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 field of medical technology, and specifically relates to a bicyclic heterocyclic compound, a preparation method thereof and a pharmaceutical composition containing the same, and use thereof as a MAT2A inhibitor in the treatment and / or prevention of diseases associated with 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. In the methylation process 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 growth, differentiation and function of cells. The metabolism of SAM mainly involves its synthesis and regeneration, and the whole process is called the methionine cycle. 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 byproduct of polyamine synthesis, methylthioadenosine (MTA), is further regenerated into methionine through the methionine recovery pathway by methylthioadenosine phosphorylase (MTAP).

[0003] MAT has three different expression forms in mammals, MAT1A, MAT2A and MAT2B, of which 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 bile duct epithelial cells, while MAT2A is widely distributed in the non-parenchymal cells of the liver and non-liver tissues. Non-liver endogenous SAM is mainly synthesized by MAT2A. Hypomethylation of the MAT2A promoter and histone acetylation lead to upregulation of MAT2A expression. Overexpression of MAT2A can promote tumor cell growth, inhibit apoptosis, and accelerate cancer development. Studies have found that MAT1A is mainly expressed in adult liver and plays an important role in metabolizing dietary methionine, but in the process of liver malignant transformation, MAT1A can be reversed to MAT2A. In addition, MAT2A is also highly expressed in human epithelial tumors such as gastric cancer and colon cancer.

[0004] The loss or mutation of tumor suppressor genes is a key driver of tumorigenesis, but due to the lack of suitable binding pockets, it is difficult to obtain therapeutic efficacy by directly targeting tumor driver factors. However, tumor-specific gene changes not only drive tumor progression, but also reveal the vulnerability of the tumor itself. Using this vulnerability to develop synthetic lethality is a feasible direction. When tumor suppressor genes are lost, it often leads to the co-deletion of genes adjacent to tumor suppressor genes. MTAP and CDKN2A are within 100Kbp of each other on chromosome 9p21, so MTAP is usually co-deleted with CDKN2A. The MTAP gene is homozygous deleted in about 15% of human malignancies, especially glioblastoma, melanoma, urothelial carcinoma, pancreatic adenocarcinoma and non-small cell lung cancer. For example, MTAP loss 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 methods and have great unmet clinical needs.

[0005] Studies have shown that MAT2A is a synthetic lethal target for MTAP-deficient tumors. ShRNA screening found that MAT2A knockout inhibited the activity of MTAP-deficient tumor cells and was a susceptibility gene for MTAP-deficient tumors. Since MTAP is the only known enzyme that catalyzes the degradation of MTA, the loss 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, increased MTA inhibits the activity of PRMT5 and is sensitive to further inhibition of SAM levels. In addition, inhibition of MAT2A can reduce PRMT5-dependent related mRNA splicing and induce DNA damage. It can produce a combined effect in MTAP-deficient tumor cells by inhibiting PRMT5 activity, providing benefits for the treatment of multiple cancers.

[0006] Given that MAT2A expression is abnormally elevated in many tumor types, and that selective inhibition of MAT2A can reduce the proliferation activity of MTAP-deficient tumor cells, selective inhibition of MAT2A can be used as an effective tumor treatment. Currently, MAT2A inhibitors have made some research progress in cancer treatment, but no MAT2A inhibitors have been marketed so far. Researchers still need to develop more MAT2A inhibitor molecules in order to select better compounds for the treatment of related tumor diseases. Summary of the invention

[0007] The present invention relates to a bicyclic heterocyclic MAT2A inhibitor compound and a preparation method and medical use thereof.

[0008] Therefore, the present invention provides a compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0009]

[0010] in:

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

[0012] X 1 , X 2 , X 3 are each independently selected from C or N;

[0013] Y 1 , Y 2 , Y 3 Each independently selected from N, NR 4 , S, O, CR 4 , CR 4 R 5 Or C=O;

[0014] The condition is, Not for

[0015] L is selected from O, S, NR 6 and single bond;

[0016] R 1 is selected from hydrogen, halogen, alkyl, hydroxy, cyano, heteroalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from halogen, alkyl, heteroalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl;

[0017] 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, alkyl, amino, hydroxy, cyano, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic;

[0018] R 3 is selected from aryl, heteroaryl and heterocyclyl; the aryl, heteroaryl and heterocyclyl are optionally substituted by one or more groups selected from halogen, hydroxy, alkyl, heteroalkyl, cyano, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl;

[0019] R 4 and R 5 are each independently selected from hydrogen, halogen, amino, NR a R b, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0020] R 6 is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0021] R a and R b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,

[0022] R a and R b Together with the nitrogen atom to which it is attached, it forms a nitrogen-containing heterocyclic group, which is optionally substituted by one or more substituents selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

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

[0024]

[0025] in:

[0026] is a single bond or a double bond;

[0027] Y 4a Selected from NR 4a , N, CR 4a , S, O, CR 4a R 5a Or C=O;

[0028] Y 5a Selected from NR 4a , N, CR 4a , S, O, CR 4a R 5a Or C=O;

[0029] R 4a and R 5a Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0030] R 1 , R 2 , R 3 , L are as defined in the general formula (I).

[0031] In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IA-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0032]

[0033] in:

[0034] Y 4a Selected from NR 4a , S, O, CR 4a R 5a Or C=O;

[0035] Y 5a Selected from N, CR 4a ;

[0036] R 4a and R 5a Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0037] R 1 , R 2 , R 3 , L are as defined in the general formula (I).

[0038] In another preferred embodiment, the compound of general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound of general formula (IB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0039]

[0040] in:

[0041] is a single bond or a double bond;

[0042] Y 4b Selected from NR 4b , N, CR 4b , S, O, CR 4b R 5b Or C=O;

[0043] Y 5b Selected from NR 4b , N, CR 4b , S, O, CR 4b R 5b Or C=O;

[0044] R 4b and R 5b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0045] R 1 , R 2 , R 3 , L are as defined in the general formula (I).

[0046] In another preferred embodiment, the compound of the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound of the general formula (IC) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0047]

[0048] in,

[0049] is a single bond or a double bond;

[0050] X 1 Selected from C or N;

[0051] X 4 Selected from C or N;

[0052] Y 1c Selected from N, NR 4c , CR 4c , CR 4c R 5c Or C=O;

[0053] Y 4c Selected from N, NR 4c , S, O, CR 4c , CR 4c R 5c Or C=O;

[0054] Y 5c Selected from N, NR 4c , S, O, CR 4c , CR 4c R 5c Or C=O;

[0055] R 4c and R 5c are each independently selected from hydrogen, halogen, amino, NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0056] R 1 , R 2 , R 3 , L, R a , R b As defined in general formula (I).

[0057] In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IC-1), (IC-2), (IC-3), (IC-4) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0058]

[0059]

[0060] in,

[0061] is a single bond or a double bond;

[0062] Y 1c1 Select from N or CR 4c1 ;

[0063] Y 4c1 Selected from NR 4c1 , S, O, CR 4c1 R 5c1 Or C=O;

[0064] Y 5c1 Select from N or CR 4c1 ;

[0065] R 4c1 and R 5c1 are each independently selected from hydrogen, halogen, amino, NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0066] Y 1c2 Select from N or CR 4c2 ;

[0067] Y 4c2 Selected from N, NR 4c2 , S, O, CR 4c2 , CR 4c2 R 5c2 Or C=O;

[0068] Y 5c2 Selected from N, NR 4c2 , S, O, CR 4c2 , CR 4c2 R 5c2 Or C=O;

[0069] R 4c2 and R 5c2 are each independently selected from hydrogen, halogen, amino, NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0070] Y 1c3 Selected from CR 4c3 R 5c3 ;

[0071] Y 4c3 Selected from N, NR 4c3 , S, O, CR 4c3 , CR 4c3 R 5c3 Or C=O;

[0072] Y 5c3 Selected from N, NR 4c3 , S, O, CR 4c3 , CR 4c3 R 5c3 Or C=O;

[0073] R 4c3 and R 5c3 are each independently selected from hydrogen, halogen, amino, NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0074] Y 1c4 Selected from CR 4c4 ;

[0075] Y 4c4 Selected from N, NR 4c4 , S, O, CR 4c4 , CR 4c4 R 5c4 Or C=O;

[0076] Y 5c4 Selected from N, NR 4c4 , S, O, CR 4c4 , CR 4c4 R 5c4 Or C=O;

[0077] R 4c4 and R 5c4 Each independently selected from halogen, amino, NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0078] R a and R b are each independently selected from hydrogen, C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally selected from halogen, C 3-6 One or more radicals are substituted on the cycloalkyl group;

[0079] R 1 , R 2 , R 3 , L are as defined in the general formula (I).

[0080] In another preferred embodiment, the compound represented by the general formula (IC) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0081] in, Selected from

[0082] R 4c and R 5c As defined in formula (IC).

[0083] In another preferred embodiment, the compound represented by the general formula (IC) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (ID), (IE), (IF), (IG), (IH) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0084] Among them, R 4c and R 5c As defined in the general formula (IC);

[0085] R 1 , R 2 , R 3 , L are as defined in the general formula (I).

[0086] In another preferred embodiment, the compound represented by the general formula (I), (IA), (IB), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (ID), (IE), (IF), (IG), (IH) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein R 2 Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl; preferably phenyl or 5- to 6-membered heteroaryl; the aryl, heteroaryl and heterocyclyl are optionally substituted by one or more groups selected from halogen, alkyl, amino, hydroxy, cyano, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl.

[0087] In another preferred embodiment, the compound represented by the general formula (I), (IA), (IB), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (ID), (IE), (IF), (IG), (IH) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, 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, hydroxy, alkyl, heteroalkyl, cyano, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl;

[0088] Preferably, R 3 is selected from the group consisting of pyridyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, benzopyridazinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxyethylene and tetrahydrobenzodioxyethylene, which is optionally substituted by one or more groups selected from halogen, hydroxy, alkyl, heteroalkyl, cyano, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl;

[0089] More preferably, R 3 Selected from pyridinyl, quinoxalinyl, The alkyl radical is substituted by one or more groups selected from halogen, hydroxy, alkyl, heteroalkyl, cyano, haloalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclyl.

[0090] In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIA) or (IIB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0091]

[0092] in:

[0093] is a single bond or a double bond;

[0094] Y 9 Selected from CR 10bR 11b or C=O; preferably C=O;

[0095] Y 10 Selected from NR 10b , N, CR 10b , S, O, CR 10b R 11b or C=O; preferably NR 10b , N, S;

[0096] Y 11 Selected from NR 10b , N, CR 10b , S, O, CR 10b R 11b or C=O; preferably NR 10b , N, CR 10b ;

[0097] R 10b and R 11b are each independently selected from hydrogen, C 1-6 alkyl;

[0098] R 7 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, amino, hydroxyl, cyano, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; preferably hydrogen, halogen, C 1-6 Alkyl, amino, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl;

[0099] R 8 Selected from hydrogen and C 1-6 alkyl;

[0100] R 9 Selected from hydrogen and C 1-6 alkyl;

[0101] m is an integer from 1 to 3;

[0102] R 1 and L are as defined in the general formula (I).

[0103] In another preferred embodiment, the compound of general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound of general formula (IIAa) or (IIBa) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0104]

[0105] in:

[0106] Y 9 Selected from CR 10b R 11b or C=O; preferably C=O;

[0107] Y 10 Selected from NR 10b , S;

[0108] Y 11 Selected from N, CR 10b ;

[0109] R 10b and R 11b are each independently selected from hydrogen, C 1-6 alkyl;

[0110] R 7 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, amino, hydroxyl, cyano, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; preferably hydrogen, halogen, C 1-6 Alkyl, amino, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl;

[0111] R 8 Selected from hydrogen and C 1-6 alkyl;

[0112] R 9 Selected from hydrogen and C 1-6 alkyl;

[0113] m is an integer from 1 to 3;

[0114] R 1 and L are as defined in the general formula (I).

[0115] In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIIA) or (IIIB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0116]

[0117] in:

[0118] Y 6 Selected from N and CR 6b ;

[0119] Y 7 Selected from S, O, NR 6b , CR 6b R 7b or C=O; preferably S;

[0120] Y 8 Selected from N, CR 6b ;

[0121] R 6b and R 7b are each independently selected from hydrogen, NR a R b , C 1-6 alkyl;

[0122] R a and R b are each independently selected from hydrogen, C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally selected from halogen, C 3-6 One or more radicals are substituted on the cycloalkyl group;

[0123] R 7 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, amino, hydroxyl, cyano, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; preferably hydrogen, halogen, C 1-6 Alkyl, amino, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl;

[0124] R 8 Selected from hydrogen and C 1-6 alkyl;

[0125] R 9 Selected from hydrogen and C 1-6 alkyl;

[0126] m is an integer from 1 to 3;

[0127] The condition is, Not for

[0128] R 1 and L are as defined in the general formula (I).

[0129] In another preferred embodiment, according to the compounds of the general formula (I), (IA), (IB), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (ID), (IE), (IF), (IG), (IH), (IIA), (IIB), (IIIA), (IIIB), (IIAa), (IIBa) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 1 Selected from halogen, C 1-6 Alkyl, C 2-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl.

[0130] In another preferred embodiment, according to the compounds of the general formula (I), (IA), (IB), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (ID), (IE), (IF), (IG), (IH), (IIA), (IIB), (IIIA), (IIIB), (IIAa), (IIBa) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein L is selected from O, S, NR 6 and single bond; R 6 Selected from hydrogen, C 1-6 alkyl.

[0131] In another preferred embodiment, the compound represented by the general formula (I), (IA), (IB), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (ID), (IE), (IF), (IG), (IH), (IIA), (IIB), (IIIA), (IIIB), (IIAa), (IIBa) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein L is selected from O or S, R 1 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group.

[0132] In another preferred embodiment, according to the compounds of the general formula (I), (IA), (IB), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (ID), (IE), (IF), (IG), (IH), (IIA), (IIB), (IIIA), (IIIB), (IIAa), (IIBa) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein L is selected from a single bond, R 1 Selected from C 3-6 Cycloalkyl, 4-6 membered heterocyclic group.

[0133] In another preferred embodiment, according to the compounds of the general formula (I), (IA), (IB), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (ID), (IE), (IF), (IG), (IH), (IIA), (IIB), (IIIA), (IIIB), (IIAa), (IIBa) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein L is a single bond; R 1 Selected from C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0134] In another preferred embodiment, the compound represented by the general formula (I), (IA), (IB), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (ID), (IE), (IF), (IG), (IH), (IIA), (IIB), (IIIA), (IIIB), (IIAa), (IIBa) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein L is O; R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl.

[0135] In another preferred embodiment, the compound represented by the general formula (I), (IA), (IB), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (ID), (IE), (IF), (IG), (IH), (IIA), (IIB), (IIIA), (IIIB), (IIAa), (IIBa) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein L is NR 6 ;

[0136] R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, the C 1-6 The alkyl group is optionally substituted with a C3-6 cycloalkyl group;

[0137] R 6 Selected from hydrogen and C 1-6 alkyl.

[0138] In another preferred embodiment, Y of the present invention 4a Selected from NR 4 , S, O; R 4a Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl.

[0139] In another preferred embodiment, Y of the present invention 5a Selected from N, CR 4a R 5a ; R 4a , R 5a are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-6 Cycloalkyl.

[0140] In another preferred embodiment, Y of the present invention 4b Selected from NR 4b , N, S; R 4b Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl.

[0141] In another preferred embodiment, Y of the present invention 5b Selected from NR 4b , N, CR 4b R 5b ; R 4b , R 5b are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl.

[0142] In another preferred embodiment, R 4c and R 5c are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 3-6 Cycloalkyl.

[0143] Typical compounds of the present invention include, but are not limited to:

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155] or its tautomer, meso racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0156] Another aspect of the present invention provides a method for preparing the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:

[0157]

[0158] In the presence of a catalyst and an alkaline agent, compound I-10 and compound I-11 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,

[0159] Wherein, the catalyst is preferably copper acetate, and the alkaline agent is preferably pyridine;

[0160] in, X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , L, R 1 , R 2 , R 3 As defined in general formula (I).

[0161] Another aspect of the present invention provides a pharmaceutical composition comprising the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0162] The present invention further provides use of the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a MAT2A inhibitor.

[0163] The present invention further provides use of the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for preventing and / or treating a disease associated with MAT2A activity.

[0164] The present invention further provides the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same, for use as a medicament.

[0165] The present invention further provides the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same, which is used as a MAT2A inhibitor.

[0166] The present invention further provides the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same, which is used for preventing and / or treating diseases related to MAT2A activity.

[0167] The present invention further provides a method for inhibiting MAT2A, comprising administering to a subject in need thereof an effective amount of a compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0168] The present invention further provides a method for preventing and / or treating a disease associated with MAT2A activity, comprising administering to a subject in need thereof a preventive or therapeutically effective amount of a compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0169] In a preferred embodiment of the present invention, the disease associated with MAT2A activity according to the present invention can be a solid tumor, such as mesothelioma, neuroblastoma, rectal cancer, colon cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, ovarian cancer, cervical cancer, uterine 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, etc. According to the conventional method in the field to which the present invention belongs, the compound of the present invention can be formed with an acid to form a pharmaceutically acceptable acid addition salt. The acid includes 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, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.

[0170] According to the conventional methods in the field of the present invention, the compounds of the present invention can form pharmaceutically acceptable basic addition salts with bases. The bases include inorganic bases and organic bases, and acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., and acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0171] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, colorants and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, corn starch or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone 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 which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release action over a longer period of time. For example, water soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time extending materials such as ethylcellulose, cellulose acetate butyrate may be used.

[0172] Oral preparations may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.

[0173] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersants or wetting agents, which may be naturally occurring phosphatides such as lecithin, or condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain fatty alcohols, for example, heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, for example, polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene oxide dehydrated sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, for example sucrose, saccharin or aspartame.

[0174] Oil suspensions can be prepared 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 thickener such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

[0175] Dispersible powders and granules suitable for preparing aqueous suspensions can provide the active ingredient and a dispersant or wetting agent, a suspending agent or one or more preservatives for mixing by adding water. Suitable dispersants or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavoring agents and coloring agents can also be added. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0176] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. Emulsions can also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs prepared with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose can be used. Such preparations can also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0177] The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable vehicles and solvents that may 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 an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol and processed to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, the solution and microemulsion may be preferably administered in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain this constant concentration, a continuous intravenous drug delivery device may be used.

[0178] The pharmaceutical composition of the present invention can be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared according to known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. The sterile injection preparation can also be a sterile injection solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be used to prepare injections.

[0179] The compounds of the invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and which will dissolve in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.

[0180] It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the combination of drugs, etc. In addition, the best treatment method, such as the mode of treatment, the daily dosage of the general compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.

[0181] The present invention may contain a compound of the general formula, and a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared 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 only active ingredient, or in combination with other drugs for treating diseases related to MAT2A activity. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately or sequentially.

[0182] Definition of terms

[0183] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0184] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention 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 replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include hydrogen (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 19 F, isotopes of chlorine include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0185] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight 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 chain isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0186] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 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 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group containing 1 to 6 carbon atoms (i.e., C 1-6 Alkylene), preferably an alkylene containing 1 to 4 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylene (-CH2CH2CH2CH2-). Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituent may be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0187] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl group containing 2 to 4 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0188] 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. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0189] 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 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls.

[0190] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O). m (wherein m is an integer 0 to 2) heteroatoms, but does not include -OO-, -OS- or -SS- ring parts, the remaining ring atoms are carbon. Preferably, 4 to 12 ring atoms are included, for example, 4 to 6, 4 to 10, 6 to 10, 6 to 12 ring atoms, of which 1 to 4 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, condensed ring and bridged heterocyclic groups.

[0191] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0192] The term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, such as phenyl and naphthyl. Aryl can be substituted or unsubstituted, and when substituted, the substituent can be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0193] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 13 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. For example, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, benzopyridazinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxyethylene and tetrahydrobenzodioxyethylene,

[0194] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0195] The term "heteroalkyl" refers to a straight or branched chain alkyl group containing 1 to 20 carbon atoms and 1 to 3 heteroatoms selected from O, N, Si and S, wherein alkyl is as defined above, and wherein N and S may be optionally oxidized and N may be optionally quaternized.

[0196] The term "alkoxy" refers to-O-(alkyl), wherein the definition of alkyl is as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents can be one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0197] The term "cycloalkoxy" refers to an -O-(cycloalkyl) group, wherein cycloalkyl is as defined above.

[0198] The term "heterocycloalkoxy" refers to -O-(heterocyclyl) wherein heterocyclyl is as defined above.

[0199] The term "cycloalkylthio" refers to -S-(cycloalkyl) wherein cycloalkyl is as defined above.

[0200] The term "heterocycloalkylthio" refers to -S-(heterocyclyl) wherein heterocyclyl is as defined above.

[0201] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0202] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0203] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0204] The term "hydroxy" refers to an -OH group.

[0205] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0206] The term "amino" refers to -NH2.

[0207] The term "cyano" refers to -CN.

[0208] The term "nitro" refers to -NO2.

[0209] The term "oxo" refers to =0.

[0210] The term "carboxy" refers to -C(O)OH.

[0211] The term "thiol" refers to -SH.

[0212] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0213] The term "acyl" refers to a compound containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0214] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0215] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0216] "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 a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0217] "Pharmaceutically acceptable salts" or "pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0218] "Carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0219] Synthesis method of the compound of the present invention

[0220] In order to achieve the purpose of the present invention, the present invention adopts the following technical scheme.

[0221] In some embodiments, the compound represented by the general formula (I) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt can be prepared by Scheme 1.

[0222]

[0223] Solution 1

[0224] Step 1: Under heating and in the presence of an alkaline agent, subjecting compound I-1 to a substitution reaction to obtain compound I-2, wherein the heating condition is preferably 70° C., and the alkaline agent is preferably sodium methoxide;

[0225] Step 2: In the presence of a halogenating agent, subjecting compound I-2 to a halogenation reaction to obtain compound I-3, wherein the halogenating agent is preferably N-bromosuccinimide;

[0226] Step 3: Under heating and in the presence of an alkaline agent, subjecting compound I-3 to a cyclization reaction to obtain compound I-4, wherein the heating condition is preferably 80° C. and the alkaline agent is preferably sodium hydroxide;

[0227] Step 4: Under heating and in the presence of a halogenating agent, subjecting compound I-4 to a halogenation reaction to obtain compound I-5, wherein the heating condition is preferably 40° C., and the halogenating agent is preferably sulfonyl chloride;

[0228] Step 5: In the presence of an alkaline agent, compound I-5 is subjected to a substitution reaction with I-6 to obtain compound I-7, wherein the alkaline agent is preferably sodium hydrogen;

[0229] Step 6: Under heating, in the presence of an alkaline agent and a catalyst, coupling reaction is performed on compound I-7 and I-8 to obtain compound I-9, wherein the heating condition is preferably 80° C., the alkaline agent is preferably potassium phosphate, and the catalyst is preferably tetrakistriphenylphosphine palladium;

[0230] Step 7: Under heating and in the presence of an acidic reagent, subjecting compound I-9 to a reduction reaction to obtain compound I-10, wherein the heating condition is preferably 80° C. and the acidic reagent is preferably hydrogen bromide;

[0231] Step 8: Under heating, in the presence of an alkaline agent and a catalyst, coupling reaction is carried out with compound I-10 and I-11 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 heating condition is preferably 45° C., the catalyst is preferably copper acetate, and the alkaline agent is preferably pyridine;

[0232] in, R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , L are as defined in the general formula (I).

[0233] In some embodiments, the compound represented by the general formula (I) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof can be prepared by Scheme 2.

[0234]

[0235] Solution 2

[0236] Step 1: In the presence of a halogenating agent, subjecting compound I-12 to a halogenation reaction to obtain compound I-13, wherein the halogenating agent is preferably N-iodosuccinimide;

[0237] Step 2: Compound I-13 and I-11 are subjected to coupling reaction under heating, in the presence of an alkaline agent and a catalyst to obtain compound I-14, wherein the heating condition is preferably 100° C., the alkaline agent is preferably potassium carbonate, and the catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

[0238] Step 3: In the presence of a halogenating agent, subjecting compound I-14 to a halogenation reaction to obtain compound I-15, wherein the halogenating agent is preferably N-iodosuccinimide;

[0239] Step 4: reacting compound I-15 with I-16 under heating conditions to obtain compound I-17, wherein the heating conditions are preferably 40°C;

[0240] Step 5: Under heating and in the presence of a catalyst, subjecting compound I-17 to a cyclization reaction to obtain compound I-18, wherein the heating condition is preferably 90° C. and the catalyst is preferably cuprous iodide;

[0241] Step 6: Under heating, in the presence of an alkaline agent and a catalyst, coupling reaction is carried out between compound I-18 and compound I-8 to obtain compound I-19, wherein the heating condition is preferably 60° C., the alkaline agent is preferably pyridine, and the catalyst is preferably copper acetate;

[0242] Step 7: Under heating and in the presence of an alkaline agent, compound I-19 is subjected to a substitution reaction with I-20 to obtain compound I-21, wherein the heating condition is preferably 90° C. and the alkaline agent is preferably sodium hydrogen;

[0243] Step 8: hydrolyzing compound I-21 under heating and in the presence of an alkaline agent to obtain a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the heating condition is preferably 60° C. and the alkaline agent is preferably potassium carbonate;

[0244] in, R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , L are as defined in the general formula (I). DETAILED DESCRIPTION

[0245] The present invention is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

[0246] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker dps300 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

[0247] LC-MS was measured using a 1100 Series LC / MSD Trap (ESI) mass spectrometer (manufacturer: Agilent).

[0248] GC-MS measurement was performed using GCMS-QP2010 SE.

[0249] The preparative liquid chromatography method used LC3000 high performance liquid chromatograph and LC6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng), and the chromatographic column was Daisogel C18 10 μm 60A (20 mm×250 mm).

[0250] 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).

[0251] 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.

[0252] Column chromatography generally uses Qingdao marine silica gel 100-200 mesh and 200-300 mesh silica gel as the carrier.

[0253] 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.

[0254] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0255] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0256] A CEM Discover SP microwave reactor was used for the microwave reaction.

[0257] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0258] Unless otherwise specified in the examples, the reaction temperature is room temperature, particularly 20°C to 30°C.

[0259] 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.

[0260] 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.

[0261] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention.

[0262] Example 1: Preparation of 4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethoxy)thiazolo[4,5-b]pyrazin-5(4H)-one (1)

[0263]

[0264] Step 1: Preparation of 6-methoxypyrazin-2-amine (1b)

[0265] At room temperature, compound 1a (20.0 g, 154.38 mmol), sodium methoxide (33.36 g, 617.54 mmol), and methanol (200 mL) were added to a reaction flask, and the temperature was raised to 70°C for 16 hours. After the reaction was completed, the temperature was lowered to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL×2). The organic phase was concentrated under reduced pressure to obtain compound 1b as a light yellow solid, 18.0 g, with a yield of 93.2%.

[0266] Step 2: Preparation of 3,5-dibromo-6-methoxypyrazin-2-amine (1c)

[0267] At room temperature, compound 1b (5.0 g, 39.96 mmol), N-bromosuccinimide (15.65 g, 87.91 mmol) and tetrahydrofuran (50 mL) were added to a reaction flask and reacted at room temperature for two hours. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1) to obtain compound 1c as a light yellow solid, 9.5 g, yield: 84.0%.

[0268] Step 3: Preparation of 6-bromo-5-methoxythiazolo[4,5-b]pyrazine-2(3H)-thione (1d)

[0269] At room temperature, compound 1c (9.4 g, 33.22 mmol), sodium hydroxide (1.99 g, 49.84 mmol) and N,N-dimethylformamide (100 mL) were added to a reaction bottle, and carbon disulfide (18.8 mL) was added in batches, and the reaction was carried out at room temperature for 2 hours, and then at 80°C for 30 minutes. The reaction solution was cooled to room temperature, water (300 mL) was added, and the pH was adjusted to 4-5 with dilute hydrochloric acid, and the solid was filtered. The solid was slurried with ethanol (50 mL) at room temperature for 30 minutes, and the solid was filtered and dried to obtain 8.0 g of the title compound as a yellow solid, with a yield of 86.5%.

[0270] Step 4: Preparation of 6-bromo-2-chloro-5-methoxythiazolo[4,5-b]pyrazine (1e)

[0271] At room temperature, compound 1d (8.0 g, 28.76 mmol) and dichloromethane (100 mL) were added to a reaction flask. The temperature was lowered to 0°C, and sulfonyl chloride (80 mL) was added in batches. After the addition, the temperature was raised to 40°C and the reaction was continued for 16 hours. The reaction solution was quenched with water (20 mL), and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The organic phase was concentrated under reduced pressure, and the residue was slurried with petroleum ether and filtered to obtain a solid. 4.4 g of the title compound was obtained as a yellow solid, with a yield of 54.5%.

[0272] Step 5: Preparation of 6-bromo-5-methoxy-2-(2,2,2-trifluoroethoxy)thiazolo[4,5-b]pyrazine (1f)

[0273] Trifluoroethanol (1.07 g, 10.69 mmol) and tetrahydrofuran (20 mL) were added to the reaction flask at room temperature. Sodium hydrogen (0.34 g, 8.56 mmol) was added under stirring, stirred for 10 minutes, and compound 1e (1.07 g, 10.69 mmol) was added to react at room temperature for 1 hour. The reaction solution was quenched with water (5 mL), extracted with ethyl acetate (60 mL), and the organic phase was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1) to obtain 1.8 g of the title compound as a white solid, with a yield of 73.4%.

[0274] Step 6: Preparation of 5-methoxy-6-(2-methyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethoxy)thiazolo[4,5-b]pyrazine (1 g)

[0275] At room temperature, compound 1f (1.8 g, 5.23 mmol), (2-methyl-2H-indazol-5-yl)boronic acid (1.89 g, 7.32 mmol), tetrakistriphenylphosphine palladium (0.30 g, 0.26 mmol), potassium phosphate (2.44 g, 11.51 mmol), water (2 mL) and 1,4-dioxane (20 mL) were added to a reaction flask, replaced with nitrogen three times, and heated to 80°C for 16 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (60 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 = 2:1) to obtain 1.0 g of the title compound as a white solid, with a yield of 48.3%.

[0276] Step 7: Preparation of 6-(2-methyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethoxy)thiazolo[4,5-b]pyrazin-5(4H)-one (1h)

[0277] At room temperature, compound 1g (1.0g, 2.53mmol) and 1,2-dichloroethane (15mL) were added to a reaction flask, and 33% hydrogen bromide acetic acid solution (15mL) was added under stirring, and the temperature was raised to 80°C for reaction for 2 hours. The reaction solution was concentrated under reduced pressure, stirred with water for 30 minutes, filtered, and dried to obtain 0.8g of the title compound as a brown solid, with a yield of 82.9%.

[0278] Step 8: Preparation of 4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethoxy)thiazolo[4,5-b]pyrazin-5(4H)-one (1)

[0279] At room temperature, compound 1h (0.2 g, 0.52 mmol), copper acetate (0.19 g, 1.05 mmol), pyridine (0.41 g, 5.24 mmol), difluoromethoxyphenylboronic acid (0.20 g, 1.05 mmol) and 1,2-dichloroethane (100 mL) were added to a reaction flask, heated to 45°C, and reacted for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 5 mg of the title compound as a yellow solid.

[0280] LC-MS: m / z 523.9 [M+H] + .

[0281] 1 H NMR(400MHz,CHCl3-d)δ9.11(s,1H),8.22(dd,J=9.3,1.7Hz,1H),7.97(s,1H),7.75(d,J=9.4Hz,1H),7 .45(d,J=8.9Hz,2H),7.35(d,J=8.5Hz,2H),6.64(t,J=73.3Hz,1H),4.74(q,J=8.0Hz,2H),4.25(s,3H).

[0282] Example 2: Preparation of 7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-5-indazolyl)-2-(2,2,2-trifluoroethylamino)thiazolo[5,4-c]pyridin-6(5H)one (2)

[0283]

[0284] Step 1: Preparation of 3-iodo-2-methoxy-4-aminopyridine (2b)

[0285] At room temperature, compound 2a (12.4 g, 100 mmol) was dispersed and dissolved in N,N-dimethylformamide (200 mL), and then N-iodosuccinimide (24.7 g, 110 mmol) was added in batches and reacted at room temperature for 2 hours. After the reaction was completed, water (500 mL) was added, and ethyl acetate (200 mL×3) was used for extraction. The organic phase was washed with saturated brine, 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 = 20:1) to obtain 23.7 g of brown oily compound with a yield of 95%.

[0286] LC-MS: m / z 250.9 [M+H] + .

[0287] Step 2: Preparation of 3-[4-(difluoromethoxy)-phenyl]-2-methoxy-4-aminopyridine (2c)

[0288] At room temperature, compound 2b (10.0 g, 40.0 mmol), potassium carbonate (11.0 g, 80.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (1.45 g, 2 mmol) and 4-difluoromethoxyphenylboronic acid pinacol ester (13.0 g, 48.0 mmol) were added to a reaction bottle, 1,4-dioxane 200 mL and water 40 mL were added in sequence, and the reaction was carried out at 100°C under a nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure, extracted with ethyl acetate (200 mL), the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to obtain 9.57 g of a white solid compound with a yield of 90%.

[0289] LC-MS: m / z 267.1[M+H] + .

[0290] Step 3: Preparation of 3-[4-(difluoromethoxy)-phenyl]-2-methoxy-5-iodo-4-aminopyridine (2d)

[0291] At room temperature, compound 2c (9.00 g, 36.0 mmol) was dispersed and dissolved in N,N-dimethylformamide (100 ml), and then N-iodosuccinimide (8.90 g, 39.6 mmol) was added in batches and reacted at room temperature for 2 hours. After the reaction, water (300 mL) was added, and ethyl acetate (100 mL*3) was extracted, and the organic phase was washed with saturated brine, 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 = 20:1) to obtain 13.1 g of brown oily compound with a yield of 93%.

[0292] LC-MS: m / z 392.9 [M+H] + .

[0293] Step 4: Preparation of N-((3-(4-(difluoromethoxy)phenyl)-5-iodo-2-methoxypyridin-4-yl)carbamothioyl)benzamide (2e)

[0294] At room temperature, compound 2d (10.0 g, 25.5 mmol) was dispersed and dissolved in dichloromethane (100 mL), and benzoyl isothiocyanate (12.5 g, 76.5 mmol) was added. The reaction was stopped after reacting at 40°C for 24 hours. After the solvent was removed under reduced pressure, water (300 mL) was added, and dichloromethane (100 mL×2) was used for extraction. The organic phase was washed with saturated brine, 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 = 10:1) to obtain 11.8 g of a yellow oily compound with a yield of 84%.

[0295] LC-MS: m / z 555.9 [M+H] + .

[0296] Step 5: Preparation of N-(7-(4-(difluoromethoxy)phenyl)-6-oxo-5,6-pyrido[5,4-c]dihydrothiazolidine 2-benzamide (2f)

[0297] At room temperature, compound 2e (5.0 g, 9.0 mmol) was dispersed and dissolved in 1,4-dioxane (50.0 mL), and cuprous iodide (171 mg, 0.9 mmol) and L-proline (207 mg, 1.8 mmol) were added in sequence. After reacting at 90°C for 12 hours, the solvent was removed under reduced pressure, extracted with ethyl acetate (200 mL), the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane: methanol = 20:1) to obtain 1.79 g of a yellow solid compound with a yield of 48.0%.

[0298] LC-MS: m / z 414.4 [M+H] + .

[0299] Step 6: Preparation of N-(7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-6-oxo-5,6-dihydrothiazolo[5,4-c]pyridin-2-yl)benzamide (2 g)

[0300] At room temperature, compound 2f (1.00 g, 2.42 mmol) was dispersed and dissolved in N,N-dimethylformamide (10.0 mL), and (2-methyl-2H-indazol-5-yl)boric acid (1i) (640 mg, 3.63 mmol), copper acetate (436 mg, 2.42 mmol) and pyridine (765 mg, 9.68 mmol) were added in sequence, and the mixture was reacted at 60°C for 12 hours. After the reaction, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane: methanol = 20:1) to obtain 828 mg of a brown solid compound with a yield of 63%.

[0301] LC-MS: m / z 544.1[M+H] + .

[0302] Step 7: Preparation of N-(7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-6-oxo-5,6-dihydrothiazolo[5,4-c]pyridin-2-yl)N-(2,2,2-trifluoroethyl)benzamide (2h)

[0303] At room temperature, compound 2g (500mg, 0.92mmol) was dispersed and dissolved in N,N-dimethylformamide (5.0mL). Sodium hydride (184mg, 4.60mmol) was added under ice bath and stirred for 1.0 hour, then 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.07g, 4.60mmol) was added and the temperature was raised to 90°C for 12 hours. The mixture was extracted with ethyl acetate (20.0mL), and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without purification.

[0304] LC-MS: m / z 626.1[M+H] + .

[0305] Step 8: Preparation of 7-(4-(difluoromethoxy)phenyl)-5-(2-methyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethylamino)thiazolo[5,4-c]pyridin-6(5H)one (2)

[0306] At room temperature, compound 2h (500 mg crude product, 0.8 mmol) was dispersed and dissolved in methanol (5.0 mL), potassium carbonate (552 mg, 4.0 mmol) was added and reacted at 60°C for 5 hours. After cooling to room temperature, the filtrate was filtered and evaporated to dryness, and separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 16.0 mg of the title compound 2 as a white solid.

[0307] LC-MS: m / z 522.09 [M+H] + .

[0308] 1 H NMR (400MHz, DMSO) δ8.45(s,1H),8.05(s,1H),7.80(d,J=1.8Hz,1H),7.64(d,J= 9.1Hz,1H),7.37(d,J=8.6Hz,2H),7.31–7.20(m,4H),4.34(s,2H),4.20(s,4H).

[0309] Example 3: Preparation of 3-(4-(difluoromethoxy)phenyl)-1-(2-methyl-2H-indazol-5-yl)-8-(2,2,2-trifluoroethoxy)-3,7-dihydro-1H-purine-2,6-dione (3)

[0310]

[0311]

[0312] Step 1: Preparation of 1-(4-(difluoromethoxy)phenyl)urea (3b)

[0313] At 0°C, compound 3a (60.00 g, 278 mmol), sodium isocyanate (54.0 g, 832 mmol) and water (500 mL) were added to a reaction flask, gradually warmed to room temperature, and reacted for 12 hours. After the reaction was completed, the title compound 3b was directly filtered to obtain a gray solid, 51.5 g, yield: 96.0%.

[0314] LC-MS: m / z 203.1[M+H] + .

[0315] Step 2: Preparation of 6-amino-1-(4-(difluoromethoxy)phenyl)pyrimidine-2,4(1H,3H)-dione (3d)

[0316] At room temperature, compound 3b (51.5 g, 253 mmol), methyl cyanoacetate (3c) (28.6 g, 253 mmol), potassium tert-butoxide (33.96 g), and methanol (300 mL) were added to a reaction flask and refluxed at 80°C for 8 hours. After the reaction, the methanol was concentrated under reduced pressure, and the residue was poured into water and directly filtered to obtain the title compound 3d as a white solid, 52.1 g, yield: 77.0%.

[0317] LC-MS: m / z 270.2 [M+H] + .

[0318] Step 3: Preparation of 6-amino-1-(4-(difluoromethoxy)phenyl)-5-nitropyrimidine-2,4(1H,3H)-dione (3e)

[0319] At room temperature, compound 3d (15.0 g, 51.9 mmol), acetic acid (150 mL), and water (150 mL) were added to a reaction flask, and sodium nitrite (7.10 g, 1.04 mmol) was added in batches, and the mixture was reacted at 50°C for 3 hours. After the reaction was completed, the mixture was cooled to 0°C and filtered to obtain the title compound 3e as a purple solid, 10.7 g, with a yield of 65.7%.

[0320] LC-MS: m / z 315.1 [M+H] + .

[0321] Step 4: Preparation of 5,6-diamino-1-(4-(difluoromethoxy)phenyl)pyrimidine-2,4(1H,3H)-dione (3f)

[0322] At room temperature, compound 3e (11.0 g, 35.0 mmol) was dissolved in aqueous ammonia (160 mL), sodium dithionite (30.5 g, 175 mmol) was added in batches, and the mixture was reacted at 50°C for 2 hours. After the reaction was completed, the mixture was filtered, the filtrate was retained, dried over anhydrous sodium sulfate, and concentrated (10 mL), and the organic phase was concentrated under reduced pressure to obtain the crude yellow oily title compound 3f, 17.0 g, yield: 100%.

[0323] LC-MS: m / z 285.0 [M+H] + .

[0324] Step 5: Preparation of 3-(4-(difluoromethoxy)phenyl)-3,7-dihydro-1H-purine-2,6-dione (3 g)

[0325] At room temperature, crude product 3f (17.0 g, 35.0 mmol), triethyl orthoformate (160 mL), and ethanol (80 mL) were added to a reaction flask and reacted at 120°C for 12 hours. After the reaction, ethanol was concentrated and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane: methanol = 20:1) to obtain the title compound 3g, 10.0 g as a yellow solid, with a yield of 96.5%.

[0326] LC-MS: m / z 295.3 [M+H] + .

[0327] Step 6: Preparation of 8-chloro-3-(4-(difluoromethoxy)phenyl)-3,7-dihydro-1H-purine-2,6-dione (3h).

[0328] At room temperature, compound 3g (7.00 g, 23.7 mmol), N-chlorosuccinimide (4.75 g, 35.6 mmol), and tetrahydrofuran (200 mL) were added to a reaction flask and reacted at 65°C for 12 hours. After the reaction, the reaction solution was directly poured into water, extracted with dichloromethane (100 mL), washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane: methanol = 4:1) to obtain the title compound 3h as a yellow solid, 5.00 g, yield: 64.5%.

[0329] LC-MS: m / z 329.0 [M+H] + .

[0330] Step 7: Preparation of 8-chloro-3-(4-(difluoromethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-1H-purine-2,6-dione (3i)

[0331] At 0°C, compound 3h (5.00 g, 15.2 mmol), potassium carbonate (4.20 g, 30.4 mmol), 2-(trimethylsilyl)ethoxymethyl chloride (7.60 g, 45.6 mmol), and N,N-dimethylformamide (60 mL) were added to a reaction flask, gradually warmed to room temperature, and reacted for 12 hours. After the reaction, the reaction solution was directly poured into water, extracted with ethyl acetate (60 mL), washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 2:1) to obtain the title compound 3i as a white solid, 2.90 g, yield: 41.4%.

[0332] LC-MS: m / z 459.3 [M+H]+ .

[0333] Step 8: Preparation of 3-(4-(difluoromethoxy)phenyl)-8-(2,2,2-trifluoroethoxy)-7-(2-(trimethylsilyl)ethoxymethyl)-3,7-dihydro-1H-purine-2,6-dione (3j)

[0334] At 0°C, compound 3i (2.90 g, 6.31 mmol), sodium hydride (884 mg, 22.1 mmol), and N,N-dimethylformamide (30 mL) were added to a reaction bottle, stirred for 20 minutes, and then 2,2,2-trifluoroethanol (1.89 g, 18.9 mmol) was added, and the temperature was gradually raised to room temperature and reacted for 12 hours. After the reaction was completed, the reaction solution was directly poured into ice water, extracted with ethyl acetate (60 mL), washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 2:1) to obtain the title compound 3j as a white solid, 2.10 g, yield: 63.7%.

[0335] LC-MS: m / z 523.2 [M+H] + .

[0336] Step 9: Preparation of 3-(4-(difluoromethoxy)phenyl)-1-(2-methyl-2H-indazol-5-yl)-8-(2,2,2-trifluoroethoxy)-7-(2-(trimethylsilyl)ethoxymethyl)-3,7-dihydro-1H-purine-2,6-dione (3k)

[0337] At room temperature and in an oxygen atmosphere, compound 3j (2.10 g, 4.02 mmol), copper acetate (1.60 g, 8.04 mmol), triethylamine (819 mg, 8.04 mmol), (2-methyl-2H-indazol-5-yl)boric acid (1.41 g, 8.04 mmol), and dichloromethane (50 mL) were added to a reaction flask and reacted at 55°C for 12 hours. After the reaction, the reaction solution was directly poured into 100 ml of water, extracted with dichloromethane (50 mL), washed with saturated sodium chloride aqueous solution (100 mL), 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 = 1:1) to obtain the title compound 3k as a white solid, 1.00 g, yield: 38.1%.

[0338] LC-MS: m / z 653.2[M+H] + .

[0339] Step 10: Preparation of 3-(4-(difluoromethoxy)phenyl)-1-(2-methyl-2H-indazol-5-yl)-8-(2,2,2-trifluoroethoxy)-3,7-dihydro-1H-purine-2,6-dione (3)

[0340] Compound 3k (1.00 g, 1.53 mmol) and 4M methanolic hydrochloric acid solution (30 mL) were added to a reaction flask at room temperature and reacted at 55°C for 12 hours. After the reaction, the organic phase was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 28.0 mg of the title compound 3 as a white solid powder.

[0341] LC-MS: m / z 523.4 [M+H] + .

[0342] 1 H NMR (400MHz, DMSO-d6) δ13.43(s,1H),8.41(s,1H),7.69–7.61(m,2H),7.57(d,J=8. 9Hz, 2H), 7.38–7.29 (m, 3H), 7.18–7.10 (m, 1H), 4.99 (q, J = 8.7Hz, 2H), 4.20 (s, 3H).

[0343] Example 4: Preparation of 3-(4-(difluoromethoxy)phenyl)-1-(2-methyl-2H-indazol-5-yl)-6-(methylthio)-8-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-purin-2-one (4)

[0344]

[0345] Step 1: Preparation of 6-chloro-3-(4-(difluoromethoxy)phenyl)-1-(2-methyl-2H-indazol-5-yl)-8-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-purin-2-one (4a)

[0346] At room temperature, compound 3 (60.0 mg, 0.115 mmol), phosphorus oxychloride (3 mL), and acetonitrile (3 mL) were added to a reaction flask and reacted at 60° C. for 72 hours. After the reaction, the organic phase was concentrated under reduced pressure to obtain the crude yellow oily title compound 4a, 60.0 mg, yield: 100.0%.

[0347] LC-MS: m / z 541.0 [M+H] + .

[0348] Step 2: Preparation of 3-(4-(difluoromethoxy)phenyl)-1-(2-methyl-2H-indazol-5-yl)-6-(methylthio)-8-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-purin-2-one (4)

[0349] Compound 4a (60.0 mg, 0.115 mmol), sodium thiomethoxide (80.5 mg, 1.150 mmol) and tetrahydrofuran (30 mL) were added to a reaction flask at room temperature and reacted for 2 hours at room temperature. After the reaction, the organic phase was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 5.70 mg of the title compound 4 as a white solid powder.

[0350] LC-MS: m / z 553.1[M+H] + .

[0351] 1 H NMR (400MHz, DMSO-d6) δ8.41 (s, 1H), 7.69–7.61 (m, 2H), 7.57 (d, J = 8.9Hz, 2H), 7.3 8–7.29(m,3H),7.18–7.10(m,1H),4.99(q,J=8.7Hz,2H),4.20(s,3H),2.43(s,3H).

[0352] Example 5: Preparation of 6-cyclopropyl-1-(4-difluoromethoxy)phenyl-3-(2-methyl-2H-indazol-5-yl)thieno[2,3-b]pyrazin-2(1H)one (5)

[0353]

[0354] Step 1: Preparation of methyl 3-amino-5-bromothiophene-2-carboxylate (5b)

[0355] At room temperature, 3-amino-thiophene-2-carboxylic acid methyl ester (5a) (32.0 g, 204 mmol) was dissolved in dichloromethane (300 mL) and methanol (300 mL), calcium carbonate (81.5 g, 814 mmol) was added and stirred for 5 minutes, phenyltrimethylammonium tribromide (230 g, 611 mmol) was added in batches and stirred for 24 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the organic phase was concentrated, poured into water, extracted with ethyl acetate again, the organic phase was dried and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 92: 8) to obtain the title compound 5b as a brown oil, 16.5 g, yield: 34.3%.

[0356] LC-MS: m / z 235.8 [M+H] + .

[0357] Step 2: Preparation of methyl 3-amino-5-cyclopropylthiophene-2-carboxylate (5c)

[0358] At room temperature, compound 5b (16.5 g, 69.9 mmol) was dissolved in anhydrous 1,4-dioxane (160 mL) and water (16 mL), cesium carbonate (45.5 g, 140 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane (23.5 g, 140 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (6.00 g, 8.39 mmol) were added, nitrogen was bubbled in, and stirred at 80°C for 16 hours. After the reaction was completed, it was poured into ice water, extracted with ethyl acetate, and the organic phase was dried and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 94:6) to obtain yellow liquid compound 5c, 8.0 g, yield: 53.0%.

[0359] LC-MS: m / z 197.9 [M+H] + .

[0360] Step 3: Preparation of methyl 5-cyclopropyl-3-(4-(difluoromethoxy)phenyl)amino)thiophene-2-carboxylate (5d)

[0361] At room temperature, compound 5c (4.50 g, 22.8 mmol) was dissolved in anhydrous 1,4-dioxane (45 mL), and compound 4-difluoromethoxyiodobenzene (9.24 g, 34.2 mmol), cesium carbonate (11.2 g, 34.2 mmol), brettphos (4.26 g, 6.84 mmol), and Pd2(dba)3 (3.13 g, 3.42 mmol) were added. The mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the organic phase was concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 97:3) to obtain the title compound 5d as a yellow oil, 6.0 g, yield: 77.5%.

[0362] LC-MS: m / z 399.9 [M+H] + .

[0363] Step 4: Preparation of methyl 5-cyclopropyl-3-(4-(difluoromethoxy)phenyl)(4-methoxybenzyl)amino)thiophene-2-carboxylate (5e)

[0364] At room temperature, compound 5d (2.0 g, 5.89 mmol) was dissolved in N,N-dimethylformamide (20 mL), cesium carbonate (3.84 g, 11.8 mmol) and 4-methoxybenzyl chloride (1.85 g, 11.9 mmol) were added, and stirred at room temperature for 16 hours. After the reaction was completed, it was poured into ice water, extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain the title compound 5e as a yellow oil, 2.2 g, yield: 81.2%.

[0365] LC-MS: m / z 459.9 [M+H] + .

[0366] Step 5: Preparation of 5-cyclopropyl-3-(4-(difluoromethoxy)phenyl)(4-methoxybenzyl)amino)thiophene-2-carboxylic acid (5f)

[0367] At room temperature, compound 5e (1.70 g, 3.70 mmol) was dissolved in tetrahydrofuran (10 mL), sodium hydroxide solution (10 mL, 4 mol / L) was added, and stirred at 80°C for 16 hours. After the reaction, the system was poured into water, the pH was adjusted to 5 with dilute hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product 5f, 1.5 g, with a yield of 91%.

[0368] LC-MS: m / z 445.9 [M+H] + .

[0369] Step 6: Preparation of tert-butyl (5-cyclopropyl-3-((4-(difluoromethoxy)phenyl)(4-methoxybenzyl)amino)thiophen-2-yl)carbamate (5 g)

[0370] At room temperature, compound 5f (1.50 g, 3.37 mmol) was dissolved in toluene (15 mL) and tert-butyl alcohol (15 mL), and triethylamine (851 mg, 8.42 mmol) and diphenylphosphoryl azide (1.58 g, 5.72 mmol) were added, and stirred at 100°C for 2 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether) to obtain compound 5g, 1.5 g, with a yield of 37.9%.

[0371] LC-MS: m / z 516.9 [M+H] + .

[0372] Step 7: Preparation of 5-cyclopropyl-N-3-(4-(difluoromethoxy)phenyl)thiophene-2,3-diamine (5h)

[0373] Compound 5g (600 mg, 1.44 mmol) was dissolved in trifluoroacetic acid (5 mL) at room temperature and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to obtain a crude compound 5i, 300 mg, with a yield of 87.1%.

[0374] LC-MS: m / z 296.9 [M+H] + .

[0375] Step 8: Preparation of 6-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-1,4-dihydrothieno[2,3-b]pyrazine-2,3-dione (5i)

[0376] Compound 5h (300 mg, 1.01 mmol) was dissolved in diethyl oxalate (3 mL) at room temperature and reacted overnight at 140° C. After the reaction, the solvent was concentrated under reduced pressure to obtain a crude compound 5i, 300 mg, with a yield of 84.6%.

[0377] LC-MS: m / z 351.0 [M+H] + .

[0378] Step 9: Preparation of 3-chloro-6-cyclopropyl-1-(4-difluoromethoxy)phenylthieno[2,3-b]pyrazin-2(1H)one (5j)

[0379] Compound 5i (300 mg, 0.856 mmol) was dissolved in diethyl oxalate (3 mL) and phosphorus oxychloride (3 mL) at room temperature and reacted at 100°C for 1 hour. After the reaction, the solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a yellow solid compound 5j, 200 mg, yield: 63.3%.

[0380] LC-MS: m / z 369.0 [M+H] + .

[0381] Step 10: Preparation of 6-cyclopropyl-1-(4-difluoromethoxy)phenyl-3-(2-methyl-2H-indazol-5-yl)thieno[2,3-b]pyrazin-2(1H)one (5)

[0382] At room temperature, compound 5j (200 mg, 0.542 mmol) was dissolved in N,N-dimethylformamide (5 mL), and (2-methyl-2H-indazol-5-yl)boric acid (191 mg, 1.08 mmol), cesium carbonate (442 mg, 1.36 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (59.0 mg, 0.081 mmol) were added. After nitrogen replacement, the mixture was placed at 100°C for 2 hours. After the reaction, cesium carbonate was filtered, the solvent was concentrated under reduced pressure, and the crude product was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile / water, gradient: 10%-100%) to obtain the title compound 5 as a white solid, 8 mg, yield: 3.18%

[0383] LC-MS: m / z 465.0 [M+H] + .

[0384] 1 H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.48(s,1H),8.13(dd,J=9.3,1.7Hz,1H),7.65(dd,J=11.8,8.8Hz,3H),7.5 6(d,J=2.6Hz,1H),7.40–7.29(m,3H),4.18(s,3H),0.73(t,J=6.1Hz,1H),0.49–0.43(m,2H),0.29–0.23(m,2H).

[0385] Example 6: Preparation of 6-cyclopropyl-1-(4-difluoromethoxy)phenyl-3-(2-methyl-2H-indazol-5-yl)-3,4-dihydrothieno[3,2-d]pyrimidin-2(1H)-one (6)

[0386]

[0387] Step 1: Preparation of (5-cyclopropyl-3-((4-(difluoromethoxy)phenyl)(4-methoxybenzyl)amino)thiophen-2-yl)methanol (6a)

[0388] Compound 5f (1.50 g, 3.26 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) at room temperature. After cooling to 0°C, the mixture was stirred for 5 minutes, and lithium aluminum tetrahydride (371 mg, 9.79 mmol) was added in batches and stirred for 25 minutes. After the reaction was complete, the reaction solution was poured into ice water, filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate, dried, and the organic phase was concentrated to obtain the title compound 6a as a brown oil, 1.20 g, yield: 85.2%.

[0389] LC-MS: m / z 432.14 [M+H] + .

[0390] Step 2: Preparation of 2-azidomethyl-5-cyclopropyl-N-(4-difluoromethoxy)phenyl-N-(4-methoxybenzyl)thiophene-3-amine (6b)

[0391] At room temperature, compound 6a (1.20 g, 2.78 mmol) was dissolved in anhydrous tetrahydrofuran (12 mL), 1.8-diazabicyclo[5.4.0]undecene-7 (635 mg, 4.17 mmol) and diphenylphosphoryl azide (1.15 g, 4.17 mmol) were added, and stirred for 2 hours. After the reaction was completed, it was poured into ice water, extracted with ethyl acetate, and the organic phase was dried and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 94:6) to obtain yellow liquid compound 6b, 1.10 g, yield: 86.6%.

[0392] LC-MS: m / z 457.14 [M+H] + .

[0393] Step 3: Preparation of 2-aminomethyl-5-cyclopropyl-N-(4-difluoromethoxy)phenyl-N-(4-methoxybenzyl)thiophene-3-amine (6c)

[0394] At room temperature, compound 6b (1.10 g, 2.41 mmol) was dissolved in anhydrous tetrahydrofuran (11 mL) and water (11 mL), and triphenylphosphine (1.26 g, 4.82 mmol) was added. Stir at room temperature for 16 hours under nitrogen atmosphere. After the reaction was completed, it was poured into water, extracted with ethyl acetate, and the organic phase was dried and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 7:3) to obtain the title compound 6c as a yellow oil, 900 mg, yield: 86.7%.

[0395] LC-MS: m / z 430.9 [M+H] + .

[0396] Step 4: Preparation of N-(5-cyclopropyl-3-(4-difluoromethoxy)phenyl)amino)thiophen-2-yl)methyl)-2-methyl-2H-indazol-5-amine (6d)

[0397] At room temperature, compound 6c (420 mg, 0.975 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 1i (257 mg, 1.46 mmol), copper acetate (177 mg, 0.975 mmol), and triethylamine (296 mg, 2.93 mmol) were added, and stirred at 60°C for 1 hour. After the reaction was completed, the mixture was poured into water, and the solid was filtered and dried to obtain the title compound 6d as a brown solid, 500 mg, with a yield of 91.4%.

[0398] LC-MS: m / z 561.2 [M-148+H] + .

[0399] Step 5: Preparation of 6-cyclopropyl-1-(4-difluoromethoxy)phenyl-3-(2-methyl-2H-indazol-5-yl)-3,4-dihydrothieno[3,2-d]pyrimidin-2(1H)-one (6)

[0400] At room temperature, compound 6d (500 mg, 1.14 mmol) was dissolved in tetrahydrofuran (5 mL), triphosgene (1.50 g, 5.06 mmol) was added, and the mixture was stirred at 80°C for 30 minutes. After the reaction was completed, the system was poured into water, extracted with ethyl acetate, and the organic phase was dried and concentrated. The crude product was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile / water, gradient: 10%-100%) to obtain the title compound 6 as a yellow solid, 8 mg, yield: 1.51%

[0401] LC-MS: m / z 467.0 [M+H] + .

[0402] 1 H NMR(400MHz, DMSO-d6)δ8.33(s,1H),7.64(d,J=2.0Hz,1H),7.55(d,J=9.2Hz,1H),7.51–7.47(m,2H),7.27(s,1H),7.25(dd,J=9.2,2.1Hz,1H),7.23–

[0403] 7.18(m,2H),6.98(s,1H).5.00(s,2H),4.16(s,3H),0.70–0.58(m,1H),0.41–0.33(m,2H),0.24(dt,J=8.2,3.1Hz,2H).

[0404] Example 7: Preparation of 6-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-2H-indazol-5-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (7)

[0405]

[0406] Step 1: Preparation of methyl 5-cyclopropyl-3-(1-(4-(difluoromethoxy)phenyl)ureido)thiophene-2-carboxylate (7a)

[0407] At room temperature, compound 5f (0.50 g, 1.47 mmol) and tetrahydrofuran (5 mL) were added to the reaction flask. The temperature was lowered to -35°C, and chlorosulfonyl isocyanate (0.27 mL, 2.21 mmol) was added dropwise, and the reaction was continued at -35°C for 1 hour. After the reaction was completed, water was added to quench the reaction under stirring, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (10 mL x 2), and concentrated under reduced pressure to obtain the title compound 7a as a white solid, 523 mg, with a yield of 93.31%.

[0408] Step 2: Preparation of 6-cyclopropyl-1-(4-(difluoromethoxy)phenyl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (7b)

[0409] At room temperature, compound 7a (523 mg, 1.37 mmol), sodium hydroxide (109.0 mg, 2.74 mmol), acetonitrile (5 mL) and water (5 mL) were added to a reaction flask and reacted at room temperature for 2 hours. After the reaction was completed, water was added to dilute the reaction solution, and the pH was adjusted to 3 with aqueous hydrochloric acid solution (3N). The product precipitated, filtered, and dried to obtain white solid compound 7b, 453 mg, with a yield of 94.53%.

[0410] Step 3: Preparation of 6-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-2H-indazol-6-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (7)

[0411] At room temperature, compound 7b (0.20 g, 0.571 mmol), (2-methyl-2H-indazol-5-yl)boronic acid (0.20 g, 1.143 mmol), copper acetate (0.20 g, 1.143 mmol), pyridine (2 mL) and 1,2-dichloroethane (100 mL) were added to a reaction flask and stirred at 45°C for 16 hours. After the reaction was completed, the reaction solution was poured into water (100 mL) for dilution and extracted with dichloromethane solution (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile / water, gradient: 10%-100%) to obtain white solid compound 7, 22 mg, yield 8.09%.

[0412] LC-MS: m / z 480.1[M+H] + .

[0413] 1 H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.73(s,1H),7.68–7.61(m,4H),7.34–7.26(m,3H),7.15–7.1 1(m,1H),4.19(s,3H),0.63(td,J=8.3,4.2Hz,1H),0.49–0.40(m,2H),0.26(dt,J=8.2,3.2Hz,2H).

[0414] Example 8: Preparation of 3-(4-difluoromethoxy)phenyl)-9-methyl-1-(2-methyl-2H-indazol-5-yl)-8-(2,2,2-trifluoroethoxy)-3,9-dihydro-1H-purine-2,6-dione (8)

[0415]

[0416] Step 1: Preparation of 3-(4-difluoromethoxy)phenyl)-9-methyl-1-(2-methyl-2H-indazol-5-yl)-8-(2,2,2-trifluoroethoxy)-3,9-dihydro-1H-purine-2,6-dione (8)

[0417] At room temperature, compound 3 (100 mg, 0.191 mmol), cesium carbonate (125 mg, 0.382 mmol), iodomethane (32.6 mg, 0.229 mmol), and N,N-dimethylformamide (1 mL) were added to a reaction flask and reacted at 80°C for 2 hours. After the reaction, the organic phase was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 7.40 mg of the title compound 8 as a white solid powder.

[0418] LC-MS: m / z 537.12 [M+H] + .

[0419] 1 H NMR(400MHz, DMSO-d6)8.40(s,1H),7.77–7.53(m,4H),7.38(d,J=8.3Hz,2H),7.21( s, 1H), 7.06 (dd, J = 9.0, 2.0Hz, 1H), 5.15 (q, J = 8.8Hz, 2H), 4.20 (s, 3H), 2.75 (s, 3H).

[0420] Example 9: Preparation of 3-(4-difluoromethoxy)phenyl)-7-methyl-1-(2-methyl-2H-indazol-5-yl)-8-(2,2,2-trifluoroethoxy)-3,7-dihydro-1H-purine-2,6-dione (9)

[0421]

[0422]

[0423] Step 1: Preparation of 3-(4-difluoromethoxy)phenyl)-7-methyl-1-(2-methyl-2H-indazol-5-yl)-8-(2,2,2-trifluoroethoxy)-3,7-dihydro-1H-purine-2,6-dione (9)

[0424] At room temperature, compound 3 (100 mg, 0.191 mmol), cesium carbonate (125 mg, 0.382 mmol), iodomethane (32.6 mg, 0.229 mmol), and N,N-dimethylformamide (1 mL) were added to a reaction flask and reacted at 80°C for 2 hours. After the reaction, the organic phase was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 24.2 mg of the title compound 9 as a white solid powder.

[0425] LC-MS: m / z 537.12 [M+H] + .

[0426] 1 H NMR(400MHz,DMSO-d6)δ8.41(s,1H),7.70–7.63(m,2H),7.60–7.52(m,2H),7.41– 7.26(m,3H),7.19–7.08(m,1H),5.04(q,J=8.7Hz,2H),4.20(s,3H),3.68(s,3H).

[0427] Example 10: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (10)

[0428]

[0429] Step 1: Preparation of 4-chloro-2-cyclopropylthiazole-5-carbonitrile (10b)

[0430] At room temperature, under nitrogen atmosphere, 1,4-dioxane (80 mL), compound 10a (5.00 g, 27.9 mmol), cyclopropylboronic acid (2.52 g, 29.3 mmol), palladium acetate (627 mg, 2.79 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.62 g, 2.79 mmol) and potassium phosphate (11.9 g, 55.9 mmol) were added to a reaction flask, and the temperature was raised to 100° C. to react overnight. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 24:1) to obtain the title compound 10b as a white solid, 3.25 g, yield: 63.0%.

[0431] Step 2: Preparation of 2-cyclopropyl-4-((-(difluoromethoxy)phenyl)amino)thiazole-5-carbonitrile (10c)

[0432] At room temperature, under nitrogen atmosphere, 1,4-dioxane (80 mL), compound 10b (1.50 g, 8.12 mmol), 4-difluoromethoxyaniline (1.55 g, 9.75 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (736 mg, 0.812 mm ol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (436 mg, 0.812 mmol) and cesium carbonate (4.76 g, 14.6 mmol) were added to a reaction bottle, the temperature was raised to 100°C for reaction for 2 hours, the reaction solution was filtered and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 19: 1) to obtain the title compound 10c as a yellow solid, 2.02 g, yield: 80.9%.

[0433] Step 3: Preparation of 2-cyclopropyl-4-((-(difluoromethoxy)phenyl)amino)thiazole-5-carboxamide (10d)

[0434] At room temperature, dimethyl sulfoxide (5 mL), compound 10c (500 mg, 1.63 mmol) and potassium carbonate (1.12 g, 8.13 mmol) were added to a reaction flask, and hydrogen peroxide (1.84 g, 16.3 mmol, 30% / wt) was added dropwise at 10°C to 20°C. After the addition, the mixture was reacted at room temperature for 2 hours. After the reaction was completed, water (100 mL) was added dropwise to the reaction solution to precipitate a solid. After stirring for 15 minutes, the solid was filtered, and the filtered solid was dissolved in ethyl acetate (20 mL), 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 = 4:1) to obtain the title compound 10d as a yellow solid, 320 mg, yield: 60.5%.

[0435] Step 4: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (10e)

[0436] At 0°C, under nitrogen atmosphere, N,N-dimethylformamide (2 mL), compound 10d (150 mg, 0.461 mmol) and sodium hydride (55.3 mg, 1.38 mmol) were added to a reaction bottle, stirred for 20 minutes, and carbonyldiimidazole (112 mg, 0.692 mmol) was added. After the addition, the mixture was reacted at 45°C for 2 hours. After the reaction was completed, water (1 mL) was added to quench the reaction, the pH was adjusted to 4-5 with dilute hydrochloric acid solution, and the mixture was extracted with ethyl acetate (10 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 10e as a yellow solid, 162 mg, yield: 100%.

[0437] Step 5: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (10)

[0438] At room temperature, 1,2-dichloroethane (100 mL), compound 10e (162 mg, 0.461 mmol), (2-methyl-2H-indazol-5-yl)boric acid (243 mg, 1.38 mmol), copper acetate (251 mg, 1.38 mmol), pyridine (365 mg, 4.61 mmol) and triethylamine (467 mg, 4.61 mmol) were added to a reaction bottle and reacted at 55° C. for 48 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile / water, gradient: 10%-100%) to obtain the title compound 10 as a white solid, 28.0 mg, yield: 12.6%.

[0439] LC-MS: m / z 481.9 [M+H] + .

[0440] 1 H NMR (400MHz, DMSO-d6) δ8.42 (s, 1H), 7.71-7.61 (m, 2H), 7.57 (d, J = 8.8Hz, 2H), 7.39-7.29 (m, 3H), 7.15 (dd, J=9.1, 2.0Hz, 1H), 4.20 (s, 3H), 1.25 (dt, J=7.1, 3.6Hz, 3H), 1.00-0.92 (m, 2H).

[0441] Example 11: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-1,2,3,4-tetrahydrobenzo[4,5-]imidazo[1,2-a]pyrazin-7-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (11)

[0442]

[0443] Step 1: Preparation of tert-butyl 4-(5-bromo-2-nitrophenyl)-3-oxopiperazine-1-carboxylate (11b)

[0444] 3-Oxapiperazine-1-carboxylic acid tert-butyl ester (15.8 g, 79.2 mmol) was added to a flask, and N,N-dimethylformamide (360 mL) was added under nitrogen protection. Sodium hydride (4.5 g, 60%) was added after stirring at room temperature for 10 minutes, and stirring was continued for 10 minutes. Finally, 4-bromo-2-fluoro-1-nitrobenzene (15.8 g, 71.8 mmol) was added and stirred at room temperature for 1 hour. After the reaction was completed, ethyl acetate and saturated aqueous solution of ammonium chloride were added, and then the organic phase was washed with water and saturated aqueous sodium chloride solution in turn, and the organic phase was concentrated to dryness. The concentrate was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 4:1) to obtain the title compound 11b, 14.5 g.

[0445] LC-MS: m / z 400.0 [M+H] + .

[0446] Step 2: Preparation of tert-butyl 7-bromo-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (11c)

[0447] 11b (14.5 g, 0.036 mol), iron powder (9.50 g, 170 mmol), and acetic acid (220 mL) were added to a flask and refluxed for 1 hour. After the reaction, the organic phase was concentrated to dryness, and the concentrate was purified by column chromatography (mobile phase: dichloromethane / methanol = 50:1) to obtain the title compound 11c, 13.6 g.

[0448] LC-MS: m / z 352.1[M+H] + .

[0449] Step 3: Preparation of 7-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (11d)

[0450] 11c (13.6 g, 0.038 mol) and dilute hydrochloric acid (4N, 60 ml) were added to a flask and refluxed for 1 hour. After the reaction, the pH was adjusted to weak alkalinity with saturated sodium bicarbonate aqueous solution, then extracted with dichloromethane, the organic phases were combined, dried and concentrated, and the concentrate was purified by column chromatography (mobile phase: dichloromethane / methanol = 20:1) to obtain the title compound 11d, 3.6 g.

[0451] LC-MS: m / z 252.0 [M+H] + .

[0452] Step 4: Preparation of 7-bromo-2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (11e)

[0453] At room temperature, compound 11d (1.4 g, 5.57 mmol) and 1,2-dichloroethane (140 mL) were added to a reaction bottle, and formaldehyde (2.75 g, 37%), glacial acetic acid (1.13 g, 18.8 mmol), and sodium triacetoxyborohydride (6.7 g, 31.6 mmol) were added, and the mixture was reacted at room temperature for 1 hour. After the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was purified by column chromatography (dichloromethane: methanol = 13: 1) to obtain the title compound 11e, 1.0 g.

[0454] LC-MS: m / z 266.1[M+H] + .

[0455] Step 5: Preparation of (2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-7-yl)boronic acid (11f)

[0456] At room temperature, compound 11e (1.0 g, 3.77 mmol), tetrahydroxydiboron (1.0 g, 90 mmol), chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (30 mg, 0.038 mmol), N,N-diisopropylethylamine (1.46 g, 11.3 mmol), and methanol (10 mL) were added to a reaction flask, replaced with nitrogen, and reacted at 53°C for 2 hours. After the reaction, the reaction solution was filtered and concentrated, and the concentrate was purified by column chromatography (dichloromethane: methanol = 33:1) to obtain the title compound 11f, 2.4 g.

[0457] LC-MS: m / z 232.1[M+H] + .

[0458] Step 6: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-1,2,3,4-tetrahydrobenzo[4,5-]imidazo[1,2-a]pyrazin-7-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (11)

[0459] At room temperature, 1,2-dichloroethane (100 mL), compound 10e (351 mg, 1.01 mmol), 11f (580 mg, 2.50 mmol), copper acetate (454 mg, 2.50 mmol), pyridine (447 mg, 6.05 mmol) and triethylamine (611 mg, 6.05 mmol) were added to a reaction bottle and reacted at 80°C for 24 hours. After the reaction, the reaction solution was filtered and concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile / water, gradient: 30%-100%) to obtain the title compound 11 as a white solid, 13.6 mg.

[0460] LC-MS: m / z 536.9 [M+H] + .

[0461] 1 H NMR (400MHz, DMSO-d6) δ7.62(d,J=8.5Hz,1H),7.56(d,J=8.9Hz,2H),7.50(d,J=1.9Hz,1H),7.38-7.29(m,3H),7. 19-7.13(m,1H),4.12(t,J=5.5Hz,2H),3.79(s,2H),2.46(s,3H),1.26(dd,J=8.2,3.3Hz,5H),1.00-0.93(m,2H).

[0462] Example 12: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-b]pyrazin-5(4H)-one (12)

[0463]

[0464] Step 1: Preparation of 6-chloro-5-(2-methyl-2H-indazol-5-yl)pyrazin-2-amine (12b)

[0465] At room temperature, 5-bromo-6-chloropyrazin-2-amine (15.0 g, 71.96 mmol), (2-methyl-2H-indazol-5-yl)boric acid (15.20 g, 86.35 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (5.22 g, 7.20 mmol), potassium carbonate (39.78 g, 287.85 mmol), water (60 mL) and 1,4-dioxane (300 mL) were added to a reaction flask, nitrogen was replaced three times, and the temperature was raised to 80°C for 18 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (600 mL), and the organic phase was concentrated under reduced pressure to obtain 10.3 g of the title compound as a white solid, with a yield of 55.1%.

[0466] Step 2: Preparation of 6-methoxy-5-(2-methyl-2H-indazol-5-yl)pyrazin-2-amine (12c)

[0467] At room temperature, compound 12b (10.3 g, 39.60 mmol), sodium methoxide (10.7 g, 198.31 mmol), and methanol (150 mL) were added to a reaction flask, and the temperature was raised to 70°C for 16 hours. After the reaction was completed, the methanol was removed by concentration, water (200 mL) was added, and the mixture was extracted with dichloromethane (200 mL×2). The organic phase was concentrated under reduced pressure to obtain 7.1 g of the title compound as a yellow solid, with a yield of 70.1%.

[0468] Step 3: Preparation of 3-bromo-6-methoxy-5-(2-methyl-2H-indazol-5-yl)pyrazin-2-amine (12d)

[0469] At room temperature, compound 12c (7.0 g, 27.4 mmol), N-bromosuccinimide (4.39 g, 24.6 mmol) and tetrahydrofuran (140 mL) were added to a reaction flask and reacted at room temperature for 2 hours. Water (300 mL) was added to the reaction solution, extracted with dichloromethane (200 mL×2), 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 = 2:1) to obtain 7.4 g of the title compound as a yellow solid, with a yield of 80.7%.

[0470] Step 4: Preparation of 5-methoxy-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-b]pyrazine-2(3H)-thione (12e)

[0471] At room temperature, 12d (7.4 g, 22.1 mmol) and N,N-dimethylformamide (74 mL) were added to a reaction flask, and sodium hydroxide (3.1 g, 77.5 mmol) and carbon disulfide (28 mL) were added, and the mixture was reacted at room temperature for 2 hours and at 80°C for 0.5 hours. Water (100 mL) was added to the reaction solution, the pH was adjusted to 3, and the title compound was filtered to obtain 7.2 g of a yellow solid, with a yield of 98.7%.

[0472] Step 5: Preparation of 2-chloro-5-methoxy-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-b]pyrazine (12f)

[0473] At room temperature, compound 12e (4.3 g, 13.0 mmol) and dichloroethane (43 mL) were added to a reaction flask, and oxalyl chloride (43 mL) was added under stirring, and the mixture was reacted at 80°C for 3 hours. The reaction solution was concentrated to dryness, quenched with water (50 mL), adjusted to pH = 7, and filtered to obtain 4.3 g of the title compound as a brown solid, with a yield of 99.2%.

[0474] Step 6: Preparation of 2-bromo-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-b]pyrazin-5(4H)-one (12 g).

[0475] At room temperature, compound 12f (4.3 g, 12.96 mmol) and 1 M boron tribromide solution (160 mL) were added to a reaction flask and reacted at 80° C. for 3 hours. The reaction solution was concentrated, quenched with water (50 mL), and filtered to obtain 4.0 g of the title compound as a brown solid, with a yield of 85.2%.

[0476] Step 7: Preparation of 2-bromo-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-b]pyrazin-5(4H)-one (12h)

[0477] At room temperature, compound 12g (4.0g, 11.04mmol), (4-(difluoromethoxy)phenyl)boric acid (4.15g, 22.09mmol), copper acetate (4.01g, 22.09mmol), pyridine (8.74g, 110.43mmol) and 1,2-dichloroethane (2000mL) were added to a reaction bottle and reacted at 45°C for 4 hours. The reaction solution was filtered, the mother liquor was concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 2:1) to obtain 0.6g of the title compound as a yellow solid, with a yield of 10.7%.

[0478] Step 8: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-b]pyrazin-5(4H)-one (12)

[0479] At room temperature, compound 12h (0.2 g, 0.39 mmol), cyclopropylboronic acid (68.1 mg, 0.79 mmol), palladium acetate (17.8 mg, 0.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (91.7 mg, 0.15 mmol), potassium phosphate (185 mg, 0.87 mmol) and 1,4-dioxane (4 mL) were added to a reaction flask, replaced with nitrogen three times, heated to 100°C, and reacted for 16 hours. The reaction solution was filtered, the mother liquor was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 110 mg of the title compound 12 as a yellow solid.

[0480] LC-MS: m / z 466.0 [M+H] + .

[0481] 1 H NMR (400MHz, DMSO-d6) δ8.97(d,J=1.4Hz,1H),8.48(s,1H),8.08(dd,J=9.2,1.7Hz,1H),7.63(d,J=9.3Hz,1H) ,7.60–7.57(m,2H),7.42–7.21(m,3H),4.18(s,3H),2.50–2.41(m,1H),1.28–1.14(m,2H),1.04–0.92(m,2H).

[0482] Example 13: Preparation of 2-ethoxy-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (13)

[0483]

[0484] Step 1: Preparation of 4-chloro-2-ethoxythiazole-5-carbonitrile (13b)

[0485] Tetrahydrofuran (50 mL), 2,4-dichloro-5-cyanothiazole (13a) (5.00 g, 27.9 mmol) and sodium ethoxide (9.50 g, 27.9 mmol, 20% / wt) were added to a reaction bottle at 0°C and reacted at room temperature for 2 hours. After the reaction, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL x 2), the organic phases were combined, 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 = 99:1) to obtain the title compound 13b as a yellow oil, 4.05 g, yield: 76.9%.

[0486] LC-MS: m / z 274.0 [M+H] + .

[0487] The remaining steps were the same as the preparation method of Example 10, except that compound 13b was used instead of compound 10b to prepare compound 13.

[0488] LC-MS: m / z 486.0 [M+H] + .

[0489] 1 H NMR (400MHz, DMSO-d6) δ8.42(s,1H),7.69(d,J=1.9Hz,1H),7.65(d,J=9.0Hz,1H),7.57(d,J=8.9Hz,2H), 7.37-7.17(m,3H),7.15(dd,J=9.1,2.0Hz,1H),4.38(q,J=7.0Hz,2H),4.20(s,3H),1.34(t,J=7.0Hz,3H).

[0490] Example 14: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-1,2,3,4-tetrahydrobenzo[4,5-]imidazo[1,2-a]pyrazin-7-yl)thieno[4,5-d]pyrimidine-5,7(4H,6H)-dione (14)

[0491]

[0492] The title compound 14 was prepared in the same manner as in Example 7, except that 11f was used instead of (2-methyl-2H-indazol-5-yl)boronic acid in step 3.

[0493] LC-MS: m / z 536.1[M+H] + .

[0494] 1H NMR (400MHz, DMSO-d6) δ7.77(s,1H),7.74(d,J=8.5Hz,1H),7.71–7.62(m,3H),7.52–7.15(m,4H),4.74(s,2H),4.42(s,2H ), 3.82 (s, 2H), 3.04 (s, 3H), 0.66 (ddd, J = 13.5, 8.3, 5.2Hz, 1H), 0.45 (dt, J = 5.8, 2.9Hz, 2H), 0.28 (dt, J = 8.2, 3.3Hz, 2H).

[0495] Example 15: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thieno[3,2-b]pyridin-5(4H)-one (15).

[0496]

[0497] Step 1: Preparation of 6-bromothieno[3,2-b]pyridine (15b)

[0498] At room temperature, tert-butyl thiophene-3-ylcarbamate (20.0 g, 100 mmol), 2-bromomalonaldehyde (15.9 g, 105 mmol), and acetic acid (200 mL) were added to a reaction flask, and the temperature was raised to 100°C for 16 hours. After the reaction was completed, the temperature was lowered to room temperature, water (200 mL) was added, and the pH was adjusted to 7 with a saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (200 mL×2), and the organic phase was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 15:1) to obtain the title compound 15b as a light yellow solid, 5.5 g, yield: 23.2%.

[0499] Step 2: Preparation of 6-bromothieno[3,2-b]pyridine 4-oxide (15c)

[0500] At room temperature, compound 15b (5.5 g, 25.6 mmol) and dichloromethane (70 mL) were added to a reaction flask, and m-chloroperbenzoic acid (5.7 g, 28.2 mmol) was added in batches, and the mixture was reacted at room temperature for two hours. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1) to obtain the title compound 15c as a yellow solid, 5.0 g, yield: 84.5%.

[0501] Step 3: Preparation of 6-bromo-5-chlorothieno[3,2-b]pyridine (15d)

[0502] Compound 15c (5.0 g, 21.7 mmol) and phosphorus oxychloride (50 mL) were added to a reaction flask at room temperature and reacted at 100°C for 2 hours. The reaction solution was concentrated, water (100 mL) was added, and the pH was adjusted to 8 with sodium hydroxide solution, and extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain the title compound 15d as a yellow solid, 4.5 g, yield: 83.3%.

[0503] Step 4: Preparation of 6-bromothieno[3,2-b]pyridin-5-ol (15e)

[0504] At room temperature, compound 15d (4.5 g, 18.1 mmol), sodium hydroxide (7.2 g, 181 mmol), water (45 mL) and dimethyl sulfoxide (45 mL) were added to a reaction flask and reacted at 100°C for 3 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to 9 with dilute hydrochloric acid solution. The title compound 15e was filtered to obtain a brown solid, 1.5 g, yield: 36.0%.

[0505] Step 5: Preparation of 6-bromo-4-(4-(difluoromethoxy)phenyl)thieno[3,2-b]pyridin-5(4H)-one (15f)

[0506] At room temperature, compound 15e (1.5 g, 6.5 mmol), (4-(difluoromethoxy)phenyl)boric acid (2.4 g, 13.0 mmol), copper acetate (2.3 g, 13.0 mmol), pyridine (5.1 g, 65.1 mmol) and 1,2-dichloroethane (450 mL) were added to a reaction flask and reacted at 45°C for 3 hours. The reaction solution was filtered, the filtrate was extracted with water (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 8:1) to obtain the title compound 15f as a yellow solid, 0.8 g, yield: 32.9%.

[0507] Step 6: Preparation of 6-(2-methyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethoxy)thiazolo[4,5-b]pyrazin-5(4H)-one (15 g)

[0508] At room temperature, under nitrogen atmosphere, diisopropylamine (0.4 g, 4.0 mmol) and tetrahydrofuran (15 mL) were added to a reaction flask, and n-butyl lithium (1.6 mL, 4.0 mmol) was added at -78 ° C. The reaction was kept warm for 20 minutes, and a tetrahydrofuran solution of compound 15f (0.6 g, 1.6 mmol) was added, and the reaction was kept warm for 20 minutes. A tetrahydrofuran solution of hexachloroethane (0.7 g, 3.2 mmol) was added, and the reaction was kept warm for 30 minutes. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (60 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 8:1) to obtain the title compound 15g, 120 mg, as a yellow solid, with a yield of 18.3%.

[0509] Step 7: Preparation of 2-chloro-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thieno[3,2-b]pyridin-5(4H)-one (15h)

[0510] At room temperature and under nitrogen atmosphere, compound 15g (0.1 g, 0.2 mmol), (2-methyl-2H-indazol-5-yl)boric acid (43.3 mg, 0.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (17.9 mg, 0.02 mmol), sodium carbonate (57.3 mg, 0.5 mmol), 1,4-dioxane (2 mL) and water (0.4 mL) were added to a reaction flask and reacted at 70°C for 2 hours. The reaction solution was separated into the aqueous layer and the organic layer was concentrated to obtain the title compound 15h as a yellow solid, 80 mg.

[0511] Step 8: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thieno[3,2-b]pyridin-5(4H)-one (15)

[0512] At room temperature and under nitrogen atmosphere, compound 15h (80.0 mg, 0.2 mmol), cyclopropylboronic acid (30.0 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (12.7 mg, 0.02 mmol), cesium carbonate (113.8 mg, 0.3 mmol), 1,4-dioxane (2 mL) and water (0.4 mL) were added to a reaction flask and reacted at 80°C for 2 hours. The reaction solution was separated into the aqueous layer, the organic layer was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 6 mg of the title compound 15 as a white solid.

[0513] LC-MS: m / z 463.8 [M+H] + .

[0514] 1 H NMR(400MHz, DMSO-d6)δ8.36(s,1H),8.24(s,1H),8.08(t,J=1.3Hz,1H),7.59–7.54(m,2H),7.54–7.48(m,2H),7.43 –7.17(m,3H),6.21(s,1H),4.17(s,3H),2.25(tt,J=8.4,5.0Hz,1H),1.12–1.03(m,2H),0.70(dt,J=6.8,4.5Hz,2H).

[0515] Example 16: Preparation of 7-amino-2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thieno[3,2-b]pyrazin-5(4H)-one (16)

[0516]

[0517] Step 1: Preparation of methyl 3-amino-5-bromothiophene-2-carboxylate (16b)

[0518] At room temperature, 3-amino-thiophene-2-carboxylic acid methyl ester (16a) (32.0 g, 204 mmol) was dissolved in dichloromethane (300 mL) and methanol (300 mL), calcium carbonate (81.5 g, 814 mmol) was added and stirred for 5 minutes, phenyltrimethylammonium tribromide (230 g, 611 mmol) was added in batches and stirred for 24 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the organic phase was concentrated, poured into water, extracted with ethyl acetate again, the organic phase was dried and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 92: 8) to obtain the title compound 16b as a brown oil, 16.5 g, yield: 34.3%.

[0519] LC-MS: m / z 235.8 [M+H] + .

[0520] Step 2: Preparation of methyl 3-amino-5-cyclopropylthiophene-2-carboxylate (16c)

[0521] At room temperature, compound 16b (16.5 g, 69.9 mmol) was dissolved in anhydrous 1,4-dioxane (160 mL) and water (16 mL), cesium carbonate (45.5 g, 140 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane (23.5 g, 140 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (6.00 g, 8.39 mmol) were added, nitrogen was bubbled in, and stirred at 80°C for 16 hours. After the reaction was completed, it was poured into ice water, extracted with ethyl acetate, and the organic phase was dried and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 94:6) to obtain yellow liquid compound 16c, 8.0 g, yield: 53.0%.

[0522] LC-MS: m / z 197.9 [M+H] + .

[0523] Step 3: Preparation of methyl 5-cyclopropyl-3-(4-(difluoromethoxy)phenyl)amino)thiophene-2-carboxylate (16d)

[0524] At room temperature, compound 16c (4.50 g, 22.8 mmol) was dissolved in anhydrous 1,4-dioxane (45 mL), and difluoromethoxy iodobenzene (9.24 g, 34.2 mmol), cesium carbonate (11.2 g, 34.2 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (4.26 g, 6.84 mmol), tris(dibenzylideneacetone)dipalladium (3.13 g, 3.42 mmol) were added. The mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the organic phase was concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 97:3) to obtain the title compound 16d as a yellow oil, 6.0 g, yield: 77.5%.

[0525] Step 4: Preparation of methyl 5-cyclopropyl-3-(N-(4-(difluoromethoxy)phenyl)-3-methoxy-3-oxopropionamido)thiophene-2-carboxylate (16e)

[0526] At room temperature, compound 16d (3.69 g, 10.87 mmol), methyl 3-chloro-3-oxopropionate (1.75 mL, 16.31 mol), potassium carbonate (3.01 g, 21.75 mmol), and 1,2-dichloroethane (40 mL) were added to a reaction flask, and chlorosulfonyl isocyanate (0.27 mL, 2.21 mmol) was added dropwise when the temperature dropped to -35°C, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, water was added to quench the mixture under stirring, and the mixture was extracted with dichloromethane (40 mL x 2). The organic phases were combined, washed with saturated brine (20 mL x 2), and concentrated under reduced pressure to obtain the title compound 16e as a yellow oil, 4.50 g, 4.50 g, with a yield of 94.14%.

[0527] LC-MS: m / z 439[M+H] + .

[0528] Step 5: Preparation of methyl 2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-5,7-dioxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate (16f)

[0529] At room temperature, compound 16e (7.34 g, 16.70 mmol), potassium tert-butoxide (5.62 g, 50.11 mmol) and tert-butanol (150 mL) were added to a reaction bottle and reacted at 60° C. for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 8.69 g of yellow powdery compound 16f.

[0530] LC-MS: m / z 407 [M+H] + .

[0531] Step 6: Preparation of methyl 7-chloro-2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxylate (16 g)

[0532] At room temperature, compound 16f (8.69 g, 0.0213 mol), N,N-diisopropylethylamine (16.52 g, 0.128 mol), phosphorus oxychloride (80 mL) and acetonitrile (80 mL) were added to a reaction bottle and stirred at 45° C. for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a black oil compound 16g, 8.69 g.

[0533] LC-MS: m / z 425 [M+H] +

[0534] Step 7: Preparation of methyl 7-amino-2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxylate (16h)

[0535] At room temperature, compound 16g (8.04 g, 18.88 mmol), ammonia water (80 mL) and acetonitrile (60 mL) were added to a reaction flask and stirred at 80°C for 16 hours. After the reaction was completed, the reaction solution was poured into water (20 mL) for dilution, extracted with ethyl acetate (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain yellow solid compound 16h, 2.55 g.

[0536] LC-MS: m / z 406 [M+H] + .

[0537] Step 8: Preparation of 7-amino-2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)thieno[3,2-b]pyridin-5(4H)-one (16i)

[0538] At room temperature, compound 16h (2.55 g, 6.27 mmol), sodium hydroxide (2.51 g, 62.75 mmol), ethanol (10 mL) and water (10 mL) were added to a reaction flask and stirred at 100° C. for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove most of the ethanol, poured into water (20 mL) for dilution, and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid compound 16i, 0.25 g, with a yield of 11.47%.

[0539] LC-MS: m / z 348 [M+H] + .

[0540] Step 9: Preparation of 7-amino-6-bromo-2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)thieno[3,2-b]pyridin-5(4H)-one (16j)

[0541] At room temperature, compound 16i (0.20 g, 0.574 mmol), N-bromosuccinimide (102 mg, 0.574 mmol) and acetonitrile (5 mL) were added to a reaction flask and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water (20 mL) for dilution, extracted with ethyl acetate (10 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain yellow solid compound 16j, 0.23 g, yield 94.26%.

[0542] LC-MS: m / z 427 [M+H] + .

[0543] Step 10: Preparation of 6-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-2H-indazol-6-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (16)

[0544] At room temperature, compound 16j (0.150 g, 0.351 mmol), (2-methyl-2H-indazol-5-yl)boric acid (105.0 mg, 0.597 mmol), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II) (58.0 mg, 0.702 mmol), cesium carbonate (228.0 mg, 0.702 mmol), water (0.4 mL) and 1,4-dioxane solution (1.6 mL) were added to a reaction bottle and the reaction was stirred at 100° C. for 2 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane: methanol = 20:1) and then by HPLC (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile / water, gradient: 10%-100%) to obtain a white solid compound 16, 10 mg.

[0545] LC-MS: m / z 480 [M+H] + .

[0546] 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),7.58–7.49(m,2H),7.42–7.35(m,2H),7.35–7.27(m,3H),7.16–7.05( m,1H),6.15(s,1H),4.15(s,3H),2.19(ddd,J=13.3,8.5,5.0Hz,1H),1.08–0.99(m,2H),0.68–0.60(m,2H).

[0547] Example 17: Preparation of 6-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)thieno[2,3-b]pyrazin-2(1H)-one (17)

[0548]

[0549] The title compound 17 was prepared in the same manner as in Example 5, except that (1-methyl-6-oxo-1,6-dihydropyridin-3-yl)boronic acid was used instead of (2-methyl-2H-indazol-5-yl)boronic acid in step 10.

[0550] LC-MS: m / z 441.80 [M+H] + .

[0551] 1 H NMR(400MHz, DMSO-d6)δ9.20(d,J=2.6Hz,1H),8.33(dd,J=9.6,2.6Hz,1H),7.67–7.60(m,2H),7.54(d,J=2.6Hz,1H),7.42–7 .30(m,3H),6.53(d,J=9.6Hz,1H),3.51(s,3H),0.72(td,J=8.2,4.0Hz,1H),0.49–0.41(m,2H),0.26(dt,J=8.3,3.2Hz,2H).

[0552] Example 18: Preparation of 2-isopropylamino-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (18)

[0553]

[0554]

[0555] Step 1: Preparation of methyl 4-((4-(difluoromethoxy)phenyl)amino)-2-(methylthio)thiazole-5-carboxylate (18b)

[0556] At room temperature, methyl 4-amino-2-(methylthio)thiazole-5-carboxylate (18a) (5.0 g, 24.9 mmol) was dissolved in 1,4-dioxane (150 mL), and 1-(difluoromethoxy)-4-iodobenzene (13.2 g, 49.0 mmol), cesium carbonate (24.0 g, 75.0 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (3.50 g, 7.50 mmol), tris(dibenzylideneacetone)dipalladium (3.53 g, 3.82 mmol) were added, and stirred at 100° C. for 5 hours under nitrogen atmosphere. The reaction system was poured into water, extracted with ethyl acetate, and the organic phase was dried and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=95:5) to obtain 8.0 g of the title compound as a yellow solid with a yield of 94.4%.

[0557] LC-MS: m / z 346.9 [M+H] + .

[0558] Step 2: Preparation of 4-((4-(difluoromethoxy)phenyl)amino)-2-(methylthio)thiazole-5-carboxylic acid (18c)

[0559] At room temperature, compound 18b (2.5 g, 7.25 mmol) was dissolved in tetrahydrofuran (25 mL), sodium hydroxide solution (25 mL, 4 M / L) was added, and stirred overnight at 80° C. The reaction system was poured into water, extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain 2.8 g of the crude product of the title compound as a yellow solid.

[0560] LC-MS: m / z 332.9 [M+H] + .

[0561] Step 3: Preparation of 4-((4-(difluoromethoxy)phenyl)amino)-N-(2-methyl-2H-indazol-5-yl)-2-(methylthio)thiazole-5-carboxamide (18d)

[0562] At room temperature, compound 18c (2.80 g, 8.43 mmol) was dissolved in N,N-dimethylformamide (25 mL), and 2-methyl-2H-indazol-5-amine (2.48 g, 16.8 mmol), 1-hydroxybenzotriazole (4.55 g, 33.7 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.46 g, 33.7 mmol), and triethylamine (5.12 g, 50.5 mmol) were added, and stirred at 60°C for 40 minutes. The reaction solution was poured into water to precipitate a brown solid, and the filter cake was filtered and dried to obtain 3.5 g of the product with a yield of 90.0%.

[0563] LC-MS: m / z 461.9 [M+H] + .

[0564] Step 4: Preparation of 4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(methylthio)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (18e)

[0565] At room temperature, compound 18d (300 mg, 650 umol) was added to N,N-dimethylformamide (10 mL), sodium hydride (7.80 mg, 60%, 195 umol) was added, stirred at 80°C for 30 minutes, CDI (211 mg, 1.30 mmol) was added, and the reaction was continued for 30 minutes. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain 300 mg of the product with a yield of 94.6%.

[0566] LC-MS: m / z 487.9 [M+H] + .

[0567] Step 5: Preparation of 4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(methylsulfinyl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (18f)

[0568] Compound 18e (300 mg, 616 umol) was added to dichloromethane (10 mL) at room temperature, and m-chloroperbenzoic acid (318 mg, 1.85 umol) was added at 0°C and stirred for 30 minutes. The reaction solution was poured into a sodium thiosulfate solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain 300 mg of the product with a yield of 96.8%.

[0569] LC-MS: m / z 503.9 [M+H] + .

[0570] Step 6: Preparation of 2-isopropylamino-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (18)

[0571] At room temperature, compound 18f (50 mg, 99.0 umol) was added to N,N-dimethylformamide (10 mL), cesium carbonate (64.5 mg, 198 umol) and 2-propylamine (46.9 mg, 792 umol) were added, and stirred at 80°C for 30 minutes. The reaction solution was filtered, washed with ethyl acetate, and the mother liquor was concentrated. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile / water, gradient: 10%-100%) to obtain 5 mg of the title compound as a yellow solid, and 300 mg of the product was obtained with a yield of 10.1%.

[0572] LC-MS: m / z 499.0 [M+H] + .

[0573] 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.39(s,1H),7.66–7.58(m,2H),7.54(dd,J=8.1,5.9H z,2H),7.36–7.25(m,3H),7.17–7.07(m,1H),4.19(s,3H),3.51(s,1H),1.17–1.11(m,6H).

[0574] Example 19: Preparation of 2-ethylamino-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (19)

[0575]

[0576] The title compound 19 was prepared in the same manner as Example 18, except that ethylamine was used instead of 2-propylamine in step 6.

[0577] LC-MS: m / z 484.8 [M+H] + .

[0578] 1 H NMR (400MHz, Methanol-d4) δ8.28 (s, 1H), 7.73–7.66 (m, 2H), 7.55–7.47 (m, 2H), δ7.22 (dd, J = 9.0, 2.0Hz, 1H), 7.32–7.19(m,2H),6.83(d,J=73.8Hz,1H),4.25(s,3H),3.33–3.24(m,2H),1.32(s,1H),1.21(t,J=7.3Hz,3H).

[0579] Example 20: Preparation of 2-cyclopropylamino-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (20)

[0580]

[0581] The title compound 20 was prepared in the same manner as in Example 18, except that cyclopropylamine was used instead of 2-propylamine in step 6.

[0582] LC-MS: m / z 496.85 [M+H] + .

[0583] 1 H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.40(s,1H),7.67–7.58(m,2H),7.56–7.49(m,2H),7.35–7 .25(m,3H),7.17–7.07(m,1H),4.19(s,3H),0.79(dt,J=7.0,3.5Hz,2H),0.54(p,J=4.4Hz,2H).

[0584] Example 21: Preparation of 4-(4-(difluoromethoxy)phenyl)-2-(ethyl(methyl)amino)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (21)

[0585]

[0586] The title compound 21 was prepared in the same manner as in Example 18, except that N-methylethylamine was used instead of 2-propylamine in step 6.

[0587] LC-MS: m / z 498.85[M+H] + .

[0588] 1 H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.68–7.59(m,2H),7.58–7.51(m,2H),7.32–7.25(m,2H ),7.25–7.04(m,2H),4.19(s,3H),3.43(q,J=7.0Hz,2H),3.02(s,3H),1.11(t,J=7.0Hz,3H).

[0589] Example 22: Preparation of 4-(4-(difluoromethoxy)phenyl)-2-(cyclopropylmethyl(methyl)amino)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (22).

[0590]

[0591] The title compound 22 was prepared in the same manner as in Example 18, except that 1-cyclopropyl-N-methylmethanamine was used instead of 2-propylamine in step 6.

[0592] LC-MS: m / z 525.05 [M+H] + .

[0593] 1 H NMR(400MHz, DMSO-d6)δ8.40(s,1H),7.65(d,J=2.0Hz,1H),7.62(d,J=9.0Hz,1H),7.56–7.52(m,2H),7.35(s,1H),7.32– 7.26(m,2H),7.19–7.09(m,1H),4.20(s,3H),3.29(s,2H),3.10(s,3H),1.04(s,1H),0.46(d,J=7.8Hz,2H),0.22(s,2H).

[0594] Example 23: Preparation of 4-(4-(difluoromethoxy)phenyl)-2-(cyclobutylamino)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (23).

[0595]

[0596] The title compound 23 was prepared in the same manner as in Example 18, except that cyclobutylamine was used instead of 2-propylamine in step 6.

[0597] LC-MS: m / z 511.13 [M+H] + .

[0598] 1 H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.76–7.70(m,1H),7.66–7.61(m,1H),7.54(dd,J=8.8,2.1Hz,2H) ,7.36–7.15(m,4H),7.14–7.06(m,1H),4.19(s,3H),2.29(s,2H),2.07–1.87(m,3H),1.75–1.61(m,2H).

[0599] Example 24: Preparation of 4-(4-(difluoromethoxy)phenyl)-2-(cyclopentylamino)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (24)

[0600]

[0601] The title compound 24 was prepared in the same manner as in Example 18, except that cyclobutylamine was used instead of 2-propylamine in step 6.

[0602] LC-MS: m / z 525[M+H] + .

[0603] 1 H NMR(400MHz, DMSO-d6)δ8.40(s,1H),7.67–7.58(m,2H),7.58–7.50(m,2H),7.34(s,1H),7.32–7.25(m,2H),7.11(dd,J= 9.0, 1.9Hz, 1H), 4.19 (s, 3H), 3.66 (s, 1H), 1.99 (p, J = 6.8, 6.1Hz, 1H), 1.90 (d, J = 9.0Hz, 2H), 1.63 (s, 2H), 1.52 (s, 4H).

[0604] Example 25: Preparation of 4-(4-(difluoromethoxy)phenyl)-2-(cyclopropylmethylamino)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (25).

[0605]

[0606] The title compound 25 was prepared in the same manner as in Example 18, except that cyclopropylmethylamine was used instead of 2-propylamine in step 6.

[0607] LC-MS: m / z 510.95[M+H] + .

[0608] 1 H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.67–7.58(m,2H),7.58–7.47(m,2H),7.32–7.26(m,2H),7.35(s,0.5H),7.16(s,0.3H), 7.18–7.08(m,1H),4.19(s,3H),3.02(t,J=6.2Hz,2H),1.26–1.22(m,2H),0.45(dd,J=8.0,4.4Hz,2H),0.20(t,J=4.6Hz,2H).

[0609] Example 26: Preparation of 6-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-7-yl)thieno[2,3-b]pyrazin-2(1H)-one (26)

[0610]

[0611] The title compound 26 was prepared in the same manner as in Example 5, except that 11f was used instead of (2-methyl-2H-indazol-5-yl)boronic acid in step 10.

[0612] LC-MS: m / z 520.0 [M+H] + .

[0613] 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.21(d,J=6.3Hz,1H),7.71–7.64(m,3H),7.57(d,J=4.2Hz,1H),7.37(d,J=8.6Hz,3H),4. 18(t,J=5.4Hz,2H),3.79(s,2H),2.96(d,J=5.5Hz,2H),2.47(s,3H),0.79–0.68(m,1H),0.51–0.42(m,2H),0.31–0.22(m,2H).

[0614] Example 27: Preparation of 7-amino-4-(4-chlorophenyl)-2-cyclopropyl-6-(quinolin-6-yl)thieno[3,2-b]pyridin-5(4H)-one (27)

[0615]

[0616] The title compound 27 was prepared by the same method as Example 16, except that 4-chloroiodobenzene was used instead of difluoromethoxyiodobenzene in step 3, and quinoline-6-boric acid was used instead of (2-methyl-2H-indazol-5-yl)boric acid in step 10.

[0617] LC-MS: m / z 445.08 [M+H] + .

[0618] 1 H NMR (400MHz, DMSO-d6) δ8.92(q,J=1.9Hz,2H),8.07(d,J=8.7Hz,1H),7.99(d,J=1.9Hz,1H),7.81(dd,J=8.7,1.9Hz,1H),7.6 3–7.57(m,2H),7.45–7.38(m,2H),6.26(s,2H),2.23(tt,J=8.4,5.0Hz,1H),1.12–1.01(m,2H),0.69(dt,J=6.8,4.5Hz,2H).

[0619] Example 28: Preparation of 2-cyclopropyl-7-((cyclopropylmethyl)amino)-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thieno[3,2-b]pyridin-5(4H)-one (28)

[0620]

[0621] The title compound 28 was prepared in the same manner as in Example 16, except that cyclopropylmethylamine was used instead of aqueous ammonia in step 7.

[0622] LC-MS: m / z 533.0 [M+H] + .

[0623] 1 H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.66–7.55(m,2H),7.27(t,J=6.8Hz,4H),7 .11(d,J=8.8Hz,1H),6.85(dd,J=73.8,2.2Hz,2H),6.11(d,J=3.1Hz,1H),4.07( s,3H),3.21(s,2H),2.05(tt,J=8.7,5.0Hz,1H),1.06–0.95(m,2H),0.85(d,J=1 1.5Hz, 1H), 0.63 (d, J = 4.9Hz, 2H), 0.32 (d, J = 7.8Hz, 2H), 0.02 (d, J = 5.0Hz, 2H).

[0624] Example 29: Preparation of 2-cyclopropyl-7-((cyclopropyl)amino)-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thieno[3,2-b]pyridin-5(4H)-one (29)

[0625]

[0626] The title compound 29 was prepared in the same manner as in Example 16, except that cyclopropylamine was used instead of aqueous ammonia in step 7.

[0627] LC-MS: m / z 518.58 [M+H] + .

[0628] 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),7.56(d,J=8.9Hz,1H),7.52(t,J=1.3Hz,1H),7.43– 7.38(m,2H),7.36–7.16(m,3H),7.04(dd,J=8.9,1.6Hz,1H),6.15(s,1H),5.38(d,J=2.2H z,1H),4.16(s,3H),2.77(dq,J=6.8,3.4Hz,1H),2.20(ddd,J=8.3,5.0,3.3Hz,1H),1.07 –1.02(m,2H),0.79–0.73(m,2H),0.69(dt,J=6.8,4.5Hz,2H),0.62(p,J=5.0,4.5Hz,2H).

[0629] Example 30: Preparation of 2-cyclopropyl-7-((difluoroethyl)amino)-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)thieno[3,2-b]pyridin-5(4H)-one (30)

[0630]

[0631] The title compound 30 was prepared in the same manner as in Example 16, except that 2,2-difluoroethane-1-amine was used instead of aqueous ammonia in step 7.

[0632] LC-MS: m / z 542.55 [M+H] + .

[0633] 1 H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.59(d,J=8.9Hz,1H),7.56–7.52(m,1H ),7.43–7.38(m,2H),7.35–7.15(m,3H),7.07(dd,J=8.9,1.6Hz,1H),6.20(s ,1H),5.52(t,J=7.1Hz,2H),4.17(s,3H),3.53(tdd,J=14.9,6.9,3.9Hz,2H) ,2.22(tt,J=8.3,5.0Hz,1H),1.09–1.01(m,2H),0.69(dt,J=6.8,4.5Hz,2H).

[0634] Example 31: Preparation of 4-(4-(1-aminoethyl)phenyl)-2-cyclopropyl-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (31)

[0635]

[0636] The title compound 31 was prepared in the same manner as in Example 10, except that 4-(1-aminoethyl)aniline was used instead of 4-difluoromethoxyaniline in step 2.

[0637] LC-MS: m / z 459.15 [M+H] + .

[0638] 1H NMR(400MHz, DMSO-d6)δ8.40(s,1H),8.31(d,J=5.6Hz,2H),7.69–7.52(m,6H),7.13(dd,J=9.1,2.0Hz,1H),4.50( p,J=6.1Hz,1H),4.18(s,3H),2.48(d,J=2.3Hz,1H),1.53(d,J=6.8Hz,3H),1.28–1.19(m,2H),0.96–0.88(m,2H).

[0639] Example 32: Preparation of 4-(4-aminophenyl)-2-cyclopropyl-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (32)

[0640]

[0641] The title compound 32 was prepared in the same manner as in Example 10, except that 4-aminoaniline was used instead of 4-difluoromethoxyaniline in step 2.

[0642] LC-MS: m / z 431.12 [M+H] + .

[0643] 1 H NMR (400MHz, DMSO-d6) δ8.39 (s, 1H), 7.67–7.58 (m, 2H), 7.24 (d, J=8.5Hz, 2H), 7.11 (dd, J= 9.0, 1.9Hz, 1H), 6.91 (d, J = 8.3Hz, 2H), 4.17 (s, 3H), 1.27–1.18 (m, 3H), 0.97–0.89 (m, 2H).

[0644] Example 33: Preparation of 4-(4-(1-hydroxyethyl)phenyl)-2-cyclopropyl-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (33)

[0645]

[0646] The title compound 33 was prepared in the same manner as in Example 10, except that 1-(4-aminophenyl)ethyl-1-ol was used instead of 4-difluoromethoxyaniline in step 2.

[0647] LC-MS: m / z 460.14 [M+H] + .

[0648] 1H NMR (400MHz, DMSO-d6) δ8.41(s,1H),7.67(s,1H),7.62(d,J=9.0Hz,1H),7.46(d,J=8.2Hz,2H),7.39(d,J=8.2Hz,2H),7.13(d,J=9.1Hz,1H), 5.31(d,J=4.3Hz,1H),4.78(t,J=5.6Hz,1H),4.18(s,3H),2.02–1.94(m,1H),1.36(d,J=6.5Hz,3H),0.95–0.91(m,2H),0.84(t,J=6.6Hz,2H).

[0649] Example 34: Preparation of 7-amino-2-cyclopropyl-4-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)thieno[3,2-b]pyrazin-5(4H)-one (34)

[0650]

[0651] The title compound 34 was prepared in the same manner as in Example 16, except that 4-chloroiodobenzene was used instead of 4-difluoromethoxyiodobenzene in step 3.

[0652] LC-MS: m / z 447.10 [M+H] + .

[0653] 1 H NMR(400MHz, DMSO-d6)δ8.29(s,1H),7.59(d,J=2.0Hz,1H),7.59–7.55(m,3H),7.41–7.34(m,2H),7.12(dd,J=9.0,1.4Hz ,1H),6.20(s,1H),5.84(s,2H),4.17(s,3H),2.21(tt,J=8.4,4.9Hz,1H),1.10–1.00(m,2H),0.67(dt,J=6.8,4.5Hz,2H).

[0654] Example 35: Preparation of 2-cyclopropyl-4-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (35)

[0655]

[0656] The title compound 35 was prepared in the same manner as in Example 10, except that 4-chloroaniline was used instead of 4-difluoromethoxyaniline in step 2.

[0657] LC-MS: m / z 450.07 [M+H] + .

[0658] 1 H NMR(400MHz, CHCl3-d)δ8.02(s,1H),7.88(d,J=9.1Hz,1H),7.70(d,J=1.9Hz,1H),7.57–7.51(m,2H),7.46–7.40(m,2H), 7.33(s,2H),7.24(dd,J=9.1,1.9Hz,1H),4.32(s,3H),2.37(tt,J=8.5,4.8Hz,1H),1.37–1.28(m,2H),1.20–1.09(m,2H).

[0659] Example 36: Preparation of 2-cyclopropyl-4-(6-(difluoromethoxy)pyridin-3-yl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (36)

[0660]

[0661] The title compound 36 was prepared in the same manner as in Example 10, except that 6-(difluoromethoxy)pyridin-3-amine was used instead of 4-difluoromethoxyaniline in step 2.

[0662] LC-MS: m / z 483.10 [M+H] + .

[0663] 1 H NMR (400MHz, DMSO-d6) δ8.45–8.39(m,2H),8.09(dd,J=8.8,2.6Hz,1H),7.80–7.58(m,3H),7.27(d,J=8.7Hz,1H),7. 13(dd,J=9.1,2.0Hz,1H),4.18(s,3H),2.53(dd,J=8.7,4.4Hz,1H),1.25(dq,J=7.9,4.5Hz,2H),1.01–0.92(m,2H).

[0664] Example 37: Preparation of 7-amino-4-(4-chlorophenyl)-2-cyclopropyl-6-(6-methoxypyridin-3-yl)thieno[3,2-b]pyridin-5(4H)-one (37)

[0665]

[0666] The title compound 37 was prepared by the same preparation method as Example 16, except that 4-chloroiodobenzene was used instead of difluoromethoxyiodobenzene in step 3, and (2-methoxypyridine)-5-boric acid was used instead of (2-methyl-2H-indazol-5-yl)boric acid in step 10.

[0667] LC-MS: m / z 424.08 [M+H] + .

[0668] 1 H NMR(400MHz, DMSO-d6)δ8.04(d,J=2.3Hz,1H),7.63–7.54(m,3H),7.40–7.33(m,2H),6.83(d,J=8.5Hz,1H),6.1 9(s,1H),6.08(s,2H),3.87(s,3H),2.21(tt,J=8.3,4.9Hz,1H),1.08–1.01(m,2H),0.66(dt,J=6.8,4.5Hz,2H).

[0669] Example 38: Preparation of 7-amino-4-(4-chlorophenyl)-2-cyclopropyl-6-(6-fluoropyridin-3-yl)thieno[3,2-b]pyridin-5(4H)-one (38)

[0670]

[0671] The title compound 38 was prepared by the same preparation method as Example 16, except that 4-chloroiodobenzene was used instead of difluoromethoxyiodobenzene in step 3, and (2-fluoropyridine)-5-boric acid was used instead of (2-methyl-2H-indazol-5-yl)boric acid in step 10.

[0672] LC-MS: m / z 412.06 [M+H] + .

[0673] 1 H NMR (400MHz, DMSO-d6) δ8.08(d,J=2.4Hz,1H),7.84(td,J=8.3,2.5Hz,1H),7.61–7.55(m,2H),7.39–7.33(m,2H),7.17(d d,J=8.4,2.8Hz,1H),6.22(d,J=19.4Hz,3H),2.21(tt,J=8.3,5.0Hz,1H),1.08–1.01(m,2H),0.66(dt,J=6.8,4.5Hz,2H).

[0674] Example 39: Preparation of 7-amino-4-(4-(difluoromethoxy)phenyl)-2-cyclopropyl-6-(6-fluoropyridin-3-yl)thieno[3,2-b]pyridin-5(4H)-one (39)

[0675]

[0676] The title compound 39 was prepared in the same manner as in Example 16, except that (2-fluoropyridine)-5-boronic acid was used instead of (2-methyl-2H-indazol-5-yl)boronic acid in step 10.

[0677] LC-MS: m / z 444.09[M+H] + .

[0678] 1 H NMR(400MHz,DMSO-d6)δ8.09(d,J=2.4Hz,1H),7.84(td,J=8.3,2.5Hz,1H),7.40–7.37(m,2H),7.33(d,J=10.2Hz,2H),7.30– 7.15(m,2H),6.22(s,2H),6.16(d,J=0.6Hz,1H),2.21(tt,J=8.3,4.9Hz,1H),1.08–1.03(m,2H),0.65(dt,J=6.7,4.5Hz,2H).

[0679] Example 40: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-6-(6-fluoropyridin-3-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (40)

[0680]

[0681] The title compound 40 was prepared in the same manner as in Example 10, except that (2-fluoropyridine)-5-boronic acid was used instead of (2-methyl-2H-indazol-5-yl)boronic acid in step 5.

[0682] LC-MS: m / z 447.07 [M+H] + .

[0683] 1 H NMR(400MHz, DMSO-d6)δ8.26(d,J=2.6Hz,1H),8.03(ddd,J=8.7,7.2,2.7Hz,1H),7.55–7 .48(m,2H),7.39–7.25(m,4H),2.56–2.49(m,1H),1.29–1.20(m,2H),0.98–0.90(m,2H).

[0684] Example 41: Preparation of 7-amino-4-(4-(difluoromethoxy)phenyl)-2-cyclopropyl-6-(6-methoxypyridin-3-yl)thieno[3,2-b]pyridin-5(4H)-one (41)

[0685]

[0686] The title compound 41 was prepared in the same manner as in Example 16, except that (2-methoxypyridine)-5-boronic acid was used instead of (2-methyl-2H-indazol-5-yl)boronic acid in step 10.

[0687] LC-MS: m / z 456.11 [M+H] + .

[0688] 1 H NMR (400MHz, DMSO-d6) δ8.04–8.02(m,1H),7.57(dd,J=8.5,2.4Hz,1H),7.39(d,J=2.4Hz,1H),7.37(s,1H),7.35–7.29(m,3H),6.82(dd,J= 8.5,0.7Hz,1H),6.15(s,1H),6.04(s,2H),3.86(s,3H),2.20(ddd,J=8.3,4.9,3.3Hz,1H),1.06–1.02(m,2H),0.64(dd,J=4.8,2.1Hz,2H).

[0689] Example 42: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)-2-fluorophenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (42)

[0690]

[0691] The title compound 42 was prepared in the same manner as in Example 10, except that 4-(difluoromethoxy)-2-fluoroaniline was used instead of 4-difluoromethoxyaniline in step 2.

[0692] LC-MS: m / z 499.95 [M+H] + .

[0693] 1H NMR (400MHz, DMSO-d6) δ8.43 (s, 1H), 7.76-7.60 (m, 4H), 7.45-7.24 (m, 2H), 7.21 (dd, J = 8.9, 2.7Hz, 1H), 7. 15(dd,J=9.0,2.0Hz,1H),4.20(s,3H),2.58-2.54(m,1H),1.27(dd,J=8.0,3.4Hz,2H),1.00-0.94(m,2H).

[0694] Example 43: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)-2-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (43)

[0695]

[0696] The title compound 43 was prepared in the same manner as in Example 10, except that 4-(difluoromethoxy)-2-chloroaniline was used instead of 4-difluoromethoxyaniline in step 2.

[0697] LC-MS: m / z 516.0 [M+H] + .

[0698] 1 H NMR (600MHz, DMSO-d6) δ8.42(s,1H),7.77(d,J=8.8Hz,1H),7.69(s,1H),7.65(d,J=9.1Hz,1H),7.60(d,J=2.7Hz,1H),7.43(s,1H) ,7.36(dd,J=8.8,2.7Hz,1H),4.19(s,3H),2.02–1.96(m,1H),1.26(dd,J=8.0,3.5Hz,2H),0.95(ddq,J=8.3,5.6,3.7,2.9Hz,2H).

[0699] Example 44: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)-2-cyclopropylphenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (44)

[0700]

[0701] The title compound 44 was prepared in the same manner as in Example 10, except that 4-(difluoromethoxy)-2-cyclopropylaniline was used instead of 4-difluoromethoxyaniline in step 2.

[0702] LC-MS: m / z 522.0 [M+H] + .

[0703] 1 H NMR(600MHz,DMSO-d6)δ8.41(s,1H),7.70(s,1H),7.64(d,J=9.1Hz,1H),7.51–7.45(m ,1H),7.29(d,J=74.0Hz,1H),7.10(dd,J=8.6,2.8Hz,2H),6.86(d,J=2.8Hz,1H),4.19 (s,3H),1.77(ddd,J=13.6,8.4,5.2Hz,1H),1.24(t,J=7.2Hz,4H),0.97-0.91(m,2H), 0.78(tt,J=8.9,5.0Hz,1H), 0.70(dq,J=10.1,5.1Hz,1H), 0.58(td,J=9.6,5.0Hz,1H).

[0704] Example 45: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)-2-methoxyphenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (45)

[0705]

[0706] The title compound 45 was prepared in the same manner as in Example 10, except that 4-(difluoromethoxy)-2-methoxyaniline was used instead of 4-difluoromethoxyaniline in step 2.

[0707] LC-MS: m / z 511.85 [M+H] + .

[0708] 1 H NMR (400MHz, DMSO-d6) δ8.40(s,1H),7.67(s,1H),7.64(d,J=9.1Hz,1H),7.51(d,J=8.6Hz,1H),7.29(d,J=73.8Hz,1H),7.09(s,1H) ,7.04(d,J=2.6Hz,1H),6.88(dd,J=8.6,2.6Hz,1H),4.19(s,3H),3.79(s,4H),1.28-1.21(m,2H),0.94(ddt,J=7.2,4.7,2.3Hz,2H).

[0709] Example 46: Preparation of 7-amino-2-cyclopropyl-4-(4-(difluoromethoxy)-2-methylphenyl)-6-(2-methyl-2H-indazol-5-yl)thieno[3,2-b]pyridin-5(4H)-one (46)

[0710]

[0711] The title compound 46 was prepared in the same manner as in Example 16, except that 4-(difluoromethoxy)-2-methyliodobenzene was used instead of 4-difluoromethoxyiodobenzene in step 2.

[0712] LC-MS: m / z 493.0 [M+H] + .

[0713] 1 H NMR (400MHz, DMSO-d6) δ8.29 (s, 1H), 7.62-7.49 (m, 2H), 7.29 (dd, J = 21.0, 12.5Hz, 3H), 7.17 -7.08(m,2H),6.04(s,1H),4.17(s,3H),2.21(tt,J=8.7,5.0Hz,1H),2.01(s,3H),1.09-1.00(m,2H),0.65(dt,J=6.7,4.5Hz,2H).

[0714] Example 47: Preparation of 7-amino-2-cyclopropyl-4-(4-(difluoromethoxy)-2-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)thieno[3,2-b]pyridin-5(4H)-one (47)

[0715]

[0716] The title compound 47 was prepared in the same manner as in Example 16, except that 4-(difluoromethoxy)-2-chloroiodobenzene was used instead of 4-difluoromethoxyiodobenzene in step 3.

[0717] LC-MS: m / z 513.0 [M+H] + .

[0718] 1H NMR(400MHz, DMSO-d6)δ8.28(s,1H),7.56(d,J=9.0Hz,4H),7.44-7.21(m,2H),7.11(d,J=9.0Hz,1H),6.11( s,1H),5.88(s,2H),4.17(s,3H),2.21(tt,J=9.1,5.2Hz,1H),1.05(d,J=8.1Hz,2H),0.66(t,J=5.2Hz,2H).

[0719] Example 48: Preparation of 7-amino-2-cyclopropyl-4-(4-(difluoromethoxy)-2,6-dimethylphenyl)-6-(2-methyl-2H-indazol-5-yl)thieno[3,2-b]pyridin-5(4H)-one (48)

[0720]

[0721] The title compound 48 was prepared in the same manner as in Example 16, except that 5-(difluoromethoxy)-2-iodo-1,3-dimethylbenzene was used instead of 4-difluoromethoxyiodobenzene in step 3.

[0722] LC-MS: m / z 507.01 [M+H] + .

[0723] 1 H NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.59–7.53(m,2H),7.29(s,1H),7.17–7.05(m,3H),5.98(s,1H),5.86(s,2 H), 4.16 (s, 3H), 2.20 (td, J = 8.4, 4.2Hz, 1H), 2.02–1.96 (m, 6H), 1.07–0.99 (m, 2H), 0.65 (dt, J = 6.5, 3.3Hz, 2H).

[0724] Example 49: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)-2-methylphenyl)-6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (49)

[0725]

[0726] The title compound 49 was prepared in the same manner as in Example 10, except that 4-(difluoromethoxy)-2-methylaniline was used instead of 4-difluoromethoxyaniline in step 2.

[0727] LC-MS: m / z 495.8 [M+H] + .

[0728] 1H NMR (400MHz, DMSO-d6) δ8.42(s,1H),7.71(d,J=1.9Hz,1H),7.65(d,J=8.9Hz,1H),7.53-7.33(m,2H),7.23(d,J=2. 8Hz,1H),7.18-7.14(m,2H),4.20(s,3H),2.54(d,J=5.0Hz,1H),2.16(s,3H),1.29-1.22(m,2H),0.97-0.91(m,2H).

[0729] Example 50: Preparation of 2-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-7-(methylamino)thieno[3,2-b]pyridin-5(4H)-one (50)

[0730]

[0731] The title compound 50 was prepared in the same manner as in Example 16, except that methylamine hydrochloride was used instead of aqueous ammonia in step 7.

[0732] LC-MS: m / z 492.14 [M+H] + .

[0733] 1 H NMR (400MHz, DMSO-d6) δ8.28(s,1H),7.54(d,J=8.5Hz,1H),7.50(d,J=1.6Hz,1H),7.38(d,J=8.7Hz,2H),7.36–7.15(m,3H),7.06(dd,J=8.9,1.6Hz,1H ),6.17(s,1H),5.54(q,J=5.3Hz,1H),4.16(s,3H),2.89(d,J=5.2Hz,3H),2 .20(tt,J=8.5,5.0Hz,1H),1.08–1.00(m,2H),0.67(dt,J=6.8,4.5Hz,2H).

[0734] Biological evaluation

[0735] Test Example 1: Test on the inhibition of MAT2A enzyme activity by the compounds of the present invention

[0736] Purpose of the experiment: To detect the inhibitory level of the compounds of the present invention on MAT2A enzyme activity.

[0737] Experimental materials: MAT2A inhibitor screening kit (BPS, 71402), Tris pH 7.5 (Invitrogen, 15567-027), DTT (Sigma, 43816), MnCl2 (Sigma, M1787), MgCl2 (Sigma, M1028), EDTA (Invitrogen, 15575020), BSA (petroleum ether, CR84-100), DMSO (Sigma, D8418).

[0738] Test steps:

[0739] The compound was dissolved in DMSO and diluted with DMSO to different concentrations. 200 nL of the diluted compound of each concentration was transferred to the reaction plate (3702, Corning) using Echo 655 (Labcyte, 655), where 10 μM reference compound was added to the positive control well, the reaction plate was sealed with a plate sealing film, and centrifuged at 1000g for 1 minute for later use. 2× kinase solution was prepared, and 10 μL kinase solution was added to each test well in the reaction plate, 10 μL test buffer was added to the negative control well, the reaction plate was sealed with a plate sealing film, and centrifuged at 1000g for 1 minute and then placed at room temperature for 30 minutes. 2× kinase substrate L-methionine and ATP mixed solution was prepared, 10 μL 2× kinase substrate and ATP mixed solution was added to each well in the reaction plate, centrifuged at 1000g for 30 seconds, and reacted at room temperature for 60 minutes. 20 μL of detection reagent was added to each well, centrifuged at 1000 g for 60 seconds, incubated at room temperature for 15 minutes in the dark, and the absorbance value was read at 630 nm using a microplate reader (BMG, PHERAstra FSX).

[0740] The enzyme activity inhibition rate was calculated as follows:

[0741] Inhibition%=100-(Signalcmpd-SignalAve_PC) / (SignalAve_VC-SignalAve_PC)×100

[0742] Among them, Signal Ave_VC : Average absorbance value of positive control wells, Signal Ave_PC : The average absorbance value of negative control wells.

[0743] The concentration and inhibition rate were fitted by nonlinear regression curve using Graphpad Prism software to obtain IC 50 value.

[0744] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0745] Where, X: logarithmic value of compound concentration; Y: percentage of inhibition rate

[0746] Table 1 provides the enzymatic in vitro activities (IC 50 ).

[0747] In Table 1, the MAT2A enzymatic in vitro activity values ​​of the compounds are shown as follows: A refers to IC 50 <100nM; B refers to 100nM <IC 50 <1000nM; C refers to 1000nM <IC 50 <10000nM; D refers to IC 50 >10000nM.

[0748] Table 1: IC inhibition of MAT2A enzyme activity by the compounds of the present invention 50

[0749]

[0750]

[0751] Results: The compounds of the present invention have good inhibitory activity against MAT2A.

[0752] Test Example 2: Test on the inhibitory activity of the compounds of the present invention on HCT-116MTAP knockout cells

[0753] Experimental purpose: To detect the inhibitory effect of the compounds of the present invention on the proliferation activity of HCT-116MTAP knockout cells.

[0754] Test materials: test compound, MCCOYS 5A MED MOD medium (invitrogen, 16600-082), fetal bovine serum (Gibco, 10099-141), penicillin / streptomycin antibiotics (Gibco, 15140122), HCT-116MTAP knockout (Pharmaron) cell line, CTG kit (Promega, G7573).

[0755] Test steps:

[0756] The compound was dissolved in DMSO and diluted with DMSO to different concentrations. Use Echo 655 (Labcyte, 655) to transfer the diluted compound working solution to each well of the reaction plate (Labcyte, P-05525-BC), transferring 40nL to each well. HCT-116MTAP knockout cells were seeded in a white 384-well plate, and 40ul of cell suspension containing 100 HCT-116MTAP knockout cells was added to each well. The cell plate was placed in a 37°C, 5% carbon dioxide incubator and cultured for 10 days. Prepare CTG detection reagent. Add 40μL CTG to each well and shake the cell plate to mix. Incubate in a light-proof 37°C, 5% CO2 incubator for 30 minutes. Set up an enzyme reader (Envision, 2105) to read the luminescence signal.

[0757] Data Analysis:

[0758] The inhibition rate was calculated as follows:

[0759] Inhibition % = 100-(Signal cmpd -Signal Ave_BL ) / (Signal Ave_VC -Signal Ave_BL )×100

[0760] Signal cmpd : Chemiluminescence value of each concentration of compound

[0761] Signal Ave_BL : Average value of chemiluminescence value on day 0 of the system

[0762] Signal Ave_VC : Average value of negative control chemiluminescence value

[0763] Calculation IC 50 , draw the compound effect dose curve:

[0764] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0765] X: Logarithmic value of compound concentration; Y: Percentage of inhibition rate

[0766] Table 2 provides the in vitro inhibitory activity (IC 50 ).

[0767] In Table 2, the in vitro inhibitory activity values ​​of the compounds against HCT-116MTAP KO cell line are shown as follows: A refers to IC 50<100nM; B refers to 100nM <IC 50 <1000nM; C refers to 1000nM <IC 50 <10000nM; D refers to IC 50 >10000nM.

[0768] Table 2: IC values ​​of the compounds of the present invention for inhibition of HCT-116MTAP KO cell line activity 50

[0769] Example <![CDATA[MAT2A IC 50 ]]> Example <![CDATA[MAT2A IC 50 ]]> 1 D 26 A 2 A 27 A 3 - 28 B 4 - 29 B 5 B 30 A 6 A 31 - 7 B 32 B 8 - 33 B 9 B 34 A 10 A 35 B 11 B 36 - 12 B 37 B 13 B 38 - 14 B 39 - 15 A 40 - 16 A 41 B 17 B 42 B 18 - 43 B 19 B 44 B 20 - 45 B 21 - 46 B 22 B 47 B 23 - 48 - 24 - 49 B 25 B 50 A

[0770] Results: The compounds of the present invention have good inhibitory activity against HCT-116MTAP KO cell line.

[0771] Experimental Example 3: Pharmacokinetic evaluation of the compound of the present invention in ICR mice

[0772] The compound of the present invention was orally administered to male 7-8 week old ICR mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.), the compound preparation solvent contained 0.5% methylcellulose and 0.2% Tween 80, and the administration volume was 10mL / kg. Blood was collected from the canthal venous plexus of mice before and after administration at 0.25, 0.50, 1.00, 2.00, 4.00, 6.00, 8.00 and 24.00 hours. The blood was anticoagulated with sodium heparin, centrifuged at 4°C, 3500rpm for 10 minutes, and plasma was obtained and stored at -20°C until testing. 10μL of the plasma sample to be tested was placed in a 96-well plate, and 100μL of acetonitrile working solution containing 5ng / mL verapamil hydrochloride (internal standard) (100223-200102, China Pharmaceutical and Biological Products Testing Institute) was added, vortexed for 5 minutes to mix thoroughly, and centrifuged at 4000rpm for 10 minutes. 50 μL of the supernatant was removed, 150 μL of acetonitrile was added and mixed, and the mixture was centrifuged at 4000 rpm for 10 min. The supernatant was taken and placed in a 96-well sample plate. The blood drug concentration was analyzed by LC / MS (Waters UPLC I Class / LC 30AD, Waters). The pharmacokinetic parameters were analyzed using MassLynx V4.2 SCN977 data processing software. The main pharmacokinetic parameters of the compounds of the present invention are shown in Table 3 below.

[0773] 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.

[0774] Table 3 Pharmacokinetic parameters of the compounds of the present invention after single oral administration to male ICR mice

[0775]

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; X 1 , X 2 , X 3 are each independently selected from C or N; Y 1 , Y 2 , Y 3 Each independently selected from N, NR 4 , S, O, CR 4 , CR 4 R 5 Or C=O; The condition is, Not for L is selected from O, S, NR 6 and single bond; R 1 is selected from hydrogen, halogen, alkyl, hydroxy, cyano, heteroalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from halogen, alkyl, heteroalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl; 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, alkyl, amino, hydroxy, cyano, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic; R 3 is selected from aryl, heteroaryl and heterocyclyl; the aryl, heteroaryl and heterocyclyl are optionally substituted by one or more groups selected from halogen, hydroxy, alkyl, heteroalkyl, cyano, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl; R 4 and R 5 are each independently selected from hydrogen, halogen, amino, NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 6 is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R a and R b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or, R a and R b Together with the nitrogen atom to which it is attached, it forms a nitrogen-containing heterocyclic group, which is optionally substituted by one or more substituents selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

2. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound of the general formula (IA) 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 4a Selected from NR 4a , N, CR 4a , S, O, CR 4a R 5a Or C=O; Y 5a Selected from NR 4a , N, CR 4a , S, O, CR 4a R 5a Or C=O; R 4a and R 5a Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 1 , R 2 , R 3 , L as defined in claim 1.

3. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound of the general formula (IB) 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 4b Selected from NR 4b , N, CR 4b , S, O, CR 4b R 5b Or C=O; Y 5b Selected from NR 4b , N, CR 4b , S, O, CR 4b R 5b Or C=O; R 4b and R 5b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 1 , R 2 , R 3 , L as defined in claim 1.

4. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IC) 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; X 1 Selected from C or N; X 4 Selected from C or N; Y 1c Selected from N, NR 4c , CR 4c , CR 4c R 5c Or C=O; Y 4c Selected from N, NR 4c , S, O, CR 4c , CR 4c R 5c Or C=O; Y 5c Selected from N, NR 4c , S, O, CR 4c , CR 4c R 5c Or C=O; R 4c and R 5c are each independently selected from hydrogen, halogen, amino, NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 1 , R 2 , R 3 , L, R a , R b As defined in claim 1.

5. The compound represented by the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IC-1), (IC-2), (IC-3), (IC-4) 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 1c1 Select from N or CR 4c1 ; Y 4c1 Selected from NR 4c1 , S, O, CR 4c1 R 5c1 Or C=O; Y 5c1 Select from N or CR 4c1 ; R 4c1 and R 5c1 are each independently selected from hydrogen, halogen, amino, NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Y 1c2 Select from N or CR 4c2 ; Y 4c2 Selected from N, NR 4c2 , S, O, CR 4c2 , CR 4c2 R 5c2 Or C=O; Y 5c2 Selected from N, NR 4c2 , S, O, CR 4c2 , CR 4c2 R 5c2 Or C=O; R 4c2 and R 5c2 are each independently selected from hydrogen, halogen, amino, NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Y 1c3 Selected from CR 4c3 R 5c3 ; Y 4c3 Selected from N, NR 4c3 , S, O, CR 4c3 , CR 4c3 R 5c3 Or C=O; Y 5c3 Selected from N, NR 4c3 , S, O, CR 4c3 , CR 4c3 R 5c3 Or C=O; R 4c3 and R 5c3 are each independently selected from hydrogen, halogen, amino, NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Y 1c4 Selected from CR 4c4 ; Y 4c4 Selected from N, NR 4c4 , S, O, CR 4c4 , CR 4c4 R 5c4 Or C=O; Y 5c4 Selected from N, NR 4c4 , S, O, CR 4c4 , CR 4c4 R 5c4 Or C=O; R 4c4 and R 5c4 Each independently selected from halogen, amino, NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, haloalkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R a and R b are each independently selected from hydrogen, C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally selected from halogen, C 3-6 One or more radicals are substituted on the cycloalkyl group; R 1 , R 2 , R 3 , L as defined in claim 1.

6. The compound represented by the general formula (I) according to claim 4 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, in, Selected from R 4c and R 5c As defined in claim 4.

7. A compound represented by the general formula (I) according to any one of claims 1 to 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclyl; preferably phenyl or 5- to 6-membered heteroaryl; the aryl, heteroaryl and heterocyclyl are optionally substituted by one or more groups selected from halogen, alkyl, amino, hydroxy, cyano, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl.

8. A compound represented by the general formula (I) according to any one of claims 1 to 7, 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 heterocyclyl are optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, heteroalkyl, cyano, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl; Preferably, R 3 is selected from the group consisting of pyridyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, benzopyridazinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxyethylene and tetrahydrobenzodioxyethylene, which is optionally substituted by one or more groups selected from halogen, hydroxy, alkyl, heteroalkyl, cyano, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl; More preferably, R 3 Selected from pyridinyl, quinoxalinyl, The alkyl radical is substituted by one or more groups selected from halogen, hydroxy, alkyl, heteroalkyl, cyano, haloalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclyl.

9. 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 (IIA) or (IIB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, in: is a single bond or a double bond; Y 9 Selected from CR 10b R 11b or C=O; preferably C=O; Y 10 Selected from NR 10b , N, CR 10b , S, O, CR 10b R 11b or C=O; preferably NR 10b , N, S; Y 11 Selected from NR 10b , N, CR 10b , S, O, CR 10b R 11b or C=O; preferably NR 10b , N, CR 10b ; R 10b and R 11b are each independently selected from hydrogen, C 1-6 alkyl; R 7 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, amino, hydroxyl, cyano, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; preferably hydrogen, halogen, C 1-6 Alkyl, amino, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; R 8 Selected from hydrogen and C 1-6 alkyl; R 9 Selected from hydrogen and C 1-6 alkyl; m is an integer from 1 to 3; R 1 and L as defined in claim 1.

10. The compound of the general formula (I) according to claim 9, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound of the general formula (IIAa) or (IIBa) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, in: Y 9 Selected from CR 10b R 11b or C=O; preferably C=O; Y 10 Selected from NR 10b , S; Y 11 Selected from N, CR 10b ; R 10b and R 11b are each independently selected from hydrogen, C 1-6 alkyl; R 7 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, amino, hydroxyl, cyano, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; preferably hydrogen, halogen, C 1-6 Alkyl, amino, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; R 8 Selected from hydrogen and C 1-6 alkyl; R 9 Selected from hydrogen and C 1-6 alkyl; m is an integer from 1 to 3; R 1 and L as defined in claim 1.

11. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IIIA) or (IIIB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: Y 6 Selected from N and CR 6b ; Y 7 Selected from S, O, NR 6b , CR 6b R 7b or C=O; preferably S; Y 8 Selected from N, CR 6b ; R 6b and R 7b are each independently selected from hydrogen, NR a R b , C 1-6 alkyl; R a and R b are each independently selected from hydrogen, C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally selected from halogen, C 3-6 One or more radicals are substituted on the cycloalkyl group; R 7 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, amino, hydroxyl, cyano, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; preferably hydrogen, halogen, C 1-6 Alkyl, amino, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; R 8 Selected from hydrogen and C 1-6 alkyl; R 9 Selected from hydrogen and C 1-6 alkyl; m is an integer from 1 to 3; The condition is, Not for R 1 and L as defined in claim 1.

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 1 Selected from halogen, C 1-6 Alkyl, C 2-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl.

13. A compound of the general formula (I) according to any one of claims 1 to 12, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L is selected from O, S, NR 6 and single bond; R 6 Selected from hydrogen, C 1-6 alkyl.

14. A compound of the general formula (I) according to any one of claims 1 to 13, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L is a single bond; R 1 Selected from C 1-6 Alkyl or C 3-6 Cycloalkyl.

15. A compound of the general formula (I) according to any one of claims 1 to 13, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L is O; R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl.

16. A compound of the general formula (I) according to any one of claims 1 to 13, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L is NR 6 ; R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, the C 1-6 The alkyl group is optionally substituted with a C3-6 cycloalkyl group; R 6 Selected from hydrogen and C 1-6 alkyl.

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-10 and compound I-11 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, X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , L, 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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