutical composition comprising a compound according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a drug.

[0125] The present invention further provides a pharmaceutical composition comprising a compound according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a MAT2A inhibitor.

[0126] The present invention further provides a pharmaceutical composition comprising a compound according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used for preventing and / or treating diseases related to MAT2A activity.

[0127] The present invention further provides a method for inhibiting MAT2A, which comprises administering to a subject in need an effective amount of a compound according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0128] The present invention further provides a method for preventing and / or treating a disease associated with MAT2A activity, which comprises administering to a subject in need thereof a prophylactically or therapeutically effective amount of a compound according to the present invention or a tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0129] In a preferred embodiment of the present invention, the disease associated with MAT2A activity according to the present invention may 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, corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer, melanoma, brain tumor, lymphoma, head and neck cancer, etc.

[0130] According to the conventional methods in the art to which the present invention pertains, the compounds of the present invention can form pharmaceutically acceptable acid addition salts with acids. The acids include inorganic acids and organic acids, and particularly preferably 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.

[0131] According to the conventional methods in the art to which the present invention pertains, the compounds of the present invention can form pharmaceutically acceptable base addition salts with bases. The bases include inorganic bases 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.

[0132] A pharmaceutical composition containing an active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft gelatin capsules, or syrups or elixirs. Oral compositions can be prepared by any known method for preparing pharmaceutical compositions in the art, and such compositions may contain one or more ingredients selected from the following: sweetening agents, flavoring agents, coloring agents, and preservatives to provide an attractive and palatable pharmaceutical preparation. Tablets contain the active ingredient and suitable non-toxic pharmaceutically acceptable excipients for mixing to prepare the tablets. These excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binding agents such as starch, gelatin, polyvinylpyrrolidone, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing a sustained-release effect over a longer period. For example, water-soluble taste-masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or extended-release substances such as ethyl cellulose, cellulose acetate butyrate may be used.

[0133] 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-soluble vehicle such as peanut oil, liquid paraffin, or olive oil.

[0134] Aqueous suspensions contain the active substance and excipients suitable for mixing to prepare the aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic; dispersing or wetting agents, which can be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydride, such as polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethyl paraben or propyl paraben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose, saccharin, or aspartame.

[0135] An oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding an antioxidant such as butylated hydroxyanisole or α-tocopherol.

[0136] By adding water, dispersible powders and granules suitable for preparing aqueous suspensions can provide the active ingredient and a dispersing or wetting agent, a suspending agent or one or more preservatives for mixing. Suitable dispersing or wetting agents and suspending agents are as described above. Other excipients such as sweetening agents, flavoring agents and coloring agents may also be added. These compositions can be preserved by adding an antioxidant such as ascorbic acid.

[0137] 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 emulsifying agents may be naturally occurring phospholipids such as soy lecithin, and esters or partial esters derived from fatty acids and sorbitan anhydrides such as sorbitan monooleate, and condensation products of said partial esters and ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening agents, flavoring agents, preservatives and antioxidants. Syrups and elixirs can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain demulcents, preservatives, coloring agents and antioxidants.

[0138] The pharmaceutical compositions of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable solvents and vehicles that can be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may 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. Then the oil solution is added to a mixture of water and glycerol and treated to form a microemulsion. The injection solution or microemulsion can be injected into the bloodstream of a patient by local bolus injection. Alternatively, the solution and microemulsion are preferably administered 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.

[0139] The pharmaceutical compositions of the present invention may be in the form of a sterile injectable aqueous or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques with those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. In addition, a sterile fixed oil can be conveniently used as a solvent or suspending medium. For this purpose, any compatible fixed oil including synthetic glycerol mono- or diesters can be used. In addition, fatty acids such as oleic acid can also be used to prepare injectables.

[0140] The compounds of the present invention can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperature but liquid in the rectum and thus melts in the rectum to release the drug. Such substances include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0141] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc. Additionally, the optimal treatment regimen, such as the mode of treatment, the daily dosage of the general formula compound, or the type of pharmaceutically acceptable salt, can be verified according to traditional treatment protocols.

[0142] The present invention may contain a compound of the general formula, and its pharmaceutically acceptable salts, hydrates or solvates as active ingredients, which are mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and formulated into a clinically acceptable dosage form. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions, etc. The compounds of the present invention can be used as the sole active ingredient or in combination with other drugs for treating diseases related to MAT2A activity. The combination therapy is achieved by administering the individual therapeutic components simultaneously, separately or sequentially.

[0143] Definition of Terms

[0144] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0145] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention are optionally further substituted by one or more of their corresponding isotopes, where 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), tritium (T, also known as superheavy hydrogen), and the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, and the isotopes of fluorine include19 F, and the isotopes of chlorine include 35 Cl and 37 Cl. The isotopes of bromine include 79 Br and 81 Br.

[0146] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain 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 various branched isomers thereof. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point, and the substituent can be one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate group.

[0147] The term "alkylene" refers to a divalent alkyl group, where the alkyl group is as defined above and 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., C 1-20 alkylene). The alkylene group preferably has an alkylene group containing 1 to 12 carbon atoms (i.e., C 1-12an alkylene group, more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 an alkylene group), still more preferably an alkylene group having 1 to 4 carbon atoms (i.e., C 1-6 an alkylene group). Non-limiting examples of the alkylene group include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 ))-), 1,2-ethylene (-CH 2 CH 2 ))-, 1,1-propylene (-CH(CH 2 CH 3 ))-), 1,2-propylene (-CH 2 CH(CH 3 ))-), 1,3-propylene (-CH 2 CH 2 CH 2 -), and 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc. The alkylene group may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point, and the substituents may be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo group.

[0148] The term "alkenyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl group having 2 to 4 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituents may be one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0149] 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 4 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 substituents can be one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0150] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

[0151] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but does not include the ring moiety of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. Preferably it contains 4 to 12 ring atoms such as 4 to 6, 4 to 10, 6 to 10, 6 to 12 ring atoms, where 1 to 4 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1,2,5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

[0152] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituents can be one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate group.

[0153] The term "aryl" refers to a 6- to 10-membered fully carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated π electron system, such as phenyl and naphthyl. An aryl group can be substituted or unsubstituted. When substituted, the substituent(s) can be one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

[0154] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 13 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Examples include benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, benzodiazinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxolyl, and tetrahydrobenzodioxolyl.

[0155] A heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent(s) can be one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

[0156] The term "heteroalkyl" refers to a straight-chain or branched-chain alkyl group containing 1 to 20 carbon atoms and 1 to 3 heteroatoms selected from O, N, Si, and S, where the alkyl group is defined as above, and where N and S can be optionally oxidized and N can be optionally quaternized.

[0157] The term "alkoxy" refers to -O-(alkyl), where the alkyl group is defined as above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. An alkoxy group can be optionally substituted or unsubstituted. When substituted, the substituent(s) can be one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

[0158] The term "cycloalkoxy" refers to -O-(cycloalkyl), where the cycloalkyl group is defined as above.

[0159] The term "heterocycloalkoxy" refers to -O-(heterocyclic group), where the heterocyclic group is defined as above.

[0160] The term "cycloalkylthio" means -S-(cycloalkyl), where cycloalkyl is as defined above.

[0161] The term "heterocycloalkylthio" means -S-(heterocyclic group), where heterocyclic group is as defined above.

[0162] The term "haloalkyl" means an alkyl group substituted by one or more halogens, where alkyl is as defined above.

[0163] The term "haloalkoxy" means an alkoxy group substituted by one or more halogens, where alkoxy is as defined above.

[0164] The term "hydroxyalkyl" means an alkyl group substituted by a hydroxy group, where alkyl is as defined above.

[0165] The term "hydroxy" means the -OH group.

[0166] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0167] The term "amino" means -NH 2 。

[0168] The term "cyano" means -CN.

[0169] The term "nitro" means -NO 2 。

[0170] The term "oxo group" means =O.

[0171] The term "carboxyl" means -C(O)OH.

[0172] The term "mercapto" means -SH.

[0173] The term "ester group" means -C(O)O(alkyl) or -C(O)O(cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0174] The term "acyl" means a compound containing a -C(O)R group, where R is alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl.

[0175] "Optionally" or "optionally" means that the subsequent described event or circumstance may but need not occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may but need not be present, and this description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.

[0176] "Substituted" means that one or more, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are each independently replaced by an appropriate number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) what is possible or impossible substitution without much effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as ethylenic) bond.

[0177] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and thus exert biological activity.

[0178] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" means a salt of a compound of the present invention, which has safety and effectiveness when used in mammals and has the appropriate biological activity.

[0179] "Carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the administered compound.

[0180] Synthesis Method of the Compounds of the Invention

[0181] To achieve the object of the present invention, the present invention adopts the following technical solutions.

[0182] In some embodiments, the compound of general formula (I) of the present invention or its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or its pharmaceutically acceptable salt can be prepared by Scheme 1.

[0183]

[0184] Scheme 1

[0185] Step 1: In the presence of heating, a basic reagent and a catalyst, the compound I-1 and I-2 are subjected to a coupling reaction to obtain the compound I-3, wherein the heating condition is preferably 75 °C, the basic reagent is preferably pyridine, and the catalyst is preferably copper acetate;

[0186] Step 2: In the presence of heating and a basic reagent, the compound I-3 is subjected to a hydrolysis reaction to obtain the compound I-4, wherein the heating condition is preferably 100 °C and the basic reagent is preferably sodium hydroxide;

[0187] Step 3: In the presence of a halogenating reagent, the compound I-4 is subjected to a halogenation reaction to obtain the compound I-5, and the halogenating reagent is preferably N-bromosuccinimide;

[0188] Step 4: In the presence of heating, a basic reagent, and a catalyst, couple compound I-5 with I-6 to obtain compound I-7. Among them, the heating condition is preferably 100 °C, the basic reagent is preferably cesium carbonate, and the catalyst is preferably dichlorobis(diphenylphosphino)ferrocene palladium(II);

[0189] Step 5: In the presence of heating, a basic reagent, and a catalyst, couple compound I-7 with I-8 to obtain the compound of general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof. Among them, the heating condition is preferably 100 °C, the catalyst is preferably copper acetate, and the basic reagent is preferably pyridine;

[0190] Among them, R 1 、R 2 、R 3 、Y 1 、Y 2 、L 1 are as defined in general formula (I). Detailed implementation manners

[0191] The present invention is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present invention.

[0192] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR chemical shift is given in units of 10 -6 (ppm). The NMR measurement is performed using a Bruker dps300 nuclear magnetic resonance instrument, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethylsilane (TMS).

[0193] The LC-MS measurement is performed using an 1100 Series LC / MSD Trap (ESI) mass spectrometer (manufacturer: Agilent).

[0194] The GC-MS measurement uses a GCMS-QP2010 SE.

[0195] Preparative liquid chromatography uses an lc3000 high-performance liquid chromatography instrument and an lc6000 high-performance liquid chromatography instrument (manufacturer: Innovent). The chromatographic column is Daisogel C18 10μm 60A (20mm×250mm).

[0196] High performance liquid chromatography (HPLC) was performed using Shimadzu LC-20AD high pressure liquid chromatograph (Agilent TC-C18 250×4.6 mm 5 μm column) and Shimadzu LC-2010AHT high pressure liquid chromatograph (Phenomenex C18 250×4.6 mm 5 μm column).

[0197] The thin layer chromatography silica gel plate used was Qingdao Ocean Chemical GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15 mm to 0.2 mm, and the specification used for thin layer chromatography separation and purification products was 0.4 mm to 0.5 mm.

[0198] Column chromatography generally uses Qingdao marine silica gel 100-200 mesh and 200-300 mesh silica gel as the carrier.

[0199] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Inokai, Nanjing Yaoshi, Anaiji Chemical and other companies.

[0200] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0201] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0202] A CEM Discover SP microwave reactor was used for the microwave reaction.

[0203] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0204] Unless otherwise specified in the examples, the reaction temperature is room temperature, particularly 20°C to 30°C.

[0205] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction are: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone, and the volume ratio of the solvent is adjusted according to the polarity of the compound.

[0206] The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds 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 a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0207] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to persons skilled in the art. In addition, any methods and materials similar or equivalent to those described may be applied to the method of the present invention.

[0208] Example 1: Preparation of 1-(cyclopropyl)-7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (1)

[0209]

[0210] Step 1: Preparation of 6-chloro-1-(cyclopropyl)-1H-pyrazolo[3,4-b]pyridine (1b)

[0211] At room temperature, N,N-dimethylformamide (50 mL), 6-chloro-1H-pyrazolo[3,4-b]pyridine (2.00 g, 13.0 mmol), cyclopropylboronic acid (1.68 g, 19.5 mmol), sodium carbonate (2.76 g, 26.1 mmol), pyridine (2.06 g, 26.1 mmol) and copper acetate (2.37 g, 13.0 mmol) were added to the reaction flask, and the temperature was raised to 75 °C for reaction for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the filter cake was washed with dichloromethane (50 mL), the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to obtain the title compound 1b as a colorless liquid, 200 mg, yield: 7.93%.

[0212] LC-MS: m / z 193.9 [M+H] + 。

[0213] Step 2: Preparation of 1-(cyclopropyl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (1c)

[0214] At room temperature, dimethyl sulfoxide (2 mL), water (2 mL), compound 1b (200 mg, 1.03 mmol) and sodium hydroxide (413 mg, 10.3 mmol) were added to the reaction flask, and the temperature was raised to 100 °C for reaction for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the pH was adjusted to 8-9 with dilute hydrochloric acid, extracted with dichloromethane (20 mL×2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 1c as a white solid, 147 mg, yield: 81.2%.

[0215] LC-MS: m / z 175.9 [M+H] + 。

[0216] Step 3: Preparation of 5-bromo-1-(cyclopropyl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (1d):

[0217] At room temperature, acetic acid (1 mL) and compound 1c (147 mg, 0.839 mmol) were added to a reaction flask, and bromine (141 mg, 0.881 mmol) was slowly added dropwise. After the addition was complete, the reaction was carried out at room temperature for 0.5 h. The reaction solution was filtered, the filter cake was washed with acetic acid (1.0 mL), and the filter cake was dried to constant weight to obtain the title compound 1c as a yellow solid, 194 mg, yield: 91.0%.

[0218] LC-MS: m / z 253.8 [M+H] + 。

[0219] Step 4: Preparation of 1-(cyclopropyl)-5-(2-methyl-2H-indazol-5-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (1e)

[0220] At room temperature, under nitrogen protection, 1,4-dioxane (5 mL), water (0.5 mL), compound 1d (194 mg, 0.764 mmol), (2-methyl-2H-indazol-5-yl)boronic acid 1f (161 mg, 0.916 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (83.1 mg, 0.115 mmol), and cesium carbonate (498 mg, 1.53 mmol) were added to a reaction flask, and the temperature was raised to 100 °C and the reaction was carried out for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, water (2 mL) was added, and extraction was carried out with ethyl acetate (4 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 15:1) to obtain the title compound 1e as a yellow solid, 150 mg, yield: 64.3%.

[0221] LC-MS: m / z 305.9 [M+H] + 。

[0222] Step 5: Preparation of 1-(cyclopropyl)-7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (1)

[0223] At room temperature, N,N-dimethylformamide (30 mL), compound 1e (150 mg, 0.491 mmol), (4-(difluoromethoxy)phenyl)boronic acid 1g (277 mg, 1.47 mmol), copper(II) acetate (268 mg, 1.47 mmol) and pyridine (289 mg, 4.91 mmol) were added to a reaction flask, and the temperature was raised to 70 °C and reacted for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the filter cake was rinsed with ethyl acetate (5 mL), the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:19) to obtain 125 mg of a brown oil. It was separated by preparative liquid chromatography (column model: Daisogei 30 mm × 250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile / water, gradient: 10%-100%) to obtain 22.0 mg of the title compound 1a as a white solid, yield: 10.0%.

[0224] LC-MS: m / z 447.9 [M+H] + 。

[0225] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.05 (s, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.60 - 7.53 (m, 1H), 7.47 (dd, J = 9.1, 1.7 Hz, 1H), 7.42 - 7.18 (m, 3H), 4.17 (s, 3H), 2.70 (tt, J = 7.0, 3.6 Hz, 1H), 0.89 (p, J = 4.9 Hz, 2H), 0.40 (td, J = 7.5, 5.3 Hz, 2H).

[0226] Example 2: Preparation of 1-(cyclopropylmethyl)-7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (2)

[0227]

[0228]

[0229] Step 1: Preparation of 6-chloro-1-(cyclopropylmethyl)-1H-pyrazolo[3,4-b]pyridine (2b)

[0230] At room temperature, N,N-dimethylformamide (25 mL), 6-chloro-1H-pyrazolo[3,4-b]pyridine (2.50 g, 16.3 mmol), chloromethylcyclopropane (1.62 g, 17.9 mmol) and cesium carbonate (7.96 g, 24.4 mmol) were added to a reaction flask, and the temperature was raised to 60 °C and reacted for 6 hours. After the reaction was completed, water (25 mL) was added to the reaction solution, and it was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:9) to obtain 2.00 g of the title compound 2b as a yellow oil, yield: 59.2%.

[0231] LC-MS: m / z 208.1 [M+H] + 。

[0232] Step 2: Preparation of 1-(cyclopropylmethyl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (2c)

[0233] At room temperature, dimethyl sulfoxide (20 mL), water (20 mL), compound 2b (2.00 g, 9.63 mmol) and sodium hydroxide (3.85 g, 96.3 mmol) were added to a reaction flask, and the temperature was raised to 100 °C and reacted for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the pH was adjusted to 5-6 with dilute hydrochloric acid, and it was extracted with dichloromethane (40 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, to obtain 1.70 g of the title compound 2c as a white solid, yield: 93.3%.

[0234] LC-MS: m / z 190.0 [M+H] + 。

[0235] Step 3: Preparation of 5-bromo-1-(cyclopropylmethyl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (2d)

[0236] At room temperature, acetic acid (17 mL) and compound 2c (1.70 g, 8.99 mmol) were added to a reaction flask, and bromine (1.51 g, 9.44 mmol) was slowly added dropwise. After the addition was complete, the reaction was carried out at room temperature for 0.5 hour. The reaction solution was filtered, the filter cake was washed with acetic acid (2.0 mL), and the filter cake was dried to constant weight to obtain 2.07 g of the title compound 2d as a white solid, yield: 85.9%.

[0237] LC-MS: m / z 267.9 [M+H] + 。

[0238] Step 4: Preparation of 1-(cyclopropylmethyl)-5-(2-methyl-2H-indazol-5-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (2e)

[0239] At room temperature under a nitrogen atmosphere, 1,4-dioxane (15 mL), water (1 mL), compound 2d (500 mg, 1.86 mmol), compound 1f (492 mg, 2.80 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (203 mg, 0.280 mmol), and cesium carbonate (1.22 g, 3.73 mmol) were added to a reaction flask. The temperature was raised to 100 °C and the reaction was carried out for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, extracted with ethyl acetate (15 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:10) to obtain the title compound 2e as a white solid, 375 mg, yield: 63.0%.

[0240] LC-MS: m / z 320.2 [M+H] + 。

[0241] Step 5: Preparation of 1-(cyclopropylmethyl)-7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (2)

[0242] At room temperature, N,N-dimethylformamide (45 mL), compound 2e (375 mg, 1.17 mmol), compound 1g (662 mg, 3.52 mmol), copper acetate (640 mg, 3.52 mmol), and pyridine (929 mg, 11.7 mmol) were added to a reaction flask. The temperature was raised to 70 °C and the reaction was carried out for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the filter cake was rinsed with ethyl acetate (15 mL), the organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:10) to obtain 400 mg of a brown oil. It was separated by preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile / water, gradient: 10% - 100%) to obtain 3.0 mg of the title compound 2a as a white solid, yield: 0.53%.

[0243] LC-MS: m / z 462.2 [M+H] + 。

[0244] 1 H NMR (400 MHz, DMSO-d 6)δ 8.35 (s, 1H), 8.08 (s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.91 (s, 1H), 7.72 - 7.65 (m, 1H), 7.63 - 7.54 (m, 2H), 7.52 - 7.41 (m, 4H), 4.17 (s, 3H), 3.22 (d, J = 6.9 Hz, 2H), 0.86 (td, J = 7.4, 3.9 Hz, 1H), 0.37 - 0.28 (m, 2H), 0.08 (dt, J = 6.3, 4.4 Hz, 2H).

[0245] Example 3: Preparation of 2-(Cyclopropylmethyl)-7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-2,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (3)

[0246]

[0247] Step 1: Preparation of 6-chloro-1-(cyclopropylmethyl)-2H-pyrazolo[3,4-b]pyridine (3a)

[0248] At room temperature, N,N-dimethylformamide (25 mL), 6-chloro-1H-pyrazolo[3,4-b]pyridine (2.50 g, 16.3 mmol), chloromethylcyclopropane (1.62 g, 17.9 mmol) and cesium carbonate (7.96 g, 24.4 mmol) were added to a reaction flask, and the temperature was raised to 60 °C and reacted for 6 hours. After the reaction was completed, water (25 mL) was added to the reaction solution, and it was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:5) to obtain the title compound 3a as a yellow oil, 1.25 g, yield: 37.5%.

[0249] LC-MS: m / z 208.1 [M + H] + .

[0250] Step 2: Preparation of 2-(Cyclopropylmethyl)-2,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (3b)

[0251] At room temperature, dimethyl sulfoxide (30 mL), water (30 mL), compound 3a (3.00 g, 14.4 mmol), and sodium hydroxide (5.77 g, 14.4 mmol) were added to a reaction flask, and the temperature was raised to 100 °C for reaction for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the pH was adjusted to 5 - 6 with dilute hydrochloric acid, extracted with dichloromethane (100 mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 3b as a white solid, 1.85 g, yield: 67.7%.

[0252] LC-MS: m / z 190.0 [M+H] + 。

[0253] Step 3: Preparation of 5-bromo-2-(cyclopropylmethyl)-2,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (3c)

[0254] At room temperature, acetic acid (20 mL) and compound 3b (1.85 g, 9.78 mmol) were added to a reaction flask, bromine (1.64 g, 10.2 mmol) was slowly added dropwise. After the addition was complete, the reaction was carried out at room temperature for 0.5 hour. The reaction solution was filtered, the filter cake was washed with acetic acid (10.0 mL), and the filter cake was dried to constant weight to obtain the title compound 3c as a white solid, 1.50 g, yield: 57.9%.

[0255] LC-MS: m / z 267.9 [M+H] + 。

[0256] Step 4: Preparation of 2-(cyclopropylmethyl)-5-(2-methyl-2H-indazol-5-yl)-2,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (3d)

[0257] At room temperature, under a nitrogen atmosphere, 1,4-dioxane (20 mL), water (2 mL), compound 3c (500 mg, 1.86 mmol), compound 1f (492 mg, 2.80 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (203 mg, 0.280 mmol), and cesium carbonate (1.22 g, 3.73 mmol) were added to a reaction flask, and the temperature was raised to 100 °C for reaction for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, extracted with ethyl acetate (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:10) to obtain the title compound 3d as a white solid, 215 mg, yield: 36.0%.

[0258] LC-MS: m / z 320.2 [M+H] + 。

[0259] Step 5: Preparation of 2-(cyclopropylmethyl)-7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-2,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (3)

[0260] At room temperature, N,N-dimethylformamide (20 mL), compound 3d (200 mg, 0.626 mmol), compound 1g (235 mg, 1.25 mmol), copper acetate (227 mg, 1.25 mmol) and pyridine (382 mg, 5.15 mmol) were added to a reaction flask, and the temperature was raised to 80 °C for reaction for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (30 mL). The organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:10) to obtain 100 mg of a brown oil. It was separated by preparative liquid chromatography (column model: Daisogei 30 mm * 250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile / water, gradient: 10% - 100%) to obtain 5.0 mg of the title compound (3) as a white solid, and the yield was 1.73%.

[0261] LC-MS: m / z 462.2 [M+H] + 。

[0262] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.36 (s, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.93 (t, J = 1.3 Hz, 1H), 7.59 - 7.49 (m, 3H), 7.47 (dd, J = 9.0, 1.7 Hz, 1H), 7.35 (dd, J = 9.0, 6.9 Hz, 3H), 4.18 (s, 3H), 3.99 (d, J = 7.2 Hz, 2H), 1.29 - 1.19 (m, 1H), 0.58 - 0.47 (m, 2H), 0.40 - 0.32 (m, 2H).

[0263] Example 4: Preparation of 7-(4-(difluoromethoxy)phenyl)-1-isopropyl-5-(2-methyl-2H-indazol-5-yl)-2,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (4)

[0264]

[0265] The preparation method was the same as that of Example 2, except that 2-iodopropane was used instead of chloromethylcyclopropane in Step 1 to obtain the title compound 4.

[0266] LC-MS: m / z 450.1 [M+H] + 。

[0267] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.38 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.53 (dd, J = 9.0, 1.7 Hz, 1H), 7.42 - 7.03 (m, 5H), 4.74 (hept, J = 6.8 Hz, 1H), 4.18 (s, 3H), 1.38 (d, J = 6.7 Hz, 6H).

[0268] Example 5: Preparation of 1-cyclopentyl-7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-2,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (5)

[0269]

[0270] The preparation method was the same as that of Example 2, except that iodocyclopentane was used instead of chloromethylcyclopropane in Step 1 to obtain the title compound 5.

[0271] LC-MS: m / z 475.18 [M+H] + 。

[0272] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.34 (s, 1H), 8.24 (s, 1H), 7.97 - 7.90 (m, 2H), 7.56 (d, J = 9.2 Hz, 2H), 7.52 - 7.48 (m, 2H), 7.45 (dd, J = 9.0, 1.7 Hz, 1H), 7.38 - 7.16 (m, 3H), 4.70 (p, J = 7.0 Hz, 1H), 4.17 (s, 3H), 2.12 - 1.99 (m, 2H), 1.92 - 1.80 (m, 2H), 1.80 - 1.67 (m, 2H), 1.62 (dtd, J = 11.9, 7.1, 3.3 Hz, 2H).

[0273] Example 6: Preparation of 2-cyclopentyl-7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-2,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (6)

[0274]

[0275] The preparation method was the same as that of Example 3, except that iodocyclopentane was used to replace chloromethylcyclopropane in Step 1, to obtain the title compound 6.

[0276] LC-MS: m / z 475.18 [M+H] + 。

[0277] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.34 (s, 1H), 8.24 (s, 1H), 7.97 - 7.90 (m, 2H), 7.56 (d, J = 9.2 Hz, 2H), 7.52 - 7.48 (m, 2H), 7.45 (dd, J = 9.0, 1.7 Hz, 1H), 7.38 - 7.16 (m, 3H), 4.70 (p, J = 7.0 Hz, 1H), 4.17 (s, 3H), 2.12 - 1.99 (m, 2H), 1.92 - 1.80 (m, 2H), 1.80 - 1.67 (m, 2H), 1.62 (dtd, J = 11.9, 7.1, 3.3 Hz, 2H).

[0278] Example 7: Preparation of 7-(4-difluoromethoxyphenyl)-5-(2-methyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethyl)-1,7-dihydropyrazolo[3,4-b]pyridin-6-one (7)

[0279]

[0280] The preparation method was the same as that of Example 3, except that 1,1,2-trifluoro-1-iodoethane was used to replace chloromethylcyclopropane in Step 1, to obtain the title compound 7.

[0281] LC-MS: m / z 489.9 [M+H] + 。

[0282] 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 19.3 Hz, 2H), 8.04 (s, 1H), 7.93 (s, 1H), 7.51 (td, J = 23.9, 23.4, 9.1 Hz, 4H), 7.40 - 7.29 (m, 2H), 7.25–6.94 (m, 1H), 5.22 (q, J = 9.0 Hz, 2H), 4.17 (s, 3H).

[0283] Example 8: Preparation of 2-Cyclopropyl-7-(4-(difluoromethoxy)phenyl)-5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-2,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (8)

[0284]

[0285] The preparation method was the same as that of Example 3, except that iodocyclopropane was used to replace chloromethyl cyclopropane in Step 1, and (1-methyl-2-oxo-1,2-dihydropyridin-4-yl)boronic acid was used to replace (2-methyl-2H-indazol-5-yl)boronic acid (1f) in Step 4, to obtain the title compound 8.

[0286] LC-MS: m / z 424.9 [M+H] + 。

[0287] 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.04 (s, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.80 (dd, J = 9.4, 2.7 Hz, 1H), 7.45 - 7.24 (m, 5H), 6.48 (d, J = 9.4 Hz, 1H), 3.63 (tt, J = 7.4, 3.8 Hz, 1H), 3.51 (s, 3H), 1.09 - 1.04 (m, 2H), 0.93 (td, J = 7.4, 4.9 Hz, 2H).

[0288] Example 9: Preparation of 2-Cyclobutyl-7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-2,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (9)

[0289]

[0290] The preparation method was the same as that of Example 3, except that iodocyclobutane was used to replace chloromethyl cyclopropane in Step 1, to obtain the title compound 9.

[0291] LC-MS: m / z 462.1 [M+H] + 。

[0292] 11H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.06 (s, 1H), 7.95 (s, 2H), 7.65 - 7.59 (m, 2H), 7.58 - 7.22 (m, 5H), 4.16 (s, 3H), 3.64 (p, J = 8.2 Hz, 1H), 2.43 (qd, J = 9.4, 2.8 Hz, 2H), 1.84 (qt, J = 8.1, 2.5 Hz, 2H), 1.64 (q, J = 10.3 Hz, 1H), 1.31 (dtd, J = 19.0, 10.6, 8.4 Hz, 1H).

[0293] Example 10: Preparation of 1-Cyclobutyl-7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-2,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (10)

[0294]

[0295]

[0296] The preparation method was the same as that of Example 2, except that iodocyclobutane was used instead of chloromethylcyclopropane in Step 1 to obtain the title compound 10.

[0297] LC-MS: m / z 462.1 [M + H] + .

[0298] 1 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.31 (s, 1H), 7.97 (s, 1H), 7.92 (d, J = 1.5 Hz, 1H), 7.58 - 7.17 (m, 7H), 4.84 (p, J = 8.4 Hz, 1H), 4.17 (s, 3H), 2.45 - 2.28 (m, 4H), 1.83 - 1.66 (m, 2H).

[0299] Example 11: Preparation of 2-Cyclopropyl-7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-2,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (11)

[0300]

[0301] The preparation method was the same as that of Example 3, except that iodocyclopropane was used instead of chloromethylcyclopropane in Step 1 to obtain the title compound 11.

[0302] LC-MS: m / z 447.9 [M + H] + .

[0303] 1 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.23 (s, 1H), 7.93 (d, J = 5.1 Hz, 2H), 7.60 - 7.54 (m, 1H), 7.54 - 7.48 (m, 2H), 7.45 (dd, J = 9.0, 1.7 Hz, 1H), 7.39 - 7.18 (m, 3H), 4.17 (s, 3H), 3.76 (tt, J = 7.4, 3.6 Hz, 1H), 1.03 (q, J = 3.8, 3.2 Hz, 2H), 1.01 - 0.93 (m, 2H).

[0304] Example 12: Preparation of 7-(4-Difluoromethoxyphenyl)-5-(2-methyl-2H-indazol-5-yl)-1-(2,2,2-trifluoroethyl)-1,7-dihydropyrazolo[3,4-b]pyridin-6-one (12)

[0305]

[0306] The preparation method was the same as that of Example 2, except that trifluoroiodoethane was used to replace chloromethylcyclopropane in Step 1 to obtain the title compound 12.

[0307] LC-MS: m / z 489.9 [M+H] + 。

[0308] 1 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 19.4 Hz, 2H), 8.04 (s, 1H), 7.93 (s, 1H), 7.59 - 7.43 (m, 4H), 7.37 - 7.32 (m, 2H), 7.20 (d, J = 21.3 Hz, 1H), 5.22 (q, J = 8.9 Hz, 2H), 4.17 (s, 3H).

[0309] Example 13: Preparation of 2-Isopropyl-7-(4-(difluoromethoxyphenyl))-5-(2-methyl-2H-indazol-5-yl)-2,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (13)

[0310]

[0311] The preparation method was the same as that of Example 3, except that isopropyl iodide was used to replace chloromethylcyclopropane in Step 1 to obtain the title compound 13.

[0312] LC-MS: m / z 450.17 [M+H] + 。

[0313] 1 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.53 (dd, J = 9.0, 1.7 Hz, 1H), 7.42–7.03 (m, 5H), 4.74 (hept, J = 6.8 Hz, 1H), 4.18 (s, 3H), 1.38 (d, J = 6.7 Hz, 6H).

[0314] Example 14: Preparation of 1-((2,2-difluorocyclopropyl)methyl)-7-(4-difluoromethoxy)phenyl-5-(2-methyl-2H-indazol-5-yl)-1,7-dihydropyrazolo[3,4-b]pyridin-6-one (14)

[0315]

[0316] The preparation method was the same as that of Example 2, except that 1,1-difluoro-2-(iodomethyl)cyclopropane was used instead of chloromethylcyclopropane in Step 1 to obtain the title compound 14.

[0317] LC-MS: m / z 498.15 [M + H] + .

[0318] 1 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.96–7.91 (m, 1H), 7.60–7.49 (m, 3H), 7.46 (dd, J = 9.0, 1.7 Hz, 1H), 7.39–7.32 (m, 2H), 4.33 (dd, J = 14.6, 7.5 Hz, 1H), 4.29–4.22 (m, 1H), 4.18 (s, 3H), 2.23 (ddt, J = 19.1, 15.0, 7.4 Hz, 1H), 1.66 (ddd, J = 16.5, 8.5, 4.8 Hz, 1H), 1.55–1.46 (m, 1H).

[0319] Example 15: Preparation of 1-(2-cyclopropylethyl)-7-(4-difluoromethoxy)phenyl-5-(2-methyl-2H-indazol-5-yl)-1,7-dihydropyrazolo[3,4-b]pyridin-6-one (15)

[0320]

[0321] The preparation method was the same as that of Example 2, except that 2-(iodoethyl)cyclopropane was used to replace chloromethylcyclopropane in Step 1, to obtain the title compound 15.

[0322] LC-MS: m / z 476.18 [M+H] + 。

[0323] 1 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.07 (s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.89 (s, 1H), 7.70–7.65 (m, 2H), 7.62–7.54 (m, 1H), 7.50–7.23 (m, 4H), 4.16 (s, 3H), 3.41–3.35 (m, 2H), 1.34 (q, J = 7.1 Hz, 2H), 0.26 (hept, J = 3.1 Hz, 3H), -0.22 (dt, J = 5.9, 2.7 Hz, 2H).

[0324] Example 16: Preparation of 1-(cyclopropylmethyl)-7-(4-difluoromethoxy)phenyl-5-(6-fluoropyridin-3-yl)-1,7-dihydropyrazolo[3,4-b]pyridin-6-one (16)

[0325]

[0326] The preparation method was the same as that of Example 2, except that (6-fluoropyridin-3-yl)boronic acid was used to replace (2-methyl-2H-indazol-5-yl)boronic acid in Step 4, to obtain the title compound 16.

[0327] LC-MS: m / z 427.13 [M+H] + 。

[0328] 1 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.5 Hz, 1H), 8.28–8.23 (m, 1H), 8.23 (s, 1H), 7.94 (s, 1H), 7.71–7.66 (m, 2H), 7.60–7.40 (m, 3H), 7.24–7.19 (m, 1H), 3.22 (d, J = 6.9 Hz, 2H), 0.85 (dqd, J = 12.2, 7.5, 4.7 Hz, 1H), 0.34–0.28 (m, 2H), 0.09–0.04 (m, 2H).

[0329] Example 17: Preparation of 1-(cyclopropylmethyl)-7-(4-difluoromethoxy)phenyl-5-(6-methoxypyridin-3-yl)-1,7-dihydropyrazolo[3,4-b]pyridin-6-one (17)

[0330]

[0331] The preparation method was the same as that of Example 2, except that (6-methoxypyridin-3-yl)boronic acid was used to replace (2-methyl-2H-indazol-5-yl)boronic acid in Step 4 to obtain the title compound 17.

[0332] LC-MS: m / z 498.15 [M+H] + 。

[0333] 1 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 2.4 Hz, 1H), 8.11 (s, 1H), 7.98 (dd, J = 8.6, 2.5 Hz, 1H), 7.91 (s, 1H), 7.70–7.58 (m, 2H), 7.46–7.22 (m, 3H), 6.84 (d, J = 8.6 Hz, 1H), 3.87 (s, 3H), 3.20 (d, J = 6.9 Hz, 2H), 0.91–0.79 (m, 1H), 0.34–0.28 (m, 2H), 0.09–0.03 (m, 2H).

[0334] Example 18: Preparation of 1-(cyclopropylmethyl)-7-(4-difluoromethoxyphenyl)-5-(6-methoxy-2-methylpyridin-3-yl)-1,7-dihydropyrazolo[3,4-b]pyridin-6-one (18)

[0335]

[0336] The preparation method was the same as that of Example 2, except that (6-methoxy-2-methylpyridin-3-yl)boronic acid was used to replace (2-methyl-2H-indazol-5-yl)boronic acid in Step 4 to obtain the title compound 18.

[0337] LC-MS: m / z 498.15 [M+H] + 。

[0338] 11H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.96–7.91 (m, 1H), 7.60–7.49 (m, 3H), 7.46 (dd, J = 9.0, 1.7 Hz, 1H), 7.39–7.32 (m, 2H), 4.33 (dd, J = 14.6, 7.5 Hz, 1H), 4.29–4.22 (m, 1H), 4.18 (s, 3H), 2.23 (ddt, J = 19.1, 15.0, 7.4 Hz, 1H), 1.66 (ddd, J = 16.5, 8.5, 4.8 Hz, 1H), 1.55–1.46 (m, 1H).

[0339] Example 19: Preparation of 5-(Benzo[d][1,3]dioxol-5-yl)-1-(cyclopropylmethyl)-7-(4-(difluoromethoxy)phenyl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (19)

[0340]

[0341]

[0342] The preparation method was the same as that of Example 2, except that benzo[d][1,3]dioxol-5-ylboronic acid was used instead of (2-methyl-2H-indazol-5-yl)boronic acid in Step 4 to obtain the title compound 19.

[0343] LC-MS: m / z 452.13 [M + H] + .

[0344] 1 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.89 (s, 1H), 7.71–7.64 (m, 2H), 7.46–7.40 (m, 3H), 7.21 (d, J = 1.8 Hz, 1H), 7.13 (dd, J = 8.1, 1.8 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.04 (s, 2H), 3.20 (d, J = 7.0 Hz, 2H), 0.85 (pd, J = 7.4, 2.8 Hz, 1H), 0.36–0.25 (m, 2H), 0.06 (dt, J = 6.2, 4.4 Hz, 2H).

[0345] Example 20: Preparation of 1-(Cyclopropylmethyl)-7-(4-(difluoromethoxy)phenyl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (20)

[0346]

[0347] The preparation method was the same as that of Example 2, except that benzo[d][1,3]dioxol-5-ylboronic acid was used to replace (2-methyl-2H-indazol-5-yl)boronic acid in Step 4 to obtain the title compound 20.

[0348] LC-MS: m / z 466.15 [M+H] + 。

[0349] 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.87 (s, 1H), 7.69–7.63 (m, 2H), 7.62–7.23 (m, 3H), 7.18 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 8.4, 2.2 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.25 (s, 4H), 3.18 (d, J = 7.0 Hz, 2H), 0.83 (ddt, J = 9.9, 7.2, 3.7 Hz, 1H), 0.35–0.25 (m, 2H), 0.09–0.02 (m, 2H).

[0350] Example 21: Preparation of 1-(cyclopropylmethyl)-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-7-(4-(difluoromethoxy)phenyl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (21)

[0351]

[0352] The preparation method was the same as that of Example 2, except that 2,2-difluorobenzo[d][1,3]dioxol-5-ylboronic acid was used to replace (2-methyl-2H-indazol-5-yl)boronic acid in Step 4 to obtain the title compound 21.

[0353] LC-MS: m / z 488.15 [M+H] + 。

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.94 (s, 1H), 7.68 (dd, J = 5.4, 3.5 Hz, 3H), 7.53–7.40 (m, 5H), 3.21 (d, J = 7.0 Hz, 2H), 0.85 (td, J = 7.6, 3.9 Hz, 1H), 0.36–0.27 (m, 2H), 0.11–0.04 (m, 2H).

[0355] Example 22: Preparation of 1-(cyclopropylmethyl)-7-(4-(difluoromethoxy)phenyl)-5-(2,3-dihydrobenzofuran-5-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (22)

[0356]

[0357] The preparation method was the same as that of Example 2, except that (2,3-dihydrobenzofuran-5-yl)boronic acid was used instead of (2-methyl-2H-indazol-5-yl)boronic acid in Step 4 to obtain the title compound 22.

[0358] LC-MS: m / z 450.16 [M+H] + 。

[0359] 1 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.87 (s, 1H), 7.68–7.60 (m, 2H), 7.50 (d, J = 1.9 Hz, 1H), 7.45–7.39 (m, 3H), 7.34 (dd, J = 8.3, 2.0 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 4.54 (t, J = 8.7 Hz, 2H), 3.18 (t, J = 8.1 Hz, 4H), 0.85 (ddt, J = 12.5, 7.7, 4.8 Hz, 1H), 0.34–0.27 (m, 2H), 0.09–0.03 (m, 2H).

[0360] Example 23: Preparation of 1-(cyclopropylmethyl)-7-(4-(difluoromethoxy)phenyl)-5-(2,3-dimethyl-2H-indazol-5-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (23)

[0361]

[0362] The preparation method was the same as that of Example 2, except that (2,3-dimethyl-2H-indazol-5-yl)boronic acid was used instead of (2-methyl-2H-indazol-5-yl)boronic acid in Step 4 to obtain the title compound 23.

[0363] LC-MS: m / z 476.15 [M+H] + 。

[0364] 11H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.94 (d, J = 1.4 Hz, 1H), 7.90 (s, 1H), 7.70–7.65 (m, 2H), 7.47 (d, J = 1.3 Hz, 2H), 7.43 (d, J = 8.5 Hz, 3H), 4.05 (s, 3H), 3.22 (d, J = 6.9 Hz, 2H), 2.60 (s, 3H), 0.86 (tt, J = 7.8, 4.7 Hz, 1H), 0.35–0.27 (m, 2H), 0.10–0.04 (m, 2H).

[0365] Biological Evaluation

[0366] Test Example 1: Inhibition Test of the Compound of the Invention on MAT2A Enzyme Activity

[0367] Test Objective: To detect the inhibition level of the compound of the invention on MAT2A enzyme activity.

[0368] Test Materials: MAT2A Inhibitor Screening Kit (BPS, 71402), Tris pH7.5 (Invitrogen, 15567-027), DTT (Sigma, 43816), MnCl 2 (Sigma, M1787), MgCl 2 (Sigma, M1028), EDTA (Invitrogen, 15575020), BSA (Petroleum Ether, CR84-100), DMSO (Sigma, D8418), AGI-24512 (MCE, HY-112130)

[0369] Test Procedure:

[0370] The compound was dissolved in DMSO and serially diluted with DMSO to different concentrations. 200 nL of each diluted compound at different concentrations was transferred into a reaction plate (3702, Corning) using an Echo 655 (Labcyte, 655). Among them, 10 μM reference compound (AGI-24512) was added to the positive control wells. The reaction plate was sealed with a sealing film and centrifuged at 1000 g for 1 minute for standby. A 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 (Tris pH 7.5) was added to the negative control wells. The reaction plate was sealed with a sealing film, centrifuged at 1000 g for 1 minute, and then incubated at room temperature for 30 minutes. A 2× kinase substrate L-methionine and ATP mixed solution was prepared, and 10 μL of the 2× kinase substrate and ATP mixed solution was added to each well in the reaction plate. It was centrifuged at 1000 g for 30 seconds and reacted at room temperature for 60 minutes. 20 μL of the detection reagent was added to each well, centrifuged at 1000 g for 60 seconds, and incubated in the dark at room temperature for 15 minutes. Then the absorbance value was read at 630 nm using a microplate reader (BMG, PHERAstra FSX).

[0371] The enzyme activity inhibition rate was calculated as follows:

[0372] Inhibition % = 100 - (Signalcmpd - SignalAve_PC) / (SignalAve_VC - SignalAve_PC) × 100

[0373] Where, Signal Ave_VC : The average absorbance value of the positive control wells, Signal Ave_PC : The average absorbance value of the negative control wells.

[0374] The concentration and the inhibition rate were subjected to non-linear regression curve fitting using Graphpad Prism software to obtain the IC 50 value.

[0375] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 - X) * HillSlope))

[0376] Where, X: The logarithm of the compound concentration; Y: The percentage of the inhibition rate

[0377] Table 1 provides the in vitro enzymatic activity (IC 50 ) of the compounds of the present invention against MAT2A.

[0378] In Table 1, the in vitro enzymatic activity value of the compound against MAT2A: A means IC 50 < 100 nM; B means 100 nM < IC 50<1000 nM; C refers to 1000 nM <IC 50 <10,000 nM; D refers to IC 50 > 10,000 nM.

[0379] Table 1: IC of the compound of the present invention for inhibiting MAT2A enzyme activity 50

[0380]

[0381]

[0382] Result: The compound of the present invention has good inhibitory activity against MAT2A.

[0383] Test Example 2: Inhibition test of the compound of the present invention on the proliferation activity of HCT-116 MTAP knockout cells

[0384] Test objective: To detect the inhibitory level of the compound of the present invention on the proliferation activity of HCT-116 MTAP knockout cells.

[0385] Test materials: Test compound, MCCOYS 5A MED MOD medium (invitrogen, 16600-082), fetal bovine serum (Gibco, 10099-141), penicillin / streptomycin antibiotic (Gibco, 15140122), HCT-116 MTAP knockout cell line (Beijing ChemPartner), CTG kit (Promega, G7573).

[0386] Test steps:

[0387] The compound was dissolved in DMSO and serially diluted with DMSO to different concentrations. The diluted compound working solution was transferred to each well of the reaction plate (Labcyte, P-05525-BC) using Echo 655 (Labcyte, 655), 40 nL was transferred to each well, and 10 μL of the test buffer was added to the negative control well. The HCT-116 MTAP knockout cells were seeded in a white 384-well plate, 40 μL of cell suspension containing 100 HCT-116 MTAP knockout cells was added to each well, and the cell plate was placed in a 37 °C, 5% CO 2 incubator for 10 days. Prepare the CTG detection reagent. Add 40 μL of CTG to each well and shake the cell plate to mix well. Incubate in the dark at 37 °C, 5% CO 2 incubator for 30 minutes. Set the microplate reader (Envision, 2105) and read the luminescence signal.

[0388] Data analysis:

[0389] The inhibition rate is calculated as follows:

[0390] Inhibition % = 100 - (Signal cmpd - Signal Ave_BL ) / (Signal Ave_VC - Signal Ave_BL ) × 100

[0391] Signal cmpd : Chemiluminescence value of the compound at each concentration

[0392] Signal Ave_BL : Average value of the chemiluminescence value of the system on day 0

[0393] Signal Ave_VC : Average value of the chemiluminescence value of the negative control

[0394] Calculate IC 50 , and plot the compound effect - dose curve:

[0395] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 - X) × HillSlope))

[0396] X: Logarithm of the compound concentration; Y: Percentage of the inhibition rate

[0397] Table 2 provides the in vitro inhibitory activity (IC 50 ) of the compounds of the present invention against HCT - 116 MTAP - knockout cells.

[0398] In Table 2, the in vitro inhibitory activity value of the compound against HCT - 116 MTAP - knockout cells: A means IC 50 < 100 nM; B means 100 nM < IC 50 < 1000 nM; C means 1000 nM < IC 50 < 10000 nM; D means IC 50 > 10000 nM.

[0399] Table 2: IC 50

[0400] Examples <![CDATA[MAT2A IC 50 > Examples <![CDATA[MAT2A IC 50 > 1 A 14 B 2 A 15 - 3 C 16 - 4 B 17 B 5 A 18 - 6 B 19 B 7 - 20 A 8 C 21 - 9 A 22 A 10 B 23 A 11 B 12 B 13 B

[0401] Result: The compounds of the present invention have good inhibitory activity against HCT - 116 MTAP - knockout cells.

[0402] Test Example 3: Pharmacokinetic evaluation of the compounds of the present invention in ICR mice

[0403] Male ICR mice aged 6 - 8 weeks (Beijing Vital River Laboratory Animal Technology Co., Ltd.) were orally administered the compound of the present invention. The compound was formulated in a solvent of 97% 20% hydroxypropyl - β - cyclodextrin solution, and the administration volume was 10 mL / kg. Blood was collected from the ophthalmic canthus venous plexus of the mice at 0.25, 0.50, 1.00, 2.00, 4.00, 6.00, 8.00, and 24.00 hours before and after administration. The blood was anticoagulated with sodium heparin, centrifuged at 3500 rpm for 10 minutes at 4°C, and the plasma was obtained and stored at - 20°C until testing. 10 μL of the plasma sample to be tested was placed in a 96 - well plate, and 100 μL of an acetonitrile working solution containing 5 ng / mL verapamil hydrochloride (internal standard) (100223 - 202103, National Institutes for Food and Drug Control) was added. The mixture was vortexed for 5 minutes to mix well and then centrifuged at 4000 rpm for 10 minutes. 50 μL of the supernatant was transferred, 150 μL of acetonitrile was added and mixed well, and then centrifuged at 4000 rpm for 10 minutes. The supernatant was taken and placed in a 96 - well injection plate for LC / MS (Waters UPLC I Class / LC 30AD, Waters) analysis to obtain the blood drug concentration. The pharmacokinetic parameters were analyzed using MassLynxV4.2 SCN977 data processing software. The main pharmacokinetic parameters of the compound of the present invention are shown in Table 3 below.

[0404] 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.

[0405] Table 3 Pharmacokinetic parameters of the compound of the present invention after single - oral administration to male ICR mice

[0406]

Claims

1. A compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: is a single bond or a double bond; Y 1 , Y 2 Each independently selected from N, NR 4 , CR 4 , CR 4 R 5 Or C=O; L 1 Selected from single bond, alkylene, O, S or NR 6 ; R 1 selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, heteroalkyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 2 is selected from aryl, heteroaryl and heterocyclic; the aryl, heteroaryl and heterocyclic are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; R 3 is selected from aryl, heteroaryl and heterocyclic; the aryl, heteroaryl and heterocyclic are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; R 4 and R 5 Each independently selected from -L 2 -R 6 ; L 2 Selected from single bond, alkylene, O, S or NR 7 ; R 6 selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, heteroalkyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 7 Selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; the alkyl, heteroalkyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

2. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound of the general formula (II), general formula (III) or general formula (IV) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, in: R 4a and R 4b Each independently selected from -L 2 -R 6 ; R 1 , R 2 , R 3 , L 1 , L 2 , R 6 As defined in claim 1.

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

4. A compound represented by the general formula (I) according to any one of claims 1 to 3, or its tautomer, mesomer, racemate, 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 and 5 to 13 membered heterocyclyl; said C 6-10 Aryl, 5- to 13-membered heteroaryl and 5- to 13-membered heterocyclic are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Preferably, R 3 is selected from the group consisting of phenyl, pyridyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, benzopyridazinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxyethylene and tetrahydrobenzodioxyethylene, It is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-10 Heteroalkyl, cyano, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 It is substituted by one or more groups of cycloalkyl or 3- to 6-membered heterocyclic groups; More preferably, R 3 Selected from It is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-10 Heteroalkyl, cyano, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 It is substituted by one or more groups of cycloalkyl or 3- to 6-membered heterocyclic groups; Most preferably, R 3 Selected from It is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-10 Heteroalkyl, cyano, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 The alkyl group is substituted by one or more groups of cycloalkyl or 3- to 6-membered heterocyclic group.

5. A compound represented by the general formula (I) according to any one of claims 1 to 3, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 Selected from 6. A compound of the general formula (I) according to any one of claims 1 to 4, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (II-1), the general formula (III-1) or the general formula (IV-1), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, X 1 , X 2 , X 3 are each independently selected from N or CH; R 8a and R 8b are independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-10 Heteroalkyl, cyano, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group; R 9 Each is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, carboxyl, 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, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group; m is an integer from 0 to 3; n is an integer from 0 to 4; R 4a , R 4b , R 1 , L 1 As defined in claim 2.

7. A compound of the general formula (I) according to any one of claims 1 to 4, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (II-1), the general formula (III-1) or the general formula (IV-1), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, X 1 , X 2 , X 3 are each independently selected from N or CH; R 8a and R 8b are independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-10 Heteroalkyl, cyano, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group; R 8c Selected from hydrogen and C 1-6 alkyl; R 9 Each is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, carboxyl, 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, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group; m is an integer from 0 to 3; n is an integer from 0 to 4; R 4a , R 4b , R 1 , L 1 As defined in claim 2.

8. A compound of the general formula (I) according to any one of claims 1 to 4, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (II-4), the general formula (III-4) or the general formula (IV-4), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, R 8a and R 8b are independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-10 Heteroalkyl, cyano, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group; R 8c Selected from hydrogen and C 1-6 alkyl; R 9 Selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, carboxyl, 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, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group; m is an integer from 0 to 3; n is an integer from 0 to 4; R 4a , R 4b , R 1 , L 1 As defined in claim 2.

9. A compound represented by the general formula (I) according to any one of claims 1 to 8, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L 1 or L 2 Select from key or C 1-6 Alkylene.

10. A compound represented by the general formula (I) according to any one of claims 1 to 9, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 or R 6 Selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, preferably C 3-6 Cycloalkyl.

11. A compound of the general formula (I) according to any one of claims 1 to 9, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl is optionally substituted with halogen.

12. A compound represented by the general formula (I) according to any one of claims 1 to 11, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 6 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl.

13. A compound of the general formula (I) according to any one of claims 5 to 12, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 8a C 1-6 Alkyl; R 8b For hydrogen.

14. A compound of the general formula (I) according to any one of claims 5 to 13, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 8c C 1-6 alkyl.

15. A compound of the general formula (I) according to any one of claims 5 to 14, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Each R 9 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy; preferably C 1-6 Haloalkoxy; n is 1.

16. A compound of the general formula (I) according to any one of claims 5 to 15, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 4a and R 4b Each independently selected from -L 2 -R 6 ; L 2 Selected from single bond, C 1-6 Alkylene; preferably a bond or methylene; R 6 Selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl.

17. A compound of the general formula (I) according to any one of claims 1 to 16, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from:

18. A method for preparing a compound represented by the general formula (I) according to any one of claims 1 to 17 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps: In the presence of a catalyst and an alkaline agent, compound I-7 and compound I-8 are subjected to a coupling reaction to obtain a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof; Wherein, the catalyst is preferably copper acetate, and the alkaline agent is preferably pyridine; in, Y 1 , Y 2 , L 1 , R 1 , R 2 , R 3 As defined in claim 1.

19. A pharmaceutical composition comprising a compound represented by the general formula (I) according to any one of claims 1 to 17 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. Use of a compound of formula (I) according to any one of claims 1 to 17 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19 in the preparation of a MAT2A inhibitor.

21. Use of a compound of formula (I) according to any one of claims 1 to 17 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19 in the preparation of a medicament for preventing and / or treating a disease associated with MAT2A activity.

22. The use according to claim 21, 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 body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer, melanoma, brain tumor, lymphoma, head and neck cancer.

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