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. In particular, the present invention relates to a compound represented by general formula (IA), a preparation method thereof, a pharmaceutical composition containing the compound, and a use thereof as a PRMT5 inhibitor. The compound and the pharmaceutical composition containing the compound can be used for treating and / or preventing PRMT5 activity related diseases, such as non-small cell lung cancer, mesothelial tissue tumor, nerve fiber sarcoma, pancreatic cancer, solid tumor and the like. Wherein the definition of each group in the general formula (IA) 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 PRMT5 inhibitor in the treatment and / or prevention of diseases associated with PRMT5 activity. Background Art

[0002] Epigenetic regulation of gene expression is an important biological factor in protein production and cell differentiation, and plays an important pathogenic role in many human diseases. Post-translational modifications are the key to proteome diversity. Modification of a protein at one or more sites can determine its conformation, subcellular localization, interaction with other proteins, stability and activity. These post-translational modifications are mediated by a variety of enzymes, including phosphorylation, acetylation, ubiquitination, methylation and hydroxylation, and are also negatively regulated by some enzymes, such as phosphatases, deubiquitinases, deacetylases and demethylases. Among them, arginine methylation plays an important role in cellular processes, including cell signaling, gene transcription, RNA processing, DNA recombination and repair, etc.

[0003] Protein arginine methyltransferases (PRMTs) catalyze the methylation of specific arginine residues by transferring a methyl group from S-adenosylmethionine (SAM) to the guanidine nitrogen of arginine. PRMTs can be divided into three categories according to the different ways of catalyzing arginine methylation: type I (PRMT1, 2, 3, 4, 6, and 8) catalyze asymmetric dimethylation, type II (PRMT5 and PRMT9) catalyze symmetric dimethylation, and type III (PRMT7) catalyzes monomethylation. Among them, PRMT5 plays an indispensable role in cell growth and development and homeostatic hematopoiesis, and is involved in the survival and renewal of stem cells in the neural, muscle, hematopoietic, and reproductive systems. PRMT5 knockout in mice is embryonic lethal, and conditional knockout of PRMT5 causes hematopoietic progenitor cell loss and fatal bone marrow atrophy. In addition, hematopoietic stem and progenitor cells lacking PRMT5 show severe cytokine signaling pathway disorders and p53 upregulation. PRMT5 interacts with the cofactor MEP50 to enhance binding to SAM and substrates and methylation activity.

[0004] The methylation function of PRMT5 is closely related to tumor occurrence and development through the regulation of gene expression, mRNA splicing, DNA damage response, cytokine signaling pathways and tumor immunity. A large number of studies have confirmed that PRMT5 is overexpressed in different types and aggressive cancers, such as brain glioma, leukemia, B cell and T cell lymphoma, metastatic melanoma, breast cancer, prostate cancer and colon cancer.

[0005] PRMT5 plays an important biological role by methylating a variety of proteins (including histones and non-histones), epigenetically regulating the expression of target genes, or directly methylating key signaling molecules. PRMT5 methylates the terminal arginine of histones to activate or inhibit the expression of related genes. PRMT5's modification of histones often leads to the silencing of tumor suppressor genes such as p53, ST7, NM23 and Rb, thereby promoting the occurrence and development of tumors.

[0006] High expression of PRMT5 in tumor cells can promote tumor progression by inhibiting the expression of histone-dependent tumor-promoting factors miRNA, such as PRMT5 inhibiting miR-33b / 96 to upregulate cyclin D1 and c-Myc in B-cell lymphoma; PRMT5 inhibiting miR-99 to upregulate FGFR3 in lung cancer; PRMT5 inhibiting miR-29b to upregulate FLT3 in AML, etc. PRMT5 methylation of H4R3 and H3R8 can promote the expression of FGFR3 and elF4E in colorectal cancer, and AR expression in prostate cancer. PRMT5 methylated H3R2 is involved in transcriptional activation, such as recruiting WDR5 and MLL coactivators to cause trimethylation of H3K4, initiating FOXP1 expression to maintain breast cancer stem cell activity, and activating the transcription of redox-related genes. PRMT5 can also activate or inhibit the expression of related genes in a non-histone-dependent manner. STRAP recruits PRMT5 in response to DNA damage, methylates p53, changes its nuclear distribution and the expression of target genes p21 and PUMA, and methylates p53 by PRMT5 to promote lymphoma formation. PRMT5 can also directly methylate E2F-1 and NF-KB / P65 to induce the expression of their target genes.

[0007] PRMT5 is responsible for pre-mRNA splicing in the spliceosome as part of the spliceosome, and can affect mRNA splicing, transport and degradation through methylation. Loss of Myc or PRMT5 leads to abnormal splicing (exon skipping or intron retention) of genes associated with cell cycle arrest or apoptosis. PRMT5 drives Myc-mediated lymphomagenesis by methylating the splicing factor SRSF1, and the splicing factor E2F-1 is also an important substrate of PRMT5. PRMT5-mediated splicing can regulate TIP60 / KAT5 to promote homologous recombination and genome integrity.

[0008] PRMT5 also plays an important role in tumor-driven growth factor signaling pathways. In lung cancer and colon cancer, PRMT5 promotes the occurrence and development of tumors by transcriptionally activating FGFR genes. PRMT5 can also directly arginine methylate growth factors such as EGFR, PDGFR, and TFG-β. These signaling pathways are essential for the proliferation, differentiation, and survival of cancer cells. In addition, PRMT5 regulates the assembly of DDR complexes and the expression of related genes through post-transcriptional modifications.

[0009] The loss of tumor suppressor genes is a key driver of tumorigenesis. When tumor suppressor genes are lost, they often lead to the co-deletion of genes adjacent to tumor suppressor genes. Loss of the tumor suppressor gene CDKN2A at chromosome 9p21 occurs in 15% of human tumors, and leads to the co-deletion of MTAP, a key enzyme in the methionine and adenine salvage pathway. Loss of MTAP leads to increased concentrations of MTA, which is structurally similar to the substrate methyl donor SAM of type II methyltransferase PRMT5. Elevated MTA competes with SAM for binding to PRMT5, placing the methyltransferase in a hypomorphic state and susceptible to further inhibition by PRMT5. Multi-genomic silencing screening on a variety of tumor cell lines found a strong correlation between MTAP loss and PRMT5 dependence. However, PRMT5 is a known essential gene for cells. Conditional knockout of PRMT5 and siRNA interference studies have shown that PRMT5 inhibition in normal tissues may lead to side effects such as pancytopenia, infertility, skeletal muscle atrophy, and cardiac hypertrophy. Therefore, new strategies are needed to exploit this metabolic vulnerability and preferentially target PRMT5 in MTAP-deficient tumors while retaining PRMT5 activity in normal tissues. Targeting PRMT5 with MTA-synergistic small molecule inhibitors can preferentially target the MTA-bound state of PRMT5. In MTAP-deficient tumor cells, the MTA-bound state of PRMT5 is more enriched, providing a therapeutic window superior to that of normal cells. Summary of the invention

[0010] After intensive research, the inventors designed and synthesized a series of bicyclic heterocyclic compounds and screened their PRMT5 activity. The results showed that the compounds are a potent and selective inhibitor of the PRMT5 / MTA complex, have a selective inhibitory effect on MTAP-deficient cells, and can be developed as drugs for the treatment and / or prevention of diseases associated with PRMT5 activity.

[0011] Therefore, the object of the present invention is to provide a compound represented by general formula (IA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

[0012]

[0013] in:

[0014] is a single bond or a double bond;

[0015] X 1 CR 5 , CR 5 R 6 , N, NR5 Or C=O;

[0016] X 2 CR 7 , CR 7 R 8 , N, NR 7 Or C=O;

[0017] Ring A 1 and Ring A 2 Each is independently selected from cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0018] Each R 1 are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, alkyl, alkenyl, alkynyl, -NR a R b , heteroalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally replaced by one or more R 1a replace;

[0019] Each R 3 are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, alkyl, heteroalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 3a replace;

[0020] R 2 is selected from hydrogen, halogen, hydroxy, amino, cyano, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-haloalkyl, -L-NR a C(=O)aryl, -L-COOH, -LC(=O)Oalkyl, -L-OR a 、-L-NR a R b 、-LC(=O)R a ,-LC(=O)OR a 、-L-NR a C(=O)R b 、-L-NR a C(=O)OR b ,-LC(=O)NR a R b 、-L-OC(=O)NR a R b ,-LS(=O)R a,-LS(=O) 2 R a 、-L-SR a ,-LS(=O)(=NR a )R b 、-L-NR a S(=O) 2 R b and-LS(=O) 2 NR a R b wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-NR a The aryl portion of C(═O)aryl, the heterocyclyl portion of —L-heterocyclyl, the cycloalkyl portion of —L-cycloalkyl, the aryl portion of —L-aryl and the heteroaryl portion of —L-heteroaryl are optionally substituted with one or more R 4 replace;

[0021] Each L is independently a bond, -O-, -NH-, alkylene, wherein the alkylene is optionally substituted with one or more groups selected from hydroxy, hydroxyalkyl and heteroaryl;

[0022] Each R 1a are independently selected from hydrogen, halogen, hydroxy, amino, cyano, cycloalkyl, heterocyclyl, -O-alkyl, heteroalkyl, haloalkyl, -O-haloalkyl, -NH-haloalkyl, hydroxyalkyl, alkyl, -(CH 2 ) p -OR a , -Q-cycloalkyl, -Q-heterocyclyl, -Q-aryl, -Q-heteroaryl, 5-20 membered spiroheterocyclyl, -SF 6 、HC(=O)-、-NR a R b 、-L-NR a R b 、-C(=O)NR a R b 、-C(=O)R a 、-NHC(=O)R a 、-CH 2 OC(=O)NR a R b 、-CH 2 NHC(=O)O alkyl, -CH 2 NHC(=O)NR a R b 、-CH 2 NHC(=O)alkyl, -CH 2 -heteroaryl, -CH 2 NHSO 2 Alkyl, -CH 2OC(=O)heterocyclyl, -OC(=O)NR a R b , -OC(=O)heterocyclyl and -CH 2 -heterocyclic group, wherein -CH 2 -heterocyclyl is optionally substituted with one or more oxo groups;

[0023] Each R 3a independently selected from hydrogen, halogen, hydroxy, amino, cyano, heterocyclyl, -O-alkyl, heteroalkyl, haloalkyl, -O-haloalkyl, -NH-haloalkyl, hydroxyalkyl, alkyl, -Q-aryl, -Q-heteroaryl, HC(=O)-, -NR a R b 、-CH 2 OC(=O)NR a R b 、-CH 2 NHC(=O)O alkyl, -CH 2 NHC(=O)NR a R b 、-CH 2 NHC(=O)alkyl, -CH 2 -heteroaryl, -CH 2 NHSO 2 Alkyl, -CH 2 OC(=O)heterocyclyl, -OC(=O)NR a R b , -OC(=O)heterocyclyl and -CH 2 -heterocyclyl, wherein the heterocyclyl of -CH2-heterocyclyl is optionally substituted by one or more oxo groups;

[0024] Each R 4 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, heterocyclyl, -O-alkyl, heteroalkyl, haloalkyl, -O-haloalkyl, -NH-haloalkyl, hydroxyalkyl, alkyl, -Q-aryl, -Q-heteroaryl, spiroheterocyclyl, -SF 6 、HC(=O)-、-NR a R b 、-CH 2 OC(=O)NR a R b 、-CH 2 NHC(=O)O alkyl, -CH 2 NHC(=O)NR a R b 、-CH 2 NHC(=O)alkyl, -CH 2 -heteroaryl, -CH 2 NHSO2 Alkyl, -CH 2 OC(=O)heterocyclyl, -OC(=O)NR a R b , -OC(=O)heterocyclyl and -CH 2 -heterocyclyl, wherein the heterocyclyl of -CH2-heterocyclyl is optionally substituted by one or more oxo groups;

[0025] each Q is independently a bond, -O- or -NH-;

[0026] R 5 , R 6 are each independently selected from hydrogen, deuterium, halogen, hydroxy, alkyl, hydroxyalkyl, aminoalkyl, haloalkyl, cyano, -CH 2 -Aryl, -CH 2 -heteroaryl, -CH 2 -cycloalkyl, -CH 2 -heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a 、-NR a R b 、-C(=O)R a 、-C(=O)OR a 、-NR a C(=O)R b 、-NR a C(=O)OR b 、-C(=O)NR a R b 、-OC(=O)NR a R b 、-S(=O)R a 、-S(=O) 2 R a 、-SR a 、-S(=O)(=NR a )R b 、-NR a S(=O) 2 R b and -S(=O) 2 NR a R b ; the alkyl group, -CH 2 -Aryl, -CH 2 -heteroaryl, -CH 2 -cycloalkyl, -CH 2- heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0027] R 7 , R 8 are each independently selected from hydrogen, deuterium, halogen, hydroxy, alkyl, hydroxyalkyl, aminoalkyl, haloalkyl, cyano, -CH 2 -Aryl, -CH 2 -heteroaryl, -CH 2 -cycloalkyl, -CH 2 -heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a 、-NR a R b 、-C(=O)R a 、-C(=O)OR a 、-NR a C(=O)R b 、-NR a C(=O)OR b 、-C(=O)NR a R b 、-OC(=O)NR a R b 、-S(=O)R a 、-S(=O) 2 R a 、-SR a 、-S(=O)(=NR a )R b 、-NR a S(=O) 2 R b and -S(=O) 2 NR a R b ; the alkyl group, -CH 2 -Aryl, -CH 2 -heteroaryl, -CH 2 -cycloalkyl, -CH 2 - heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0028] Or, R 5 or R 6 With R7 or R 8 and the atoms to which they are attached together form a saturated or partially saturated cycloalkyl, a saturated or partially saturated heterocyclyl, an aryl or a heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0029] R 12 Each is independently selected from halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0030] R a and R b Each is independently selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,

[0031] 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 with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0032] m 1 is 0, 1, 2, or 3;

[0033] m 2 is 0, 1, 2, or 3;

[0034] m 4 is 1 or 2;

[0035] p is an integer of 1-6.

[0036] Another object of the present invention is to provide a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0037]

[0038]

[0039] in:

[0040] is a single bond or a double bond;

[0041] X 1 CR 5 , CR 5 R 6 , N, NR 5 Or C=O;

[0042] X 2 CR 7 , CR 7 R 8 , N, NR 7 Or C=O;

[0043] Ring A 1 and Ring A 2 Each is independently selected from cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0044] Each R 1 are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, alkyl, alkenyl, alkynyl, -NR a R b , heteroalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally replaced by one or more R 1a replace;

[0045] Each R 3 are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, alkyl, heteroalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 3a replace;

[0046] R 2 is selected from hydrogen, halogen, hydroxy, amino, cyano, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-haloalkyl, -L-NR aC(=O)aryl, -L-COOH, -LC(=O)Oalkyl, -L-OR a 、-L-NR a R b 、-LC(=O)R a ,-LC(=O)OR a 、-L-NR a C(=O)R b 、-L-NR a C(=O)OR b ,-LC(=O)NR a R b 、-L-OC(=O)NR a R b ,-LS(=O)R a ,-LS(=O) 2 R a 、-L-SR a ,-LS(=O)(=NR a )R b 、-L-NR a S(=O) 2 R b and-LS(=O) 2 NR a R b wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-NR a The aryl portion of C(═O)aryl, the heterocyclyl portion of —L-heterocyclyl, the cycloalkyl portion of —L-cycloalkyl, the aryl portion of —L-aryl and the heteroaryl portion of —L-heteroaryl are optionally substituted with one or more R 4 replace;

[0047] Each L is independently a bond, -O-, -NH-, alkylene, wherein the alkylene is optionally substituted with one or more groups selected from hydroxy, hydroxyalkyl and heteroaryl;

[0048] Each R 1a are independently selected from hydrogen, halogen, hydroxy, amino, cyano, cycloalkyl, heterocyclyl, -O-alkyl, heteroalkyl, haloalkyl, -O-haloalkyl, -NH-haloalkyl, hydroxyalkyl, alkyl, -(CH 2 ) p -OR a , -Q-cycloalkyl, -Q-heterocyclyl, -Q-aryl, -Q-heteroaryl, HC(=O)-, -NR a R b 、-CH 2 OC(=O)NR a R b 、-L-NR aR b 、-C(=O)NR a R b 、-C(=O)R a 、-NHC(=O)R a 、-CH 2 NHC(=O)O alkyl, -CH 2 NHC(=O)NR a R b 、-CH 2 NHC(=O)alkyl, -CH 2 -heteroaryl, -CH 2 NHSO 2 Alkyl, -CH 2 OC(=O)heterocyclyl, -OC(=O)NR a R b , -OC(=O)heterocyclyl and -CH 2 -heterocyclic group, wherein -CH 2 -heterocyclyl is optionally substituted with one or more oxo groups;

[0049] Each R 3a independently selected from hydrogen, halogen, hydroxy, amino, cyano, heterocyclyl, -O-alkyl, heteroalkyl, haloalkyl, -O-haloalkyl, -NH-haloalkyl, hydroxyalkyl, alkyl, -Q-aryl, -Q-heteroaryl, HC(=O)-, -NR a R b 、-CH 2 OC(=O)NR a R b 、-CH 2 NHC(=O)O alkyl, -CH 2 NHC(=O)NR a R b 、-CH 2 NHC(=O)alkyl, -CH 2 -heteroaryl, -CH 2 NHSO 2 Alkyl, -CH 2 OC(=O)heterocyclyl, -OC(=O)NR a R b , -OC(=O)heterocyclyl and -CH 2 -heterocyclyl, wherein the heterocyclyl of -CH2-heterocyclyl is optionally substituted by one or more oxo groups;

[0050] Each R 4are independently selected from hydrogen, halogen, hydroxy, amino, cyano, heterocyclyl, -O-alkyl, heteroalkyl, haloalkyl, -O-haloalkyl, -NH-haloalkyl, hydroxyalkyl, alkyl, -Q-aryl, -Q-heteroaryl, spiroheterocyclyl, -SF 6 、HC(=O)-、-NR a R b 、-CH 2 OC(=O)NR a R b 、-CH 2 NHC(=O)O alkyl, -CH 2 NHC(=O)NR a R b 、-CH 2 NHC(=O)alkyl, -CH 2 -heteroaryl, -CH 2 NHSO 2 Alkyl, -CH 2 OC(=O)heterocyclyl, -OC(=O)NR a R b , -OC(=O)heterocyclyl and -CH 2 -heterocyclic group, wherein -CH 2 -heterocyclyl is optionally substituted with one or more oxo groups;

[0051] each Q is independently a bond, -O- or -NH-;

[0052] R 5 , R 6 are each independently selected from hydrogen, deuterium, halogen, hydroxy, alkyl, hydroxyalkyl, aminoalkyl, haloalkyl, cyano, -CH 2 -Aryl, -CH 2 -heteroaryl, -CH 2 -cycloalkyl, -CH 2 -heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a 、-NR a R b 、-C(=O)R a 、-C(=O)OR a 、-NR a C(=O)R b 、-NR a C(=O)OR b 、-C(=O)NR a R b 、-OC(=O)NR a R b 、-S(=O)R a 、-S(=O) 2 Ra 、-SR a 、-S(=O)(=NR a )R b 、-NR a S(=O) 2 R b and -S(=O) 2 NR a R b ; the alkyl group, -CH 2 -Aryl, -CH 2 -heteroaryl, -CH 2 -cycloalkyl, -CH 2 - heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0053] R 7 , R 8 are each independently selected from hydrogen, deuterium, halogen, hydroxy, alkyl, hydroxyalkyl, aminoalkyl, haloalkyl, cyano, -CH 2 -Aryl, -CH 2 -heteroaryl, -CH 2 -cycloalkyl, -CH 2 -heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a 、-NR a R b 、-C(=O)R a 、-C(=O)OR a 、-NR a C(=O)R b 、-NR a C(=O)OR b 、-C(=O)NR a R b 、-OC(=O)NR a R b 、-S(=O)R a 、-S(=O) 2 R a 、-SR a 、-S(=O)(=NR a )R b 、-NR a S(=O) 2 R b and -S(=O) 2 NR a R b; the alkyl group, -CH 2 -Aryl, -CH 2 -heteroaryl, -CH 2 -cycloalkyl, -CH 2 - heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0054] Or, R 5 or R 6 With R 7 or R 8 and the atoms to which they are attached together form a saturated or partially saturated cycloalkyl, a saturated or partially saturated heterocyclyl, an aryl or a heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0055] R a and R b Each is independently selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,

[0056] 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 with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0057] m 1 is 0, 1, 2, or 3;

[0058] m 2 is 0, 1, 2, or 3;

[0059] p is an integer of 1-6.

[0060] In a preferred embodiment, the compound represented by general formula (I) or general formula (IA) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0061] is a double bond;

[0062] X 1 CR 5 or NR 5 ;

[0063] X 2 CR 7 or NR 7 ;

[0064] R 5 , R 7 As defined in general formula (I) or (IA).

[0065] In another preferred embodiment, the compound represented by general formula (I) or general formula (IA) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0066] is a double bond;

[0067] X 1 CR 5 or NR 5 ;

[0068] X 2 CR 7 or NR 7 ;

[0069] R 5 With R 7 and the atoms to which it is connected together form a saturated or partially saturated C 5 -C 6 cycloalkyl, saturated or partially saturated 5- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl, the C 5 -C 6 Cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0070] In another preferred embodiment, the compound represented by general formula (I) or general formula (IA) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0071] is a double bond;

[0072] X 1 CR 5 or NR 5 ;

[0073] X 2 CR 7 or NR 7 ;

[0074] R 5 With R 7 and the atoms to which it is connected together form a saturated or partially saturated C 5 -C 6 Cycloalkyl, saturated or partially saturated 5- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl, preferably cyclopentyl, cyclohexyl, dihydrofuranyl, pyrazolyl; which is optionally selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5- to 6-membered heterocyclic group, C 6-10 The aryl group or the 5- to 10-membered heteroaryl group may be substituted with one or more groups.

[0075] In another preferred embodiment, the compound represented by general formula (I) or general formula (IA) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0076] is a double bond;

[0077] X 1 CR 5 or NR 5 ;

[0078] X 2 CR 7 or NR 7 ;

[0079] R 5 With R 7 and the atoms to which it is connected together form a saturated or partially saturated C 5 -C 6 Cycloalkyl, saturated or partially saturated 5- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl, preferably cyclopentyl, cyclohexyl, dihydrofuranyl, pyrazolyl; which is optionally substituted by C 1-6 Alkyl substituted.

[0080] In another preferred embodiment, the compound represented by general formula (I) or general formula (IA) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A 1 Selected from C 5-7 Cycloalkyl or 5- to 7-membered heterocyclic group.

[0081] In another preferred embodiment, the compound represented by general formula (I) or general formula (IA) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A 1 Selected from cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl, tetrahydrofuranyl, oxepanyl.

[0082] In another preferred embodiment, the compound represented by general formula (I) or general formula (IA) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A 2 Selected from saturated or partially saturated C 5-7 Cycloalkyl, saturated or partially saturated 5- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl.

[0083] 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, wherein ring A 2 is selected from phenyl or 5- to 6-membered heteroaryl.

[0084] In another preferred embodiment, the compound represented by general formula (I) or general formula (IA) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A 2 Selected from phenyl, pyridyl, furyl, pyrazolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl.

[0085] 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 (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0086]

[0087] in:

[0088] Ring A 2a Selected from saturated or partially saturated C 5-6 Cycloalkyl, saturated or partially saturated 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl;

[0089] X 3 , X 4 are each independently selected from a bond, CH 2 , O, S or NH;

[0090] n is 0, 1 or 2;

[0091] X 1 , X 2 , R 1 , R 2 , R 3 、m 1 、m 2 As defined in general formula (I).

[0092] In another preferred embodiment, the compound represented by the general formula (IA) 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 (II-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0093]

[0094] in:

[0095] Ring A 2a Selected from saturated or partially saturated C 5-6 Cycloalkyl, saturated or partially saturated 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl;

[0096] X 3 , X 4 are each independently selected from a bond, CH 2 , O, S or NH;

[0097] n is 0, 1 or 2;

[0098] X 1 , X 2 , R 1 , R 2 , R 3 , R 12 、m 1 、m 2 、m 4 As defined in formula (IA).

[0099] In another preferred embodiment, the compound represented by the general formula (I) or the general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, is a compound represented by the general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

[0100]

[0101] in:

[0102] Ring A 2a , X 3 , X 4 , n is as defined in general formula (II);

[0103] R 1 , R 2 , R 3 , R 5 , R 7 、m 1 、m 2 As defined in general formula (I).

[0104] In another preferred embodiment, the compound represented by the general formula (IA) or the general formula (II-1) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIA-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0105]

[0106] in:

[0107] Ring A 2a , X 3 , X 4, n is as defined in general formula (II-1);

[0108] R 1 , R 2 , R 3 , R 5 , R 7 , R 12 、m 1 、m 2 、m 4 As defined in formula (IA).

[0109] In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention is a compound represented by general formula (IIB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0110]

[0111]

[0112] in:

[0113] Ring E is selected from saturated or partially saturated 5-6 membered cycloalkyl, saturated or partially saturated 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

[0114] Each R 10 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0115] s is 0, 1, 2, or 3;

[0116] Ring A 2a , X 3 , X 4 , n is as defined in general formula (II);

[0117] R 1 , R 2 , R3 , R 5 , R 7 、m 1 、m 2 As defined in general formula (I).

[0118] In another preferred embodiment, the compound represented by the general formula (IA), general formula (II-1), general formula (IIA-1) 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 (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0119]

[0120] in:

[0121] Ring E is selected from saturated or partially saturated 5-6 membered cycloalkyl, saturated or partially saturated 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

[0122] Each R 10 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0123] s is 0, 1, 2, or 3;

[0124] Ring A 2a , X 3 , X 4 , n is as defined in general formula (II-1);

[0125] R 1 , R 2 , R 3 , R 5 , R 7 , R 12 、m 1 、m 2 、m 4 As defined in formula (IA).

[0126] In another preferred embodiment, the compound represented by the general formula (II), (IIA), (IIB), (IIA-1), (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein ring A 2a Selected from phenyl or 5- to 6-membered heteroaryl; preferably phenyl, pyridyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, imidazolyl.

[0127] In another preferred embodiment, the compound represented by the general formula (II), (IIA), (IIB), (IIA-1), (IIB-1) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0128] Selected from

[0129] Among them, X 3 Selected from CH 2 , O, NH and S;

[0130] n is 0, 1 or 2;

[0131] R 1 , R 3 、m 1 、m 2 As defined in general formula (I).

[0132] In another preferred embodiment, the compound represented by the general formula (II), (IIA), (IIB), (IIA-1), (IIB-1) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Selected from

[0133] R 1 , R 3 、m 1 、m 2 As defined in general formula (I).

[0134] In another preferred embodiment, according to the compound represented by general formula (II), general formula (IIA) or general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring E is selected from R 10a and R 10b Each is independently selected from hydrogen, halogen, amino, hydroxyl, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, preferably selected from hydrogen and C 1-6 alkyl;

[0135] R 10c Selected from halogen, amino, hydroxyl, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, preferably selected from hydrogen and C 1-6 alkyl.

[0136] In another preferred embodiment, according to the compound represented by general formula (II), general formula (IIA) or general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring E is selected from R 10a Selected from C 1-6 alkyl.

[0137] In another preferred embodiment, according to the compound represented by general formula (II), general formula (IIA) or general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring E is selected from R 10b Selected from hydrogen or C 1-6 alkyl.

[0138] In another preferred embodiment, according to the compound represented by general formula (II), general formula (IIA) or general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring E is selected from R 10a Selected from hydrogen or C 1-6 Alkyl; R 10c Selected from hydrogen, C 1-6 Alkyl, C 1-6 Cyanoalkyl.

[0139] In another preferred embodiment, the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein:

[0140] Each R 1 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR a R b , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally substituted by one or more R 1a replace;

[0141] Each R 1a are independently selected from hydrogen, halogen, hydroxy, amino, cyano, 3- to 6-membered cycloalkyl, 4- to 8-membered heterocyclyl, -OC 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, -NH-C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl, -(CH 2 ) p -OR a , -Q-3 to 6-membered cycloalkyl, -Q-4 to 8-membered heterocyclyl, -Q-phenyl, -Q-5 to 6-membered heteroaryl, HC(=O)-, -NR a R b 、-L-NR a R b 、-C(=O)NR a R b 、-C(=O)R a 、-NHC(=O)R a 、-CH 2 OC(=O)NR a R b 、-CH 2 NHC(=O)OC 1-6 Alkyl, -CH 2 NHC(=O)NR a R b 、-CH 2 NHC(=O)-C 1-6 Alkyl, -CH 2 -5 to 6 membered heteroaryl, -CH 2 NHSO 2 -C 1-6 Alkyl, -CH 2 OC(=O)-4 to 8 membered heterocyclic group, -OC(=O)NR a R b , -OC(=O)-4 to 8 membered heterocyclic group and -CH 2 -4 to 8 membered heterocyclic group, wherein -CH 2 -4 to 8 membered heterocyclyl optionally substituted by one or more oxo groups;

[0142] m 1 is 0 or 1;

[0143] Q, R a , R b As defined in general formula (I).

[0144] In another preferred embodiment, the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein:

[0145] Each R 1 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, the C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally substituted by one or more R 1a replace;

[0146] Each R 1a are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl;

[0147] m 1 is 1.

[0148] In another preferred embodiment, the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein:

[0149] Each R 1 are each independently selected from hydrogen, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, the C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally substituted by one or more R 1a replace;

[0150] Each R 1a are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(CH 2 ) p -OR a , halogen, cyano, 3-6 membered cycloalkyl, 4-8 membered heterocyclic group, -Q-3-6 membered cycloalkyl, -L-NR a R b 、-C(=O)NR a R b 、-C(=O)R a 、-NHC(=O)R a ;

[0151] Q is -O-;

[0152] L is -CH 2 -;

[0153] R a Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl;

[0154] R b Selected from hydrogen, C 1-6 Alkyl; or

[0155] R a and R b Together with the nitrogen atom to which it is attached, it forms a 4-8 membered nitrogen-containing heterocyclic group, wherein the 4-8 membered nitrogen-containing heterocyclic group is optionally selected from halogen, C 1-6 One or more groups of the alkyl group are substituted;

[0156] p is an integer from 1 to 4;

[0157] m 1 is 1.

[0158] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 is pyrazolyl, which is optionally further selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6The alkyl group is substituted by one or more groups of heteroalkyl, 3-6 membered cycloalkyl or 4-8 membered heterocyclyl.

[0159] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 C 2-6 Alkynyl, which is optionally further substituted with C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, -L-NR a R b replace;

[0160] L is -CH 2 -;

[0161] R a Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl;

[0162] R b Selected from hydrogen, C 1-6 Alkyl; or

[0163] R a and R b Together with the nitrogen atom to which it is attached, it forms a 4-8 membered nitrogen-containing heterocyclic group, wherein the 4-8 membered nitrogen-containing heterocyclic group is optionally selected from halogen, C 1-6 The alkyl group is substituted with one or more groups.

[0164] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 is pyrimidinyl, which is optionally further substituted with C 1-6 Alkyl or C 1-6 Haloalkyl substitution.

[0165] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 is pyridyl, which is optionally further selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -NR a R b 、-C(=O)NR a R b 、-NHC(=O)R a is substituted by one or more groups;

[0166] R a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl;

[0167] R b Selected from hydrogen, C 1-6 Alkyl; or

[0168] R a and R b Together with the nitrogen atom to which it is attached, it forms a 4-8 membered nitrogen-containing heterocyclic group, wherein the 4-8 membered nitrogen-containing heterocyclic group is optionally selected from halogen, C 1-6 The alkyl group is substituted with one or more groups.

[0169] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkoxy.

[0170] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Halogenated alkyl.

[0171] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Halogenated alkoxy.

[0172] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 C 3-6 Cycloalkyl.

[0173] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 -NHC(=O)R a ; R a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl.

[0174] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 is a 4-10 membered heterocyclic group, preferably a 4-6 membered heterocyclic group, which is optionally further selected from halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, -C(=O)R a 、-C(=O)NR a R b is substituted by one or more groups;

[0175] R a Selected from C 1-6 Alkyl, C3-6 Cycloalkyl;

[0176] R b Selected from hydrogen.

[0177] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 is a 5-6 membered heteroaryl group, which is optionally further selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, -C(=O)R a 、-C(=O)NR a R b 、-NHC(=O)R a 、-(CH 2 ) p -OR a is substituted by one or more groups;

[0178] R a Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0179] R b Selected from hydrogen.

[0180] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, which is optionally further selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 Cycloalkyl, -OC 3-6 The cycloalkyl group is substituted with one or more radicals.

[0181] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 It is a halogen.

[0182] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA) or general formula (IIB) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 It is cyano.

[0183] In another preferred embodiment, the compound represented by general formula (I) or (IA) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Selected from

[0184]

[0185] Where R 1 Selected from hydrogen, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, the 4- to 10 membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl being optionally substituted by one or more R 1a Replacement, R 1a As defined in general formula (I);

[0186] R a , R b , R 3 , R 9 、m 1 、m 2 、m 3 As defined above.

[0187] In another preferred embodiment, the compound represented by general formula (I) or (IA) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Selected from Where R c Selected from C 1-6 alkyl.

[0188] In another preferred embodiment, the compound represented by general formula (I) or (IA) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Selected from Where R d Selected from C 1-6 alkyl.

[0189] In another preferred embodiment, the compound represented by general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein: Selected from

[0190] Where R c Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 heteroalkyl, 3-6 membered cycloalkyl or 4-8 membered heterocyclyl; R d Selected from C 1-6 Alkoxy.

[0191] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen, C 1-6 alkyl, -L-phenyl, -L-5 to 6-membered heteroaryl, wherein the phenyl portion of the -L-phenyl or the heteroaryl portion of the -L-5 to 6-membered heteroaryl is optionally substituted with one or more R 4 replace;

[0192] L is each independently a bond or -CH 2 -, wherein the -CH 2 - optionally selected from hydroxyl, C 1-6 substituted with one or more of hydroxyalkyl and 5- to 6-membered heteroaryl groups;

[0193] Each R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Halogenated alkyl.

[0194] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, -L-phenyl, -L-5 to 10 membered heteroaryl, wherein the phenyl portion of the -L-phenyl or the heteroaryl portion of the -L-5 to 10 membered heteroaryl is optionally substituted with one or more R 4 replace;

[0195] L is each independently a bond or -CH 2 -, wherein the -CH 2 - optionally selected from hydroxyl, C 1-6 substituted with one or more of hydroxyalkyl and 5- to 6-membered heteroaryl groups;

[0196] Each R 4 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Halogenated alkyl.

[0197] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl.

[0198] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen, C 1-6 Alkyl, -CH 2 -phenyl, -CH 2 -5 to 6 membered heteroaryl, wherein the -CH 2 -phenyl part or -CH 2 The heteroaryl portion of the 5- to 6-membered heteroaryl is optionally substituted by one or more R 4 Replacement, R 4 Selected from halogen.

[0199] In another preferred embodiment, according to the compound represented by general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen, C 1-6 Alkyl, -CH 2 -phenyl, -CH 2 -pyridinyl, wherein the -CH 2 -phenyl part or -CH 2 The pyridyl part of the -pyridyl radical is optionally substituted by one or more halogens.

[0200] In another preferred embodiment, according to the compound of formula (IA), formula (II), formula (IIA), formula (IIB), formula (IIA-1), formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen, C 1-6 Alkyl groups, especially C 1-4 alkyl, R f Selected from halogen, preferably fluorine.

[0201] In another preferred embodiment, according to the compound of formula (IA), formula (II), formula (IIA), formula (IIB), formula (IIA-1), formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from

[0202] in:

[0203] Y 1 , Y 2 , Y 3 are each independently selected from CH or N;

[0204] R g are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl;

[0205] t is 0, 1, or 2.

[0206] In another preferred embodiment, according to the compound of formula (IA), formula (II), formula (IIA), formula (IIB), formula (IIA-1), formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from -CH 2 -9-10 membered heteroaryl, which is optionally further selected from halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 The haloalkyl group is substituted with one or more groups.

[0207] In another preferred embodiment, according to the compounds of the general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (II-1), general formula (IIA-1), general formula (IIB-1) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, each R 3 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 4 to 8 membered heterocyclyl, phenyl, 5 to 6 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4 to 8 membered heterocyclyl, phenyl, 5 to 6 membered heteroaryl are optionally substituted with one or more R 3a replace;

[0208] Each R 3a are independently selected from hydrogen, halogen, hydroxy, amino, cyano, 4 to 8 membered heterocyclic group, -OC 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, -NH-C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 alkyl, -Q-phenyl, -Q-5 to 6-membered heteroaryl, HC(=O)-, -NR a R b 、-CH 2 OC(=O)NR a R b 、-CH 2 NHC(=O)OC 1-6 Alkyl, -CH 2 NHC(=O)NR a R b 、-CH 2 NHC(=O)-C 1-6 Alkyl, -CH 2 -5 to 6 membered heteroaryl, -CH 2 NHSO 2 -C 1-6 Alkyl, -CH 2 OC(=O)-4 to 8 membered heterocyclic group, -OC(=O)NR a R b , -OC(=O)-4 to 8 membered heterocyclic group and -CH 2 -4 to 8 membered heterocyclic group, wherein -CH 2 -4 to 8 membered heterocyclyl optionally substituted by one or more oxo groups;

[0209] m 2 is 0, 1, or 2;

[0210] Q, R a , R b As defined in general formula (I);

[0211] Preferably, m2 is 0.

[0212] In another preferred embodiment, according to the compounds of the general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (II-1), general formula (IIA-1), general formula (IIB-1) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 3 For hydrogen.

[0213] In another preferred embodiment, according to the compounds of the general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (II-1), general formula (IIA-1), general formula (IIB-1) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein m 2 is 0.

[0214] In another preferred embodiment, according to the compounds of the general formula (I), general formula (IA), general formula (II), general formula (IIA), general formula (IIB), general formula (II-1), general formula (IIA-1), general formula (IIB-1) or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein m 1 is 1.

[0215] In another preferred embodiment, the compound represented by general formula (I), general formula (IA), general formula (II), general formula (II-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein:

[0216] R 5 , R 6 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C l -C 6 Alkyl, C l -C 6 Hydroxyalkyl, C l -C 6 Aminoalkyl, C l -C 6 Haloalkyl, cyano, -CH 2 -C 6-10 Aryl, -CH 2 -5-6 membered heteroaryl, -CH 2 -C 3-8 Cycloalkyl, -CH2 -4-8 membered heterocyclic group, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OR a 、-NR a R b 、-C(=O)R a 、-C(=O)OR a 、-NR a C(=O)R b 、-NR a C(=O)OR b 、-C(=O)NR a R b 、-OC(=O)NR a R b 、-S(=O)R a 、-S(=O) 2 R a 、-SR a 、-S(=O)(=NR a )R b 、-NR a S(=O) 2 R b and -S(=O) 2 NR a R b ; said C l -C 6 Alkyl, -CH 2 -C 6-10 Aryl, -CH 2 -5-6 membered heteroaryl, -CH 2 -C 3-8 Cycloalkyl, -CH 2 -4-8 membered heterocyclic group, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C l -C 6 Alkyl, C l -C 6 Alkoxy, C l -C 6 Haloalkyl, C l -C 6 Hydroxyalkyl, C l -C 6 Aminoalkyl, C l -C 6 Halogenated alkoxy, C 2 -C6 Alkenyl, C 2 -C 6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 It is substituted by one or more groups of aryl or 5-6 membered heteroaryl;

[0217] R a and R b Each is independently selected from hydrogen, halogen, hydroxyl, thiol, C l -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, the C l -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C l -C 6 Alkyl, C l -C 6 Alkoxy, C l -C 6 Haloalkyl, C l -C 6 Hydroxyalkyl, C l -C 6 Aminoalkyl, C l -C 6 Halogenated alkoxy, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 aryl, 5-6 membered heteroaryl or one or more groups; or

[0218] R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 8-membered nitrogen-containing heterocyclic group, wherein the 4- to 8-membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C l -C 6 Alkyl, Cl -C 6 Alkoxy, C l -C 6 Haloalkyl, C l -C 6 Hydroxyalkyl, C l -C 6 Aminoalkyl, C l -C 6 Halogenated alkoxy, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 The aryl group or the 5-6-membered heteroaryl group is substituted by one or more groups.

[0219] In another preferred embodiment, the compound represented by general formula (I), general formula (IA), general formula (II), general formula (II-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein:

[0220] R 7 , R 8 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C l -C 6 Alkyl, C l -C 6 Hydroxyalkyl, C l -C 6 Aminoalkyl, C l -C 6 Haloalkyl, cyano, -CH 2 -C 6-10 Aryl, -CH 2 -5-6 membered heteroaryl, -CH 2 -C 3-8 Cycloalkyl, -CH 2 -4-8 membered heterocyclic group, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OR a 、-NR a R b 、-C(=O)R a 、-C(=O)OR a 、-NR a C(=O)R b 、-NR a C(=O)OR b 、-C(=O)NR a Rb 、-OC(=O)NR a R b 、-S(=O)R a 、-S(=O) 2 R a 、-SR a 、-S(=O)(=NR a )R b 、-NR a S(=O) 2 R b and -S(=O) 2 NR a R b ; said C l -C 6 Alkyl, -CH 2 -C 6-10 Aryl, -CH 2 -5-6 membered heteroaryl, -CH 2 -C 3-8 Cycloalkyl, -CH 2 -4-8 membered heterocyclic group, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C l -C 6 Alkyl, C l -C 6 Alkoxy, C l -C 6 Haloalkyl, C l -C 6 Hydroxyalkyl, C l -C 6 Aminoalkyl, C l -C 6 Halogenated alkoxy, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 It is substituted by one or more groups of aryl or 5-6 membered heteroaryl;

[0221] R a and R b Each is independently selected from hydrogen, halogen, hydroxyl, thiol, C l -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, the C l -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C l -C 6 Alkyl, C l -C 6 Alkoxy, C l -C 6 Haloalkyl, C l -C 6 Hydroxyalkyl, C l -C 6 Aminoalkyl, C l -C 6 Halogenated alkoxy, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 aryl, 5-6 membered heteroaryl or one or more groups; or

[0222] R a and R b Together with the nitrogen atom to which it is attached, it forms a 4- to 8-membered nitrogen-containing heterocyclic group, wherein the 4- to 8-membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C l -C 6 Alkyl, C l -C 6 Alkoxy, C l -C 6 Haloalkyl, C l -C 6 Hydroxyalkyl, C l -C 6 Aminoalkyl, C l -C 6 Halogenated alkoxy, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10The aryl group or the 5-6-membered heteroaryl group is substituted by one or more groups.

[0223] In another preferred embodiment, according to the compound represented by general formula (IA), general formula (II-1), general formula (IIA-1), general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 12 Selected from halogen, m 4 is 1.

[0224] Typical compounds of the present invention include, but are not limited to:

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241] Its tautomer, meso racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt.

[0242] 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:

[0243]

[0244] In the presence of a condensation agent and an alkaline agent, compound Ie and compound IIff are subjected to a condensation reaction 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,

[0245] Among them, the condensation reagent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline reagent is preferably N-methylimidazole;

[0246] in, Ring A 1 , Ring A 2 , R 1 , R 2 , R 3 、m 1 、m 2 , X 1 , X 2 As defined in general formula (I).

[0247] Another aspect of the present invention provides a method for preparing the compound represented by the general formula (IA) 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:

[0248]

[0249] In the presence of a condensation agent and an alkaline agent, compound Ie is subjected to a condensation reaction with compound IAF to obtain a compound represented by general formula (IA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0250] Among them, the condensation reagent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline reagent is preferably N-methylimidazole;

[0251] in, Ring A 1 , Ring A 2 , R 1 , R 2 , R 3 , R 12 、m1 、m 2 、m 4 , X 1 , X 2 As defined in formula (IA).

[0252] Another aspect of the present invention provides a method for preparing the compound represented by general formula (II) 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:

[0253]

[0254] In the presence of a condensation agent and an alkaline agent, compound IIe is subjected to a condensation reaction with compound If to obtain a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0255] Among them, the condensation reagent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline reagent is preferably N-methylimidazole;

[0256] in, Ring A 2a , X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 、m 1 、m 2 , n is as defined in the general formula (II).

[0257] Another aspect of the present invention provides a method for preparing the compound represented by the general formula (II-1) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the following steps:

[0258]

[0259] In the presence of a condensation agent and an alkaline agent, compound IIe and compound IAF are subjected to a condensation reaction to obtain a compound represented by general formula (II-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0260] Among them, the condensation reagent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline reagent is preferably N-methylimidazole;

[0261] in, Ring A 2a , X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 12 、m 1 、m 2 , n, m 4 As defined in general formula (II-1).

[0262] Another aspect of the present invention provides a method for preparing the compound represented by general formula (IIA) 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:

[0263]

[0264] In the presence of a condensation agent and an alkaline agent, compound IIe and compound IIf are subjected to a condensation reaction to obtain a compound represented by general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0265] Among them, the condensation reagent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline reagent is preferably N-methylimidazole;

[0266] Among them, ring A 2a , X 3 , X 4 , R 1 , R 2 , R 3 , R 5 , R 7 、m 1 、m 2 , n is as defined in the general formula (IIA).

[0267] Another aspect of the present invention provides a method for preparing the compound represented by general formula (IIA-1) 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:

[0268]

[0269] In the presence of a condensation agent and an alkaline agent, compound IIe and compound IIAf are subjected to a condensation reaction to obtain a compound represented by general formula (IIA-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0270] Among them, the condensation reagent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline reagent is preferably N-methylimidazole;

[0271] Among them, ring A 2a , X 3 , X 4 , R 1 , R 2 , R 3 , R 5 , R 7 , R 12 、m 1 、m 2 , n, m 4 As defined in general formula (IIA-1).

[0272] Another aspect of the present invention provides a method for preparing the compound represented by general formula (IIB) 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:

[0273]

[0274] In the presence of a condensation agent and an alkaline agent, compound IIe is subjected to a condensation reaction with compound IIf-2 to obtain a compound represented by general formula (IIB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0275] Among them, the condensation reagent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline reagent is preferably N-methylimidazole;

[0276] Among them, ring A 2a , Ring E, X 3 , X 4 , R 1 , R 2 , R 3 , R 10 、m 1 、m 2 , n, and s are as defined in the general formula (IIB).

[0277] Another aspect of the present invention provides a method for preparing the compound represented by general formula (IIB-1) 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:

[0278]

[0279] In the presence of a condensation agent and an alkaline agent, compound IIe is subjected to a condensation reaction with compound IIAf-2 to obtain a compound represented by general formula (IIB-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0280] Among them, the condensation reagent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline reagent is preferably N-methylimidazole;

[0281] Among them, ring A 2a , Ring E, X 3 , X 4 , R 1 , R 2 , R 3 , R 10 , R 12 、m 1 、m 2 ,n,s,m 4 As defined in general formula (IIB-1).

[0282] 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 a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0283] 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 its pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of a PRMT5 inhibitor.

[0284] The present invention further provides the use of 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 in the preparation of a drug for preventing and / or treating diseases associated with PRMT5 activity.

[0285] 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.

[0286] 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 PRMT5 inhibitor.

[0287] The present invention further provides 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, for use in preventing and / or treating diseases associated with PRMT5 activity.

[0288] The present invention further provides a method for inhibiting PRMT5, which comprises 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 a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0289] The present invention further provides a method for preventing and / or treating diseases associated with PRMT5 activity, which comprises 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 a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0290] In a preferred embodiment of the present invention, the disease associated with PRMT5 activity according to the present invention may be a solid tumor, such as non-small cell lung cancer, mesothelial tumor, neurofibrosarcoma, pancreatic cancer, and the like.

[0291] According to the conventional method in the field of the present invention, the compounds of the present invention can form pharmaceutically acceptable acid addition salts with acids. 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.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] 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.

[0302] 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.

[0303] The present invention may contain a compound represented by the general formula (I), 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 may 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 may be used as the sole active ingredient, or in combination with other drugs for treating diseases associated with PRMT5 activity. Combination therapy is achieved by administering each therapeutic component simultaneously, separately or sequentially.

[0304] Definition of terms

[0305] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0306] 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 protium (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, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0307] 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.

[0308] 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 1-6 Non-limiting examples of alkylene include, but are not limited to, methylene (—CH 2-), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 )-、1,1-propylene(-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -) and 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc. 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.

[0309] 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.

[0310] 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.

[0311] 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.

[0312] The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0313]

[0314] The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include:

[0315]

[0316] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0317]

[0318] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, tetrahydrobenzofuranyl, tetrahydrobenzoxazolyl, tetrahydrobenzisoxazolyl, cyclopentathienyl, tetrahydrobenzothiazolyl, etc. The cycloalkyl 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.

[0319] 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 from 0 to 2) heteroatoms, but does not include -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. Preferably, it contains 4 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 7 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.

[0320] The term "spiro heterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 12 yuan. According to the number of shared spiral atoms between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0321]

[0322] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 12 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0323] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system, and one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, and more preferably 7 to 12 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0324]

[0325] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include: wait.

[0326] 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.

[0327] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

[0328]

[0329] The aryl 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, carboxyl or carboxylate.

[0330] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0331]

[0332] 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.

[0333] 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.

[0334] 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.

[0335] The term "cycloalkoxy" refers to an -O-(cycloalkyl) group, wherein cycloalkyl is as defined above.

[0336] The term "heterocycloalkoxy" refers to -O-(heterocyclyl) wherein heterocyclyl is as defined above.

[0337] The term "cycloalkylthio" refers to -S-(cycloalkyl) wherein cycloalkyl is as defined above.

[0338] The term "heterocycloalkylthio" refers to -S-(heterocyclyl) wherein heterocyclyl is as defined above.

[0339] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0340] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0341] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0342] The term "hydroxy" refers to an -OH group.

[0343] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0344] The term "amino" refers to -NH 2 .

[0345] The term "cyano" refers to -CN.

[0346] The term "nitro" refers to -NO 2 .

[0347] The term "oxo" refers to =0.

[0348] The term "carboxy" refers to -C(O)OH.

[0349] The term "thiol" refers to -SH.

[0350] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0351] The term "acyl" refers to a compound containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0352] "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.

[0353] "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.

[0354] "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.

[0355] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0356] "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.

[0357] Synthesis method of the compound of the present invention

[0358] In order to achieve the purpose of the present invention, the present invention adopts the following technical scheme.

[0359] 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.

[0360]

[0361] Solution 1

[0362] Step 1: Compound Ic is coupled with compound Id under heating, in the presence of an alkaline agent and a catalyst to obtain compound Ie, wherein the heating condition is preferably 100° C., the alkaline agent is preferably sodium carbonate, and the catalyst is preferably DPPF palladium dichloride catalyst;

[0363] Step 2: In the presence of an alkaline agent, compound Ie is subjected to a condensation reaction with compound If 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 condensation agent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline agent is preferably N-methylimidazole;

[0364] in, Ring A 1 , Ring A 2 , R 1 , R 2 , R 3 、m 1 、m 2 , X 1 , X 2 As defined in general formula (I).

[0365] In some embodiments, the compound represented by the general formula (IA) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt can be prepared by Scheme 2.

[0366]

[0367] Solution 2

[0368] Step 1: Compound Ic is coupled with compound Id under heating, in the presence of an alkaline agent and a catalyst to obtain compound Ie, wherein the heating condition is preferably 100° C., the alkaline agent is preferably sodium carbonate, and the catalyst is preferably DPPF palladium dichloride catalyst;

[0369] Step 2: In the presence of an alkaline agent, compound Ie is subjected to a condensation reaction with compound IAF to obtain a compound represented by the general formula (IA) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the condensation agent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline agent is preferably N-methylimidazole;

[0370] in, Ring A 1 , Ring A 2 , R 1 , R 2 , R 3 , R 12 、m 1 、m 2 、m 4 , X 1 , X 2 As defined in formula (IA).

[0371] In some embodiments, the compound represented by the general formula (II) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt can be prepared by Scheme 3.

[0372]

[0373] Solution 3

[0374] Step 1: Under heating, in the presence of an alkaline agent and a catalyst, compound IIa and compound Ib are subjected to coupling reaction to obtain compound IIb, wherein the heating condition is preferably 100° C., the alkaline agent is preferably sodium carbonate, and the catalyst is preferably DPPF palladium dichloride catalyst;

[0375] Step 2: Reaction of IIb and Id in the presence of a reducing agent to obtain IIe, wherein the reducing agent is preferably sodium cyanoborohydride;

[0376] Step 3: In the presence of an alkaline agent, compound IIe is subjected to a condensation reaction with compound If to obtain a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the condensation agent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline agent is preferably N-methylimidazole;

[0377] in, Ring A 2a , X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 、m 1 、m 2 , n is as defined in the general formula (II).

[0378] In some embodiments, the compound represented by the general formula (II) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt can be prepared by Scheme 4.

[0379]

[0380] Solution 4

[0381] Step 1: Under heating, in the presence of an alkaline agent and a catalyst, compound IIa and compound Ib are subjected to coupling reaction to obtain compound IIb, wherein the heating condition is preferably 100° C., the alkaline agent is preferably sodium carbonate, and the catalyst is preferably DPPF palladium dichloride catalyst;

[0382] Step 2: In the presence of a reducing agent, IIb is reacted with ammonium acetate to obtain IIc, wherein the reducing agent is preferably sodium cyanoborohydride;

[0383] Step 3: Reaction of IIc and IId in the presence of a reducing agent to obtain IIe, wherein the reducing agent is preferably sodium acetylborohydride;

[0384] Step 4: In the presence of an alkaline agent, compound IIe is subjected to a condensation reaction with compound If to obtain a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the condensation agent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline agent is preferably N-methylimidazole;

[0385] in, Ring A 2a , X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 、m 1 、m 2 , n is as defined in the general formula (II).

[0386] In some embodiments, the compound represented by the general formula (IIA) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt can be prepared by Scheme 5.

[0387]

[0388] Solution 5

[0389] Step 1: In the presence of an alkaline agent, compound IIe and compound IIf are subjected to a condensation reaction to obtain a compound represented by the general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the condensation agent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline agent is preferably N-methylimidazole;

[0390] Among them, ring A 2a , X 3 , X 4 , R 1 , R 2 , R 3 , R 5 , R 7 、m 1 、m 2 , n is as defined in the general formula (IIA).

[0391] In some embodiments, the compound represented by the general formula (IIB) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt can be prepared by Scheme 6.

[0392]

[0393] Solution 6

[0394] Step 1: In the presence of an alkaline agent, compound IIc is subjected to a condensation reaction with compound IIf-2 to obtain a compound represented by general formula (IIB) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the condensation agent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline agent is preferably N-methylimidazole;

[0395] Among them, ring A 2a , Ring E, X 3 , X 4 , R 1 , R 2 , R 3 , R 10 、m 1 、m 2 , n, and s are as defined in the general formula (IIB). DETAILED DESCRIPTION

[0396] 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.

[0397] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The NMR measurements were performed using a Bruker dps300 NMR spectrometer and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).

[0398] LC-MS was measured using a 1100 Series LC / MSD Trap (ESI) mass spectrometer (manufacturer: Agilent).

[0399] GC-MS measurement was performed using GCMS-QP2010 SE.

[0400] 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).

[0401] 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).

[0402] 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.

[0403] Column chromatography generally uses Qingdao marine silica gel 100-200 mesh and 200-300 mesh silica gel as the carrier.

[0404] 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.

[0405] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0406] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0407] A CEM Discover SP microwave reactor was used for the microwave reaction.

[0408] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0409] Unless otherwise specified in the examples, the reaction temperature is room temperature, particularly 20°C to 30°C.

[0410] 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.

[0411] 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.

[0412] 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.

[0413] Example 1: Preparation of 4-amino-N-((3-fluoropyridin-2-yl)methyl)-1-methyl-N-(7-(1-methyl-1H-pyrazol-4-yl)chroman-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (1)

[0414]

[0415] Step 1: Preparation of 5-bromo-1-methyl-1H-pyrazole-4-carbonitrile (1i)

[0416] At room temperature, tert-butyl nitrite (6.33 g, 61.41 mmol), acetonitrile (50 mL), and copper bromide (10.97 g, 49.13 mmol) were added to the reaction bottle and reacted at 50°C for 1 hour. 5-Amino-1-methyl-1H-pyrazole-4-carbonitrile (1h) was dissolved in acetonitrile (50 mL) and added dropwise to the reaction system and reacted at 45°C for 2 hours. Filter, add water (100 mL), extract with ethyl acetate (100 mL), wash with saturated sodium chloride aqueous solution (100 mL), dry with anhydrous sodium sulfate, and concentrate. The concentrated product was dissolved in ethyl acetate (5 mL), petroleum ether (25 ml-30 ml) was added dropwise, and filtered to obtain gray solid compound 1i, 5 g, yield: 66%.

[0417] Step 2: Preparation of methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1k)

[0418] At room temperature, methyl 4-amino-3-bromobenzoate (1j) (5 g, 21.74 mmol), 1.4-dioxane (8 mL), water (2 mL), potassium acetate (6.38 g, 65.20 mmol), and biboronic acid pinacol ester (8.28 g, 32.61 mmol) were added to a reaction bottle, and the atmosphere was replaced with nitrogen 2-3 times. DPPF palladium dichloride (0.79 g, 1.06 mmol) was added, and the atmosphere was replaced with nitrogen 2-3 times. The reaction was carried out at 80°C for 2 hours. The mixture was filtered and concentrated, and the residue was washed twice with dichloromethane (50 mL) and filtered to obtain compound 1k as an off-white solid, 3.1 g, with a yield of 50%.

[0419] Step 3: Preparation of methyl 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate (1l) Compound 1k (3.0 g, 10.82 mmol), 1.4-dioxane (32 mL), water (8 mL), potassium phosphate (4.58 g, 21.64 mmol), and compound 1i (3.01 g, 16.23 mmol) were added to a reaction flask at room temperature, replaced with nitrogen 2-3 times, added with dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (77 mg, 0.11 mmol), replaced with nitrogen 2-3 times, and reacted at 90°C for 2 hours. Filter, add water (50 mL), extract with ethyl acetate (50 mL), wash with saturated sodium chloride aqueous solution (50 mL), dry with anhydrous sodium sulfate, and concentrate to obtain compound 1l, 2.0 g, yield: 72%.

[0420] Step 4: Preparation of 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (1m)

[0421] At room temperature, compound 11 (4.05 g, 15.81 mmol) was dissolved in THF:MeOH:H2O=1:1:1 (40 mL), solid lithium hydroxide (1.14 g, 47.43 mmol) was added, and the mixture was reacted at 80°C for 2 hours. Water (120 ml) was added, and the pH was adjusted to 3-4 to precipitate a solid. The solid was washed twice with water (20 ml) and dried to obtain a gray powder solid 1m, 3 g, with a yield of 78%.

[0422] Step 5: Preparation of 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl chloride (1 g)

[0423] At room temperature, compound 1m (2.42 g, 10.0 mmol), dichloromethane (40 mL), and thionyl chloride (20.00 mL) were added to a reaction flask and reacted at 50° C. for two hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a light yellow solid, 2.01 g, with a yield of 77.3%.

[0424] Step 6: Preparation of 7-(1-methyl-1H-pyrazol-4-yl)chroman-4-one (1c)

[0425] At room temperature, 7-bromochroman-4-one 1a (2.00 g, 8.81 mmol), 1,4-dioxane (10 mL) and water (1.0 mL) were added to a reaction flask, potassium phosphate (3.74 g, 17.6 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1b (2.8 g, 13.3 mmol) and DPPF palladium dichloride (650 mg, 0.881 mmol) were added, and the reaction was carried out at 85°C for 12 hours under a nitrogen atmosphere. The reaction solution was extracted with ethyl acetate (50 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain the title compound as a yellow solid, 1.50 g, yield: 41.8%.

[0426] LC-MS: m / z 229.2 [M+H] + .

[0427] Step 7: Preparation of 7-(1-methyl-1H-pyrazol-4-yl)chroman-4-amine (1d)

[0428] At room temperature, compound 1c (1.00 g, 4.39 mmol), ammonium acetate (1.00 g, 13.2 mmol), sodium cyanoborohydride (830 mg, 13.2 mmol) and ethanol (10 mL) were added to a reaction flask and reacted at 95 °C for 3 hours under a nitrogen atmosphere. Water was added to quench the reaction solution, extracted with ethyl acetate (50 mL × 2), the aqueous phase was adjusted to pH 8-9 with sodium bicarbonate solution, and extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound as a yellow solid, 900 mg, yield: 89.6%.

[0429] LC-MS: m / z 230.2 [M+H] + .

[0430] Step 8: Preparation of N-((3-fluoropyridin-2-yl)methyl)-7-(1-methyl-1H-pyrazol-4-yl)chroman-4-amine (1f)

[0431] At room temperature, compound 1d (1.00 g, 4.39 mmol), 3-fluoropyridine carboxaldehyde 1e (550 mg, 4.39 mml), sodium triacetoxyborohydride (1.39 g, 6.59 mmol) and dichloromethane (10 mL) were added to a reaction bottle and reacted at room temperature for 3 hours under a nitrogen atmosphere. Water was added to quench the reaction solution, extracted with ethyl acetate (50 mL×2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain the title compound as a yellow oily liquid, 500 mg, yield: 36.8%.

[0432] LC-MS: m / z 339.2 [M+H] + .

[0433] Step 9: Preparation of 4-amino-N-((3-fluoropyridin-2-yl)methyl)-1-methyl-N-(7-(1-methyl-1H-pyrazol-4-yl)chroman-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (1)

[0434] At room temperature, compound 1f (129 mg, 0.380 mmol), triethylamine (76.8 mg, 0.76 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl chloride 1 g (100 mg, 0.38 mmol) and 1,2-dichloroethane (10 mL) were added to a reaction flask and reacted at 40°C for 2 hours. Water (5 mL) was added, extracted with ethyl acetate (50 mL×3), the organic phases were combined, 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: 10%-100%) to obtain the title compound as a white solid, 66.0 mg, yield: 30.6%.

[0435] LC-MS: m / z 563.1[M+H] + .

[0436] 1 H NMR (400 MHz, DMSO-d 6)δ8.46(s,1H),8.25(s,1H),8.12(s,1H),7.83(s,1H),7.66(s,2H),7.36(s,2H),7.16(s,3H),6.97(d,J=1.8Hz,1H),5.40 (s,1H),4.87(s,1H),4.33(s,2H),4.24(d,J=11.5Hz,2H),4.06(d,J=31.3Hz,2H),3.85(s,3H),3.67(s,3H),2.24(s,2H).

[0437] Example 2: Preparation of 4-amino-N-((3-fluoropyridin-2-yl)methyl)-3-methyl-N-(7-(1-methyl-1H-pyrazol-4-yl)chroman-4-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (2)

[0438]

[0439]

[0440] Step 1: Preparation of 2-methyl-3-cyano-4-oxotetrahydrofuran (2b)

[0441] At room temperature, sodium hydride (5.55 g, 60%, 138.77 mmol), ultra-dry tetrahydrofuran (250 ml), and methyl 2-hydroxyacetate 2a (25 g, 277.54 mmol) were added to the reaction bottle, the temperature was raised to 65°C, and trans-crotononitrile (22.34 g, 333.04 mmol) was slowly added. After 2 hours, the temperature was lowered to 25°C, quenched with sodium hydroxide aqueous solution (2N, 250 ml), extracted with ether (500 ml), the aqueous phase was retained, the pH was adjusted to 2 with 2M hydrochloric acid, extracted with dichloromethane (250 mL), washed with saturated sodium chloride aqueous solution (250 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE:EA=90:10) to obtain the title compound as a brown solid, 14 g, yield: 40.31%.

[0442] Step 2: Preparation of 4-cyano-5-methyl-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (2c)

[0443] At room temperature, compound 2b (1.1 g, 8.79 mmol) was dissolved in ultra-dry dichloromethane (20 ml), cooled to -78°C, N,N-diisopropylethylamine (2.27 g, 17.58 mmol) and trifluoromethanesulfonic anhydride (3.47 g, 12.31 mmol) were added, stirred for 30 minutes, returned to room temperature, added with water (250 ml), extracted with dichloromethane (25 mL), washed with saturated aqueous sodium chloride solution (25 mL), dried over anhydrous sodium sulfate, filtered, concentrated, added with diethyl ether to the residue, stirred for 10 minutes and filtered, the mother liquor was concentrated to give the brown title compound, 1.8 g, yield: 79%.

[0444] Step 3: Preparation of methyl 4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylate (2d)

[0445] At room temperature, compound 2c (1.0 g, 3.89 mmol), 1,4-dioxane (10 mL), water (2 mL), potassium phosphate (2.47 g, 11.67 mmol), and compound 1k (1.08 g, 3.89 mmol) were added to a reaction flask, and the nitrogen atmosphere was replaced 2-3 times. DPPF palladium dichloride (500.94 mg, 0.39 mmol) was added, and the nitrogen atmosphere was replaced 2-3 times. After stirring at 80°C for 16 hours, the mixture was filtered, added with water (10 mL), extracted with ethyl acetate (10 mL), washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: PE:EA=1:1) to obtain a brown solid compound, 0.8 g, yield: 80%.

[0446] Step 4: Preparation of 4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid (2e)

[0447] Compound 2d (1.0 g, 3.87 mmol) was dissolved in THF:MeOH:H 2 O=1:1:1 (10mL), solid lithium hydroxide (278.64mg, 11.61mmol) was added, and stirred at 50°C for 2 hours. Water (30ml) was added, and 2M hydrochloric acid was used to adjust the pH to 3-4, and a solid was precipitated. The obtained solid was washed twice with water (20ml) and dried to obtain a gray powdery solid compound, 0.5g, yield: 53%.

[0448] Step 5: Preparation of 4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carbonyl chloride (2f)

[0449] At room temperature, compound 2e (2.43 g, 10.0 mmol), dichloromethane (40 mL), and thionyl chloride (20.00 mL) were added to a reaction flask and reacted at 50° C. for two hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a light yellow solid, 2.17 g, with a yield of 83.1%.

[0450] Step 6: Preparation of 4-amino-N-((3-fluoropyridin-2-yl)methyl)-3-methyl-N-(7-(1-methyl-1H-pyrazol-4-yl)chroman-4-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (2)

[0451] The title compound was prepared in the same manner as in Example 1, except that compound 2f was used instead of compound 1g.

[0452] LC-MS: m / z 565.1[M+H] + .

[0453] 1 H NMR (400 MHz, CHCl 3 -d)δ8.45(s,1H),8.11(s,1H),7.83(s,1H),7.64(s,3H),7.47(s,1H),7. 39–7.33(m,1H),7.27(dd,J=8.0,2.5Hz,1H),7.12(s,1H),6.97(d,J=1.7 Hz,1H),6.61(s,2H),5.41(s,1H),5.27(s,2H),4.86(s,2H),4.24(s,1H) ,4.02(s,1H),3.85(s,3H),2.19(d,J=48.3Hz,2H),1.39(t,J=6.0Hz,3H).

[0454] Example 3: Preparation of 4-amino-N,1-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (3)

[0455]

[0456] Step 1: Preparation of 2-bromo-6,7-dihydrobenzofuran-4(5H)-one (3b)

[0457] At room temperature, 6,7-dihydrobenzofuran-4(5H)-one 3a (7.00 g, 41.4 mmol), N-bromosuccinimide (10.1 g, 56.5 mmol), and N,N-dimethylformamide (80 mL) were added to a reaction flask and reacted at room temperature for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate (50 mL), washed with saturated sodium chloride aqueous solution (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 19:1) to obtain the title compound as a white solid, 6.00 g, yield: 77.4%.

[0458] LC-MS: m / z 215.1 [M+H] + .

[0459] Step 2: Preparation of 2-bromo-N-methyl-4,5,6,7-tetrahydrobenzofuran-4-amine (3c)

[0460] At room temperature, compound 3b (3.00 g, 14.0 mmol), methylamine hydrochloride (9.45 g, 140 mmol), acetic acid (0.3 mL), and methanol (50 mL) were added to a reaction flask, and sodium cyanoborohydride (2.10 g, 33.6 mmol) was added in batches, and the reaction was carried out at 80°C for 12 hours. After the reaction was completed, the reaction solution was distilled under reduced pressure, the residue was poured into water, extracted with ethyl acetate (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 = 9:1) to obtain the title compound as a white solid, 2.23 g, yield: 69.5%.

[0461] LC-MS: m / z 230.0 [M+H] + .

[0462] Step 3: Preparation of N-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzofuran-4-amine (3e)

[0463] At room temperature, compound 3c (1.81 g, 7.87 mmol), 1.4-dioxane (20 mL), water (4 mL), potassium carbonate (2.17 g, 15.7 mmol), compound 1b (1.80 g, 8.65 mmol), DPPF palladium dichloride (1.13 g, 1.57 mmol) were added to the reaction bottle, nitrogen was replaced 3 times, and the reaction was carried out at 80°C for 2 hours. The reaction solution was filtered, water (60 mL) was added, and ethyl acetate (50 mL) was extracted. The organic phase was washed with saturated sodium chloride aqueous solution (50 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 as a black solid, 1.00 g, yield: 54.8%.

[0464] Step 4: Preparation of 4-amino-N,1-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (3)

[0465] At room temperature, compound 3e (50.0 mg, 0.216 mmol), N,N-dimethylformamide (4 mL), compound 1m (62.6 mg, 0.259 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (90.9 mg, 0.324 mmol) were added to a reaction flask, stirred for 10 minutes, and then methylimidazole solution (53.20 mg, 0.648 mmol) was added dropwise. The reaction mixture was reacted for 16 hours at room temperature. Water (10 mL) was added to the reaction solution, and ethyl acetate (10 mL) was used for extraction. 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, 100 A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain the title compound as a white solid powder, 54.0 mg, yield: 54.6%.

[0466] LC-MS: m / z 456.0 [M+H] + .

[0467] 1 H NMR (400 MHz, DMSO-d 6 )δ8.28(d,J=17.9Hz,2H),8.15(s,1H),7.97(s,1H),7.71(s,1H),7.62(s,2H),7.17(s,2H), 4.93(s,1H),4.37(s,3H),3.86(s,3H),2.78(s,3H),2.63(s,2H),2.18–1.68(m,4H).(s,3H).

[0468] Example 4: Preparation of 4-amino-N,3-dimethyl-N-(8-(1-methyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepan-5-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (4)

[0469]

[0470] Step 1: Preparation of 8-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydrobenzo[b]oxepan-5(2H)-one (4b)

[0471] Under nitrogen atmosphere, 8-bromo-3,4-dihydrobenzo[b]oxepan-5(2H)-one 4a (1.20 g, 4.98 mmol), compound 1b (1.55 g, 7.47 mmol), sodium carbonate (1.58 g, 14.9 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene] (0.326 g, 0.498 mmol), 1,4-dioxane solution (10 mL) and water (2 mL) were added to a reaction flask at room temperature and stirred at 80°C for 16 hours. The reaction solution was filtered, water (10 mL) was added to the filtrate, and extracted with ethyl acetate (5 mL x 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the title compound 4b as a brown oil, 1.01 g, yield: 83.7%.

[0472] LC-MS: m / z 243.1[M+H] + .

[0473] Step 2: Preparation of N-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepan-5-amine (4c)

[0474] At room temperature, compound 4b (700 mg, 2.89 mml), sodium cyanoborohydride (364 mg, 5.78 mmol), methylamine hydrochloride (1.96 g, 28.9 mml) and methanol (10 mL) were added to a reaction flask and reacted at 80°C for 16 hours. After the reaction, the reaction solution was diluted with water (30 mL), the pH was adjusted to 12 with sodium hydroxide, and extracted with ethyl acetate (10 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 4c as a yellow oil, 500 mg, with a yield of 67.2%.

[0475] LC-MS: m / z 257.3 [M+H] + .

[0476] Step 3: Preparation of 4-amino-N,3-dimethyl-N-(8-(1-methyl-1H-pyrazol-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepan-5-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (4)

[0477] At room temperature, compound 4c (100 mg, 0.391 mmol), 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid 2e (124 mg, 0.508 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (165 mg, 0.587 mmol), N-methylimidazole (96.0 mg, 1.17 mmol) and N,N-dimethylformamide (2 mL) were added to a reaction bottle and reacted at room temperature for 16 hours. After the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL x 2), the combined organic phases were dried over anhydrous sodium sulfate, 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, 100A, mobile phase: acetonitrile / water, gradient: 10%-100%) to obtain the title compound 4 as a white solid, 48.0 mg.

[0478] Chiral separation [chromatographic column model: CHIRALPAK IA 3 4.6*50mm, 3μm, mobile phase (n-hexane: dichloromethane = 3:1) (0.1% diethanolamine): ethanol = 70:30] was performed to obtain 4A: 6.0 mg, 4B: 5.0 mg, 4C: 5.0 mg and 4D: 5.0 mg. LC-MS: m / z 484.2 [M+H] + .

[0479] 1 H NMR (400 MHz, CH 3 OH-d 4 )δ7.57(q,J=44.4,40.7Hz,5H),7.28(s,1H),7.20(d,J=4.4Hz,1H),6.44(s,1H),5.45(s,2H),5.10(d,J=16.7Hz,2H),4.77–4.62(m,1H),4.3 3(d,J=37.7Hz,1H),3.95(s,3H),3.59(s,1H),3.18(d,J=61.2Hz,2H),2.18(d,J=17.8Hz,2H),1.97(t,J=39.4Hz,2H),1.50(d,J=19.4Hz,3H).

[0480] Example 5: Preparation of 4-amino-N,3-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (5)

[0481]

[0482] The title compound 5 was prepared in the same manner as in Example 3, except that compound 2e was used instead of compound 1m.

[0483] Example 6: Preparation of 4-amino-1-methyl-N-(4-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,4-b]furan-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (6)

[0484]

[0485]

[0486] Step 1: Preparation of 1-methyl-1H-pyrazole-4-carbonyl chloride (6b)

[0487] At room temperature, 1-methyl-1H-pyrazole-4-carboxylic acid 6a (30.0 g, 238 mmol) and dichlorothionyl (120 mL) were added to a reaction flask and the temperature was raised to reflux for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the title compound 6b as a white solid, 34.4 g, yield: 100%.

[0488] LC-MS: m / z 141.1 [M+H] + .

[0489] Step 2: Preparation of ethyl 3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanoate (6c)

[0490] Under nitrogen atmosphere, tetrahydrofuran (627 mL) and lithium diisopropylamide (2M, 237 mL, 475 mmol) were added to the reaction bottle at 0°C. The temperature was lowered to -78°C, ethyl acetate (62.7 g, 712 mmol) was slowly added dropwise, and the mixture was stirred at -78°C for 1 hour. Compound 6b (34.4 g, 238 mmol, dissolved in 150 mL tetrahydrofuran) was slowly added dropwise, and the mixture was stirred at -78°C for 1 hour. The pH was adjusted to 5-6 with 4M hydrochloric acid, the aqueous phase was extracted with dichloromethane (343 mL), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 6c as a yellow solid, 46.6 g, yield: 99.8%.

[0491] LC-MS: m / z 197.0 [M+H] + .

[0492] Step 3: Preparation of (Z)-ethyl 3-amino-3-(1-methyl-1H-pyrazol-4-yl)acrylate (6d)

[0493] At room temperature, methanol (420 mL), compound 6c (42.0 g, 214 mmol) and ammonium formate (67.5 g, 1.07 mol) were added to the reaction flask and the temperature was raised to reflux for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, water (675 mL) was added to the residue and stirred for 30 minutes, extracted with ethyl acetate (420 mL×2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 6d as a yellow solid, 39.8 g, yield: 95.2%.

[0494] LC-MS: m / z 196.1[M+H] + .

[0495] Step 4: Preparation of ethyl (Z)-2-(amino(1-methyl-1H-pyrazol-4-yl)methylene)-4-chloro-3-oxobutanoate (6e)

[0496] At -20°C, THF (110 mL), compound 6d (11.0 g, 56.4 mmol) and pyridine (6.69 g, 84.5 mmol) were added to a reaction flask, and chloroacetyl chloride (9.55 g, 84.5 mmol) was slowly added dropwise. After the addition, the mixture was reacted at -20°C for 4 hours. After the reaction was completed, water (67 mL) was added, and the mixture was extracted with ethyl acetate (220 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 6e as a reddish brown solid, 15.9 g, with a yield of 103%.

[0497] LC-MS: m / z 271.8 [M+H] + .

[0498] Step 5: Preparation of ethyl 4-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)thiophene-3-carboxylate (6f)

[0499] At room temperature, ethanol (159 mL) and compound 6e (15.9 g, 58.5 mmol) were added to the reaction bottle, and 30% sodium hydrosulfide solution (15.6 g, 211 mmol) was slowly added dropwise. After the addition, the mixture was reacted at room temperature for 30 minutes. After the reaction was completed, water (480 mL) was added, and the mixture was extracted with ethyl acetate (300 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (150 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 = 3:1) to obtain the title compound 6f as a brown solid, 3.50 g, yield: 23.7%.

[0500] LC-MS: m / z 252.9 [M+H] + .

[0501] Step 6: Preparation of ethyl 4-(3-ethoxy-3-oxoethoxy)-2-(1-methyl-1H-pyrazol-4-yl)thiophene-3-carboxylate (6 g)

[0502] At room temperature, N,N-dimethylformamide (25 mL), compound 6f (3.50 g, 13.9 mmol) and potassium carbonate (3.83 g, 27.8 mmol) were added to a reaction flask and reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered, water (50 mL) was added to the filtrate, and extracted with ethyl acetate (70 mL×2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 6 g, 4.20 g, as a brown solid, with a yield of 89.5%.

[0503] LC-MS: m / z 339.1[M+H] + .

[0504] Step 7: Preparation of ethyl 4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydrothieno[3,4-b]furan-2-carboxylate (6h)

[0505] Under nitrogen atmosphere, tetrahydrofuran (100 mL) and compound 6g (4.20 g, 12.4 mmol) were added to a reaction bottle at 0°C, potassium tert-butoxide (2.79 g, 24.8 mmol) was added in small amounts several times, and the mixture was reacted at 10°C to 25°C for 2 hours. After the reaction, water (50 mL) was added, the pH was adjusted to 5 to 6 with 1N dilute hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (150 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 6h as a reddish brown solid, 2.52 g, yield: 69.5%.

[0506] LC-MS: m / z 292.9 [M+H] + .

[0507] Step 8: Preparation of 4-(1-methyl-1H-pyrazol-4-yl)thieno[3,4-b]furan-3(2H)-one (6i)

[0508] At room temperature, water (2.5 mL), 12N concentrated hydrochloric acid (2.5 mL), 1,4-dioxane (5.0 mL) and compound 6h were added to the reaction bottle and reacted at 60°C for 2 hours. After the reaction was completed, dichloromethane (25.0 mL×2) was added for extraction, the organic phases were combined and 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 = 3:1) to obtain the title compound 6i as a yellow solid, 1.30 g, yield: 68.5%.

[0509] LC-MS: m / z 220.9 [M+H] + .

[0510] Step 9: Preparation of 4-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,4-b]furan-3-amine (6j)

[0511] At room temperature, methanol (3.0 mL), compound 6i (150 mg, 0.681 mmol), ammonium acetate (1.05 g, 13.6 mmol) and sodium cyanoborohydride (427 mg, 6.81 mmol) were added to a reaction flask and heated to reflux for 8 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to the reaction solution, extracted with ethyl acetate (15 mL × 2), the combined organic phases were 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 = 3: 1) to obtain the title compound 6j as a yellow-green solid, 56.0 mg, yield: 37.1%.

[0512] LC-MS: m / z 222.0 [M+H] + .

[0513] Step 10: Preparation of 4-amino-1-methyl-N-(4-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,4-b]furan-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (6)

[0514] At room temperature, N,N-dimethylacetamide (3.0 mL), compound 6j (56.0 mg, 0.253 mmol), compound 1m (79.7 mg, 0.329 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (107 mg, 0.380 mmol) and N-methylimidazole (62.3 mg, 0.759 mmol) were added to a reaction bottle and reacted at room temperature for 8 hours. After the reaction, the reaction solution 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 white solid, 26.0 mg, yield: 23.1%.

[0515] LC-MS: m / z 446.0 [M+H] + .

[0516] 1 H NMR (400 MHz, DMSO-d 6 )δ8.62(d,J=1.7Hz,1H),8.26(s,1H),8.17(s,1H),8.01-7.92(m,2H),7.61-7.53(m,2H),7.25(s,2H),6.19(s,1H ), 5.84 (td, J = 8.0, 4.3Hz, 1H), 5.21 (dd, J = 9.4, 8.0Hz, 1H), 4.69 (dd, J = 9.4, 4.3Hz, 1H), 4.38 (s, 3H), 3.78 (s, 3H).

[0517] Example 7: Preparation of 4-amino-N,1-dimethyl-N-(4-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,4-b]furan-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (7)

[0518]

[0519] Step 1: Preparation of tert-butyl (4-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,4-b]furan-3-yl)carbamate (7a)

[0520] At room temperature, dichloromethane (1.0 mL), compound 6j, triethylamine (35.7 mg, 0.353 mmol) and Boc anhydride (77.0 mg, 0.353 mmol) were added to a reaction flask and reacted at room temperature for 2 hours. Water (5 mL) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (5 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 7a as a brown solid, 110 mg, which was used directly in the next step.

[0521] LC-MS: m / z 321.9 [M+H] + .

[0522] Step 2: Preparation of tert-butyl methyl(4-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,4-b]furan-3-yl)carbamate (7b)

[0523] At room temperature, tetrahydrofuran (2.0 mL) and compound 7a (100 mg, 0.311 mmol) were added to a reaction bottle, and sodium hydride (8.20 mg, 0.342 mmol) was added under nitrogen atmosphere, and stirred at room temperature for 30 minutes, and iodomethane (48.6 mg, 0.342 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was quenched with water, extracted with dichloromethane (5 mL×2), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 7b as a brown oil, 102 mg, yield: 97.7%.

[0524] LC-MS: m / z 336.0 [M+H] + .

[0525] Step 3: Preparation of N-methyl-4-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,4-b]furan-3-amine (7c)

[0526] At room temperature, 4N hydrochloric acid-methanol solution (3 mL) and compound 7b (102 mg, 0.304 mmol) were added to the reaction flask and reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was added with sodium bicarbonate solution, extracted with dichloromethane (5 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 7c as a brown solid, 60.0 mg, yield: 83.8%.

[0527] LC-MS: m / z 236.1[M+H] + .

[0528] Step 4: Preparation of 4-amino-N,1-dimethyl-N-(4-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,4-b]furan-3-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (7)

[0529] At room temperature, N,N-dimethylacetamide (3.0 mL), compound 7c (60.0 mg, 0.255 mmol), compound 1m (80.3 mg, 0.331 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (122 mg, 0.433 mmol) and N-methylimidazole (62.8 mg, 0.765 mmol) were added to a reaction bottle and reacted at room temperature for 8 hours. The reaction solution 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 7 as a white solid, 17.0 mg, yield: 14.5%.

[0530] LC-MS: m / z 460 [M+H] + .

[0531] 1 H NMR (400 MHz, DMSO-d 6 )δ8.19(s,1H),8.09(s,1H),7.55(s,2H),7.44(s,1H),7.11(s,2H),6.32(s,2H),6.15(s,1H), 5.63(s,1H),5.15(dd,J=9.9,8.1Hz,1H),4.88(s,1H),4.22(s,3H),3.79(s,3H),2.63(s,3H).

[0532] Example 8: Preparation of 4-amino-N,3-dimethyl-N-(4-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydrothieno[3,4-b]furan-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (8)

[0533]

[0534]

[0535] The title compound 8 was prepared in the same manner as in Example 7, except that compound 2e was used instead of compound 1m.

[0536] LC-MS: m / z 462.1[M+H] + .

[0537] 1 H NMR (400 MHz, DMSO-d 6 )δ7.98(s,1H),7.67–7.53(m,2H),7.47(d,J=7.9Hz,2H),6.64(s,2H),6.37(s,1H),6.22(s,1H),5.43(s,1H),5.3 2(dd,J=13.7,3.8Hz,1H),5.26–5.13(m,2H),4.91(s,1H),3.87(s,3H),2.64(s,3H),1.40(dd,J=6.2,2.1Hz,3H).

[0538] Example 9: Preparation of 4-amino-N,1-dimethyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (9)

[0539]

[0540] Step 1: Preparation of 2-bromocyclohex-2-en-1-one (9b)

[0541] At room temperature, dichloromethane (160 mL) and cyclohex-2-en-1-one 9a (6.00 g, 62.4 mmol) were added to the reaction flask. The temperature was lowered to 0°C, and bromine (10.2 g, 63.7 mmol, dissolved in 160 mL dichloromethane) was slowly added dropwise. After the addition was complete, triethylamine (10.7 g, 106 mmol) was added and the reaction was allowed to react at room temperature for 30 minutes. 2N dilute hydrochloric acid solution was added to the reaction solution to adjust the pH to 5-6, the aqueous phase was extracted with dichloromethane (120 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 9b as an off-white solid, 14.4 g, yield: 90.9%.

[0542] LC-MS: m / z 174.9 [M+H] + .

[0543] Step 2: Preparation of (E)-1-methyl-1H-pyrazole-4-carbaldehyde oxime (9d)

[0544] At room temperature, methanol (160 mL), 1-methyl-1H-pyrazole-4-carboxaldehyde 9c (6.00 g, 54.5 mmol), hydroxylamine hydrochloride (5.68 g, 81.7 mmol) and sodium acetate (8.94 g, 109 mmol) were added to a reaction flask and reacted at room temperature for 6 hours. After the reaction was completed, the reaction solution was filtered, the solid was rinsed with methanol (32 mL), and the filtrate was concentrated under reduced pressure to obtain the title compound 9d as a white solid, 6.35 g, yield: 93.1%.

[0545] LC-MS: m / z 126.1 [M+H] + .

[0546] Step 3: Preparation of 3-(1-methyl-1H-pyrazol-4-yl)-5,6-dihydrobenzo[d]isoxazol-7(4H)-one (9e)

[0547] At room temperature, N,N-dimethylformamide (70 mL) and compound 9d (6.35 g, 50.8 mmol) were added to the reaction bottle. The temperature was lowered to 0°C, N-bromosuccinimide (8.13 g, 60.9 mmol) was added, and the reaction was carried out at 0°C for 15 minutes, and then the temperature was raised to room temperature for 1.5 hours. At room temperature, sodium bicarbonate (8.53 g, 101 mmol) and compound 9b (11.6 g, 66.0 mmol) were added to the reaction solution, and the reaction was carried out at room temperature for 2 hours. Water (70 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (150 mL×2). The organic phases were combined and 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 = 1:9) to obtain the title compound 9e as an off-white solid, 2.58 g, yield: 23.4%.

[0548] LC-MS: m / z 218.0 [M+H] + .

[0549] Step 4: Preparation of N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-amine (9f)

[0550] At room temperature, methanol (15 mL), 9e (500 mg, 2.30 mmol), methylamine hydrochloride (3.11 g, 46.0 mmol) and sodium cyanoborohydride (1.45 g, 23.0 mmol) were added to the reaction flask and the temperature was raised to reflux for 8 hours. The reaction solution was concentrated, and the residue was added with saturated sodium bicarbonate solution and extracted with ethyl acetate (60 mL×2). The combined organic phases were 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 = 15:1) to obtain the title compound 9f as a white solid, 450 mg, yield: 84.2%.

[0551] LC-MS: m / z 233.0 [M+H] + .

[0552] Step 5: Preparation of 4-amino-N,1-dimethyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (9)

[0553] At room temperature, N,N-dimethylacetamide (8.0 mL), compound 9f (200 mg, 0.861 mmol), compound 1m (271 mg, 1.12 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (362 mg, 1.29 mmol) and N-methylimidazole (212 mg, 2.58 mmol) were added to a reaction bottle and reacted at room temperature for 8 hours. The reaction solution 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 9 as a white solid, 49.0 mg, yield: 12.5%.

[0554] LC-MS: m / z 457.2 [M+H] + .

[0555] 1 H NMR (400 MHz, DMSO-d 6 )δ8.26(d,J=2.8Hz,3H),7.85(s,1H),7.63(s,2H),7.19(s,2H),5.29(d,J=30.7Hz ,1H),4.39(s,3H),3.91(s,3H),2.80(s,3H),2.60(s,2H),2.01(d,J=18.2Hz,4H).

[0556] Example 10: Preparation of 4-amino-N,3-dimethyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (10)

[0557]

[0558] The title compound 10 was prepared in the same manner as in Example 9, except that compound 2e was used instead of compound 1m.

[0559] LC-MS: m / z 459.1[M+H] + .

[0560] 1 H NMR (400 MHz, DMSO-d 6 )δ8.64(s,2H),8.26(d,J=4.7Hz,1H),7.91-7.79(m,4H),5.81(s,1H),5.57-5.42(m,3H),4.93(s,1H ), 3.91 (s, 3H), 2.81-2.70 (m, 3H), 2.60 (d, J = 19.9Hz, 2H), 2.23-1.79 (m, 4H), 1.44 (d, J = 5.9Hz, 3H).

[0561] Example 11: Preparation of 4-amino-N,1-dimethyl-N-(3-(1-methyl-1H-pyrazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (11)

[0562]

[0563] Step 1: Preparation of 3-(2,5-dichlorothiophen-3-yl)propanoic acid (11b)

[0564] At room temperature, 3-thiophene-3-ylpropionic acid 11a (8.00 g, 51.3 mmol), sulfonyl chloride (45.0 g, 333 mmol), and toluene (50 ml) were added to a reaction flask, and the temperature was raised to 70°C for 4 hours. The reaction solution was poured onto crushed ice to quench, extracted with ethyl acetate (150 mL × 3), 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 (petroleum ether: ethyl acetate = 10: 1) to obtain the title compound as a colorless liquid, 8.80 g, yield: 76.6%.

[0565] LC-MS: m / z 225.0 [M+H] + .

[0566] Step 2: Preparation of 3-(2,5-dichlorothiophen-3-yl)propanoyl chloride (11c)

[0567] At room temperature, compound 11b (8.00 g, 35.7 mmol) and thionyl chloride (100 mL) were added to the reaction flask and reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and used directly in the next step, yielding 10 g of crude product.

[0568] Step 3: Preparation of 1,3-dichloro-5,6-dihydro-4H-cyclopenta[c]thiophene-4-one (11d)

[0569] At room temperature, compound 11c (10 g, 41.3 mmol), aluminum chloride (44 g, 331 mmol), and dichloromethane (100 ml) were added to a reaction flask and stirred at room temperature for 4 hours. The reaction solution was poured onto crushed ice and extracted with ethyl acetate (100 mL x 2). The combined organic phases were 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 the title compound 11d as a yellow solid, 2.5 g, yield: 29.4%.

[0570] LC-MS: m / z 207 [M+H] + .

[0571] Step 4: Preparation of 1-chloro-3-(1-methyl-1H-pyrazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-4-one (11e)

[0572] Compound 11d (2 g, 9.71 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 9.71 mmol), water (1 mL), 1,4-dioxane (10 mL), potassium carbonate (2.68 g, 19.4 mmol) and DPPF palladium dichloride (710 mg, 0.971 mmol) were added to a reaction flask at room temperature and reacted at 70°C for 16 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to obtain the title compound 11e as a yellow solid, 700 mg, yield: 28.6%.

[0573] LC-MS: m / z 253.0 [M+H] + .

[0574] Step 5: Preparation of 3-(1-methyl-1H-pyrazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-4-one (11f)

[0575] At room temperature, compound 11e (300 mg, 1.38 mmol), ammonia water (10.0 mL), and zinc powder (358 mg, 5.52 mmol) were added to a reaction flask and stirred at 50°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to obtain the title compound, 240 mg, yield: 98.4%.

[0576] LC-MS: m / z 219.0 [M+H] + .

[0577] Step 6: Preparation of N-methyl-3-(1-methyl-1H-pyrazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-4-amine (11 g)

[0578] At room temperature, compound 11f (140 mg, 0.642 mmol), methylamine hydrochloride (430 mg, 6.42 mmol), zinc powder (430 mg, 6.42 mmol) and methanol (15 mL) were added to a reaction flask and reacted at 70°C for 30 minutes. The reaction solution was filtered and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane: methanol = 15:1) to obtain the title compound 11g, 110 mg, as a yellow solid, with a yield of 73.3%.

[0579] Step 7: Preparation of 4-amino-N,1-dimethyl-N-(3-(1-methyl-1H-pyrazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophen-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (11)

[0580] At room temperature, compound 11g (110 mg, 0.472 mmol), compound 1m (149 mg, 0.613 mmol), NMI (58 mg, 0.708 mmol), TCFH (198 mg, 0.708 mmol), and DMF (5 ml) were added to a reaction bottle and reacted at 45°C for 16 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, 100A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain the title compound 11 as a white solid powder, 25 mg.

[0581] LC-MS: m / z 458.0 [M+H] + .

[0582] 1 H NMR (400 MHz, DMSO-d 6)δ8.62(s,1H),7.95(s,1H),7.81(s,1H),7.73(s,1H),7.62(d,J=17.1Hz,1H),6.95(s,1H), 6.85(s,1H),6.24(s,1H),5.28(s,2H),4.38(s,3H),3.86(s,3H),2.87(s,4H),2.68(s,3H).

[0583] Example 12: Preparation of 4-amino-1-methyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (12)

[0584]

[0585] Step 1: Preparation of 3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-amine (12a)

[0586] At room temperature, methanol (15 mL), compound 9e (200 mg, 0.921 mmol), ammonium acetate (1.42 g, 18.4 mmol) and sodium cyanoborohydride (578 mg, 9.21 mmol) were added to a reaction flask and reacted at 80°C for 6 hours. The reaction solution was concentrated, and the residue was added with sodium bicarbonate solution (15 mL), extracted with dichloromethane (30 mL×2), and the combined organic phases were 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 = 15:1) to obtain the title compound 12a as a white solid, 130 mg, yield: 64.5%.

[0587] LC-MS: m / z 219.0 [M+H] + .

[0588] Step 2: Preparation of 4-amino-1-methyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (12)

[0589] At room temperature, N,N-dimethylacetamide (3.0 mL), compound 12a (130 mg, 0.596 mmol), compound 3f (188 mg, 0.774 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (284 mg, 1.01 mmol) and N-methylimidazole (147 mg, 1.79 mmol) were added to a reaction bottle and reacted at 60°C for 4 hours. The reaction solution was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100A, mobile phase: acetonitrile / water, gradient: 10%-100%) to obtain the title compound 12 as a white solid, 60.0 mg, yield: 22.8%.

[0590] LC-MS: m / z 443.1[M+H] + .

[0591] 1 H NMR (400 MHz, DMSO-d 6 )δ9.00(d,J=8.1Hz,1H),8.69(d,J=2.0Hz,1H),8.26(d,J=5.8Hz,2H),8.01(dd,J=8.7,2.0Hz,1H),7.86(s,1H),7.59(d,J=8.7Hz ,1H),7.24(s,2H),5.39(q,J=6.8Hz,1H),4.45(s,3H),3.92(s,3H),2.61(d,J=6.0Hz,2H),2.16-1.98(m,2H),1.97-1.81(m,2H).

[0592] Example 13: Preparation of 4-amino-1-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (13)

[0593]

[0594] Step 1: Preparation of 2-bromo-6,7-dihydrobenzofuran-4(5H)-one (13b)

[0595] At room temperature, 6,7-dihydrobenzofuran-4(5H)-one 13a (7.00 g, 41.4 mmol), N-bromosuccinimide (10.10 g, 56.5 mmol), and N,N-dimethylformamide (80 mL) were added to a reaction flask and reacted at room temperature for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate (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: PE: EA = 95:5) to obtain the title compound 13b as a white solid, 6.00 g, yield: 77.4%.

[0596] LC-MS: m / z 214.9 [M+H] + .

[0597] Step 2: Preparation of 2-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydrobenzofuran-4(5H)-one (13c)

[0598] Compound 13b (400.0 mg, 2.94 mmol), 1.4-dioxane (20 mL), water (4 mL), sodium carbonate (935.0 mg, 8.82 mmol), 1b (917 mg, 4.41 mmol), Pd(dppf)Cl 2 (192.0 mg, 0.294 mmol) was added to the reaction bottle, nitrogen was replaced 3 times, and the reaction was carried out at 80°C for 2 hours. The reaction solution was filtered, water (60 mL) was added, and ethyl acetate (50 mL) was extracted. The organic phase was washed with a saturated sodium chloride aqueous solution (50 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: PE: EA = 80: 20) to obtain the title compound 13c as a black solid, 300.0 mg, yield: 47.2%.

[0599] LC-MS: m / z 217.0 [M+H] + .

[0600] Step 3: Preparation of 2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzofuran-4-amine (13d)

[0601] At room temperature, compound 13c (200.0 mg, 14.0 mmol), ammonium acetate (1.09 g, 14.0 mmol), and methanol (50 mL) were added to a reaction flask, and sodium cyanoborohydride (71.0 mg, 1.13 mmol) was added in batches, and the mixture was reacted at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was poured into 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: PE: EA = 90: 10) to obtain the title compound 13d as a black solid, 183.0 mg, yield: 77.3%.

[0602] LC-MS: m / z 218.1 [M+H] + .

[0603] Step 4: Preparation of 4-amino-1-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (13)

[0604] At room temperature, compound 13d (183.0 mg, 0.843 mmol) was dissolved in N,N-dimethylformamide (4 mL), compound 1m (244.8 mg, 1.01 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (354.7 mg, 1.264 mmol) were added, stirred for 10 minutes, methylimidazole solution (207.6 mg, 2.529 mmol) was added dropwise, and the mixture was reacted at room temperature for 16 hours. After the reaction was completed, water (10 mL) was added, and ethyl acetate (10 mL) was extracted, 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, 100 A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 57.0 mg of the title compound as a white solid powder, yield: 15.1%.

[0605] LC-MS: m / z 442.2 [M+H] + .

[0606] 1 H NMR (400 MHz, DMSO-d 6)δ8.73(d,J=8.2Hz,1H),8.68(s,1H),8.26(s,1H),8.02(d,J=9.5Hz,1H),7.96(s,1H),7.68(s,1H),7.58(d,J=8.7Hz,1 H),7.21(s,2H),6.42(s,1H),5.13(s,1H),4.46(s,3H),3.83(s,3H),2.64(s,2H),2.12–1.95(m,2H),1.90–1.71(m,2H).

[0607] Example 14: Preparation of 4-amino-N,1-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzothiazol-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (14)

[0608]

[0609] Step 1: Preparation of 2-bromo-5,6-dihydrobenzothiazol-7(4H)one (14b)

[0610] 2-Amino-5,6-dihydrobenzothiazol-7(4H)one 14a (10 g, 5.95 mmol) was dissolved in ACN (100 ml) at room temperature and CuBr was added. 2 (26.5 g, 11.9 mmol), tert-butyl nitrite (14 ml, 11.9 mmol) was added, and stirred at 85°C overnight under nitrogen atmosphere. After the reaction was completed, EA (50 ml × 3) was extracted and concentrated under reduced pressure. The residue was separated by column chromatography (DCM: MeOH = 20: 1) to obtain the title compound 14b as a yellow solid, 5 g, yield: 68.8%.

[0611] LC-MS: m / z 232.2 [M+H] + .

[0612] Step 2: Preparation of 2-(1-methylpyrazol-4-yl)-5,6-dihydrobenzothiazol-7(4H)one (14c)

[0613] Compound 14b (1 g, 4.33 mmol) was dissolved in dioxane (10 ml) at room temperature and Pd(dppf)Cl was added. 2 (300 mg, 0.43 mmol), sodium carbonate (922 mg, 8.66 mmol) was added, and stirred at 85°C overnight under nitrogen atmosphere. The reaction solution was extracted with EA (50 ml × 3), concentrated under reduced pressure, and the residue was separated by column chromatography (DCM: MeOH = 20: 1) to obtain the title compound 14c as a yellow solid, 200 mg, yield: 20.2%

[0614] LC-MS: m / z 234.2 [M+H] + .

[0615] Step 3: Preparation of (N-methyl-2-(1-methylpyrazol-4-yl)-4,5,6,7-tetrahydrobenzothiazol-7-amine (14d)

[0616] At room temperature, compound 14c (1 g, 4.29 mmol) was dissolved in EtOH (10 ml), methylamine (1 g, 42.9 mmol) and sodium cyanoborohydride (830 mg, 13.2 mmol) were added, and stirred at 95°C for three hours under a nitrogen atmosphere. The reaction was quenched by adding water, extracted with EA (50 ml × 2), extracted with EA (100 ml × 3), and concentrated under reduced pressure to obtain the title compound 14d as a yellow solid, 200 mg, yield: 21.3%.

[0617] LC-MS: m / z 249.2 [M+H] + .

[0618] Step 4: Preparation of 4-amino-N,1-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzothiazol-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (14)

[0619] At room temperature, compound 14d (100 mg, 0.40 mmol) was dissolved in DCE (10 ml), TEA (80.8 mg, 0.80 mmol) was added, compound 1g (104 mg, 0.40 mmol) was added, and the mixture was stirred at 40°C for two hours. The reaction solution was extracted with EA (50 ml × 3), 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: 10% -100%) to obtain the title compound 14 as a white solid, 20.0 mg, yield: 10.5%.

[0620] LC-MS: m / z 473.1[M+H] + .

[0621] 1 H NMR (400 MHz, DMSO-d 6)δ8.32–8.24(m,3H),7.89(d,J=0.8Hz,1H),7.61(q,J=8.8Hz,2H),7.18(s,2H),4.42(s ,3H),3.89(s,3H),2.83(s,3H),2.68(s,2H),2.10(s,2H),1.99(q,J=11.1,10.7Hz,2H).

[0622] Example 15: Preparation of 4-amino-N,3-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzothiazol-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (15)

[0623]

[0624] The title compound 17 was prepared in the same manner as in Example 14, except that compound 2f was used instead of compound 1g.

[0625] LC-MS: m / z 475.1[M+H] + .

[0626] 1 H NMR (400 MHz, CHCl 3 -d)δ8.30(s,1H),7.88(s,1H),7.59(t,J=7.5Hz,3H),6.65(s,2H),5.30(d,J=12.7Hz,3H),5.09(s,1H),3.8 8(s,3H),2.77(s,3H),2.72(s,2H),2.06(s,2H),1.96(q,J=11.0,10.2Hz,2H),1.41(dd,J=6.3,3.2Hz,3H).

[0627] Example 16: Preparation of 4-amino-N,1-dimethyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (16)

[0628]

[0629]

[0630] Step 1: Preparation of (E)-1-methyl-1H-pyrazole-4-aminoacetaldehyde oxime (16b).

[0631] At room temperature, compound 16a (5.50 g, 50.0 mmol) was dissolved in ethanol (100 mL), and a solution of hydroxylamine hydrochloride (3.83 g, 55.0 mmol) in water (50 mL) was added. A solution of sodium hydroxide (2.40 g, 60.0 mmol) in water (10 mL) was added below 0°C, and the resulting mixture was stirred and reacted for 16 hours. After the reaction was completed, the reaction solution was concentrated under vacuum, diluted with saturated sodium chloride solution (60 mL) and dichloromethane (60 mL), and the pH was adjusted to 10-11 with potassium carbonate, the organic phase was separated, the aqueous phase was extracted with dichloromethane (40 mL*3), anhydrous sodium sulfate was added to the combined organic phase for drying, filtered, and the filtrate was collected and concentrated under vacuum to obtain 6.35 g of the title compound as a white solid, which was used without further purification.

[0632] LCMS: m / z 126.06 [M+H] + .

[0633] Step 2: Preparation of 1-methyl-1H-pyrazole-4-nitroxide (16c).

[0634] Compound 16b (4.78 g, 38.3 mmol) was dissolved in ethanol (30 mL) at room temperature, and a solution of N-bromosuccinimide (6.81 g, 38.3 mmol) in ethanol (30 mL) was added, and the mixture was stirred for 40 minutes, and a solution of triethylamine (5.81 g, 57.5 mmol) in ethanol (15 mL) was added, and the resulting mixture was stirred for 30 minutes. After the reaction, the reaction solution was used without further purification.

[0635] LCMS: m / z 124.04 [M+H] + .

[0636] Step 3: Preparation of 3-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydrobenzo[d]isoxazol-4(5H)-one (16d).

[0637] At room temperature, cyclohexane-1,3-dione (3.36 g, 30.0 mmol) was dissolved in a solution of compound 16c (20.0 mmol) in ethanol (75 mL), triethylamine (2.83 g, 28.0 mmol) was added, and the resulting mixture was stirred at 60° C. for 16 hours. After the reaction was completed, the reaction solution was concentrated under vacuum, and the resulting residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 0-60%) to obtain 850 mg of the title compound as a yellow oil, with a three-step yield of 10.2%.

[0638] LCMS: m / z 218.09 [M+H] + .

[0639] Step 4: Preparation of N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-4-amine (16e).

[0640] At room temperature, compound 16d (621 mg, 2.86 mmol) was dissolved in tetrahydrofuran (20 mL), and a tetrahydrofuran solution of methylamine (2.0 M, 14 mL, 28.0 mmol) and tetraethyl titanate (1.96 g, 8.58 mmol) were added. The resulting mixture was stirred at 80°C for 36 hours under a nitrogen atmosphere, and sodium cyanoborohydride (1.80 g, 28.6 mmol) and methanol (20 mL) were added at room temperature. The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under vacuum, and the resulting residue was purified by column chromatography (eluent: methanol / dichloromethane = 0-10%) to obtain 381 mg of the title compound as an orange oil, with a yield of 57.3%.

[0641] LCMS: m / z 233.13 [M+H] + .

[0642] Step 5: Preparation of 4-amino-N,1-dimethyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (16).

[0643] At room temperature, compound 16e (140 mg, 0.600 mmol) was dissolved in tetrahydrofuran (4 mL), compound 1m (175 mg, 0.720 mmol) and 2-chloro-1-methylpyridinium iodide (200 mg, 0.780 mmol) were added, and the mixture was stirred for 5 minutes. N,N-diisopropylethylamine (233 mg, 1.80 mmol) was added, and the resulting mixture was stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under vacuum, 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 42.0 mg of the title compound as a white solid, with a yield of 15.3%.

[0644] LCMS: m / z 457.20 [M+H] + .

[0645] 1 H NMR (400 MHz, DMSO-d 6)δ8.26(s,1H),8.16(s,1H),7.99(s,1H),7.75(s,1H),7.56(d,J=8.5Hz,1H),7.30(d,J=8.0Hz,1H),7.22(s,2H),5.95(d,J=6.1Hz ,1H),4.25(s,3H),3.87(s,3H),2.80(d,J=9.9Hz,2H),2.56(s,3H),2.14(dd,J=11.9,5.0Hz,1H),2.04(s,1H),1.97–1.74(m,2H).

[0646] Example 17: Preparation of 4-amino-N,3-dimethyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-4-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (17)

[0647]

[0648] The title compound 17 was prepared in the same manner as in Example 16, except that compound 2e was used instead of compound 1m.

[0649] LCMS: m / z 459.21 [M+H] + .

[0650] 1 H NMR (400 MHz, DMSO-d 6 )δ8.16(s,1H),8.04(d,J=3.2Hz,1H),7.73(d,J=2.1Hz,1H),7.52(d,J=8.6Hz,1H),7.22–7.12(m,1H),6.64(s,2H),5.90(d,J=5.5Hz,1H),5.42 (s,1H),5.36–5.11(m,2H),3.86(d,J=4.6Hz,3H),2.78(s,2H),2.46(s, 3H), 2.17–1.97 (m, 2H), 1.95–1.71 (m, 2H), 1.40 (dd, J = 6.0, 3.7Hz, 3H).

[0651] Example 18: Preparation of 4-amino-N-((3-fluoropyridin-2-yl)methyl)-1-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (18)

[0652]

[0653] The title compound 18 was prepared in the same manner as in Example 3, except that compound 1e was used instead of methylamine hydrochloride.

[0654] LC-MS: m / z 551.2 [M+H] + .

[0655] 1 H NMR (400 MHz, CHCl 3 -d)δ8.44(s,2H),7.95(s,1H),7.77(s,2H),7.65(s,1H),7.56(s,1H),7.32(s,1H),7.20(s,1H),6.37(s,1H),5.49 (s,2H),5.08(d,J=66.7Hz,2H),4.46(s,4H),3.95(s,3H),2.59(s,2H),2.19–2.09(m,2H),1.99(d,J=15.9Hz,2H).

[0656] Example 19: Preparation of 4-amino-N-(8-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepan-5-yl)-N,3-dimethyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (19)

[0657]

[0658] The title compound 19 was prepared in the same manner as in Example 4, except that methanol was used instead of compound 1b.

[0659] LC-MS: m / z 434.2 [M+H] + .

[0660] 1 H NMR (400 MHz, DMSO-d 6 )δ8.87(s,2H),7.80(d,J=86.5Hz,2H),7.04(d,J=53.2Hz,1H),6.85–6.46(m,2H),5.49(s,2H),5.38–4.63 (m, 2H), 4.17 (d, J = 57.4Hz, 2H), 3.74 (s, 4H), 2.94 (d, J = 61.0Hz, 3H), 2.05 (d, J = 53.9Hz, 4H), 1.45 (s, 3H).

[0661] Example 20: Preparation of 4-amino-N-(8-methoxy-2,3,4,5-tetrahydrobenzo[b]oxepan-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (20)

[0662]

[0663] The title compound 20 was prepared in the same manner as in Example 19, except that compound 1m was used instead of compound 2e.

[0664] LC-MS: m / z 432.2 [M+H] + .

[0665] 1 H NMR (400 MHz, D 2 O)δ7.68(d,J=1.8Hz,1H),7.49(s,1H),7.40(s,1H),7.22(s,1H),7.07(d,J=8.8Hz,1H),6.97(s,1H),6.80(dd,J=18.8,9.2Hz, 2H), 4.88–4.79 (m, 1H), 3.50 (s, 3H), 3.19 (t, J = 5.0Hz, 2H), 2.76 (s, 3H), 2.01 (s, 3H), 1.59 (d, J = 5.2Hz, 2H), 1.10–0.76 (m, 3H).

[0666] Example 21: Preparation of 4-amino-N,1-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (21)

[0667]

[0668] Step 1: Preparation of (5-bromothiophen-3-yl)methanol (21b)

[0669] At room temperature, 5-bromothiophene-3-carboxylic acid 21a (5.00 g, 24.2 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to below 0°C under nitrogen atmosphere, and tetrahydrofuran borane complex (1.0 M, 73 mL 72.6 mmol) was added dropwise. The resulting mixture was stirred at this temperature for 15 minutes, and stirred at room temperature for 16 hours. After the reaction was completed, methanol (20 mL) was added dropwise to the reaction solution at 0°C, water (20 mL) was added to dilute, and extracted with ethyl acetate (60 mL×3), the organic phases were combined and washed with saturated sodium chloride solution, anhydrous sodium sulfate was added to the organic phase for drying, filtered, and the filtrate was collected and concentrated under vacuum to obtain 4.81 g of the title compound as a yellow oil, which was used without further purification.

[0670] LCMS: m / z 192.92 [M+H] + .

[0671] Step 2: Preparation of 2-((5-bromothiophen-3-yl)methoxy)acetic acid (21c)

[0672] At room temperature, 60% sodium hydride (2.03 g, 50.6 mmol) was dissolved in tetrahydrofuran (40 mL), cooled to below 0°C under nitrogen atmosphere, and compound 21b (4.81 g, 23.0 mmol) was added dropwise, and the resulting mixture was kept at this temperature and stirred for 1 hour. A solution of 2-bromoacetic acid (2.56 g, 18.4 mmol) in tetrahydrofuran (30 mL) was added dropwise below 0°C, and the resulting mixture was naturally heated and stirred for 16 hours. After the reaction was completed, water (80 mL) was added to the reaction solution at 0°C to dilute it, and the pH was adjusted to 2-3 with 4.0 M aqueous hydrogen chloride solution, extracted with ethyl acetate (60 mL), and the organic phase was washed with saturated sodium chloride solution, and anhydrous sodium sulfate was added to the organic phase to dry it, filtered, and the filtrate was collected and concentrated under vacuum to obtain 6.84 g of the title compound as a brown oil, which was used without further purification.

[0673] LCMS: m / z 250.93 [M+H] + .

[0674] Step 3: Preparation of 2-bromo-4H-thieno[3,2-c]pyran-7(6H)-one (21d)

[0675] Compound 21c (6.84 g, 16.0 mmol) was dissolved in toluene (22 mL) at room temperature, and trifluoroacetic anhydride (33.6 g, 160 mmol) was added. The resulting mixture was stirred at 40°C for 16 hours under a nitrogen atmosphere. After the reaction, the reaction solution was poured into ice water, the pH was adjusted to 8-9 with a saturated sodium carbonate solution, ethyl acetate was added for extraction, and the organic phase was concentrated under vacuum. The obtained residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 0-20%) to obtain 2.28 g of the title compound as an orange-yellow solid, with a three-step yield of 40.6%.

[0676] LCMS: m / z 232.92 [M+H] + .

[0677] Step 4: Preparation of 2-(1-methyl-1H-pyrazol-4-yl)-4H-thieno[3,2-c]pyran-7(6H)-one (21e)

[0678] Compound 21d (2.27 g, 9.78 mmol) was dissolved in 1,4-dioxane (30 mL) at room temperature, and compound 1b (2.25 g, 10.8 mmol), Pd(dppf)Cl 2 -CH2 Cl 2 (161 mg, 0.196 mmol), potassium carbonate (2.72 g, 19.6 mmol) and water (3 mL), the resulting mixture was stirred at 100 ° C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under vacuum, and the obtained residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 0-70%) to obtain 1.15 g of the title compound as a yellow solid, with a yield of 50.2%.

[0679] LCMS: m / z 235.05 [M+H] + .

[0680] Step 5: Preparation of N-methyl-2-(1-methylpyrazol-4-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-7-amine (21f)

[0681] At room temperature, compound 21e (1.16 g, 5.00 mmol) was dissolved in tetrahydrofuran (12.5 mL), and a tetrahydrofuran solution of methylamine (2.0 M, 12.5 mL, 25.0 mmol) and tetraethyl titanate (3.42 g, 15.0 mmol) were added. The resulting mixture was stirred at 80°C for 24 hours under a nitrogen atmosphere, and sodium cyanoborohydride (3.15 g, 50.0 mmol) was added at room temperature, and the mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under vacuum, and the resulting residue was purified by column chromatography (eluent: methanol / dichloromethane = 0-10%) to obtain 952 mg of the title compound as a yellow solid, with a yield of 77.0%.

[0682] LCMS: m / z 250.09 [M+H] + .

[0683] Step 6: Preparation of 4-amino-N,1-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (21)

[0684] At room temperature, compound 21f (167 mg, 0.670 mmol) was dissolved in tetrahydrofuran (8 mL), compound 1m (213 mg, 0.871 mmol) and 2-chloro-1-methylpyridinium iodide (223 mg, 0.871 mmol) were added, stirred for 5 minutes, N,N-diisopropylethylamine (260 mg, 2.01 mmol) was added, and the resulting mixture was stirred for 4 hours. After the reaction, the reaction solution was concentrated under vacuum, 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 142 mg of the title compound as a white solid, with a yield of 44.6%.

[0685] LC-MS: m / z 474.03[M+H] + .

[0686] 1 H NMR (400 MHz, D 2 O)δ8.29(s,1H),8.04(s,1H),7.72(s,1H),7.66–7.58(m,3H),7.18(s,2H),6.94(s,1H),5.33(t,J=4.0H z,1H),4.73–4.77(m,1H),4.50(s,1H),4.43(s,3H),4.27(s,1H),4.04(s,1H),3.86(s,3H),2.92(s,3H).

[0687] Example 22: Preparation of 4-amino-N,3-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (22)

[0688]

[0689] The title compound 22 was prepared in the same manner as Example 21, except that compound 2e was used instead of compound 1m.

[0690] LCMS: m / z 476.17 [M+H] + .

[0691] 1 H NMR (400 MHz, DMSO-d 6)δ8.14(s,1H),8.04(s,1H),7.72(s,1H),7.65(s,1H),7.62(s,2H),6.94(s,1H),6.84(s,1H),5.64(s,1H),5.45(d,J=4.6Hz,1H),5.38 –5.33(m,1H),5.29(m,1H),4.74(s,1H),4.51(s,1H),4.25(s,1H),4.01(s,1H),3.85(s,3H),2.86(s,3H),1.42–1.41(d,J=5.9Hz,3H).

[0692] Example 23: Preparation of 4-amino-N-(3-fluoropyridin-2-yl)methyl)-3-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (23)

[0693]

[0694] The title compound 23 was prepared in the same manner as in Example 18, except that compound 2e was used instead of compound 1m.

[0695] LC-MS: m / z 553.3 [M+H] + .

[0696] 1 H NMR (400 MHz, DMSO-d 6 )δ8.46(d,J=9.4Hz,2H),8.02–7.78(m,3H),7.67(s,2H),7.35(s,2H),6.58(s,1H),6.37(s,1H),5.48(d,J=20.3Hz,4 H),4.78(s,1H),4.67–4.39(m,1H),4.27(d,J=15.7Hz,1H),3.85(s,3H),2.56(s,1H),2.14–1.64(m,4H),1.42(s,3H).

[0697] Example 24: Preparation of 4-amino-N-cyclopropyl-3-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (24)

[0698]

[0699] The title compound 24 was prepared in the same manner as Example 23, except that cyclopropylamine was used instead of compound 1e.

[0700] LC-MS: m / z 484.2 [M+H] + .

[0701] 1 H NMR (400 MHz, DMSO-d 6 )δ8.69(s,2H),8.02(d,J=8.5Hz,1H),7.96(s,2H),7.79(d,J=8.6Hz,1H),7.67(s,1H),6.38(s,1H),5.59–5.39( m,4H),3.85(s,3H),2.65(d,J=18.7Hz,2H),2.15(s,4H),1.83(s,1H),1.46(d,J=4.4Hz,3H),0.53–0.12(m,4H).

[0702] Example 25: Preparation of 4-amino-N-isopropyl-3-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (25)

[0703]

[0704] The title compound 25 was prepared in the same manner as in Example 23, except that isopropylamine was used instead of compound 1e.

[0705] LC-MS: m / z 486.2[M+H] + .

[0706] 1 H NMR (400 MHz, DMSO-d 6 )δ7.99(s,1H),7.72(s,1H),7.55(d,J=11.5Hz,3H),6.75(s,1H),6.65(s,1H),5.48–5.15(m, 3H), 4.66 (s, 1H), 3.86 (s, 3H), 2.63 (d, J = 37.0Hz, 2H), 2.07–1.63 (m, 4H), 1.55–1.26 (m, 9H).

[0707] Example 26: Preparation of 4-amino-N-(3-fluoropyridin-2-yl)methyl)-3-methyl-N-(4-(1-methylpyrazol-4-yl)-2,3-dihydrothieno[3,4-b]furan-3-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (26)

[0708]

[0709] The title compound 26 was prepared in the same manner as in Example 8, except that compound 1e was used instead of methylamine hydrochloride.

[0710] LC-MS: m / z 557.1[M+H] + .

[0711] 1 H NMR (400MHz, DMSO-d6) δ8.79(s,2H),8.23(s,1H),7.92(d,J=22.8Hz,2H),7.76(s,1H),7.62(s,1H),7.43(s,1H),7.25(s,1H),6.12(d,J=45 .1Hz,2H),5.52(s,1H),5.35(s,2H),5.07(ddd,J=10.3,7.7,2.7Hz,1H),4.89(s,1H),4.48–4.35(m,3H),3.91(s,3H),1.42(d,J=6.2Hz,3H).

[0712] Example 27: Preparation of 4-amino-N-methyl-N-(4-(1-methylpyrazol-4-yl)-2,3-dihydrothieno[3,4-b]furan-3-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (27)

[0713]

[0714]

[0715] Step 1: Preparation of 4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid (27e)

[0716] The title compound was prepared in the same manner as intermediate 2e, except that acrylonitrile was used instead of trans-crotononitrile.

[0717] LCMS: m / z 230.96 [M+H] + .

[0718] Step 2: Preparation of 4-amino-N-methyl-N-(4-(1-methylpyrazol-4-yl)-2,3-dihydrothieno[3,4-b]furan-3-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (27)

[0719] At room temperature, N,N-dimethylacetamide (3.0 mL), compound 7c (60.0 mg, 0.255 mmol), compound 27e (80.3 mg, 0.331 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (122 mg, 0.433 mmol) and N-methylimidazole (62.8 mg, 0.765 mmol) were added to a reaction bottle and reacted at room temperature for 8 hours. After the reaction, the reaction solution 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 as a white solid, 51.0 mg, yield: 40.5%.

[0720] LC-MS: m / z 448 [M+H] + .

[0721] 1 H NMR (400 MHz, DMSO-d 6 )δ9.08–8.94(m,2H),8.00(s,1H),7.81(d,J=8.8Hz,1H),7.72(d,J=8.8Hz,2H),7.64(s,1H),6.38(s ,1H),6.25(s,1H),5.45(s,3H),5.25–5.16(m,1H),5.11(s,3H),4.93(d,J=11.4Hz,1H),3.88(s,3H).

[0722] Example 28: Preparation of 4-amino-N,3-dimethyl-N-(3-(1-methylpyrazol-4-yl)-5,6-dihydro-4H-cyclopentylthiophen-4-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (28)

[0723]

[0724] The title compound 28 was prepared in the same manner as in Example 11, except that compound 2e was used instead of compound 1m.

[0725] LC-MS: m / z 460.31 [M+H] + .

[0726] 1 H NMR (400 MHz, DMSO-d 6)δ7.89-7.56(m,2H),7.30(s,1H),7.17(s,1H),7.04(s,1H),6.59(br,4H),5.39-5 .52(m,3H),3.86(s,3H),2.82(s,3H),260-2.70(m,2H),1.44(s,3H),1.24(s,2H).

[0727] Example 29: Preparation of 4-amino-N,3-dimethyl-N-(3-(1-methylpyrazol-4-yl)-4,5,6,7-tetrahydrobenzothiophen-4-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (29)

[0728]

[0729] Step 1: Preparation of 4-(2,5-dichlorothiophen-3-yl)-4-oxobutanoic acid (29b)

[0730] At room temperature, under nitrogen atmosphere, 2-dihydrofuran-2,5-dione (10.0 g, 100 mmol) and aluminum chloride (39.9 g, 300 mmol) were dissolved in dichloromethane (300 mL), and 2,5-dichlorothiophene 29a (3.4 g, 90 mmol) was added under stirring, and the reaction was continued for 48 hours. The reaction system was adjusted to pH = 12 with 2M sodium hydroxide aqueous solution, extracted with dichloromethane (500 mL x 2), and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 10:1-5:1) to obtain 7.4 g of the title compound as a yellow solid, with a yield of 32.6%.

[0731] LC-MS: m / z 253 [M+H] + .

[0732] Step 2: Preparation of 4-(2,5-dichlorothiophen-3-yl)butanoic acid (29c)

[0733] At 0°C, under nitrogen atmosphere, trimethylsilyl chloride (4.84 g, 32.3 mmol) was dissolved in tetrahydrofuran (30.0 mL), compound 29b (7.4 g, 29.3 mmol) and triethylamine (3.26 g, 32.3 mmol) were added dropwise, reacted at 0°C for 15 minutes, filtered, the filtrate was concentrated under reduced pressure, dichloromethane (30.0 mL), titanium tetrachloride (16.7 g, 87.9 mmol) and triethylsilyl hydride (10.2 g, 87.9 mmol) were added, and reacted at room temperature for 3 hours. The system was added to ice water, extracted with dichloromethane (50.0 mL x 3), washed with saturated brine (50.0 mL x 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 10:1-5:1) to obtain 5.2 g of the title compound as a yellow liquid, with a yield of 74.5%.

[0734] LC-MS: m / z 239[M+H] + .

[0735] Step 3: Preparation of 1,3-dichloro-6,7-dihydrobenzo[c]thiophen-4-(5H)-one (29d)

[0736] Under nitrogen atmosphere, compound 29c (5.2 g, 21.8 mmol) was dissolved in concentrated sulfuric acid (15.0 mL), reacted at room temperature for 24 hours, added with 50.0 mL of water, extracted with EA (50.0 mL x 3), washed with saturated brine (50.0 mL x 1), 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: PE / EA=10:1-5:1) to obtain 3.2 g of the title compound as a yellow liquid. Yield: 66.7%.

[0737] LC-MS: m / z 221[M+H] + .

[0738] Step 4: Preparation of 1-chloro-3-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydrobenzo[c]thiophen-4-(5H)-one (29e)

[0739] Under nitrogen atmosphere, compound 29d (3.2 g, 14.5 mmol) and compound 1b (4.5 g, 21.8 mmol), Pd(dppf)Cl 2-DCM (0.182 g, 0.29 mmol) and potassium acetate (2.84 g, 29.0 mmol) were dissolved in dioxane (30.0 mL) and water (3.00 mL) and reacted at 100°C for 12 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 10:1-5:1) to obtain 1.5 g of the title compound as a yellow liquid, with a yield of 38.9%.

[0740] LC-MS: m / z 267 [M+H] + .

[0741] Step 5: Preparation of 3-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydrobenzo[c]thiophen-4-(5H)-one (29f)

[0742] Under nitrogen atmosphere, compound 29e (1.5 g, 5.63 mmol) was dissolved in acetonitrile (5.00 mL), and zinc powder (1.84 g, 28.1 mmol) and ammonia water (5.00 mL) were added under stirring, and the mixture was reacted at 80°C for 12 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 450 mg of the title compound as a yellow liquid, with a yield of 34.4%.

[0743] LC-MS: m / z 233 [M+H] + .

[0744] Step 6: Preparation of N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-4-amine (29 g)

[0745] At 0°C, under nitrogen atmosphere, compound 29f (450 mg, 1.94 mmol) was dissolved in tetrahydrofuran (2.00 mL), and methylamine tetrahydrofuran solution (10.0 mL) and titanium tetrachloride (184 mg, 0.97 mmol) were added under stirring. The mixture was reacted at room temperature for 3 hours, filtered, and the filtrate was concentrated under reduced pressure. Methanol (5.00 mL) and sodium borohydride (146 mg, 3.88 mmol) were added, and the mixture was reacted at room temperature for 3 hours. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=3:1-1:1) to obtain 210 mg of the title compound as a yellow solid, with a yield of 43.8%.

[0746] LC-MS: m / z 248 [M+H] + .

[0747] Step 7: Preparation of 4-amino-N-3-dimethyl-N-(3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (29)

[0748] Under nitrogen atmosphere, compound 29g (210 mg, 0.850 mmol) was dissolved in tetrahydrofuran (3.00 mL), and compound 2e (249 mg, 1.02 mmol), CMPI (433 mg, 1.70 mmol), and DIPEA (219 mg, 1.70 mmol) were added under stirring, and the mixture was reacted at room temperature for 3 hours. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by C18 silica gel column chromatography (mobile phase ACN / water = 1:2) to obtain 26.0 mg of the title compound as a white solid, with a yield of 6.46%.

[0749] LC-MS: m / z 474 [M+H] + .

[0750] 1 H NMR (400 MHz, DMSO-d 6 )δ14.36(s,1H),8.98–8.84(m,3H),7.84(d,J=3.8Hz,1H),7.72(d,J=8.6Hz,1H),7.60(d,J=5.5 Hz,1H),7.29–7.16(m,1H),7.13(d,J=4.5Hz,2H),5.94(t,J=7.3Hz,1H),5.57–5.33(m,3H),3.76 (d,J=12.4Hz,3H),2.81–2.72(m,1H),2.72–2.61(m,2H),2.32(d,J=1.9Hz,3H),2.12(dt,J=10. 7, 6.4Hz, 1H), 1.91 (dd, J = 11.2, 5.4Hz, 1H), 1.71 (q, J = 11.4Hz, 2H), 1.45 (dd, J = 6.2, 4.0Hz, 4H).

[0751] Example 30: Preparation of 4-amino-N-(3-fluoropyridin-2-yl)methyl)-3-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzothiazol-7-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (30)

[0752]

[0753] The title compound 30 was prepared in the same manner as in Example 15, except that compound 1e was used instead of methylamine hydrochloride.

[0754] LCMS: m / z 570.15 [M+H] + .

[0755] 1H NMR (400 MHz, DMSO-d 6 )δ8.76(s,2H),8.25(s,1H),8.08–7.91(m,2H),7.90–7.73(m,2H),5.62 –5.43(m,4H),3.88(s,3H),2.76(s,1H),2.55(s,1H),2.40(t,J=11.2Hz ,1H),2.32(s,1H),2.18(d,J=13.3Hz,1H),1.90(d,J=10.8Hz,1H),1.46 (d,J=5.9Hz,3H),0.56(d,J=8.7Hz,1H),0.42–0.18(m,2H),0.06(s,1H).

[0756] Example 31: Preparation of 4-amino-N-cyclopropyl-3-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzothiazol-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (31)

[0757]

[0758] The title compound 31 was prepared in the same manner as in Example 15, except that cyclopropylamine was used instead of methylamine hydrochloride.

[0759] LCMS: m / z 501.15 [M+H] + .

[0760] 1 H NMR (400 MHz, DMSO-d 6 )δ8.76(s,2H),8.25(s,1H),8.08–7.91(m,2H),7.90–7.73(m,2H),5.62 –5.43(m,4H),3.88(s,3H),2.76(s,1H),2.55(s,1H),2.40(t,J=11.2Hz ,1H),2.32(s,1H),2.18(d,J=13.3Hz,1H),1.90(d,J=10.8Hz,1H),1.46 (d,J=5.9Hz,3H),0.56(d,J=8.7Hz,1H),0.42–0.18(m,2H),0.06(s,1H).

[0761] Example 32: Preparation of 4-amino-N,1-dimethyl-N-(2-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrano[2,3-d]thiazol-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (32)

[0762]

[0763] Step 1: Preparation of 3-((tert-butyldimethylsilyl)oxy)-1-(2,4-dichlorothiazol-5-yl)propan-1-ol (32b)

[0764] At -78°C, 2.4-dichlorothiazole 32a (12.0 g, 78.4 mmol), lithium diisopropylamide (118 mL, 118 mmol), and tetrahydrofuran (120 mL) were added to a reaction bottle, and the mixture was reacted at -78°C for 0.5 hours under a nitrogen atmosphere. Then, 3-((tert-butyldimethylsilyl)oxy)propanol (14.7 g, 78.4 mmol) was added to the reaction solution, and the mixture was reacted at -78°C for 2 hours. After the reaction, water (50.0 mL) and ethyl acetate (100 mL) were added for extraction, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1) to obtain the title compound as a light yellow oil, 8.50 g, with a yield of 31.8%.

[0765] Step 2: Preparation of 3-((tert-butyldimethylsilyl)oxy)-1-(2,4-dichlorothiazol-5-yl)propan-1-one (32c)

[0766] At room temperature, compound 32b (8.50 g, 24.9 mmol), manganese dioxide (10.7 g, 125 mmol), and dichloromethane (100 mL) were added to a reaction flask and reacted at room temperature for 2 hours under a nitrogen atmosphere. After the reaction, water (50.0 mL) was added and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1) to obtain the title compound as a light yellow oil, 7.35 g, with a yield of 86.9%.

[0767] Step 3: Preparation of 1-(2.4-dichlorothiazol-5-yl)-3-hydroxypropyl-1-one (32d)

[0768] Compound 32c (7.20 g, 21.2 mmol) and concentrated hydrochloric acid (10.0 mL) were added to a reaction flask at room temperature and reacted at room temperature for 2 hours under a nitrogen atmosphere. After the reaction, water (50.0 mL) was added and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 3:1) to obtain the title compound as a light yellow oil, 3.40 g, with a yield of 71.6%.

[0769] Step 4: Preparation of 1-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)thiazol-5-yl)-3-hydroxypropyl-1-one (32e)

[0770] At room temperature, compound 32d (3.20 g, 14.3 mmol), compound 1b (4.45 g, 21.4 mmol), 1,1-bis(diphenylphosphino)diferronichloridopalladium (1.05 g, 1.43 mmol), sodium carbonate (5.07 g, 47.9 mmol), dioxane (100 mL), and water (5.00 mL) were added to a reaction flask and reacted at 80°C for 2 hours under a nitrogen atmosphere. After the reaction, water (50.0 mL) was added and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1) to obtain the title compound as a light yellow oil, 2.70 g, with a yield of 69.7%.

[0771] Step 5: Preparation of 2-(1-methyl-1H-pyrazol-4-yl)-5.6-dihydro-7H-pyrazolo[2.3-d]thiazol-7-one (32f)

[0772] At room temperature, compound 32e (2.70 g, 9.96 mmol), palladium acetate (0.226 g, 0.996 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.42 g, 2.99 mmol), cesium carbonate (4.94 g, 15.0 mmol), and dioxane (100 mL) were added to a reaction flask and reacted at 80°C for 12 hours under a nitrogen atmosphere. After the reaction, water (50.0 mL) was added and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1) to obtain the title compound as a light yellow oil, 1.40 g, with a yield of 59.7%.

[0773] Step 6: Preparation of N-methyl-2-(1-methyl-1H-pyrazol-4-yl)-6.7-dihydro-5H-pyrazo[2.3-d]thiazol-7-amine (32 g)

[0774] At room temperature, compound 32f (0.400 g, 1.70 mmol), methylamine tetrahydrofuran (17.0 mL), titanium tetrachloride (0.481 g, 2.55 mmol), and tetrahydrofuran (10.0 mL) were added to a reaction bottle and reacted at room temperature for 2 hours under a nitrogen atmosphere. After the reaction, water (50.0 mL) was added and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, 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 as a light yellow oil, 260 mg, yield 61.4%.

[0775] Step 7: Preparation of 4-amino-N,1-dimethyl-N-(2-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrano[2,3-d]thiazol-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (32)

[0776] At room temperature, compound 32g (240 mg, 1.04 mmol), compound 2e (250 mg, 1.04 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (438 mg, 1.56 mmol) and N-methylimidazole (168 mg, 2.08 mmol), N,N-dimethylformamide (5.00 mL) were added to a reaction bottle and reacted at room temperature for 8 hours. After the reaction, the reaction solution 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 52.0 mg of the title compound as a white solid, yield: 10.5%.

[0777] LC-MS: m / z 477.1[M+H] + .

[0778] 1 H NMR (400 MHz, DMSO-d 6 )δ8.64(s,1H),8.39(s,1H),8.29(s,1H),7.87(d,J=4.8Hz,3H),4.51(s,3H),4.41(s,1H),3.89(s,3H),2.85(s,3H),2.30(s,2H).

[0779] Example 33: Preparation of 4-amino-N,3-dimethyl-N-(2-(1-methylpyrazol-4-yl)-4,5,6,7-tetrahydro-2H-indazol-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (33)

[0780]

[0781] Step 1: Preparation of 2-ethoxycyclohex-2-en-1-one (33b)

[0782] At room temperature, cyclohexane-2-dione 33a (14.0 g, 125 mmol), p-toluenesulfonic acid (1.10 g), ethanol (260 mL), and toluene (150 mL) were added to a reaction flask and refluxed for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was directly filtered, the filtrate was collected, and it was 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 the title compound as a light yellow solid, 17.0 g, with a yield of 80.9%.

[0783] LC-MS: m / z 141.1 [M+H] + .

[0784] Step 2: Preparation of (Z)-6-((dimethylamino)methylene)-2-ethoxycyclohex-2-en-1-one (33c)

[0785] At room temperature, compound 33b (11.0 g, 78.6 mmol) and 1-tert-butoxy-N,N',N'-tetramethylmethanediamine (30.0 mL) were added to a reaction flask and refluxed for 2 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was directly concentrated under reduced pressure and used in the next step.

[0786] LC-MS: m / z 196.3 [M+H] + .

[0787] Step 3: Preparation of 7-ethoxy-4,5-dihydro-1H-indazole (33d)

[0788] At room temperature, compound 33c (14.0 g, 71.8 mmol), hydrazine hydrate (30.0 mL), and ethanol (100 mL) were added to a reaction flask and refluxed for 3 hours under a nitrogen atmosphere. After the reaction, the reaction solution was directly filtered, the filtrate was collected, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 3:1) to obtain 7.00 g of the title compound as a light yellow solid, with a yield of 73.2%.

[0789] Step 4: Preparation of 1,4,5,6-tetrahydro-7H-indazol-7-one (33e)

[0790] At room temperature, compound 33d (3.00 g, 18.3 mmol), hydrochloric acid (3.00 mL), and ethanol (30.0 mL) were added to a reaction flask and refluxed for 1 hour under a nitrogen atmosphere. After the reaction, the reaction solution was directly filtered, the filtrate was collected, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 3:1) to obtain 1.00 g of the title compound as a light yellow solid, with a yield of 64.2%.

[0791] LC-MS: m / z 137.1[M+H] + .

[0792] Step 5: Preparation of 2-(1-methyl-1H-pyrazol-4-yl)2,4,5,6-tetrahydro-7H-indazol-7-one (33f)

[0793] At room temperature, compound 33e (400 mg, 2.94 mmol), 4-bromo-1methyl-1H-pyrazole (564 mg, 3.53 mmol), NN-dimethylethane-1,2-diamine (517 mg, 5.88 mmol), cuprous iodide (167 mg, 0.882 mmol), and dioxane (10.0 mL) were added to a reaction bottle and refluxed for 16 hours under a nitrogen atmosphere. After the reaction, the reaction solution was directly filtered, the filtrate was collected, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 3:1) to obtain 400 mg of the title compound as a light yellow solid, with a yield of 63.2%.

[0794] LC-MS: m / z 217.1 [M+H] + .

[0795] Step 6: Preparation of N-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4.6.7tetrahydro-2H-indazol-7-amine (33 g)

[0796] At room temperature, compound 33f (50.0 mg, 0.231 mmol), titanium tetrachloride (50.0 mg), and methylamine tetrahydrofuran solution (2.00 mL) were added to a reaction flask and reacted at room temperature for 3 hours under a nitrogen atmosphere. After the reaction, the reaction solution was directly filtered, the filtrate was collected, and concentrated under reduced pressure to obtain 60.0 mg of the title compound as a light yellow solid, with a yield of 83.2%.

[0797] LC-MS: m / z 232.1[M+H] + .

[0798] Step 7: Preparation of 4-amino-N,3-dimethyl-N-(2-(1-methylpyrazol-4-yl)-4,5,6,7-tetrahydro-2H-indazol-7-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (33)

[0799] At room temperature, compound 33g (150 mg, 0.584 mmol) was dissolved in DMF (5.00 mL), and compound 2e (157 mg, 0.642 mmol), TCFH (304 mg, 1.08 mmol), and NMI (88.4 mg, 1.08 mmol) were added under stirring, and stirred at room temperature for 3 hours. 5.00 mL of water was added, and EA was extracted (5.00 mL x 3), washed with saturated brine (5.00 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was 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 27.0 mg of the title compound as a brown solid. Yield: 12.7%.

[0800] LC-MS: m / z 458.1[M+H] + .

[0801] 1 H NMR (400 MHz, DMSO-d 6 )δ8.86(d,J=2.3Hz,1H),8.37(s,1H),8.13–8.04(m,2H),7.94–7.81(m,2H), 7.75(d,J=11.4Hz,1H),7.64(d,J=8.3Hz,1H),4.94(dd,J=8.4,4.5Hz,1H),4 .24(t,J=6.7Hz,1H),2.37(s,3H),2.19–2.08(m,1H),1.91(d,J=37.4Hz,2H) ,1.75(t,J=14.3,9.2Hz,1H),1.61–1.46(m,2H),1.23(dd,J=9.6,5.2Hz,3H).

[0802] Example 34: Preparation of 4-amino-N,1-dimethyl-N-(2-(1-methylpyrazol-4-yl)-4,5,6,7-tetrahydro-2H-indazol-7-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (34)

[0803]

[0804] The title compound 34 was prepared in the same manner as Example 33, except that compound 1m was used instead of compound 2e.

[0805] LC-MS: m / z 455.1[M+H] + .

[0806] 1 H NMR (400 MHz, DMSO-d 6 )δ8.65–8.62(m,1H),8.59(s,1H),8.19(s,1H),7.98–7.91(m,2H),7.85(d,J=9.2Hz,2H),4. 99(t,J=8.2Hz,1H),4.23(s,3H),2.81(s,3H),1.90(d,J=30.9Hz,3H),1.49(d,J=8.0Hz,1H).

[0807] Example 35: Preparation of 4-amino-N,3-dimethyl-N-(5-(1-methylpyrazol-4-yl)-2,3-dihydrothieno[3,2-b]furan-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (35)

[0808]

[0809] Step 1: Preparation of 5-bromo-3-hydroxythiophene-2-carboxylic acid methyl ester (35b)

[0810] At room temperature, phenyltrimethylammonium tribromide (35.7 g, 94.9 mmol) was added to a solution of 3-hydroxythiophene-2-carboxylic acid methyl ester 35a (5 g, 31.6 mmol) in methanol and dichloromethane (1:1), followed by calcium carbonate (12.6 g, 126.4 mmol) and reacted at room temperature for 20 hours. The reaction suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was redissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine in turn, the organic phase was dried over sodium sulfate, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=5:1-2:1) to obtain 2.36 g of the title compound as a yellow solid, yield: 31.6%.

[0811] LC-MS: m / z 237[M+H] + .

[0812] Step 2: Preparation of methyl 5-bromo-3-(2-methoxy-2-oxoethoxy)thiophene-2-carboxylate (35c)

[0813] At room temperature, compound 35b (2.36 g, 10 mmol) and methyl 2-bromoacetate (3.06 g, 20 mmol) were dissolved in DMF (15 mL), potassium carbonate (4.14 g, 30 mmol) was added, and the mixture was reacted for 1 hour. Water was added, and the mixture was extracted with EA (50 mL x 3). The organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain 2.68 g of the title compound as a black oil, with a yield of 87.0%.

[0814] LC-MS: m / z 309 [M+H] + .

[0815] Step 3: Preparation of methyl 5-bromo-3-oxo-2,3-dihydrothieno[3,2-b]furan-2-carboxylate (35d)

[0816] At room temperature, compound 35c (2.68 g, 8.7 mmol) was dissolved in tetrahydrofuran (20.0 mL). Sodium tert-butoxide (2.5 g, 26.1 mmol) was added at 0°C and reacted for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain 2.26 g of the title compound as a yellow solid, with a yield of 94.1%.

[0817] LC-MS: m / z 277 [M+H] + .

[0818] Step 4: Preparation of 5-bromothieno[3,2-b]furan-3(2H)-one (35e)

[0819] At room temperature, compound 35d (2.26 g, 8.19 mmol) was dissolved in methanol (16.0 mL), 6 M hydrochloric acid (10 ml) was added, and the mixture was reacted at 80° C. for 30 min. The reaction solution was concentrated under reduced pressure to obtain 1.45 g of the title compound as a yellow solid, with a yield of 81.2%.

[0820] LC-MS: m / z 219 [M+H] + .

[0821] Step 5: Preparation of 5-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-b]furan-3(2H)-one (35f)

[0822] At room temperature, compound 35e (1.45 g, 6.65 mmol) and compound 1b (2.1 g, 9.97 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.54 g, 0.66 mmol), potassium carbonate (1.84 g, 13.3 mmol) were dissolved in dioxane and water (20.0 mL, 5:1). The mixture was stirred at 100°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA=3:1-1:1) to obtain 800.0 mg of the title compound as a yellow solid, with a yield of 54.7%.

[0823] LC-MS: m / z 221[M+H] + .

[0824] Step 6: Preparation of N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-b]furan-3-amine (35 g)

[0825] At room temperature, compound 35f (0.8 g, 3.63 mmol) was dissolved in tetrahydrofuran (10.0 mL), and a 2M tetrahydrofuran solution of methylamine (9.1 mL, 18.15 mmol) was added, and the mixture was reacted at 8°C for 12 hours. After cooling to room temperature, sodium borohydride (0.69 g, 18.15 mmol) was added, and the mixture was reacted at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM / MeOH=20:1-5:1) to obtain 150 mg of the title compound as a yellow oil, with a yield of 17.6%.

[0826] LC-MS: m / z 236 [M+H] + .

[0827] Step 7: Preparation of 4-amino-N,3-dimethyl-N-(5-(1-methylpyrazol-4-yl)-2,3-dihydrothieno[3,2-b]furan-3-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (35)

[0828] At room temperature, compound 35g (150 mg, 0.64 mmol) and compound 2e (150 mg, 0.51 mmol) were dissolved in DMF (3.0 mL), TCFH (360 mg, 1.28 mmol) and NMI (210 mg, 2.56 mmol) were added, and the mixture was reacted at room temperature for 1 hour. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by C18 silica gel column chromatography (mobile phase ACN / water = 1:2) to obtain 41.0 mg of the title compound as a white solid, with a yield of 13.9%.

[0829] LC-MS: m / z 462[M+H] + .

[0830] 1 H NMR (400 MHz, DMSO-d 6 )δ7.96(s,1H),7.76(d,J=0.7Hz,1H),7.59(d,J=7.3Hz,4H),6.65(s,2H),5.48–5.24(m,3 H), 5.07 (d, J = 10.1Hz, 1H), 3.85 (s, 3H), 3.32 (s, 2H), 2.72 (s, 3H), 1.41 (d, J = 6.1Hz, 3H).

[0831] Example 36: Preparation of 4-amino-N-cyclopropyl-3-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (36)

[0832]

[0833] The title compound 36 was prepared in the same manner as in Example 22, except that cyclopropylamine was used instead of methylamine tetrahydrofuran solution.

[0834] LCMS: m / z 502.18 [M+H] + .

[0835] 1H NMR (400MHz, DMSO-d 6 )δ8.67(s,2H),8.01(t,J=3.6Hz,2H),7.95(s,1H),7.78(d,J=8.7Hz,1H),7.70(s,1H ),6.92(s,1H),5.59–5.39(m,4H),4.75(d,J=14.7Hz,1H),4.59(d,J=13.9Hz,1H),4. 40(dd,J=12.1,3.0Hz,1H),4.10(dd,J=12.0,4.5Hz,1H),3.85(s,3H),2.91(d,J=3.3 Hz, 1H), 1.46 (d, J = 5.9 Hz, 3H), 0.35 ( d, J = 36.8 Hz, 2H), 0.17 ( dd, J = 20.2, 4.8 Hz, 2H).

[0836] Example 37: Preparation of 4-amino-N-isopropyl-3-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-7-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (37)

[0837]

[0838] The title compound 37 was prepared in the same manner as in Example 22, except that isopropylamine was used instead of methylamine tetrahydrofuran solution.

[0839] LCMS: m / z 504.20 [M+H] + .

[0840] 1 H NMR (400 MHz, DMSO-d 6 )δ8.14(s,1H),8.03(s,1H),7.71(s,1H),7.59(s,1H),7.50(s,2H),6.90(s,1H),6.60(s,1H),5.36(ddd,J=51.9,21.2,8.0Hz,4H),4.82( s,1H),4.75–4.55(m,2H),4.50(d,J=14.1Hz,1H),3.92(s,1H),3.85(d,J=2.6Hz,3H),1.41(dd,J=5.9,3.0Hz,6H),1.34(d,J=6.3Hz,3H).

[0841] Example 38: Preparation of 4-amino-N-(3-fluoropyridin-2-yl)methyl)-3-methyl-N-(2-(1-methylpyrazol-4-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-7-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (38)

[0842]

[0843] The title compound 38 was prepared in the same manner as in Example 22, except that the methylamine tetrahydrofuran solution was replaced by compound 1e.

[0844] LCMS: m / z 571.18 [M+H] + .

[0845] 1 H NMR (400 MHz, DMSO-d 6)δ8.78(s,1H),8.44(s,1H),7.96(d,J=13.9Hz,2H),7.73(d,J=8.6Hz,1H),7. 65(s,1H),7.39(dd,J=27.5,23.8Hz,2H),6.85(s,1H),5.71(s,1H),5.50(s,2 H),5.32(dd,J=41.1,15.4Hz,2H),4.79(d,J=18.1Hz,2H),4.63(d,J=14.8Hz, 2H), 4.45 (d, J = 16.0Hz, 2H), 4.19 (d, J = 12.1Hz, 1H), 3.86 (s, 3H), 1.42 (s, 3H).

[0846] Example 39: Preparation of 4-amino-N-(2,6-difluorobenzyl)-3-methyl-N-(2-(1-methylpyrazol-4-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (39)

[0847]

[0848] The title compound 39 was prepared in the same manner as in Example 22, except that 2,6-difluorophenylmethanamine was used instead of methylamine tetrahydrofuran solution.

[0849] LCMS: m / z 588.18 [M+H] + .

[0850] 1 H NMR (400 MHz, DMSO-d 6 )δ7.99(d,J=8.6Hz,1H),7.85(d,J=8.4Hz,1H),7.71(s,1H),7.61(s,1H),7.51(s,1H), 7.28(s,2H),7.16–7.03(m,1H),6.72(s,2H),6.62(s,1H),5.56(ddd,J=19.1,10.4,4.3H z,3H),5.44(d,J=15.1Hz,1H),4.90(s,2H),4.68(d,J=14.0Hz,1H),4.50(d,J=14.7Hz, 1H), 4.31 (d, J = 11.2Hz, 1H), 3.96 (s, 3H), 3.92 (d, J = 11.3Hz, 1H), 1.61 (d, J = 6.2Hz, 3H).

[0851] Example 40: Preparation of 4-amino-N,3-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (40)

[0852]

[0853] Step 1: Preparation of 2-bromo-6,7-dihydrobenzo[b]thiophen-4(5H)-one (40b)

[0854] At room temperature, 6,7-dihydrobenzo[b]thiophene-4(5H)-one 40a (5.02 g, 33.0 mmol) was dissolved in glacial acetic acid (18 mL), water (18 mL) was added, and the mixture was stirred for 30 minutes. A solution of bromine (5.81 g, 36.3 mmol) in glacial acetic acid (32 mL) was added, and the resulting mixture was stirred for 2 hours. After the reaction was completed, the glacial acetic acid in the reaction solution was concentrated under vacuum, diluted with methyl tert-butyl ether (100 mL), washed with 1.0 M sodium hydroxide solution (70 mL), the aqueous phase was extracted with methyl tert-butyl ether (70 mL), the organic phases were combined and washed with saturated sodium chloride solution, anhydrous sodium sulfate was added to the organic phase for drying, filtered, and the filtrate was collected and concentrated under vacuum to obtain 7.44 g of the title compound as a brown solid, which was used without further purification.

[0855] LCMS: m / z 230.94 [M+H] + .

[0856] Step 2: Preparation of 2-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydrobenzo[b]thiophen-4(5H)-one (40c)

[0857] Compound 40b (7.38 g, 25.0 mmol) was dissolved in 1,4-dioxane (70 mL) at room temperature, and compound 1b (5.72 g, 27.5 mmol), Pd(dppf)Cl 2 -CH 2 Cl 2 (409 mg, 0.500 mmol), potassium carbonate (6.90 g, 50.0 mmol) and water (7 mL), the resulting mixture was stirred at 100 ° C for 16 hours under a nitrogen atmosphere. After the reaction, the reaction solution was concentrated under vacuum, and the obtained residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 0-50%) to obtain 4.10 g of the title compound as a brown solid, with a two-step yield of 70.6%.

[0858] LCMS: m / z 233.07 [M+H]+ .

[0859] Step 3: Preparation of N-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-4-amine (40d)

[0860] Compound 40c (1.16 g, 5.00 mmol) was dissolved in tetrahydrofuran (12.5 mL) at room temperature, and a tetrahydrofuran solution of methylamine (2.0 M, 12.5 mL, 25.0 mmol) and tetraethyl titanate (3.42 g, 15.0 mmol) were added. The resulting mixture was stirred at 80°C for 24 hours under a nitrogen atmosphere. Sodium cyanoborohydride (3.15 g, 50.0 mmol) was added at room temperature, and the mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under vacuum, and the resulting residue was purified by column chromatography (eluent: methanol / dichloromethane = 0-10%) to obtain 952 mg of the title compound as a yellow solid, with a yield of 77.0%.

[0861] LCMS: m / z 248.11 [M+H] + .

[0862] Step 4: Preparation of 4-amino-N,3-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (40)

[0863] At room temperature, compound 40d (148 mg, 0.600 mmol) was dissolved in tetrahydrofuran (2 mL), compound 2e (176 mg, 0.720 mmol) and 2-chloro-1-methylpyridinium iodide (200 mg, 0.780 mmol) were added, stirred for 5 minutes, N,N-diisopropylethylamine (233 mg, 1.80 mmol) was added, and the resulting mixture was stirred for 4 hours. After the reaction was completed, the reaction solution was concentrated under vacuum, 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 6.5 mg of the title compound as a white solid, with a yield of 2.3%.

[0864] LCMS: m / z 474.19 [M+H] + .

[0865] 1 H NMR (400 MHz, DMSO-d 6)δ8.04(s,1H),7.74(s,1H),7.67(s,1H),7.63(s,1H),7.59(s,1H),7.05(s,1H),6.61(s,2H),5.42(s,2H),5.29( s,1H),4.78(s,1H),3.84(s,3H),2.72(s,3H),2.67(s,2H),1.92(dd,J=47.4,31.7Hz,4H),1.41(d,J=6.0Hz,3H).

[0866] Example 41: Preparation of 4-amino-N-(3-fluoropyridin-2-yl)methyl)-3-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzothiophen-4-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (41)

[0867]

[0868] The title compound 41 was prepared in the same manner as in Example 40, except that the methylamine tetrahydrofuran solution was replaced by compound 1e.

[0869] LCMS: m / z 569.21 [M+H] + .

[0870] 1 H NMR (400 MHz, DMSO-d 6 )δ8.45(s,1H),8.01(s,1H),7.68(s,4H),7.34(s,2H),7.06(s,1H),6.6 2(s,2H),5.50–5.10(m,3H),4.88(d,J=55.4Hz,1H),4.55(d,J=75.0Hz, 1H),4.16(d,J=12.8Hz,1H),3.85(s,3H),2.65(s,2H),2.06(dd,J=27.3 ,7.4Hz,1H),1.82(d,J=49.8Hz,2H),1.55(s,1H),1.39(d,J=5.8Hz,3H).

[0871] Example 42: Preparation of 4-amino-N,3-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[b]thiophen-7-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (42)

[0872]

[0873] Step 1: Preparation of methyl 2-amino-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (42b)

[0874] At room temperature, cyclohexane-1,3-dione 42a (20 g, 178.36 mmol), methyl 2-cyanoacetate (17.68 g, 178.36 mmol), sulfur (5.70 g, 178.36 mmol), triethylamine (20 g, 178.36 mmol), and 1.4-dioxane (200 mL) were added to a reaction flask and stirred at 100°C for 16 hours. After cooling to room temperature, 1M aqueous hydrochloric acid solution was added, the temperature was lowered to 0°C, the temperature was controlled and stirred for 30 minutes, filtered, the filter cake was washed with water, and dried to obtain 9.4 g of the title compound as a gray solid, with a yield of 23.5%.

[0875] Step 2: Preparation of methyl 2-bromo-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (42c)

[0876] At room temperature, tert-butyl nitrite (5.49 g, 53.33 mmol), copper bromide (9.96 g, 42.66 mmol), and acetonitrile (10 mL) were added to the reaction flask, and the temperature was raised to 50°C and stirred for 1 hour. Compound 42b was dissolved in acetonitrile (10 mL) and added dropwise to the reaction solution at 50°C and reacted for 2 hours. The mixture was filtered, and water (10 mL) was added to the filtrate, and extracted with ethyl acetate (50 mL). The organic phase was washed twice with saturated sodium chloride aqueous solution (50 mL), dried over sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: PE: EA = 97:3) to obtain 8.0 g of a white solid compound with a yield of 77.2%.

[0877] Step 3: Preparation of methyl 2-(1-methyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (42d)

[0878] At room temperature, compound 42c (8.7 g, 30.31 mmol), compound 1b (9.46 g, 45.47 mmol), potassium carbonate (8.36 g, 60.62 mmol) were added to 1.4-dioxane (100 mL) and water (20 mL). After replacing nitrogen three times, DPPF palladium dichloride (870 mg) was added, the temperature was raised to 80°C, stirred for 2 hours, and filtered. The filtrate was added with water (100 mL), extracted with ethyl acetate (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: mobile phase: PE: EA = 1:1) to obtain 8.0 g of the title compound as a yellow solid, yield: 91.9%.

[0879] Step 4: Preparation of 2-(1-methyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (42e)

[0880] At room temperature, compound 42d (8.0 g, 27.58 mmol), THF (80 mL) and sodium hydroxide aqueous solution (3.3 g, 82.75 mmol, 80 ml) were added to the reaction flask and stirred at 80°C for 3 hours. The mixture was cooled to room temperature and concentrated, and the pH was adjusted to 3 to precipitate a solid, which was filtered and dried to obtain 6.2 g of the title compound as a yellow solid, with a yield of 82.8%.

[0881] Step 5: Preparation of 2-(1-methyl-1H-pyrazol-4-yl)-5,6-dihydrobenzo[b]thiophen-7(4H)-one (42f)

[0882] At room temperature, compound 42e (6.2 g, 22.46 mmol), cuprous oxide (3.2 g, 22.46 mmol), and quinoline (80 mL) were added to a sealed tube and stirred at 170°C for 1 hour. After cooling to room temperature, water (100 mL) was added to quench the mixture, and ethyl acetate (100 mL) was added. After filtration through celite, the pH was adjusted to 10, and the mixture was extracted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: PE:EA=92:8) to obtain 3.1 g of the title compound as a gray solid, with a yield of 59.6%.

[0883] Step 6: Preparation of N-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-7-amine (42 g)

[0884] At room temperature, compound 42f (2.3 g, 9.91 mmol), methylamine tetrahydrofuran solution (10 mL, 19.83 mmol), tetraethyl titanate (2.26 g, 9.91 mmol), and methanol (30 mL) were added to a reaction flask and stirred at 80°C for 16 hours. After cooling to room temperature, sodium cyanoborohydride (3.1 g, 49.55 mmol) was added to the reaction flask in batches and stirred at 80°C for 1 hour. After cooling to room temperature again, the mixture was extracted with ethyl acetate (50 mL), washed with saturated sodium chloride aqueous solution (50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.1 g of the title compound as a crude black oil.

[0885] Step 7: Preparation of 4-amino-N,3-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[b]thiophen-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (42)

[0886] At room temperature, compound 42g (1.0 g, 4.31 mmol) was dissolved in N,N-dimethylformamide (2 mL), compound 2e (1.58 mg, 6.47 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.82 g, 6.47 mmol) were added, stirred for 10 minutes, methylimidazole solution (1.06 mg, 12.93 mmol) was added dropwise, and the mixture was reacted at room temperature for 16 hours. Water (50 mL) and ethyl acetate (50 mL) were added for extraction, 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, 100 A, mobile phase: acetonitrile / water, gradient: 30%-80%) to obtain 50.0 mg of white solid powder compound.

[0887] LC-MS: m / z 474.2 [M+H] + .

[0888] 1 H NMR (400 MHz, DMSO-d 6 )δ8.00(s,1H),7.69(s,1H),7.61(s,1H),7.59(s,1H),6.89(s,1H),6.63(s,2H),5.86(s,0H),5.53–5.18(m,3H) ,4.99(s,1H),3.84(s,3H),3.33(s,1H),2.77(s,3H),1.92(q,J=11.4,10.9Hz,4H),1.41(dd,J=6.2,3.7Hz,3H).

[0889] Example 43: Preparation of 4-amino-N-(3-fluoropyridin-2-yl)methyl)-3-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[b]thiophen-7-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (43)

[0890]

[0891] The title compound 43 was prepared in the same manner as Example 42, except that the methylamine tetrahydrofuran solution was replaced by compound 1e.

[0892] LC-MS: m / z 569.2 [M+H] + .

[0893] 1 H NMR (400 MHz, DMSO-d 6)δ8.50–8.40(m,1H),8.17(d,J=27.0Hz,2H),7.99(s,1H),7.78(d,J=28.9H z,2H),7.68(s,1H),7.37(dt,J=8.5,4.4Hz,1H),6.87(s,1H),5.46(d,J=22. 4Hz,2H),5.02(d,J=53.0Hz,2H),4.59(dd,J=60.9,18.3Hz,1H),4.24(s,1H ), 3.85 (s, 3H), 2.31–1.95 (m, 2H), 1.94–1.47 (m, 4H), 1.42 (t, J = 6.3Hz, 3H).

[0894] Example 44: Preparation of 4-amino-N-cyclopropyl-3-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[b]thiophen-7-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (44)

[0895]

[0896] The title compound 44 was prepared in the same manner as Example 42, except that cyclopropylamine was used instead of methylamine tetrahydrofuran solution.

[0897] LCMS: m / z 500.25 [M+H] + .

[0898] 1 H NMR (400 MHz, DMSO-d 6 )δ8.77(s,1H),8.00(dt,J=8.7,1.5Hz,1H),7.93(s,1H),7.79(d,J=8.6Hz, 1H),7.63(s,1H),6.84(s,1H),5.73–5.26(m,6H),3.82(s,3H),2.92(s,2H), 2.40–2.32(m,1H),2.25(s,1H),2.12–2.04(m,1H),1.80(s,1H),1.46(d,J=6 .0Hz,3H),0.50(td,J=7.6,7.1,4.1Hz,1H),0.32(s,2H),0.11–0.01(m,1H).

[0899] Example 45: Preparation of 4-amino-3-methyl-N-(2-(1-methylpyrazol-4-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-7-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (45)

[0900]

[0901] The title compound 45 was prepared in the same manner as in Example 22, except that (5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride was used instead of methylamine tetrahydrofuran solution.

[0902] LCMS: m / z 621.18 [M+H] + .

[0903] 1 H NMR (400 MHz, DMSO-d 6 )δ8.86(s,1H),8.67(s,2H),7.93(d,J=21.3Hz,4H),7.65(d,J=10.9Hz,1H),6.84(d,J=32.4Hz,1H),5.52(s,2H),5.42–5.15(m,2H),4.97(d ,J=21.3Hz,1H),4.81–4.57(m,3H),4.46(d,J=15.0Hz,1H),4.28(s,1H),3.93(dd,J=12.0,3.8Hz,2H),3.85(s,3H),1.43(d,J=16.1Hz,3H).

[0904] Example 46: Preparation of 4-amino-3-methyl-N-(2-(1-methylpyrazol-4-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-7-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (46)

[0905]

[0906] The title compound 46 was prepared in the same manner as in Example 22, except that (5-bromopyridin-2-yl)methanamine was used instead of methylamine tetrahydrofuran solution.

[0907] LC-MS: m / z 631.07 [M+H] + .

[0908] 1 H NMR (400 MHz, DMSO-d 6)δ8.78(s,1H),8.61(d,J=2.4Hz,1H),7.99(s,2H),7.87(s,2H),7.79–7.64( m,2H),7.26(s,1H),7.14(s,1H),7.01(s,1H),6.84(s,1H),5.71(s,1H),5.5 1(s,2H),5.30(dt,J=53.8,16.1Hz,1H),4.88(d,J=72.9Hz,1H),4.67–4.58( m, 2H), 4.46 (d, J = 15.2Hz, 1H), 4.26 (d, J = 10.3Hz, 1H), 1.44 (d, J = 7.9Hz, 3H).

[0909] Example 47: Preparation of N-(1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)-4-amino-3-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-7-yl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (47)

[0910]

[0911] The title compound 47 was prepared in the same manner as in Example 22, except that 1H-pyrrolo[2,3-b]pyridine-4-methylamine was used instead of methylamine tetrahydrofuran solution.

[0912] LCMS: m / z 592.0 [M+H] + .

[0913] 1 H NMR (400 MHz, DMSO-d 6 )δ11.58(s,1H),8.15(d,J=3.6Hz,1H),8.02(s,1H),7.69(s,1H),7.35( s,1H),7.07(t,J=4.2Hz,1H),6.85(s,1H),6.62(s,2H),6.38(s,1H),5. 39(s,3H),4.98(s,2H),4.80(s,1H),4.59(d,J=14.8Hz,1H),4.41(d,J= 14.8Hz,1H),4.16(s,1H),4.03–3.96(m,1H),3.85(s,3H),1.38(s,3H).

[0914] Example 48: Preparation of 4-amino-N-cyclopropyl-3-methyl-N-(5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-b]furan-3-yl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (48)

[0915]

[0916] The title compound 48 was prepared in the same manner as in Example 35, except that cyclopropylamine was used instead of methylamine tetrahydrofuran solution.

[0917] LC-MS: m / z 488[M+H] + .

[0918] 1 H NMR (400 MHz, DMSO-d 6 )δ7.96(s,1H),7.76(d,J=0.7Hz,1H),7.59(d,J=7.3Hz,4H),6.65(s,2H),5.47–5.26(m,4 H), 5.07 (d, J = 10.1Hz, 2H), 3.85 (s, 3H), 3.32 (s, 1H), 2.72 (s, 3H), 1.41 (d, J = 6.1Hz, 3H).

[0919] According to the preparation method of Example 2, the following compound was prepared from the corresponding raw materials:

[0920]

[0921]

[0922]

[0923]

[0924] Biological evaluation

[0925] Test Example 1: Inhibition level of the compound of the present invention on PRMT5-MTA binding

[0926] Reagent preparation:

[0927]

[0928]

[0929] PRMT5 solution (5 μL / well) Final concentration (μM) PRMT5 (BPS, Cat#51045) 0.00380 Assay buffer 1

[0930] SAM solution (5 μL / well) Final concentration (μM) Histone H4 (1-21) peptide (GL Biochem, Cat# 30128582) 0.16 SAM (10%) (NEB, Cat# B9003S) 1.3 Assay buffer 1

[0931]

[0932] The biochemical activity of the compound was evaluated by detecting the inhibitory level of the compound on PRMT5-MTA binding. PRMT5 (BPS, Cat#51045)-2.6μM MTA (Sigma, Cat#D5011) solution was prepared with experimental buffer. The reference compound MRTX9768 (MCE, Cat#HY-138684) was diluted with DMSO at concentrations of 1000μM, 8μM, 64nM, and 0.51nM; the test compound was diluted with DMSO with a starting concentration of 9.901μM, 10 concentration gradients, and 5-fold dilutions. Use an ECHO pipette (Labcyte) to draw 0.1μL of the compound into a 384-well plate (Corning, 3657), add 5μL of the PRMT5-MTA mixed solution, and centrifuge at 1000rpm for 30 seconds. Place the experimental plate at 25°C and incubate for 30 minutes. Prepare SAM solution with assay buffer, add 5 μL SAM solution to the assay plate, centrifuge at 1000 rpm for 30 seconds, and incubate the assay plate at 25°C for 90 minutes. Prepare ULight-streptavidin detection solution with 1x concentration of LANCE buffer (PE, Cat#CR97-100), add 10 μL detection solution (ULight-streptavidin / peptide-biotin 1:6) to the assay plate after 90 minutes, and read fluorescence data at 665 nm wavelength (excitation light is 320 or 340 nm) using Envision multi-label analyzer (2104) after 60 minutes.

[0933] The raw data were converted into inhibition rate using the equation: (1-(sample-SignalAve_PC) / (SignalAve_VC-SignalAve_PC))×100, where SignalAve_PC is the average fluorescence intensity of the positive control and SignalAve_VC is the average fluorescence intensity of the negative control. IC 50 The values ​​of were obtained by four-parameter curve fitting ("log(inhibitor) vs. response - variable slope" mode in GraphPad Prism 8).

[0934] Table 1 provides the in vitro enzymatic inhibitory activity (IC 50 ). In the table, A refers to the IC value of the compound's in vitro enzymatic inhibition activity against PRMT5+2.6μM MTA. 50 <100nM; B refers to 100nM≤IC 50 <1μM; C refers to IC 50 ≥1μM.

[0935] Table 1 Enzymatic activity of the compounds of the present invention on PRMT5 in the presence of MTA

[0936]

[0937]

[0938] Conclusion: The above data results show that the compounds of the present invention have a significant inhibitory effect on the PRMT5 / MTA complex.

[0939] Experimental Example 2: Inhibitory effects of the compounds of the present invention on proliferation of wild-type HCT-116 and MTAP knockout HCT-116 cells

[0940] The cell activity and selectivity of the compounds were evaluated by detecting the inhibitory levels of the compounds on the proliferation of wild-type and MTAP gene knockout HCT-116 cells.

[0941] On day 0, 100 ul of cell suspension containing 500 HCT-116 parental cells (Horizon, HD PAR-034) or HCT-116 MTAP knockout cells (Horizon, HD R02-033) was added to each well of a white 96-well plate and cultured overnight in a 37°C, 5% carbon dioxide incubator.

[0942] On the first day, the test compound was diluted, starting from 10000 μM, and paclitaxel (paclitaxel injection, Shuanglu Pharmaceutical) was diluted 3 times in 100% DMSO, 9+0 concentrations, and a double-well experiment was set up. The culture medium was added to the middle plate, and then the gradient dilution compound of each well was transferred to the middle plate according to the corresponding position; after mixing, 50 μL of the compound was transferred to each well of the cell plate. The cell plate was placed in a 37°C, 5% carbon dioxide incubator for 5 days.

[0943] On the 6th day, cells were digested, 75 μL of Trypsin-EDTA solution (Invitrogen, 25200056) was added to each well, and the 96-well cell plate was placed in a 37°C, 5% carbon dioxide incubator for 3 minutes, and 125 μL of culture medium was added to each well to terminate digestion. 135 ul of fresh culture medium was added to a new 96-well plate, 10 μL of cell suspension was transferred to a new 96-well plate (1:20 dilution), and the same concentration of compound as on the first day was added, and the 96-well cell plate was placed in a 37°C, 5% carbon dioxide incubator for 5 days.

[0944] On the 11th day, Promega CellTiter-Glo assay was performed. The 96-well plate was taken out and equilibrated at room temperature for 20 minutes. 40 μL CTG (Promega, G7572) was added to each well, vortexed to mix, and incubated at room temperature for 30 minutes. The fluorescence signal was read by Envision multi-label analyzer.

[0945] The raw data were converted into inhibition rate using the equation: 100-(sample-SignalAve_PC) / (SignalAve_VC-SignalAve_PC)×100, where SignalAve_PC: average fluorescence intensity of positive control (blank), SignalAve_VC: average fluorescence intensity of negative control (0.1% DMSO). IC 50 The values ​​of can be obtained by four-parameter curve fitting (obtained in "log (inhibitor) vs. response - variable slope" mode in GraphPadPrism 8).

[0946] Table 2 provides the inhibitory activity of the compounds of the present application on the proliferation of HCT-116 parent cells and HCT-116 MTAP knockout cells. In the table, a and aa refer to the inhibitory activity IC of the compounds on the proliferation of HCT-116 parent cells and HCT-116 MTAP knockout cells, respectively. 50 <100nM; b and bb refer to 100nM≤IC 50 <1000nM; c and cc refer to IC 50 ≥1000nM.

[0947] Table 2 Inhibitory activity of the compounds of the present invention on proliferation of HCT-116 parental cells and HCT-116 MTAP knockout cells

[0948]

[0949]

[0950] Conclusion: The above data show that the compounds of the present invention have obvious proliferation inhibitory activity on HCT-116 MTAP knockout cells, and the inhibitory activity on HCT-116 MTAP knockout cells is higher than that on HCT-116 parental cells.

[0951] Experimental Example 3: Pharmacokinetic evaluation of the compound of the present invention in ICR mice

[0952] 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 Control 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.

[0953] In the table, A* refers to the AUC of the compound. 0-t (μg / L*h)>3000; B* refers to 1000 <AUC 0-t (μg / L*h)<3000; C* refers to 500 <AUC 0-t (μg / L*h)<1000; D* refers to AUC 0-t (μg / L*h)<500.

[0954] Table 3 Pharmacokinetic parameters of the compounds of the present invention after single oral administration to male ICR mice

[0955]

Claims

1. A compound represented by 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; X 1 CR 5 , CR 5 R 6 , N, NR 5 Or C=O; X 2 CR 7 , CR 7 R 8 , N, NR 7 Or C=O; Ring A1 and Ring A2 are each independently selected from cycloalkyl, heterocyclyl, aryl, heteroaryl; Each R 1 are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 1a replace; Each R 3 are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, alkyl, heteroalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 3a replace; R 2 is selected from hydrogen, halogen, hydroxy, amino, cyano, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-haloalkyl, -L-NR a C(=O)aryl, -L-COOH, -LC(=O)Oalkyl, -L-OR a 、-L-NR a R b ,-LC(=O)R a 、-LC(=O)OR a 、-L-NR a C(=O)R b 、-L-NR a C(=O)OR b ,-LC(=O)NR a R b 、-L-OC(=O)NR a R b ,-LS(=O)R a ,-LS(=O)2R a 、-L-SR a ,-LS(=O)(=NR a )R b 、-L-NR a S(=O)2R b and -LS(=O)2NR a R b wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-NR a The aryl portion of C(═O)aryl, the heterocyclyl portion of —L-heterocyclyl, the cycloalkyl portion of —L-cycloalkyl, the aryl portion of —L-aryl and the heteroaryl portion of —L-heteroaryl are optionally substituted with one or more R 4 replace; Each L is independently a bond, -O-, -NH-, alkylene, wherein the alkylene is optionally substituted with one or more groups selected from hydroxy, hydroxyalkyl and heteroaryl; Each R 1a are independently selected from hydrogen, halogen, hydroxy, amino, cyano, cycloalkyl, heterocyclyl, -O-alkyl, heteroalkyl, haloalkyl, -O-haloalkyl, -NH-haloalkyl, hydroxyalkyl, alkyl, -(CH2) p -OR a , -Q-cycloalkyl, -Q-heterocyclyl, -Q-aryl, -Q-heteroaryl, 5-20 membered spiroheterocyclyl, -SF 6 、HC(=O)-、-NR a R b 、-CH2OC(=O)NR a R b 、-L-NR a R b 、-C(=O)NR a R b 、-C(=O)R a 、-NHC(=O)R a , -CH2NHC(=O)Oalkyl, -CH2NHC(=O)NR a R b , -CH2NHC(=O)alkyl, -CH2-heteroaryl, -CH2NHSO2alkyl, -CH2OC(=O)heterocyclyl, -OC(=O)NR a R b , -OC(=O)heterocyclyl and -CH2-heterocyclyl, wherein the heterocyclyl of -CH2-heterocyclyl is optionally substituted with one or more oxo groups; Each R 3a independently selected from hydrogen, halogen, hydroxy, amino, cyano, heterocyclyl, -O-alkyl, heteroalkyl, haloalkyl, -O-haloalkyl, -NH-haloalkyl, hydroxyalkyl, alkyl, -Q-aryl, -Q-heteroaryl, HC(=O)-, -NR a R b 、-CH2OC(=O)NR a R b , -CH2NHC(=O)Oalkyl, -CH2NHC(=O)NR a R b , -CH2NHC(=O)alkyl, -CH2-heteroaryl, -CH2NHSO2alkyl, -CH2OC(=O)heterocyclyl, -OC(=O)NR a R b , -OC(=O)heterocyclyl and -CH2-heterocyclyl, wherein the heterocyclyl of -CH2-heterocyclyl is optionally substituted with one or more oxo groups; Each R 4 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, heterocyclyl, -O-alkyl, heteroalkyl, haloalkyl, -O-haloalkyl, -NH-haloalkyl, hydroxyalkyl, alkyl, -Q-aryl, -Q-heteroaryl, spiroheterocyclyl, -SF 6 、HC(=O)-、-NR a R b 、-CH2OC(=O)NR a R b , -CH2NHC(=O)Oalkyl, -CH2NHC(=O)NR a R b , -CH2NHC(=O)alkyl, -CH2-heteroaryl, -CH2NHSO2alkyl, -CH2OC(=O)heterocyclyl, -OC(=O)NR a R b , -OC(=O)heterocyclyl and -CH2-heterocyclyl, wherein the heterocyclyl of -CH2-heterocyclyl is optionally substituted with one or more oxo groups; each Q is independently a bond, -O- or -NH-; R 5 , R 6 Each is independently selected from hydrogen, deuterium, halogen, hydroxy, alkyl, hydroxyalkyl, aminoalkyl, haloalkyl, cyano, -CH2-aryl, -CH2-heteroaryl, -CH2-cycloalkyl, -CH2-heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a 、-NR a R b 、-C(=O)R a 、-C(=O)OR a 、-NR a C(=O)R b 、-NR a C(=O)OR b 、-C(=O)NR a R b 、-OC(=O)NR a R b 、-S(=O)R a 、-S(=O)2R a 、-SR a 、-S(=O)(=NR a )R b 、-NR a S(=O)2R b and -S(=O)2NR a R b ; The alkyl, -CH2-aryl, -CH2-heteroaryl, -CH2-cycloalkyl, -CH2-heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 7 , R 8 Each is independently selected from hydrogen, deuterium, halogen, hydroxy, alkyl, hydroxyalkyl, aminoalkyl, haloalkyl, cyano, -CH2-aryl, -CH2-heteroaryl, -CH2-cycloalkyl, -CH2-heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a 、-NR a R b 、-C(=O)R a 、-C(=O)OR a 、-NR a C(=O)R b 、-NR a C(=O)OR b 、-C(=O)NR a R b 、-OC(=O)NR a R b 、-S(=O)R a 、-S(=O)2R a 、-SR a 、-S(=O)(=NR a )R b 、-NR a S(=O)2R b and -S(=O)2NR a R b ; The alkyl, -CH2-aryl, -CH2-heteroaryl, -CH2-cycloalkyl, -CH2-heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Or, R 5 or R 6 With R 7 or R 8 and the atoms to which they are attached together form a saturated or partially saturated cycloalkyl, a saturated or partially saturated heterocyclyl, an aryl or a heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 12 Each is independently selected from halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R a and R b Each is independently selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or, R a and R b together with the nitrogen atom to which it is attached, form a nitrogen-containing heterocyclic group, which is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl; m1 is 0, 1, 2, or 3; m2 is 0, 1, 2 or 3; m4 is 1 or 2; p is an integer of 1-6.

2. A compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: is a single bond or a double bond; X 1 CR 5 , CR 5 R 6 , N, NR 5 Or C=O; X 2 CR 7 , CR 7 R 8 , N, NR 7 Or C=O; Ring A1 and Ring A2 are each independently selected from cycloalkyl, heterocyclyl, aryl, heteroaryl; Each R 1 are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a R b wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 1a replace; Each R 3 are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, alkyl, heteroalkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 3a replace; R 2 is selected from hydrogen, halogen, hydroxy, amino, cyano, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-haloalkyl, -L-NR a C(=O)aryl, -L-COOH, -LC(=O)Oalkyl, -L-OR a 、-L-NR a R b ,-LC(=O)R a 、-LC(=O)OR a 、-L-NR a C(=O)R b 、-L-NR a C(=O)OR b ,-LC(=O)NR a R b 、-L-OC(=O)NR a R b ,-LS(=O)R a ,-LS(=O)2R a 、-L-SR a ,-LS(=O)(=NR a )R b 、-L-NR a S(=O)2R b and -LS(=O)2NR a R b wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-NR a The aryl portion of C(═O)aryl, the heterocyclyl portion of —L-heterocyclyl, the cycloalkyl portion of —L-cycloalkyl, the aryl portion of —L-aryl and the heteroaryl portion of —L-heteroaryl are optionally substituted with one or more R 4 replace; Each L is independently a bond, -O-, -NH-, alkylene, wherein the alkylene is optionally substituted with one or more groups selected from hydroxy, hydroxyalkyl and heteroaryl; Each R 1a are independently selected from hydrogen, halogen, hydroxy, amino, cyano, cycloalkyl, heterocyclyl, -O-alkyl, heteroalkyl, haloalkyl, -O-haloalkyl, -NH-haloalkyl, hydroxyalkyl, alkyl, -(CH2) p -OR a , -Q-cycloalkyl, -Q-heterocyclyl, -Q-aryl, -Q-heteroaryl, 5-20 membered spiroheterocyclyl, -SF 6 、HC(=O)-、-NR a R b 、-CH2OC(=O)NR a R b 、-L-NR a R b 、-C(=O)NR a R b 、-C(=O)R a 、-NHC(=O)R a , -CH2NHC(=O)Oalkyl, -CH2NHC(=O)NR a R b , -CH2NHC(=O)alkyl, -CH2-heteroaryl, -CH2NHSO2alkyl, -CH2OC(=O)heterocyclyl, -OC(=O)NR a R b , -OC(=O)heterocyclyl and -CH2-heterocyclyl, wherein the heterocyclyl of -CH2-heterocyclyl is optionally substituted with one or more oxo groups; Each R 3a independently selected from hydrogen, halogen, hydroxy, amino, cyano, heterocyclyl, -O-alkyl, heteroalkyl, haloalkyl, -O-haloalkyl, -NH-haloalkyl, hydroxyalkyl, alkyl, -Q-aryl, -Q-heteroaryl, HC(=O)-, -NR a R b 、-CH2OC(=O)NR a R b , -CH2NHC(=O)Oalkyl, -CH2NHC(=O)NR a R b , -CH2NHC(=O)alkyl, -CH2-heteroaryl, -CH2NHSO2alkyl, -CH2OC(=O)heterocyclyl, -OC(=O)NR a R b , -OC(=O)heterocyclyl and -CH2-heterocyclyl, wherein the heterocyclyl of -CH2-heterocyclyl is optionally substituted with one or more oxo groups; Each R 4 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, heterocyclyl, -O-alkyl, heteroalkyl, haloalkyl, -O-haloalkyl, -NH-haloalkyl, hydroxyalkyl, alkyl, -Q-aryl, -Q-heteroaryl, spiroheterocyclyl, -SF 6 、HC(=O)-、-NR a R b 、-CH2OC(=O)NR a R b , -CH2NHC(=O)Oalkyl, -CH2NHC(=O)NR a R b , -CH2NHC(=O)alkyl, -CH2-heteroaryl, -CH2NHSO2alkyl, -CH2OC(=O)heterocyclyl, -OC(=O)NR a R b , -OC(=O)heterocyclyl and -CH2-heterocyclyl, wherein the heterocyclyl of -CH2-heterocyclyl is optionally substituted with one or more oxo groups; each Q is independently a bond, -O- or -NH-; R 5 , R 6 Each is independently selected from hydrogen, deuterium, halogen, hydroxy, alkyl, hydroxyalkyl, aminoalkyl, haloalkyl, cyano, -CH2-aryl, -CH2-heteroaryl, -CH2-cycloalkyl, -CH2-heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a 、-NR a R b 、-C(=O)R a 、-C(=O)OR a 、-NR a C(=O)R b 、-NR a C(=O)OR b 、-C(=O)NR a R b 、-OC(=O)NR a R b 、-S(=O)R a 、-S(=O)2R a 、-SR a 、-S(=O)(=NR a )R b 、-NR a S(=O)2R b and -S(=O)2NR a R b ; The alkyl, -CH2-aryl, -CH2-heteroaryl, -CH2-cycloalkyl, -CH2-heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 7 , R 8 Each is independently selected from hydrogen, deuterium, halogen, hydroxy, alkyl, hydroxyalkyl, aminoalkyl, haloalkyl, cyano, -CH2-aryl, -CH2-heteroaryl, -CH2-cycloalkyl, -CH2-heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a 、-NR a R b 、-C(=O)R a 、-C(=O)OR a 、-NR a C(=O)R b 、-NR a C(=O)OR b 、-C(=O)NR a R b 、-OC(=O)NR a R b 、-S(=O)R a 、-S(=O)2R a 、-SR a 、-S(=O)(=NR a )R b 、-NR a S(=O)2R b and -S(=O)2NR a R b ; The alkyl, -CH2-aryl, -CH2-heteroaryl, -CH2-cycloalkyl, -CH2-heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Or, R 5 or R 6 With R 7 or R 8 and the atoms to which they are attached together form a saturated or partially saturated cycloalkyl, a saturated or partially saturated heterocyclyl, an aryl or a heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R a and R b Each is independently selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or, R a and R b together with the nitrogen atom to which it is attached, form a nitrogen-containing heterocyclic group, which is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl; m1 is 0, 1, 2, or 3; m2 is 0, 1, 2 or 3; p is an integer of 1-6.

3. The compound according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: is a double bond; X 1 CR 5 or NR 5 ; X 2 CR 7 or NR 7 ; R 5 , R 7 As defined in claim 1.

4. The compound according to any one of claims 1 to 3, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: is a double bond; X 1 CR 5 or NR 5 ; X 2 CR 7 or NR 7 ; R 5 With R 7 and the atoms to which they are connected together form a saturated or partially saturated C5-C6 cycloalkyl, a saturated or partially saturated 5- to 6-membered heterocyclyl, a phenyl or a 5- to 6-membered heteroaryl, wherein the C5-C6 cycloalkyl, the 5- to 6-membered heterocyclyl, the phenyl or the 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

5. The compound according to any one of claims 1 to 4, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A1 is selected from C 5-7 Cycloalkyl or 5- to 7-membered heterocyclic group.

6. The compound according to any one of claims 1 to 5, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A2 is selected from saturated or partially saturated C 5-7 Cycloalkyl, saturated or partially saturated 5- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl.

7. A compound according to any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in: Ring A 2a Selected from saturated or partially saturated C 5-6 Cycloalkyl, saturated or partially saturated 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl; X 3 , X 4 are each independently selected from a bond, CH2, O, S or NH; n is 0, 1 or 2; X 1 , X 2 , R 1 , R 2 , R 3 , m1, m2 as defined in claim 2.

8. A compound according to any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in: Ring A 2a Selected from saturated or partially saturated C 5-6 Cycloalkyl, saturated or partially saturated 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl; X 3 , X 4 are each independently selected from a bond, CH2, O, S or NH; n is 0, 1 or 2; X 1 , X 2 , R 1 , R 2 , R 3 , R 12 , m1, m2, m4 as defined in claim 1.

9. A compound according to any one of claims 1 to 8, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIA) or (IIA-1), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in: Ring A 2a , X 3 , X 4 , n as defined in claim 7; R 1 , R 2 , R 3 , R 5 , R 7 , R 12 , m1, m2, m4 as defined in claim 1.

10. A compound according to any one of claims 1 to 8, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIB) or (IIB-1), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in: Ring E is selected from saturated or partially saturated 5-6 membered cycloalkyl, saturated or partially saturated 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; Each R 10 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; s is 0, 1, 2, or 3; Ring A 2a , X 3 , X 4 , n as defined in claim 7; R 1 , R 2 , R 3 , R 5 , R 7 , R 12 , m1, m2, m4 as defined in claim 1.

11. The compound according to any one of claims 7 to 10, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A 2a Selected from phenyl or 5- to 6-membered heteroaryl; preferably phenyl, pyridyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, imidazolyl.

12. A compound according to any one of claims 7 to 11 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Selected from Among them, X 3 is selected from CH2, O, NH and S; n is 0, 1 or 2; R 1 , R 3 , m1, m2 as defined in claim 1.

13. A compound according to any one of claims 10 to 12, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring E is selected from R 10a and R 10b Each is independently selected from hydrogen, halogen, amino, hydroxyl, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, preferably selected from hydrogen and C 1-6 alkyl; R 10c Selected from halogen, amino, hydroxyl, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, preferably selected from hydrogen and C 1-6 alkyl.

14. A compound according to any one of claims 1 to 13 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Each R 1 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR a R b , C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally substituted by one or more R 1a replace; Each R 1a are independently selected from hydrogen, halogen, hydroxy, amino, cyano, 3- to 6-membered cycloalkyl, 4- to 8-membered heterocyclyl, -OC 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, -NH-C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl, -(CH2) p -OR a , -Q-3 to 6-membered cycloalkyl, -Q-4 to 8-membered heterocyclyl, -Q-phenyl, -Q-5 to 6-membered heteroaryl, HC(=O)-, -NR a R b 、-L-NR a R b 、-C(=O)NR a R b 、-C(=O)R a 、-NHC(=O)R a 、-CH2OC(=O)NR a R b 、-CH2NHC(=O)OC 1-6 Alkyl, -CH2NHC(=O)NR a R b 、-CH2NHC(=O)-C 1-6 alkyl, -CH2-5 to 6-membered heteroaryl, -CH2NHSO2-C 1-6 alkyl, -CH2OC(=O)-4 to 8 membered heterocyclic group, -OC(=O)NR a R b , -OC(=O)-4 to 8 membered heterocyclyl and -CH2-4 to 8 membered heterocyclyl, wherein the heterocyclyl of the -CH2-4 to 8 membered heterocyclyl is optionally substituted with one or more oxo groups; m1 is 0 or 1; Q, R a , R b As defined in claim 1; Preferably, Each R 1 are each independently selected from hydrogen, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, the C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally substituted by one or more R 1a replace; Each R 1a are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(CH2) p -OR a , halogen, cyano, 3-6 membered cycloalkyl, 4-8 membered heterocyclic group, -Q-3-6 membered cycloalkyl, -L-NR a R b 、-C(=O)NR a R b 、-C(=O)R a 、-NHC(=O)R a ; Q is -O-; L is -CH2-; R a Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl; R b Selected from hydrogen, C 1-6 Alkyl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a 4-8 membered nitrogen-containing heterocyclic group, wherein the 4-8 membered nitrogen-containing heterocyclic group is optionally selected from halogen, C 1-6 The alkyl group is substituted by one or more groups; p is an integer from 1 to 4; m1 is 1.

15. A compound according to any one of claims 1 to 14 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, -L-phenyl, -L-5 to 10 membered heteroaryl, wherein the phenyl portion of the -L-phenyl or the heteroaryl portion of the -L-5 to 10 membered heteroaryl is optionally substituted with one or more R 4 replace; L is each independently a bond or -CH2-, wherein the -CH2- is optionally selected from hydroxyl, C 1-6 substituted with one or more of hydroxyalkyl and 5- to 6-membered heteroaryl groups; Each R 4 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Halogenated alkyl.

16. A compound according to any one of claims 1 to 15, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Each R 3 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 4 to 8 membered heterocyclyl, phenyl, 5 to 6 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4 to 8 membered heterocyclyl, phenyl, 5 to 6 membered heteroaryl are optionally substituted with one or more R 3a replace; Each R 3a are independently selected from hydrogen, halogen, hydroxy, amino, cyano, 4 to 8 membered heterocyclic group, -OC 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, -NH-C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 alkyl, -Q-phenyl, -Q-5 to 6-membered heteroaryl, HC(=O)-, -NR a R b 、-CH2OC(=O)NR a R b 、-CH2NHC(=O)OC 1-6 Alkyl, -CH2NHC(=O)NR a R b 、-CH2NHC(=O)-C 1-6 alkyl, -CH2-5 to 6-membered heteroaryl, -CH2NHSO2-C 1-6 alkyl, -CH2OC(=O)-4 to 8 membered heterocyclic group, -OC(=O)NR a R b , -OC(=O)-4 to 8 membered heterocyclyl and -CH2-4 to 8 membered heterocyclyl, wherein the heterocyclyl of the -CH2-4 to 8 membered heterocyclyl is optionally substituted with one or more oxo groups; m2 is 0, 1 or 2; Q, R a , R b As defined in claim 1; Preferably, m2 is 0.

17. A compound according to any one of claims 1 to 16, or a 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 general formula (I) 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 condensation agent and an alkaline agent, compound Ie is subjected to a condensation reaction with compound If 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, Among them, the condensation reagent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline reagent is preferably N-methylimidazole; in, Ring A1, Ring A2, R 1 , R 2 , R 3 , m1, m2, X 1 , X 2 As defined in claim 2.

19. A method for preparing a compound represented by general formula (IA) 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 condensation agent and an alkaline agent, compound Ie is subjected to a condensation reaction with compound IAF to obtain a compound represented by general formula (IA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, Among them, the condensation reagent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline reagent is preferably N-methylimidazole; in, Ring A1, Ring A2, R 1 , R 2 , R 3 , R 12 , m1, m2, m4, X 1 , X 2 As defined in claim 1.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. Use of a compound 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 20 in the preparation of a PRMT5 inhibitor.

22. Use of a compound 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 20 in the preparation of a medicament for preventing and / or treating a disease associated with PRMT5 activity.

23. The use according to claim 22, wherein the disease associated with PRMT5 activity is a solid tumor, such as non-small cell lung cancer, mesothelial tumor, neurofibrosarcoma, pancreatic cancer.

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