Tricyclic derivative inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a tricyclic derivative inhibitor as well as a preparation method and application thereof. In particular, the invention relates to a tricyclic derivative compound, a preparation method thereof, a pharmaceutical composition containing the compound, and an application of the compound in treating cancers.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and specifically relates to a tricyclic derivative inhibitor and a preparation method and application thereof. Background Art

[0002] Protein arginase methyltransferases (PRMTs) are divided into three categories based on catalytic activity and product type: type I, type II, and type III. Type I mainly includes PRMT1 / 2 / 3 / 4 / 6 / 8, which catalyze the substrate to form asymmetric dimethylarginine (ADMA); type II includes PRMT5 / 9, which catalyzes the substrate to form symmetric dimethylarginine (SDMA); type III only includes PRMT7, which is responsible for catalyzing the substrate to form monomethylarginine (MMA). PRMT5 uses S-adenosyl-L-methionine (SAM) as a methyl donor to transfer methyl groups to substrates such as DNA, RNA, and histones. The arginine residues of the substrate undergo symmetrical dimethylation to generate SDMA, thereby regulating multiple key cellular processes, including transcription, translation, and DNA repair, maintaining cell homeostasis, and also participating in regulating the growth and survival pathways of tumor cells and promoting tumor occurrence and development. Increased expression of PRMT5 has also been shown to be associated with poor prognosis in a variety of cancers, making it a highly potential epigenetic target.

[0003] Methylthioadenosine phosphorylase (MTAP) catalyzes methylthioadenosine (MTA) to generate methionine, which is essential for maintaining normal cell function. The deletion mutation of the MTAP gene causes MTA to accumulate in cells. MTA competes with the substrate SAM of PRMT5, which reduces the activity of PRMT5 and produces a large number of PRMT5-MTA complexes. The deletion of the MTAP gene increases the dependence of tumors on PRMT5. Inhibiting PRMT5 can have a "synthetic lethal" effect in tumors with MTAP deletion. PARP inhibitors based on the "synthetic lethal" theory have achieved great success in the field of precision treatment of tumors. The MTAP gene is adjacent to the most common tumor suppressor gene CDKN2A in human cancers, and is often co-deleted with CDKN2A. This co-deletion accounts for 10%-15% of all cancers, mainly occurring in non-small cell lung cancer (12%-20%), glioma (53%), pancreatic cancer (30%), and DLBCL (20%), with huge market prospects.

[0004] Currently, there are no PRMT5 inhibitors on the market. Early PRMT5 inhibitors are non-selective substrate SAM competitive inhibitors, which have serious blood toxicity and side effects in clinical practice and a small safety window. The first-generation PRMT5 inhibitors GSK-3326595, JNJ-64619178 and PF-06939999 have not made good clinical progress. The new generation of PRMT5 inhibitors targeting the PRMT5-MTA complex are only effective against MTAP-deficient and MTA-enriched tumors, have high selectivity for wild-type MTAP, reduce blood toxicity from a mechanistic perspective, and have been verified in preclinical studies, which is expected to significantly increase the safety window.

[0005] This patent involves a new PRMT5-MTA selective inhibitor, which is only active against MTAP-deficient cells and has weak inhibition on MTAP wild-type cells, thus avoiding the side effects such as blood toxicity caused by the clinical inhibition of MTAP wild-type by non-selective PRMT5 inhibitors. As a new type of PRMT5-MTA inhibitor, highly selective PRMT5-MTA inhibitors can be used to treat various tumors, cancers and other diseases. Summary of the invention

[0006] The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) has the following structure:

[0007]

[0008] X is selected from C, N or O; M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -;

[0009] Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

[0010] Ring B is selected from C 8-14 Cycloalkyl, 8-14 membered heterocyclic group, C 9-14 Aryl or 8-14 membered heteroaryl;

[0011] Ring C is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0012] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12 membered heterocyclic group, -(CH2) n1 -C 6-12 Aryl, -(CH2) n1 -5-12 membered heteroaryl, -(CH2) n1 OR c 、-(CH2) n1 NR c R d 、-(CH2) n1 C(O)R c 、-(CH2) n1 C(O)NR c R d 、-(CH2) n1 P(O)R c R d or =R c R d , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0013] Or any two R1 atoms are linked to their adjacent atoms to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0014] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -OR e 、-NR e R f 、-C(O)R e 、-C(O)NR e R f or -P(O)R e R f , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0015] R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -OR g 、-NR g R h 、-C(O)R g 、-C(O)NR g R h or -P(O)R g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0016] R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -OR g 、-NR g R h 、-C(O)R g 、-C(O)NR g R h or -P(O)R g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0017] R a , R b , R c , R d , R e , R f , R g and R h are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0018] x is selected from 0, 1, 2, 3, 4, 5 or 6; y is selected from 0, 1, 2, 3, 4, 5 or 6;

[0019] z is selected from 0, 1, 2, 3, 4, 5 or 6; p is selected from 0, 1, 2, 3, 4, 5 or 6; and

[0020] n1 is selected from 0, 1, 2, 3 or 4.

[0021] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, is characterized in that ring B is selected from naphthyl, benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl phenyl or 5-6 membered heteroaryl and 5-6 membered heteroaryl;

[0022] Ring B is preferred

[0023] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that ring C is selected from C 3-8 Cycloalkylphenyl, C 3-8 Cycloalkyl 5-8 membered heteroaryl, 3-8 membered heterocyclyl phenyl or 3-8 membered heterocyclyl 5-8 membered heteroaryl;

[0024] Ring C is preferred ·It is a spiro atom.

[0025] The present invention also provides a compound represented by general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0026]

[0027] M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -; M3 is selected from -N- or -CR 5e -;

[0028] Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0029] Ring D is selected from a saturated or unsaturated 3-8 membered heterocyclic group, a 5-12 membered spiro heterocyclic group, a 5-12 membered bridged heterocyclic group or a 5-12 membered fused heterocyclic group;

[0030] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -OR e 、-NR e R f 、-C(O)R e 、-C(O)NR e R f or -P(O)R e R f , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0031] R 5a , R 5b , R 5c , R 5d and R 5e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -OR j 、-NR j R k 、-C(O)R j 、-C(O)NR j R k or -P(O)R j R k , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0032] or R 5d and R 5e The atoms adjacent to it, R 5c and R 5d The atoms adjacent to it, R 5b and R 5c The adjacent atoms or R 5a and R 5b Each of its neighboring atoms independently links to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0033] R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n2 -C 3-12 Cycloalkyl, -(CH2) n2 -3-12 membered heterocyclic group, -(CH2) n2 -C 6-12 Aryl, -(CH2) n2 -5-12 membered heteroaryl, -(CH2) n2 OR m 、-(CH2) n2 NR m R n 、-(CH2) n2 C(O)R m 、-(CH2) n2 C(O)NR m R n 、-(CH2) n2 P(O)R m R n or =R m R n , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0034] R a , R b , R e , R f , R j , R k , R m and R n are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0035] y is selected from 0, 1, 2, 3, 4, 5 or 6; q is selected from 0, 1, 2, 3, 4, 5 or 6; and n2 is selected from 0, 1, 2, 3 or 4.

[0036] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that:

[0037] Ring D is selected from

[0039] The present invention also provides a compound represented by general formula (III) or (III-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0040]

[0041] M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -;

[0042] Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0043] Ring E is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; preferably 3-6 membered heterocyclic group;

[0044] Ring F is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; preferably C 3-8 Cycloalkylphenyl, C 3-8Cycloalkyl 5-8 membered heteroaryl, 3-8 membered heterocyclyl phenyl or 3-8 membered heterocyclyl 5-8 membered heteroaryl;

[0045] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -OR e 、-NR e R f 、-C(O)R e 、-C(O)NR e R f or -P(O)R e R f , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0046] R7 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n4 -C 3-12 Cycloalkyl, -(CH2) n4 -3-12 membered heterocyclic group, -(CH2) n4 -C 6-12 Aryl, -(CH2) n4 -5-12 membered heteroaryl, -(CH2) n4 OR o 、-(CH2) n4 NR o R p 、-(CH2) n4 C(O)R o 、-(CH2) n4 C(O)NR o R p or -(CH2) n4 P(O)R o R p , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0047] R8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -OR u 、-NR u R v 、-C(O)R u 、-C(O)NR u R v or -P(O)R u R v , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0048] R a , R b , R e , R f, R o , R p , R u and R v are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0049] y is selected from 0, 1, 2, 3, 4, 5 or 6; r is selected from 0, 1, 2, 3, 4, 5 or 6; s is selected from 0, 1, 2, 3, 4, 5 or 6; and n4 is selected from 0, 1, 2, 3 or 4.

[0050] The present invention also provides a compound represented by general formula (IV-A) or (IV-B), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0051]

[0052] M3 is selected from -N- or -CR 5e -;

[0053] Ring G is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; preferably C 6-10 Aryl, 5-10 membered nitrogen-containing heteroaryl, C 5-10 Cycloalkylphenyl, C 5-10 Cycloalkyl and 5-10 membered heteroaryl, 5-10 membered heterocyclyl and phenyl, 5-10 membered heterocyclyl and 5-10 membered heteroaryl, benzo 5-10 Cycloalkyl, benzo 5-10 membered heterocyclyl, benzo 5-10 membered heteroaryl, 5-10 membered heteroarylphenyl, 5-10 membered heteroarylphenyl, 5-10 membered heteroarylphenyl and 5-10 membered heteroaryl or 12-14 membered triphenylphenyl;

[0054] Ring H is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0055] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12 membered heterocyclic group, -(CH2) n1 -C 6-12 Aryl, -(CH2) n1 -5-12 membered heteroaryl, -(CH2) n1 OR c 、-(CH2) n1 NR c R d 、-(CH2) n1 C(O)R c 、-(CH2) n1 C(O)NR c R d 、-(CH2) n1 P(O)R cR d or =R c R d , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0056] Or any two R1 atoms are linked to their adjacent atoms to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents in aryl and 5-12 membered heteroaryl

[0057] R 5a , R 5b , R 5c , R 5d and R 5eare each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -OR j 、-NR j R k 、-C(O)R j 、-C(O)NR j R k or -P(O)R j R k , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0058] or R 5d and R 5e The atoms adjacent to it, R 5c and R 5d The atoms adjacent to it, R 5b and R5c The adjacent atoms or R 5a and R 5b Each of its neighboring atoms independently links to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0059] R9 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -OR q 、-NR q R r 、-C(O)R q 、-C(O)NR q R r or -P(O)R q R r , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0060] R 10 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -OR q 、-NR q R r 、-C(O)R q 、-C(O)NR q R r or -P(O)R q R r , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0061] R c , R d , R j , R k , R q and R r are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0062] x is selected from 0, 1, 2, 3, 4, 5 or 6; u is selected from 0, 1, 2, 3, 4, 5 or 6; v is selected from 0, 1, 2, 3, 4, 5 or 6; and n1 is selected from 0, 1, 2, 3 or 4.

[0063] The present invention also provides a compound represented by the general formula (VA) or (VB), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0064]

[0065] M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -; M3 is selected from -N- or -CR 5e -;

[0066] Ring I is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0067] Ring J is selected from 5-membered heteroaryl; preferably pyrrolyl, pyrazolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl or triazolyl;

[0068] Ring K is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0069] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12 membered heterocyclic group, -(CH2) n1 -C 6-12 Aryl, -(CH2) n1 -5-12 membered heteroaryl, -(CH2) n1 OR c、-(CH2) n1 NR c R d 、-(CH2) n1 C(O)R c 、-(CH2) n1 C(O)NR c R d 、-(CH2) n1 P(O)R c R d or =R c R d , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0070] Or any two R1 atoms are linked to their adjacent atoms to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0071] R 5a , R 5b , R 5c , R 5d and R 5e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -OR j 、-NR j R k 、-C(O)R j 、-C(O)NR j R k or -P(O)R j R k , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0072] or R 5d and R 5e The atoms adjacent to it, R 5c and R 5d The atoms adjacent to it, R 5b and R 5c The adjacent atoms or R 5a and R 5b Each of its neighboring atoms independently links to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0073] R 11 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -OR s 、-NR s R t 、-C(O)R s 、-C(O)NR s R t or -P(O)R s R t , the amino group, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0074] R 12 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -OR s 、-NR s R t 、-C(O)R s 、-C(O)NR s R t or -P(O)R s R t , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0075] R a , R b , R c , R d , R j , R k , R s and R t are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0076] x is selected from 0, 1, 2, 3, 4, 5 or 6; a is selected from 0, 1, 2, 3, 4, 5 or 6; b is selected from 0, 1, 2, 3, 4, 5 or 6; and n1 is selected from 0, 1, 2, 3 or 4.

[0077] The present invention also provides a compound represented by general formula (VI) or (VI-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0078]

[0079] M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -; M3 is selected from -N- or -CR 5e -; M4 is selected from N or C; Ring A is selected from C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

[0080] Select from

[0081] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n1 -3-12 membered heterocyclic group, -(CH2)n1 -C 6-12 Aryl, -(CH2) n1 -5-12 membered heteroaryl, -(CH2) n1 OR c 、-(CH2) n1 NR c R d 、-(CH2) n1 C(O)R c 、-(CH2) n1 C(O)NR c R d 、-(CH2) n1 P(O)R c R d or =R c R d , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0082] Or any two R1 atoms are linked to their adjacent atoms to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0083] R 5a , R 5b , R 5c , R 5d and R 5e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -OR j 、-NR j R k 、-C(O)R j 、-C(O)NR j R k or -P(O)R j R k , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0084] or R 5d and R 5e The atoms adjacent to it, R 5c and R 5d The atoms adjacent to it, R 5b and R 5c The adjacent atoms or R 5a and R 5b Each of its neighboring atoms independently links to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0085] R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n3 OR x 、-(CH2)n3 NR x R y 、-(CH2) n3 C(O)R x 、-(CH2) n3 C(O)NR x R y or -(CH2) n3 P(O)R x R y , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0086] R 2c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n3 OR x 、-(CH2)n3 NR x R y 、-(CH2) n3 C(O)R x 、-(CH2) n3 C(O)NR x R y or -(CH2) n3 P(O)R x R y , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0087] R a , R b , R c , R d , R j , R k , R x and R y are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0088] x is selected from 0, 1, 2, 3, 4, 5 or 6; c is selected from 0, 1, 2, 3, 4, 5 or 6; and

[0089] n3 is selected from 0, 1, 2, 3 or 4.

[0090] The present invention also provides a compound represented by general formula (VII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0091]

[0092] M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -; M3 is selected from -N- or -CR 5e -;

[0093] Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0094] L1 is selected from a bond, -(CR aa R bb ) n7 -、-(CR aa R bb ) n7 O-、-(CR aa R bb ) n7 S-、-(CR aa R bb ) n7 C(O)-or-(CR aa R bb ) n7 NR cc -;

[0095] R 1a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl or =R x R y , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0096] Or, R 1a and R 5e The atoms adjacent to it, R 1a and R 5d The adjacent atoms or R 1a and R 5c Each of its neighboring atoms is linked to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0097] R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n3 OR x 、-(CH2) n3 NR x R y 、-(CH2) n3 C(O)R x 、-(CH2) n3 C(O)NR x Ry or -(CH2) n3 P(O)R x R y , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0098] R 2c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n3 OR x 、-(CH2) n3 NR x R y 、-(CH2) n3 C(O)R x 、-(CH2) n3 C(O)NR x Ry or -(CH2) n3 P(O)R x R y , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0099] R 5a , R 5b , R 5c , R 5d and R 5e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -OR j 、-NR j R k 、-C(O)R j 、-C(O)NR j Rk or -P(O)R j R k , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0100] Or, R 5d and R 5e The atoms adjacent to it, R 5c and R 5d The atoms adjacent to it, R 5b and R 5c The adjacent atoms or R 5a and R 5b Each of its neighboring atoms is linked to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0101] R a , R b , R x , R y , R j and R k are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0102] R aa , R bb and R ccare each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0103] or R aa and R bb Link Form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0104] x is selected from 0, 1, 2, 3, 4, 5 or 6; c is selected from 0, 1, 2, 3, 4, 5 or 6; n5 is selected from 0, 1, 2 or 3; n6 is selected from 0, 1, 2 or 3; and n7 is selected from 0, 1, 2 or 3.

[0105] The present invention also provides a compound represented by general formula (VIII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0106]

[0107] M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -;

[0108] Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

[0109] Ring M is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; preferably C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; more preferably C 3-6 Cycloalkylphenyl, C 3-6 Cycloalkyl 5-6 membered heteroaryl, 3-6 membered heterocyclyl phenyl or 3-6 membered heterocyclyl 5-6 membered heteroaryl;

[0110] L2 is selected from a bond, -(CR dd R ee ) n8 -、-(CR dd R ee ) n8 O-、-(CR dd R ee ) n8 S-、-(CR dd R ee ) n8 C(O)-、-(CR dd Ree ) n8 NR ff -、C 3-8 Cycloalkylene, 3-8 membered heterocyclylene, C 6-10 Arylene or 5-10 membered heteroarylene, the C 3-8 Cycloalkylene, 3-8 membered heterocyclylene, C 6-10 Arylene and 5-10 membered heteroarylene, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0111] R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n3 OR x 、-(CH2) n3 NR x R y 、-(CH2) n3 C(O)R x 、-(CH2) n3 C(O)NR x R y or -(CH2) n3 P(O)R x R y , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0112] R 2c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n3 OR x 、-(CH2) n3 NR x R y 、-(CH2) n3 C(O)R x 、-(CH2) n3 C(O)NR x R y or -(CH2) n3 P(O)R x R y , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0113] R 13 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0114] or two R on the same carbon atom 13 Substituents link to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0115] R a , R b , R x and R y are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0116] R dd , R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0117] x is selected from 0, 1, 2, 3, 4, 5 or 6; d is selected from 0, 1, 2, 3, 4, 5 or 6; n8 is selected from 0, 1, 2 or 3.

[0118] The present invention also provides a compound represented by general formula (IX), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0119]

[0120] M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -; M4 is selected from C or N;

[0121] Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0122] Ring I is selected from 6-20 membered tricyclic heterocyclic group; preferably 6-15 membered tricyclic fused heterocyclic group or 6-15 membered tricyclic monospiro heterocyclic group;

[0123] R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n3 ORx 、-(CH2) n3 NR x R y 、-(CH2) n3 C(O)R x 、-(CH2) n3 C(O)NR x R y or -(CH2) n3 P(O)R x R y , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0124] R 2c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n3 ORx 、-(CH2) n3 NR x R y 、-(CH2) n3 C(O)R x 、-(CH2) n3 C(O)NR x R y or -(CH2) n3 P(O)R x R y , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0125] R 14 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -C(O)R m、-S(O) m1 R m 、-C(O)NR m R n or -SF5, the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR p R q is substituted by one or more substituents;

[0126] R m , R n , R x and R y are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0127] R p and R q are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0128] x is selected from 0, 1, 2, 3, 4, 5 or 6; e is selected from 0, 1, 2, 3, 4, 5 or 6; m1 is selected from 0, 1 or 2; n3 is selected from 0, 1, 2 or 3.

[0129] Another object of the present invention is to provide a compound represented by general formula (A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0130]

[0131] X1 is selected from C or N; X2 is selected from C or N; X3 is selected from CR c or N; X4 is selected from CR d or N;

[0132] Ring A-1 is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0133] Ring B-1 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0134] Ring C-1 is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0135] L 2-1 Select from key, C 2-6 Alkenylene, C 2-6 Alkyne, -(CR aa R bb ) n1 -、-NR cc -、-C(O)-、-NR cc C(O)-、-C(O)NR cc-、-C(O)NR aa NR bb -、-C(O)N=N-、-NR cc C(O)-C 1-3 Alkylene-, -C(O)NR cc -C 1-3 Alkylene-, -S(O) m1 -、-NR cc S(O) m1 -or-S(O) m1 NR cc -;

[0136] R 1-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0137] R2-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0138] R 3-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -N=S(O)R a1 R a2 、-S(O)R a1 =NR a2 、-P(O)R a1 R a2 or =CR a1 R a2 , optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =CR e R f and-(CR e R f ) n2 -C≡CR g is substituted by one or more substituents, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0139] Or any two R 3-1 Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0140] R 4-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -N=S(O)R b1 R b2 、-S(O)Rb1 =NR b2 、-P(O)R b1 R b2 、-C(O)NR b1 R b2 or =CR b1 R b2 , optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0141] R c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-amino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0142] R d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-amino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0143] R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-amino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0144] R g is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-amino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0145] R a1 and R a2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0146] R b1 and R b2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0147] R aa is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0148] R bb is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0149] or R aa and R bb Link Form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0150] R cc is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12aryl and 5-12 membered heteroaryl are substituted with one or more substituents, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl and 5-12 membered heteroaryl substituents are optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0151] x-1 is selected from 0, 1, 2, 3 or 4; y-1 is selected from 0, 1, 2, 3, 4, 5 or 6; z-1 is selected from 0, 1, 2, 3, 4, 5 or 6; m1 is selected from 0, 1 or 2; n1 is selected from 0, 1, 2, 3 or 4; and

[0152] n2 is selected from 0, 1, 2, 3 or 4.

[0153] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, is characterized in that Ring A-1 is selected from a 3-8 membered heterocyclic group or a 5-6 membered heteroaryl group;

[0154] Best

[0155] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that: The structure is selected from

[0156] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that it is further a compound represented by general formula (AI), its stereoisomer or a pharmaceutically acceptable salt thereof:

[0157]

[0158] Ring B-1 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; preferably C 3-8 Cycloalkyl, C 6-14 fused cycloalkyl, 3-8 membered heterocyclic group, 6-14 membered fused heterocyclic group, C 6-12Aryl or 5-12 membered heteroaryl;

[0159] Ring C-1 is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0160] L 2-1 Select from key, C 2-6 Alkenylene, C 2-6 Alkyne, -(CR aa R bb ) n1 -、-NR cc -、-C(O)-、-NR cc C(O)-、-C(O)NR cc -、-NR cc C(O)-C 1-3 Alkylene-, -C(O)NR cc -C 1-3 Alkylene-, -S(O) m1 -、-NR cc S(O) m1 -or-S(O) m1 NR cc -;

[0161] R 3-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -N=S(O)R a1 Ra2 、-S(O)R a1 =NR a2 、-P(O)R a1 R a2 or =CR a1 R a2 , optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =CR e R f and-(CR e R f ) n2 -C≡CR g is substituted by one or more substituents;

[0162] Or any two R 3-1 Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0163] R 4-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -N=S(O)R b1 R b2 、-S(O)R b1 =NR b2 、-P(O)R b1 R b2 or =CR b1 R b2 , optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0164] R a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6Alkyl, -C(O)-amino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0165] R b , R c and R d are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-amino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0166] R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-amino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0167] R g is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-amino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0168] R aa is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0169] R bb is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0170] R cc is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl and 5-12 membered heteroaryl substituents are optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0171] y-1 is selected from 0, 1, 2, 3, 4, 5 or 6; z-1 is selected from 0, 1, 2, 3, 4, 5 or 6; m1 is selected from 0, 1 or 2; n1 is selected from 0, 1, 2, 3 or 4; and n2 is selected from 0, 1, 2, 3 or 4.

[0172] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that it is further a compound represented by general formula (A-II), its stereoisomer or a pharmaceutically acceptable salt thereof:

[0173]

[0174] R a-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents selected from aryl and 5-12 membered heteroaryl; R b-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl group and the 5- to 12-membered heteroaryl group may be substituted by one or more substituents.

[0175] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that it is further a compound represented by general formula (A-III), its stereoisomer or a pharmaceutically acceptable salt thereof:

[0176]

[0177] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, is characterized in that ring C-1 is selected from a 5-membered heterocyclic group, a 6-membered heterocyclic group or a 7-membered heterocyclic group; preferably pyrrolidinyl, furanyl, piperidinyl, pyranyl or morpholinyl;

[0178] More preferred

[0179] Alternatively, ring C is selected from C 3-6 Cycloalkyl, 5-7 membered heterocyclic group; preferably cyclopentyl, cyclohexyl, pyrrolidinyl, furyl, piperidinyl, pyranyl or morpholinyl;

[0180] More preferred

[0181] It indicates that the atom in ring C is connected to L2.

[0182] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that R 4-1is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -N=S(O)R b1 R b2 、-S(O)R b1 =NR b2 、-P(O)R b1 R b2 or =CR b1 R b2 , optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may be substituted by one or more substituents.

[0183] In a preferred embodiment of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt is characterized in that ring B is selected from 3-6 membered heterocyclic group, 6-10 membered fused heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably

[0185] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that R 3-1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -N=S(O)R a1 R a2 、-S(O)R a1 =NR a2 、-P(O)R a1 R a2 or =CR a1 R a2 , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =CR e R f and-(CRe R f ) n2 -C≡CR g is substituted by one or more substituents;

[0186] Or any two R3 atoms are linked to their adjacent atoms to form a C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0187] R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0188] R g is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may be substituted by one or more substituents.

[0189] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that L 2-1 Select from key, C 2-4 Alkenylene, C 2-4 Alkynylidene, -CH2-, -C(O)-, -C(O)NR cc -、-C(O)NR cc -C 1-3 Alkylene- or -S(O) m1 NR cc -;

[0190] R cc is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl are substituted with one or more substituents, wherein the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl substituents are optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl and cyano substituted C 1-3 The alkyl group is substituted with one or more substituents.

[0191] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that R c is preferably selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may be substituted by one or more substituents.

[0192] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that R d is preferably selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C6-10 The aryl group and the 5- to 10-membered heteroaryl group may be substituted by one or more substituents.

[0193] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound shown in any one of the embodiments, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0194] The present invention further relates to the use of the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of PRMT5 inhibitor drugs.

[0195] The present invention further relates to the use of the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating cancer, wherein the cancer is selected from MTAP-related cancers.

[0196] The present invention further relates to a method for preparing a method for treating cancer using a compound, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as shown in any embodiment, wherein the cancer is selected from MTAP-related cancers.

[0197] In some embodiments, the cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, lymphoma, non-Hodgkin lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colon cancer, colorectal cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung carcinoma or adenocarcinoma of the lung; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

[0198] The present invention also relates to a method for preventing and / or treating cancer, which comprises administering to a patient a therapeutically effective dose of a compound shown in any embodiment, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0199] The present invention also relates to a method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0200] In certain embodiments of the present invention, the weight percentage of the compound, its stereoisomer or pharmaceutically acceptable salt thereof in the pharmaceutical composition, calculated as free base, is 0.1% to 95%, preferably 90%, 85%, 80%, 75%, 70%, 60%, 50%.

[0201] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, preferably, further comprising a filler, optionally a disintegrant, or further comprising one or more of a glidant or a lubricant.

[0202] In certain embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0203] In certain embodiments of the present invention, the pharmaceutical composition, calculated as a free base, has a unit dose of 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0204] In certain embodiments of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt can be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and pharmaceutical compositions adjusted accordingly. In certain embodiments of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0205] In some embodiments, the method relates to the treatment of conditions such as lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, lymphoma, non-Hodgkin lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colon cancer, colorectal cancer, or bile duct cancer.

[0206] In some embodiments, the lung cancer is selected from non-small cell lung cancer, lung squamous cell carcinoma, or lung adenocarcinoma; and the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

[0207] Detailed description of the invention

[0208] Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Specifically, the terms used in the specification and claims have the following meanings.

[0209] The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, which may be optionally substituted with one or more substituents. In a specific embodiment, an alkyl group refers to a saturated aliphatic hydrocarbon group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 ) carbon atoms, or a straight-chain saturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. The straight chain C 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl". 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. 1-6The alkyl group contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) 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-ethylpentyl, 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, and the like. In one embodiment, the alkyl group is an optionally substituted alkyl group described elsewhere herein.

[0210] The term "alkylene" refers to a further substitution of a hydrogen atom of an alkyl group, wherein "alkyl" is as defined above. Non-limiting examples of "alkylene" include: methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-) or butylene (-(CH2)4-). In one embodiment, the alkylene group is an optionally substituted alkyl group described elsewhere herein.

[0211] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond and the carbon-carbon double bond can be located at any position within the alkenyl group, and the alkenyl group can be optionally substituted with one or more substituents. In a specific embodiment, the alkenyl group is a group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 The alkenyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl groups include: One of ordinary skill in the art will appreciate that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, groups having "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl described elsewhere herein.

[0212] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and the carbon-carbon triple bond can be located at any position within the alkynyl group, and the alkynyl group can be optionally substituted with one or more substituents. In a specific embodiment, the alkynyl group is a 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6 Alkynyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 Alkynyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group described elsewhere herein.

[0213] The term "cycloalkyl" refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic, polycyclic (two or more) cyclic group, which may be optionally substituted with one or more substituents. In a specific embodiment, the cycloalkyl ring contains 3 to 20 (C 3-20 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring contains 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) carbon atoms; it may contain one or more double bonds, but does not have a completely conjugated π electron system. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl or cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls and bridged cycloalkyls in one embodiment. In one embodiment, the cycloalkyl is an optionally substituted cycloalkyl described elsewhere herein or a cycloalkyl optionally fused to a heterocyclyl, aryl or heteroaryl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.

[0214] The term "spirocycloalkyl" refers to an aliphatic polycyclic group in which the single rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. In a specific embodiment, the spirocycloalkyl contains 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of shared spiro atoms between rings, spirocycloalkyl is divided into single spirocycloalkyl, double spirocycloalkyl or multi-spirocycloalkyl, and in one embodiment is single spirocycloalkyl and double spirocycloalkyl. In one embodiment, it is 4 yuan / 4 yuan, 3 yuan / 5 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spirocycloalkyl. In one embodiment, the spirocycloalkyl is an optionally substituted spirocycloalkyl described elsewhere herein. Non-limiting examples of spirocycloalkyl include:

[0215]

[0216] The term "fused cycloalkyl" refers to an 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. In a specific embodiment, the fused cycloalkyl contains 5 to 20 (C 5-20), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, in one embodiment, bicyclic or tricyclic, and further in one embodiment, 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. In one embodiment, the condensed cycloalkyl is an optionally substituted condensed cycloalkyl described elsewhere herein or a condensed cycloalkyl optionally fused to a heterocyclic group, an aryl group or a heteroaryl group. Non-limiting examples of condensed cycloalkyls include:

[0217]

[0218] The term "bridged cycloalkyl" refers to a full-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. In a specific embodiment, the bridged cycloalkyl contains 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic or tricyclic. In one embodiment, the bridged cycloalkyl is an optionally substituted bridged cycloalkyl described elsewhere herein. Non-limiting examples of bridged cycloalkyl include:

[0219]

[0220] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, wherein the nitrogen, phosphorus or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, the ring carbon atom may be optionally substituted by oxygen, but does not include the ring part of -OO-, -OS-, and the remaining ring atoms are carbon, which may contain one or more double bonds, but does not have a completely conjugated π electron system. In a specific embodiment, the heterocyclyl contains 3 to 20, 3 to 12, 3 to 8 or 3 to 6 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heterocyclyl contains 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10 or 7 to 11 ring atoms; in one embodiment, the heterocyclyl contains 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. The limiting examples of monocyclic heterocyclic radical include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl etc..Polycyclic heterocyclic radical includes spiro heterocyclic radical, condensed heterocyclic radical and bridge heterocyclic radical.In one embodiment, the heterocyclic radical is the optionally substituted described elsewhere herein, or the heterocyclic radical further and ring-connected with other cycloalkyl, heterocyclic radical, aryl and heteroaryl by any two or more atoms on the ring.

[0221] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the rings share one atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. In a specific embodiment, the spiro heterocyclyl contains 5 to 20, 6 to 15 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; according to the number of spiro atoms shared between rings, the spiro heterocyclyl is divided into a monospiro heterocyclyl, a bispiro heterocyclyl or a polyspiro heterocyclyl; monospiro heterocyclyl and bispiro heterocyclyl are preferred; in one embodiment, the spiro heterocyclyl is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiro heterocyclyl; in one embodiment, the spiro heterocyclyl is an optionally substituted spiro heterocyclyl described elsewhere herein; non-limiting examples of spiro heterocyclyls include:

[0222]

[0223] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which 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 heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a specific embodiment, the fused heterocyclic group is a heterocyclic group containing 5 to 20, 6 to 15 or 6 to 14 ring atoms, and in one embodiment contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; 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 group; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is a fused heterocyclic group that is optionally substituted or fused with a cycloalkyl, heterocyclic group, aryl or heteroaryl group as described elsewhere herein; non-limiting examples of fused heterocyclic groups include:

[0224]

[0225]

[0226] The term "bridged heterocyclic group" refers to a 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, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a specific embodiment, the bridged heterocyclic group contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group; preferably a bicyclic, tricyclic or tetracyclic group; in one embodiment, it is a bicyclic or tricyclic group; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:

[0227]

[0228] The term "tricyclic heterocyclic group" refers to a heterocyclic group having three rings in the system, wherein the three rings may be a paracyclic system, a spirocyclic system or a bridged ring system. In one embodiment, the tricyclic heterocyclic group is a system in which at least one of the three rings is a heterocyclic group, and the other two rings may be cycloalkyl, heterocyclic group, aryl or heteroaryl. The definitions of cycloalkyl, heterocyclic group, aryl or heteroaryl are as described above, and non-limiting examples thereof are preferably the following tricyclic heterocyclic groups:

[0229]

[0230] wait.

[0231] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group containing at least one conjugated π electron system, which may be optionally substituted by one or more substituents. In specific embodiments, the aryl group contains 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from a benzo 5-10 membered heteroaryl, a benzo 3-10 membered cycloalkyl, or a benzo 3-10 membered heterocyclyl. In one embodiment, the aryl group is selected from a benzo 5-6 membered heteroaryl, a benzo 3-6 membered cycloalkyl, or a benzo 3-6 membered heterocyclyl, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetralinyl),

[0232] The term "arylene group" refers to a divalent aromatic group formed by further replacing one hydrogen atom of an aryl group, wherein the arylene group is optionally substituted or unsubstituted, and the aryl group is as defined above.

[0233] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system containing at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S and N. In specific embodiments, the heteroaryl group contains 5 to 20, 5 to 15 or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl group contains 5 or 6 ring atoms; in specific embodiments, the heteroaryl group may further refer to a bicyclic, tricyclic or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated, partially unsaturated carbocyclic rings or rings containing one or more heteroatoms independently selected from O, S and N. In one embodiment, the heteroaryl group is selected from heteroaryl and 6-10 membered aryl, heteroaryl and 3-10 membered cycloalkyl or heteroaryl and 3-10 membered heterocyclyl; further in one embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl and 6-10 membered aryl, 5- or 6-membered heteroaryl and 3-6 membered cycloalkyl, 5- or 6-membered heteroaryl and 3-6 membered heterocyclyl, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms or sulfur atoms. Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothiophenyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl , indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl, acridinyl, benzindolyl, carbazolyl, bibenzofuranyl, phenanthrolinyl, phenanthridinyl, phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,

[0235] The term "heteroarylene" refers to a divalent heteroaryl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the heteroarylene group is optionally substituted or unsubstituted, and the heteroaryl group is as defined above.

[0236] The term "heteroalkyl" refers to a stable straight or branched chain, or cyclic hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (in one embodiment, one to three) heteroatoms selected from O, N, Si, and S, and wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. In one embodiment, the heteroatoms O, N, and S may be placed at any interior position of the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position (e.g., interior or terminal position) of the heteroalkyl group, including the position where the alkyl group is attached to the remainder of the molecule. Non-limiting examples thereof include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In a particular embodiment, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0237] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy. In one embodiment, the alkoxy is an optionally substituted alkoxy described elsewhere herein.

[0238] The term "alkylacyl" refers to a -C(O)-alkyl group, wherein alkyl is as previously defined.

[0239] The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein the definition of alkyl is the same as above. Non-limiting examples of the haloalkyl group include: trifluoromethyl, -CH2CF3,

[0240] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.

[0241] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0242] The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio or cyclohexylthio. In one embodiment, the alkylthio is an optionally substituted alkylthio described elsewhere herein.

[0243] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogens, wherein alkylthio is as defined above.

[0244] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, or butenylcarbonyl. In one embodiment, the alkenylcarbonyl is an optionally substituted alkenylcarbonyl described elsewhere herein.

[0245] The term "aminocarbonyl" refers to NH2-C(O)-.

[0246] The term "alkylaminocarbonyl" refers to an aminocarbonyl (NH2-C(O)-) group in which one or both of the two hydrogen atoms are replaced by alkyl groups, wherein the alkyl group has the same definition as above.

[0247] The term "alkylamino" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.

[0248] The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably in the specification.

[0249] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0250] The term "oxo" or "oxo" refers to =0.

[0251] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In a particular embodiment, one or more positions occupied by hydrogen in the compound may be enriched with deuterium and / or tritium. Such isotopically enriched analogs may be prepared from suitable isotopically labeled starting materials obtained from commercial sources or prepared by known literature procedures.

[0252] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, sulfhydryl, hydroxyl, nitro, cyano, azido, oxime, phosphate, oxo, thio, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkyloxy, cycloalkylthio, or heterocycloalkylthio.

[0253] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

[0254] "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.

[0255] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is linked.

[0256] "Substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable in one embodiment. In one embodiment. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent may be arbitrary on the basis of chemical realization. It goes without saying that the substituent is only in their possible chemical position, and those skilled in the art can determine (by experiment or theory) possible or impossible substitution without paying too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.

[0257] In this specification and the claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular, unless stated to the contrary.

[0258] "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.

[0259] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0260] "Stereoisomers" encompass all enantiomerically / diastereomerically / stereomerically pure and enantiomerically / diastereomerically / stereomerically enriched forms of the compounds of the invention.

[0261] "Stereomerically pure" refers to a composition comprising one stereoisomer of a compound and being substantially free of another stereoisomer of the compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of another stereoisomer of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of another stereoisomer of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of another stereoisomer of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of another stereoisomer of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of another stereoisomer of the compound.

[0262] "Stereoisomerically enriched" refers to a composition comprising greater than about 55%, greater than about 60%, greater than about 70%, or greater than about 80% by weight of one stereoisomer of a compound.

[0263] "Enantiomerically pure" refers to a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereomerically enriched composition of a compound having one chiral center.

[0264] "Optically active" and "enantiomeric activity" refer to a combination of molecules having an enantiomeric or diastereomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer, based on the total weight of the racemate.

[0265] When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule with respect to its chiral center. (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) of the optical rotation have nothing to do with the absolute configuration, R and S, of the molecule. DETAILED DESCRIPTION

[0266] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0267] Example

[0268] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0269] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0270] HPLC was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C 18 150×4.6 mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0271] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0272] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.2mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

[0273] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals and other companies.

[0274] Unless otherwise specified in the embodiments, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere. Argon atmosphere or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a volume of about 1L. Hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of about 1L. The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator. The hydrogenation reaction is usually evacuated, filled with hydrogen, and the operation is repeated 3 times. The microwave reaction uses a CEM Discover-S908860 microwave reactor.

[0275] Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0276] 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.

[0277] The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds include: A: n-hexane and ethyl acetate system, B: n-hexane and tetrahydrofuran 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.

[0278] The preparation of the compounds in the embodiments of the present invention is prepared by referring to the preparation steps of the following examples:

[0279] Example 1

[0280]

[0281] Step 1: 2-Carbonyl-1,2-dihydroquinoxaline-6-carboxylic acid methyl ester and 3-Carbonyl-3,4-dihydroquinoxaline-6-carboxylic acid methyl ester

[0282] Dissolve methyl 3,4-diaminobenzoate 1a (2 g, 12.04 mmol) in ethanol (50 mL), add ethyl glyoxylate (50% toluene solution) (5.04 M, 2.8 mL), replace nitrogen three times, and heat the reaction system to 90 ° C and stir for 3 hours. Cool to room temperature, filter, wash the filter residue with a small amount of ethyl acetate, and spin dry to obtain a mixture of methyl 2-carbonyl-1,2-dihydroquinoxaline-6-carboxylate 1b-1 and methyl 3-carbonyl-3,4-dihydroquinoxaline-6-carboxylate 1b-2 (1.80 g), yield: 73.2%. MS m / z (ESI): 205 [M+1]

[0283] Step 2: 4-Carbonyl-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester and 4-Carbonyl-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid methyl ester

[0284] A mixture of 2-carbonyl-1,2-dihydroquinoxaline-6-carboxylic acid methyl ester 1b-1 and 3-carbonyl-3,4-dihydroquinoxaline-6-carboxylic acid methyl ester 1b-2 (1.6 g, 7.84 mmol) was dissolved in N,N-dimethylformamide (20 mL), p-toluenesulfonylmethyl isocyanide (1.91 g, 9.80 mmol) and potassium carbonate (2.17 g, 15.67 mmol) were added, and the system was heated to 180 ° C in a microwave reactor for 10 minutes. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography with eluent system C to obtain a mixture of 4-carbonyl-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester 1c-1 and 4-carbonyl-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid methyl ester 1c-2 (0.30 g), yield: 31.5%. MS m / z (ESI): 244 [M+1]

[0285] Step 3: 4-chloroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester and 4-chloro-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid methyl ester

[0286] A mixture of 4-carbonyl-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester 1c-1 and 4-carbonyl-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid methyl ester 1c-2 (300 mg, 1.23 mmol) was dissolved in trichlorophosphine oxide (189 mg, 1.23 mmol, 5 mL), nitrogen was evacuated three times, and the reaction system was heated to 130°C and stirred for 2 hours. The system was cooled to room temperature and concentrated. The residue was poured into saturated sodium carbonate to quench, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of 4-chloroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester 1d-1 and 4-chloro-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid methyl ester 1d-2 (0.25 g, crude product). MS m / z(ESI):262[M+1]

[0287] Step 4: 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester and 4-((4-methoxybenzyl)amino)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid methyl ester

[0288] A mixture of 4-chloroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester 1d-1 and 4-chloro-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid methyl ester 1d-2 (0.20 g, 0.76 mmol) and potassium carbonate (317 mg, 2.29 mmol) were dissolved in N,N-dimethylformamide (5 mL), 4-methoxybenzylamine (210 mg, 1.53 mmol, 0.2 mL) was added, and the reaction system was heated in a microwave reactor at 120 ° C for 1.5 hours. The mixture was cooled to room temperature, filtered, concentrated, quenched with water, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography with eluent system A to obtain a mixture of methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 1e-1 and methyl 4-((4-methoxybenzyl)amino)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylate 1e-2 (0.15 g), yield: 54.2%. MS m / z (ESI): 363 [M+1]

[0289] Step 5: 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid and 4-((4-methoxybenzyl)amino)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid

[0290] A mixture of 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester 1e-1 and 4-((4-methoxybenzyl)amino)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid methyl ester 1e-2 (0.22 g, 0.61 mmol) and lithium hydroxide monohydrate (29 mg, 1.21 mmol) were dissolved in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL), and the reaction system was heated to 50° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature, concentrated, and the pH was adjusted to about 5-6 with 2M hydrochloric acid, filtered, and the residue was washed with a small amount of water and petroleum ether, and the residue was dried to obtain a mixture of 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid 1f-1 and 4-((4-methoxybenzyl)amino)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid 1f-2 (0.11 g, crude product). MS m / z(ESI):349[M+1]

[0291] Step 6: (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone and (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxalin-7-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[0292] A mixture of 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid 1f-1 and 4-((4-methoxybenzyl)amino)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid 1f-2 (108 mg, 0.31 mmol), 3-(4-(trifluoromethyl)phenyl)morpholine (60 mg, 0.26 mmol, and a mixture of 1f-1 and 1f-2 (108 mg, 0.31 mmol) and 3-(4-(trifluoromethyl)phenyl)morpholine (60 mg, 0.26 mmol) were prepared by a known method “Chemical Science, 2019, vol. 10, # 41, p. 9591-9596”), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (117.48 mg, 311.40 μmol) was dissolved in N, N-dimethylformamide (6 mL), N, N-diisopropylethylamine (134 mg, 1.04 mmol, 0.18 mL) was added, nitrogen was replaced three times, and the reaction system was stirred at 25 ° C for 12 hours. The reaction was quenched with water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent System C to give (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 1h-1 (15 mg, white solid) in a yield of 10.3%; and (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxalin-7-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 1h-2 (40 mg) in a yield of 27.5%. MS m / z(ESI):562[M+1]

[0293] Step 7: (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[0294] (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 1h-1 (15 mg, 27 μmol) was dissolved in trifluoroacetic acid (3 mL), nitrogen was purged three times, and the reaction system was heated to 80°C for 12 hours. After cooling to room temperature, it was concentrated. The residue was purified by silica gel column chromatography with eluent system C to give (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-7-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 1-1 (5 mg) in a yield of 50.7%. MS m / z(ESI):442[M+1]

[0295] 1H NMR(400MHz,DMSO)δ9.11(s,1H),8.23(d,1H),7.84(s,1H),7.76-7.56(m,4H) ,7.45-7.28(m,4H),5.54(s,1H),4.43(d,1H),3.87(d,1H),3.79-3.48(m,3H).

[0296] Step 8: 4-aminoimidazo[1,5-a]quinoxaline-7-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[0297] Referring to the synthesis method of the seventh step of Example 1, (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-7-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 1h-2 (40 mg, 71 μmol) was used to obtain (4-aminoimidazo[1,5-a]quinoxaline-7-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 1-2 (24 mg), yield: 76%. MSm / z(ESI):442[M+1]

[0298] 1 H NMR(400MHz,DMSO)δ9.12(s,1H),8.22(d,1H),7.91(s,1H),7.79(d,2H),7.42(d,3H),7.3 0(d,1H),5.70(s,1H),4.49(s,1H),3.93(dd,1H),3.80(d,1H),3.60(t,2H),3.18(s,1H).

[0299] Example 2

[0300]

[0301] Step 1: 1-(3-(4-(trifluoromethyl)phenyl)morpholine)propyl-2-yn-1-one

[0302] 3-(4-(Trifluoromethyl)phenyl)morpholine 2a (2 g, 8.66 mmol, synthesized by the known method "Chemical Science (2021), 12 (20), 6977-6982") and N,N'-dicyclohexylcarbodiimide (2.06 g, 10 mmol) were dispersed in 50 mL of dichloromethane, and propiolic acid 2b (700 mg, 10 mmol) was added dropwise at 0°C, and the mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 1-(3-(4-(trifluoromethyl)phenyl)morpholine)propyl-2-yn-1-one 2c (1.72 g), with a yield of 69.9%. MS m / z (ESI): 284 [M+1]

[0303] Step 2: 3-(4-amino-1,3-dihydrofuran[3,4-c]pyridin-7-yl)-1-(3-(4-trifluoromethylphenyl)morpholine)propyl-2-yn-1-one

[0304] 1-(3-(4-(trifluoromethyl)phenyl)morpholine)propyl-2-yn-1-one 2c (100 mg, 0.35 mmol) and 7-bromo-1,3-dihydrofuran[3,4-c]pyridin-4-amine 2d (75 mg, 0.35 mmol, synthesized by the known method "Patent CN105461714 A") were dispersed in 5 mL of tetrahydrofuran and 5 mL of triethylamine, and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and cuprous iodide (4 mg, 0.02 mmol) were added. The reaction was stirred at 70°C for 12 hours under a nitrogen atmosphere. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 6-ethyl-2-methyl-2,6-dihydropyrrolo[2,3-c]pyrazole 2 (45 mg) with a yield of 30.6%. MS m / z(ESI):418[M+1]

[0305] Example 3

[0306]

[0307] Step 1: 5-(4-methoxybenzyl)-2-oxa-5-azabicyclo[2.2.1]hept-1(6)-en-6-yl trifluoromethanesulfonic acid

[0308] Potassium bis(trimethylsilyl)amide (10.3 mL, 5.14 mmol, 0.5 M in toluene) was placed in a reaction bottle, nitrogen was replaced three times, and the reaction was cooled to -78°C. 5-(4-methoxybenzyl)-2-oxa-5-azabicyclo[2.2.1]heptane-6-one 3a (1 g, 4.29 mmol, synthesized by the known method "Organic Letters, 2016, vol.18, #21, p.5748-5751") was dissolved in 10 mL of tetrahydrofuran and added dropwise to the system. The reaction was carried out at -78°C for 1.5 hours. N-phenylbis(trifluoromethanesulfonyl)imide (1.84 g, 5.14 mmol) was dissolved in 10 mL of tetrahydrofuran and added dropwise to the system. The reaction was carried out at -78°C for 1 hour, the temperature was naturally raised to room temperature, and the reaction was carried out for 1 hour. 20 mL of 10% sodium hydroxide solution was added to quench, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain 5-(4-methoxybenzyl)-2-oxa-5-azabicyclo[2.2.1]hept-1(6)-en-6-yltrifluoromethanesulfonic acid 3b (900 mg), yield: 57.5%. MS m / z (ESI): 366 [M+1]

[0309] Step 2: 5-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-oxa-5-azabicyclo[2.2.1]hept-1(6)-ene

[0310] -(4-Methoxybenzyl)-2-oxa-5-azabicyclo[2.2.1]hept-1(6)-en-6-yl trifluoromethanesulfonic acid 3b (0.70 g, 1.92 mmol), bipyraclostrobin (0.73 g, 2.87 mmol), potassium carbonate (0.80 g, 5.75 mmol) and bistriphenylphosphine palladium dichloride (134 mg, 0.19 mmol) were dissolved in 10 mL of 1,4-dioxane, nitrogen was replaced three times, and the system was heated to 90 ° C for 16 hours. 20 mL of water was added to quench, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give 5-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-oxa-5-azabicyclo[2.2.1]hept-1(6)-ene 3c (350 mg). Yield: 53.2%. MS m / z(ESI):344[M+1]

[0311] Step 3: 5-(4-methoxybenzyl)-6-(5-(trifluoromethyl)pyridin-2-yl)-2-oxa-5-azabicyclo[2.2.1]hept-1(6)-ene

[0312] 5-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-oxa-5-azabicyclo[2.2.1]hept-1(6)-ene 3c (0.30 g, 0.87 mmol), 2-bromo-5-(trifluoromethyl)pyridine (198 mg, 0.87 mmol), cesium hydroxide (262 mg, 1.75 mmol) and tetrakistriphenylphosphine palladium (101 mg, 0.09 mmol) were dissolved in 10 mL of 1,4-dioxane, nitrogen was replaced three times, and the system was heated to 90 ° C for 16 hours. 10 mL of water was added to quench, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give 5-(4-methoxybenzyl)-6-(5-(trifluoromethyl)pyridin-2-yl)-2-oxa-5-azabicyclo[2.2.1]hept-1(6)-ene 3d (230 mg). Yield: 72.6%. MSm / z(ESI):363[M+1]

[0313] Step 4: 6-(5-(trifluoromethyl)pyridin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0314] 5-(4-methoxybenzyl)-6-(5-(trifluoromethyl)pyridin-2-yl)-2-oxa-5-azabicyclo[2.2.1]hept-1(6)-ene 3d (0.20 g, 0.55 mmol) and 10% palladium hydroxide on carbon (39 mg, 27 umol) were dissolved in 5 mL of ethanol, and the hydrogen was replaced three times. The system was heated to 50 ° C for 15 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 6-(5-(trifluoromethyl)pyridin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane 3e (110 mg), yield: 81.6%. MS m / z (ESI): 245 [M+1]

[0315] Step 5: (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(6-(5-(trifluoromethyl)pyridin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)methanone

[0316] Reference Example 1 The synthesis method of the sixth step was used, and 6-(5-(trifluoromethyl)pyridin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane 3e (50 mg, 0.20 mmol) and 4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid 3f (47 mg, 0.20 mmol, synthesized by the known method "Patent WO22022192745") were used to obtain the title product (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(6-(5-(trifluoromethyl)pyridin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)methanone 3 (18 mg) with a yield of 19.3%. MS m / z(ESI):457[M+1]

[0317] Example 4

[0318]

[0319] Example 5

[0320]

[0321] Step 1: 8-Oxa-2,5-diaza[3.5]nonane-5-carboxylic acid tert-butyl ester

[0322] 8-Oxa-2,5-diaza[3.5]nonane 5a (1 g, 7.8 mmol), Boc2O (1.7 g, 7.8 mmol), DMAP (114.35 mg, 0.936 mmol) and THF (20 mL) were stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give tert-butyl 8-oxa-2,5-diaza[3.5]nonane-5-carboxylate 5b (780 mg) in a yield of 43.8%.

[0323] Step 2: tert-Butyl 2-(4-(trifluoromethyl)phenyl)-8-oxa-2,5-diaza[3.5]nonane-5-carboxylate

[0324] 8-Oxa-2,5-diaza[3.5]nonane-5-carboxylic acid tert-butyl ester 5b (780 mg, 3.42 mmol, 1-fluoro-4-(trifluoromethyl)benzene (560.69 mg, 3.42 mmol), Cs2CO3 (2.23 g, 6.84 mmol) were dissolved in 10 mL DMSO solvent and stirred at 80°C for 12 hours. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-oxa-2,5-diaza[3.5]nonane-5-carboxylate 5c (816 mg) in a yield of 65.4%. MS m / z (ESI): 373 [M+1]

[0325] Step 3: 2-(4-(trifluoromethyl)phenyl)-8-oxa-2,5-diaza[3.5]nonane 2-(4-(trifluoromethyl)phenyl)-8-oxa-2,5-diaza[3.5]nonane-5-carboxylic acid tert-butyl ester 5c (816 mg, 2.19 mmol) was dissolved in 5 mL TFA and stirred at room temperature for 1 hour. The reaction solution was directly concentrated and dried to give the crude product 2-(4-(trifluoromethyl)phenyl)-8-oxa-2,5-diaza[3.5]nonane 5d (620 mg, crude product). MS m / z(ESI):273[M+1]

[0326] Reference Example 1 The synthesis method of step 6 was used to obtain the title product (4-amino-1,3-dihydrofuran[3,4-c]quinolin-8-yl)(2-(4-(trifluoromethyl)phenyl)-8-oxa-2,5-diaza[3.5]nonane 5d (310 mg, 1.10 mmol) and 4-amino-1,3-dihydrofuran[3,4-c]quinoline-8-carboxylic acid 5e (252.0 mg, 1.10 mmol, synthesized by the known method "Patent WO22022132914") (52.8 mg) with a yield of 10.0%. MS m / z (ESI): 485 [M+1]

[0327] Example 6

[0328]

[0329] Step 1: tert-Butyl 3-((2-bromo-5-(trifluoromethyl)phenyl)carbamoyl)azetidine-1-carboxylate

[0330] 1-(tert-Butoxycarbonyl)azetidine-3-carboxylic acid 6a (4.2 g, 20.87 mmol), 2-bromo-5-(trifluoromethyl)aniline 6b (5 g, 20.83 mmol), dissolved in 50 mL of dichloromethane, then added with pyridine (3.4 g, 42.44 mmol) and phosphorus oxychloride (7.8 g, 50.87 mmol), stirred at 20°C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain tert-butyl 3-((2-bromo-5-(trifluoromethyl)phenyl)carbamoyl)azetidine-1-carboxylate 6c (5.8 g), yield: 65.8%. MS m / z (ESI): 423 [M+1]

[0331] Step 2: tert-Butyl 3-((2-bromo-5-(trifluoromethyl)phenyl)(methyl)carbamoyl)azetidine-1-carboxylate

[0332] 3-((2-bromo-5-(trifluoromethyl)phenyl)carbamoyl)azetidine-1-carboxylic acid tert-butyl ester 6c (5.8 g, 13.70 mmol) was dissolved in 50 mL of tetrahydrofuran, followed by addition of cesium carbonate (6.7 g, 20.56 mmol) and iodomethane (3 g, 21.14 mmol), and stirred at 20°C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give 3-((2-bromo-5-(trifluoromethyl)phenyl)(methyl)carbamoyl)azetidine-1-carboxylic acid tert-butyl ester 6d (5 g), yield: 83.4%. MS m / z (ESI): 437 [M+1]

[0333] Step 3: tert-Butyl 1'-methyl-2'-carbonyl-6'-(trifluoromethyl)spiro[azetidin-3,3'-dihydroindole]-1-carboxylate

[0334] 3-((2-bromo-5-(trifluoromethyl)phenyl)(methyl)carbamoyl)azetidine-1-carboxylic acid tert-butyl ester 6d (5 g, 11.43 mmol) was dissolved in 50 mL of toluene, followed by the addition of 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene](3-chloropyridine)palladium dichloride (0.777 g, 1.143 mmol) and sodium tert-butoxide (2.032 g, 21.14 mmol), and the mixture was stirred at 100°C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give tert-butyl 1'-methyl-2'-carbonyl-6'-(trifluoromethyl)spiro[azetidine-3,3'-dihydroindole]-1-carboxylate 6e (1.1 g) in a yield of 27.0%. MS m / z (ESI): 357 [M+1]

[0335] Step 4: 1'-Methyl-6'-(trifluoromethyl)spiro[azetidin-3,3'-dihydroindole]-2'-one

[0336] 1'-Methyl-2'-carbonyl-6'-(trifluoromethyl)spiro[azetidin-3,3'-dihydroindole]-1-carboxylic acid tert-butyl ester 6e (1.1 g, 3.087 mmol) was dissolved in 50 mL of dioxane hydrochloride (4 M) and stirred at 30°C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure to obtain 1'-methyl-6'-(trifluoromethyl)spiro[azetidin-3,3'-dihydroindole]-2'-one 6f (700 mg), 88.5%. MS m / z (ESI): 257 [M+1]

[0337] Referring to the synthesis method of the sixth step of Example 1, 1'-methyl-6'-(trifluoromethyl)spiro[azetidin-3,3'-dihydroindole]-2'-one 6f (100 mg, yellow solid) was used to obtain the title product 1-(4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carbonyl)-1'-methyl-6'-(trifluoromethyl)spiro[azetidin-3,3'-dihydroindole]-2'-one 6 (30 mg), yield: 16.4%. MS m / z (ESI): 469 [M+1]

[0338] Example 7

[0339]

[0340] Referring to the synthesis method of the second to fourth steps of Example 5, 4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(5-(4-(trifluoromethyl)phenyl)-2,5-diazaspiro[3.4]octan-2-yl)methanone 7 (60 mg) was obtained from tert-butyl 2,5-diazaspiro[3.4]octane-2-carboxylate 7a (200 mg, 0.94 mmol), yield: 13.2%. MS m / z (ESI): 469 [M+1]

[0341] 1 H NMR(400MHz,DMSO)δ8.05(d,1H),7.98(s,1H),7.77(d,1H),7.58(d,2H),6.94(d,2H),5.48(s,2H),5.09(d,2H ),4.94(d,1H),4.64(d,1H),4.28(d,1H),4.11(d,1H),3.40(d,3H),2.92(s,1H),2.35(dd,2H),1.86(dd,2H).

[0342] Example 8

[0343]

[0344] With reference to the synthesis method of the sixth step of Example 1, 6-(4-trifluoromethylphenyl)octahydro-1H-pyrrolo[2,3-c]pyridine 8a (65 mg, 0.24 mmol, synthesized by the known method "Patent WO201721920") and 4-amino-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid (46 mg, 0.20 mmol, synthesized by the known method "Patent WO2022132914") were used to obtain the title product (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(6-(4-trifluoromethylphenyl)octahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl ketone 8 (34 mg), yield: 35.1%. MS m / z(ESI):483[M+1]

[0345] Example 9

[0346]

[0347] Step 1: (E)-1-Benzothiazol-6-yl-N-(2-(tributylstannyl)methoxy)ethyl)methylamine

[0348] Benzothiazole-6-carboxaldehyde 9b (350 mg, 2.14 mmol) was added to the reaction flask, and dichloromethane (15 mL) was added. Molecular sieves (1.6 g, 2.14 mmol), 2-((tributyltinyl)methoxy)ethane-1-amine 9a (710.1 mg, 1.95 mmol, synthesized by a known method in the literature "Organic Letters, 2014, 16 (4), 1236-1239"), stirred at 25 ° C for 17 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain (E)-1-benzothiazol-6-yl-N-(2-(tributyltinyl)methoxy)ethyl)methylamine 9c (625 mg), yield: 63.0%. MS m / z (ESI): 509.3 [M+1]

[0349] Step 2: 3-(Benzothiazol-6-yl)morpholine

[0350] Copper trifluoromethanesulfonate (38.2 mg, 0.11 mmol), (4S,4'S)-2,2'-(propane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole) (17.6 mg, 0.05 mmol), (4R,4'R)-2,2'-(propane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole) (17.6 mg, 0.05 mmol) and 5 mL of hexafluoroisopropanol were added to a reaction flask and stirred at 25° C. for 7 hours; (E)-1-benzothiazol-6-yl-N-(2-(tributylstannyl)methoxy)ethyl)methylamine 9c (269 mg, 1.25 mmol) was added, and the reaction system was replaced with nitrogen for 10 minutes. Under nitrogen protection, The reaction was stirred at 25°C for 16 hours; 30% ammonia solution and saturated brine (1:1, 10 mL) were added to the reaction solution to quench and stirred vigorously at 25°C for 1 hour; dichloromethane extraction (20 mL) and saturated brine (20 mL) were added, and the aqueous layer was extracted with dichloromethane extraction (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A, and the residue was purified by silica gel column chromatography with eluent system D (the crude residue was purified by flash chromatography (0-100%, 3:1=ethyl acetate:ethanol) to obtain 3-(benzothiazol-6-yl)morpholine 9d (70.0 mg), yield: 60.0%. MS m / z (ESI): 220.4 [M+1]

[0351] Step 3: (4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(3-(benzothiazol-6-yl)morpholinyl)methanone

[0352] With reference to the fifth step of Example 3, 3-(benzothiazol-6-yl)morpholine 9d (609 mg, 0.27 mmol) and 4-amino-1,3-dihydrofuran [3,4-c]quinoline-8-carboxylic acid 9e (69 mg, 0.30 mmol, synthesized by the known method "Patent WO2022132914 (A1)") were used to obtain the title product 9 (4-amino-1,3-dihydrofuran [3,4-c]quinoline-8-yl) (3-(benzothiazol-6-yl)morpholine)methanone (20 mg), yield: 16.9%. MS m / z (ESI): 432.5 [M+1]

[0353] Example 10

[0354]

[0355] Step 1: 4-amino-2-methyl-2H-[1,2,3]triazolo[4,5-c]quinoline-8-carboxylic acid methyl ester

[0356] 4-Amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester 10a (1.56 g, 5.61 mmol, obtained by the known method "WO2022 / 132914"), 5-chloro-2-methyl-2H-1,2,3-triazole-4-carbonitrile (1.00 g, 7.02 mmol, obtained by the known method "Chemistry of Heterocyclic Compounds, 1988, p.756) were used. -759" obtained), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (551 mg, 0.70 mmol), potassium phosphate (5.96 g, 28.06 mmol) were dissolved in 20 mL of 1,4-dioxane and 4 mL of water mixed solvent, nitrogen was replaced three times, and the system was heated to 90 ° C and stirred for 16 hours. Cooled to room temperature, filtered, the filter residue was washed with a small amount of ethyl acetate, and dried to obtain 4-amino-2-methyl-2H-[1,2,3]triazolo[4,5-c]quinoline-8-carboxylic acid methyl ester 10b (1.20 g), yield: 83.2%. MS m / z (ESI): 258 [M+1]

[0357] Step 2: 4-amino-2-methyl-2H-[1,2,3]triazolo[4,5-c]quinoline-8-carboxylic acid 4-amino-2-methyl-2H-[1,2,3]triazolo[4,5-c]quinoline-8-carboxylic acid methyl ester 10b (0.30 g, 1.17 mmol) was dissolved in a mixed solvent of 2 mL methanol, 2 mL tetrahydrofuran and 2 mL water, and lithium hydroxide (42 mg, 1.75 mmol) was added. The system was heated to 50 °C and stirred for 5 hours. Cooled to room temperature, concentrated, 3M HCl solution was added to adjust the pH to 5, filtered, the filter cake was washed with water and petroleum ether, and the filtrate was concentrated to dryness to obtain 4-amino-2-methyl-2H-[1,2,3]triazolo[4,5-c]quinoline-8-carboxylic acid 10c (0.20 g), yield: 70.5%. MS m / z (ESI): 244 [M+1]

[0358] Step 3: (2-methyl-2H-[1,2,3]triazolo[4,5-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[0359] 4-Amino-2-methyl-2H-[1,2,3]triazolo[4,5-c]quinoline-8-carboxylic acid 10c (70 mg, 0.29 mmol), 3-(4-(trifluoromethyl)phenyl)morpholine (67 mg, 0.29 mmol, obtained by the known method "Chemical Science, 2019, vol.10, #41, p.9591-9596"), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (130 mg, 0.35 mmol) were dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (149 mg, 1.15 mmol) was added, nitrogen was replaced three times, and the system was stirred at 25 ° C for 2 hours. The reaction was quenched with water, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography with eluent system C to obtain 4-amino-2-methyl-2H-[1,2,3]triazolo[4,5-c]quinoline-8-carboxylic acid 10c (38 mg), yield: 28.7%. MS m / z(ESI):457[M+1]

[0360] 1 H NMR(400MHz,DMSO)δ9.21(s,2H),8.21(d,1H),7.84-7.65(m,6H),5.47(s,1H),4.58 (s,3H),4.45(d,1H),3.98(dd,1H),3.82(dd,2H),3.67-3.60(m,1H),3.26(ddd,1H).

[0361] Embodiment 11

[0362]

[0363] Referring to the synthesis method of the first to third steps of Example 10, (4-amino-2H-[1,2,3]triazolo[4,5-c]quinolin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 11 (25 mg) was obtained by 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester 11a (2.80 g, 10.12 mmol, obtained by the known method "WO2022 / 132914") and 5-chloro-1H-1,2,3-triazole-4-carbonitrile (1.30 g, 10.12 mmol, obtained by the known method "Chemistry of Heterocyclic Compounds, 1983, p.1113-1115"), yield: 0.56%. MS m / z (ESI): 443 [M+1]

[0364] 1 H NMR(400MHz,DMSO)δ8.25(d,1H),7.80-7.69(m,4H),7.67(d,1H),7.61(dd,1H),7.51(s,2H)5.55 (s,1H),4.48(d,1H),4.01-3.92(m,1H),3.88-3.76(m,2H),3.73-3.56(m,2H),3.34-3.22(m,1H).

[0365] Example 12

[0366]

[0367] Referring to the synthesis method of the first to third steps of Example 11, 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester 12a (1.56 g, 5.61 mmol, obtained by the known method "WO2022 / 132914") and 4-chloro-1-methyl-1H-1,2,3-triazole-5-carbonitrile (1.00 g, 7.02 mmol, obtained by the known method "Chemistry of Heterocyclic Compounds, 1988, p.756-759") were used to obtain (4-amino-3-methyl-3H-[1,2,3]triazolo[4,5-c]quinoline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 12 (12 mg), yield: 0.5%. MSm / z(ESI):457[M+1]

[0368] 1 H NMR(400MHz,DMSO)δ8.34(d,1H),8.19(s,1H),7.81-7.67(m,4H),7.61(dd,1H),6.119(s,2H), 5.54(s,1H),4.56(s,3H),4.48(d,1H),3.99(dd,1H),3.84(dd,2H),3.66(td,1H),3.32(d,1H).

[0369] Example 13

[0370]

[0371] Referring to the synthesis method of the second to fourth steps of Example 5, 4-amino-1,3-dihydrofurano[3,4-c]quinolin-8-yl)(5-(4-(trifluoromethyl)phenyl)-2,5-diazaspiro[3.4]octan-2-yl)methanone 13 (17 mg) was obtained from tert-butyl 2,5-diazaspiro[3.4]octane-2-carboxylate 13a (200 mg, 0.94 mmol), yield: 3.5%. MS m / z (ESI): 470 [M+1]

[0372] 1 H NMR (400MHz, DMSO) δ8.25(d,1H),7.79-7.68(m,3H),7.50(d,1H),6.70(s,2H),6.61(d,1H),5.30(q,2H),4.95( d,2H),4.88(d,1H),4.75(d,1H),4.20(d,1H),3.85(d,1H),3.58-3.54(m,2H),2.29(t,2H),1.89-1.77(m,2H).

[0373] Embodiment 14

[0374]

[0375] Step 1: tert-Butyl 3-methoxy-2-oxopiperidine-1-carboxylate

[0376] 3-Methoxy-2-oxopiperidine 14a (1 g, 7.75 mmol) was dispersed in 10 mL of pyridine, di-tert-butyl dicarbonate (2.18 g, 10 mmol) and 4-dimethylaminopyridine (122 mg, 1 mmol) were added, and the mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product tert-butyl 3-methoxy-2-oxopiperidine-1-carboxylate 14b (1.50 g, white solid) with a yield of 84.5%. MS m / z (ESI): 230 [M+1]

[0377] Step 2: tert-Butyl (4-methoxy-5-oxo-5-(4-(trifluoromethyl)phenyl)pentyl)carbamate

[0378] 1-Bromo-4-(trifluoromethyl)benzene 14c (1.47 g, 6.55 mmol) was dispersed in 20 mL of tetrahydrofuran, and n-butyl lithium (2.8 mL, 7 mmol, 2.5 M / L n-hexane solution) was added dropwise at -78°C, and the mixture was stirred at -78°C for 1 hour. 3-Methoxy-2-oxopiperidine-1-carboxylic acid tert-butyl ester 14b (1.50 g, 6.55 mmol) was added at -78°C, and the mixture was stirred at -78°C for 1 hour. The mixture was quenched with 10 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product (tert-butyl (4-methoxy-5-oxo-5-(4-(trifluoromethyl)phenyl)pentyl)carbamate 14d (1.59 g, yellow solid), yield: 64.9%. MS m / z (ESI): 376 [M+1]

[0379] Step 3: 3-methoxy-2-(4-(trifluoromethyl)phenyl)piperidine

[0380] Tert-butyl (4-methoxy-5-oxo-5-(4-(trifluoromethyl)phenyl)pentyl)carbamate 14d (1.00 g, 2.67 mmol) was dispersed in 5 mL of trifluoroacetic acid and stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure and the residue was dispersed in 5 mL of methanol. Sodium borohydride (122 mg, 3.20 mmol) was added and stirred at 25°C for 1 hour. The mixture was quenched with 10 mL of water and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 3-methoxy-2-(4-(trifluoromethyl)phenyl)piperidine 14e (200 mg, yellow oil) in a yield of 28.9%. MS m / z(ESI):260[M+1]

[0381] Step 4: (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-methoxy-2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

[0382] 3-Methoxy-2-(4-(trifluoromethyl)phenyl)piperidine 14e (50 mg, 0.19 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 14f (60 mg, 0.25 mmol, synthesized by the known method "Patent WO2022169948A1"), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (114 mg, 0.30 mmol) and N,N-diisopropylethylamine (129 mg, 1 mmol) were dispersed in 3 mL of dichloromethane and stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title product (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-methoxy-2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 14 (32 mg) in a yield of 34.9%. MS m / z (ESI): 484 [M+1]

[0383] 1 H NMR (400MHz, DMSO) δ8.55(s,2H),8.31(s,1H),7.83-7.77(m,4H),7.71(d,2H),5.84(s,1H),4. 37(s,3H),3.92-3.77(m,2H),3.34(d,3H),3.23-2.86(m,2H),2.11-1.92(m,1H),1.73(t,3H).

[0384] Embodiment 15

[0385]

[0386] Step 1: tert-Butyl 6-(2-(((tert-butyldimethylsilyl)hydroxy)methyl)-4-(trifluoromethyl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylate

[0387] Tert-butyl 6-((diphenoxyphosphoryl)hydroxy)-3,4-dihydropyridine-1(2H)-carboxylate 15a (4.00 g, 9.28 mmol, synthesized by the known method "Patent WO2019138017 A1") and (2-(((t-tert-butyldimethylsilyl)hydroxy)methyl)-4-(trifluoromethyl)phenyl)boric acid 15b (3.34 g, 10 mmol, synthesized by the known method "Patent WO2012046771 A1") were dispersed in 40 mL of tetrahydrofuran and 10 mL of water, and sodium carbonate (3.18 g, 30 mmol) and tetrakis(triphenylphosphine)palladium (566 mg, 0.49 mmol) were added, and the reaction was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to give the title product, tert-butyl 6-(2-(((tert-butyldimethylsilyl)hydroxy)methyl)-4-(trifluoromethyl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylate 15c (2.21 g). Yield: 50.1%. MS m / z (ESI): 472 [M+1]

[0388] Step 2: tert-Butyl 6-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylate

[0389] 6-(2-(((tert-butyldimethylsilyl)hydroxy)methyl)-4-(trifluoromethyl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 15c (2.21 g, 4.69 mmol) was dispersed in 20 mL of tetrahydrofuran, and tetrabutylammonium fluoride (10 mL, 10 mmol, 1M / L tetrahydrofuran solution) was added, and the mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title product tert-butyl 6-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylate 15d (1.05 g) in a yield of 62.7%. MS m / z (ESI): 358 [M+1]

[0390] Step 3: 8-(Trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-1H-benzoisopyrano[4,3-b]pyridine-1-carboxylic acid tert-butyl ester

[0391] 6-(2-(Hydroxymethyl)-4-(trifluoromethyl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 15d (1.05 g, 2.94 mmol) was dispersed in 20 mL of dichloromethane, N-iodosuccinimide (794 mg, 3.53 mmol) was added, and the mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dispersed in 20 mL of tetrahydrofuran, Raney nickel (10 g) was added, and the mixture was stirred at 25°C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product 8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-1H-benzoisopyrano[4,3-b]pyridine-1-carboxylic acid tert-butyl ester 15e (410 mg), with a yield of 39.0%. MS m / z(ESI):358[M+1]

[0392] Step 4: 8-(Trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-1H-benzoisopyrano[4,3-b]pyridine

[0393] 8-(Trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-1H-benzoisopyrano[4,3-b]pyridine-1-carboxylic acid tert-butyl ester 15e (410 mg, 1.15 mmol) was dispersed in 4 mL of dichloromethane and 2 mL of trifluoroacetic acid, and stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the title product 8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-1H-benzoisopyrano[4,3-b]pyridine 15f (210 mg), with a yield of 71.1%. MS m / z (ESI): 258 [M+1]

[0394] Step 5: (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-1H-benzoisopyrano[4,3-b]pyridin-1-yl)methanone

[0395] 8-(Trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-1H-benzoisopyrano[4,3-b]pyridine 15f (50 mg, 0.19 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 15g (60 mg, 0.25 mmol, synthesized by the known method "Patent WO2022169948 A1"), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (114 mg, 0.30 mmol) and N,N-diisopropylethylamine (129 mg, 1 mmol) were dispersed in 3 mL of dichloromethane and stirred at 25 ° C for 16 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent System A to give the title product (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-1H-benzoisopyrano[4,3-b]pyridin-1-yl)methanone 15 (21 mg) in a yield of 22.4%.

[0396] MS m / z(ESI):482[M+1]

[0397] Example 16

[0398]

[0399] Step 1: (Z)-2-methyl-N-(2-(trifluoromethyl)-6H-pyrano[3,4-b]pyridin-5(8H)-ylidene)propane-2-sulfenamide

[0400] 2-(Trifluoromethyl)-6H-pyrano[3,4-b]pyridine-5(8H)-one 16a (1.3 g, 5.99 mmol, synthesized by the known method "Patent WO2022169948 A1"), 5-2-methylpropane-2-sulfenamide (1.45 g, 11.97 mmol) and tetraisopropyl titanate (3.4 g, 11.97 mmol) were dissolved in 15 mL of tetrahydrofuran and stirred at 60 ° C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and Na2CO3 was added to quench it, and then 20 mL of water and 200 mL of ethyl acetate were added to the mixed solution. The organic phase was washed three times with saturated brine, 20 mL each time, and then the organic phase was dried and spin-dried. The resulting residue was purified by silica gel column chromatography with eluent system A to give (Z)-2-methyl-N-(2-(trifluoromethyl)-6H-pyrano[3,4-b]pyridin-5(8H)-ylidene)propane-2-sulfenamide 16b (0.9 g) in a yield of 46.9%. MS m / z (ESI): 321 [M+1]

[0401] Step 2: N-(5-allyl-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-2-methylpropane-2-sulfenamide

[0402] (Z)-2-Methyl-N-(2-(trifluoromethyl)-6H-pyrano[3,4-b]pyridin-5(8H)-ylidene)propane-2-sulfenamide 16b (700 mg, 2.19 mmol) and allylmagnesium bromide (952.42 mg, 6.56 mmol) were dissolved in 10 mL of tetrahydrofuran and stirred at -55 °C for 2 hours. 20 mL of water was added to quench, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain N-(5-allyl-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-2-methylpropane-2-sulfinamide 16c (450 mg), yield: 56.0%. MS m / z(ESI):363[M+1]

[0403] Step 3: N-(5-(3-hydroxypropyl)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-2-methylpropane-2-sulfenamide

[0404] N-(5-allyl-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-2-methylpropane-2-sulfinamide 16c (770 mg, 2.12 mmol) was dissolved in 20 mL of tetrahydrofuran, borane (59 mg, 4.25 mmol) was added, and the mixture was stirred at 20°C for 1 hour. NaOH (170 mg, 4.25 mmol) and H2O2 (144 mg, 4.25 mmol) were added under ice bath, and the mixture was stirred at 20°C for 2 hours. 20 mL of saturated sodium carbonate solution was added to quench, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain N-(5-(3-hydroxypropyl)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-2-methylpropane-2-sulfinamide 16d (350 mg). Yield: 43%. MS m / z(ESI):381[M+1]

[0405] Step 4: 3-(5-((tert-butylsulfinyl<sulfinyl>)amino)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)propyl methanesulfonate

[0406] N-(5-(3-Hydroxypropyl)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-2-methylpropane-2-sulfinamide 16d (290 mg, 0.762 mmol), methanesulfonic anhydride (200 mg, 1.14 mmol) and diisopropylethylamine (295 mg, 2.29 mmol) were dissolved in 5 mL of dichloromethane and stirred at 20°C for 16 hours. 10 mL of water was added to quench, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain 3-(5-((tert-butylsulfinyl<sulfinyl>)amino)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)propyl methanesulfonate 16e (230 mg), yield: 65.8%. MS m / z(ESI):459[M+1]

[0407] Step 5: 1'-(tert-butylsulfinyl<sulfinyl>)-2-(trifluoromethyl)-6H,8H-spiro[pyrano[3,4-b]pyridine-5,2'-pyrrolidine]

[0408] 3-(5-((tert-butylsulfinyl<sulfinyl>)amino)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)propyl methanesulfonate 16e (250 mg, 0.545 mmol) and cesium carbonate (533 mg, 1.64 mmol) were dissolved in 12 mL of N,N-dimethylformamide and stirred at 50° C. for 2 hours. 20 mL of water was added to quench, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain 1'-(tert-butylsulfinyl<sulfinyl>)-2-(trifluoromethyl)-6H,8H-spiro[pyrano[3,4-b]pyridine-5,2'-pyrrolidine]16f (120 mg), yield: 60%. MS m / z(ESI):363[M+1]

[0409] Step 6: 2-(Trifluoromethyl)-6H,8H-spiro[pyrano[3,4-b]pyridine-5,2'-pyrrolidine]

[0410] 1'-(tert-butylsulfinyl<sulfinyl>)-2-(trifluoromethyl)-6H,8H-spiro[pyrano[3,4-b]pyridine-5,2'-pyrrolidine]16f (30 mg, 0.083 mmol) and HCl (9 mg, 0.248 mmol) were dissolved in 2 mL of ethanol and stirred at 20°C for 1 hour. 20 mL of saturated sodium carbonate solution was added to quench the mixture, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-(trifluoromethyl)-6H,8H-spiro[pyrano[3,4-b]pyridine-5,2'-pyrrolidine]16g (15 mg). The yield was 70%. MS m / z(ESI):259[M+1]

[0411] Step 7: (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(trifluoromethyl)-6H,8H-spiro[pyrano[3,4-b]pyridine-5,2'-pyrrolidine]-1'-yl)methanone 2-(trifluoromethyl)-6H,8H-spiro[pyrano[3,4-b]pyridine-5,2'-pyrrolidine] 16g (32mg, 0.124mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 16h (30mg, 0.124mmol, using the known method "Patent WO2022169948 A1" was synthesized), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (70 mg, 0.248 mmol) and N-methylimidazole (51 mg, 0.619 mmol) were dissolved in 3 mL of N,N-dimethylformamide and stirred at 50 ° C for 1 hour. 10 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(trifluoromethyl)-6H,8H-spiro[pyrano[3,4-b]pyridine-5,2'-pyrrolidine]-1'-yl)methanone 16 (6 mg). Yield: 8.3%. MS m / z(ESI):483[M+1]

[0412] 1HNMR(400MHz,MeOD)δ8.39(s,1H),8.23–8.18(m,2H),7.81–7.77(m,1H),7.70(t,2H),4.89(s,2H),4.58(dd,1H) ,4.47(s,3H),4.15–4.08(m,1H),3.95(d,1H),3.80(dd,1H),2.71–2.65(m,1H),2.17(d,1H),2.14–2.08(m,2H).

[0413] Embodiment 17

[0414]

[0415] Step 1: Methyl 3-(2-methylimidazol-4-yl)-4-nitrobenzoate

[0416] 2-Methyl-1H-imidazole 17a (5 g, 60.89 mmol) was dissolved in thionyl chloride (50 mL), 8-diazabicyclo[5.4.0]undec-7-ene (13.91 g, 91.35 mmol, 14 mL) and methyl 3-fluoro-4-nitrobenzoate (13.34 g, 66.99 mmol) were slowly added, and the reaction was stirred at 25°C for 2 hours. Water (200 mL) was added to the reaction solution, and it was extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with saturated brine (200 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give methyl 3-(2-methylimidazol-4-yl)-4-nitrobenzoate 17b (9 g), yield: 56.6%. MS m / z (ESI): 262 [M+1]

[0417] Step 2: Methyl 4-amino-3-(2-methylimidazol-1-yl)benzoate

[0418] 3-(2-methylimidazol-4-yl)-4-nitrobenzoic acid methyl ester 17b (2g, 7.66mmol) was dissolved in methanol (20mL), Pd / C (816mg, 0.77mmol, 10% purity) was added, and hydrogen was replaced three times. Under the protection of hydrogen, the reaction was stirred at 50°C for 12 hours; the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the filter cake was stirred with a mixed solvent of methanol: ethyl acetate = 1:10 (10mL) for 15 minutes, filtered, and the filter cake was dried under reduced pressure to obtain 4-amino-3-(2-methylimidazol-1-yl)benzoic acid methyl ester 17c (1.45g), yield: 81.9%. MS m / z (ESI): 232 [M+1]

[0419] Step 3: 4-[(4-methoxyphenyl)methylcarbamoylamino]-3-(2-methylimidazol-1-yl)benzoic acid methyl ester

[0420] Methyl 4-amino-3-(2-methylimidazol-1-yl)benzoate 17c (1 g, 4.32 mmol) was dissolved in dichloromethane (15 mL), and 4-dimethylaminopyridine (265 mg, 2.16 mmol) and 1-(isocyanatemethyl)-4-methoxybenzene (1.06 g, 6.49 mmol, 926 μL) were added. The reaction was stirred at 80°C for 16 hours, and the reaction solution was concentrated under reduced pressure. Dichloromethane (10 mL) and methyl tert-butyl ether (10 mL) were added to the concentrated residue, and stirred for 15 minutes, filtered, and the filter cake was collected and dried under reduced pressure to obtain methyl 4-[(4-methoxyphenyl)methylcarbamoylamino]-3-(2-methylimidazol-1-yl)benzoate 17d (750 mg). Yield: 45.8%. MS m / z (ESI): 380 [M+1]

[0421] Step 4: 4-[(4-methoxyphenyl)methylamino]-1-methyl-imidazolyl-[1,5-a]quinoxaline-8-carboxylic acid methyl ester

[0422] 4-[(4-methoxyphenyl)methylcarbamoylamino]-3-(2-methylimidazol-1-yl)benzoic acid methyl ester 17d (600 mg, 1.52 mmol) was dissolved in pyridine (2 mL), phosphorus oxychloride (280 mg, 1.83 mmol, 171 μL) was added, and the reaction was stirred at 120°C for 16 hours; the reaction solution was concentrated under reduced pressure, water (50 mL) was added to the concentrated residue, and extracted with ethyl acetate (50 mL×3); the organic phases were combined, washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give 4-[(4-methoxyphenyl)methylamino]-1-methyl-imidazolyl-[1,5-a]quinoxaline-8-carboxylic acid methyl ester 17e (250 mg), yield: 43.7%. MS m / z(ESI):377[M+1]

[0423] Step 5: 4-[(4-methoxyphenyl)methylamino]-1-methyl-imidazolyl-[1,5-a]quinoline-8-carboxylic acid

[0424] 4-[(4-methoxyphenyl)methylamino]-1-methyl-imidazolyl-[1,5-a]quinoxaline-8-carboxylic acid methyl ester 17e (250 mg, 664 μmol) was dissolved in water (2 mL), methanol (2 mL) and tetrahydrofuran (6 mL), and lithium hydroxide (32 mg, 1.33 mmol) was added. The reaction was stirred at 80°C for 3 hours, the system pH was adjusted to 5 with 0.5 M hydrochloric acid, filtered, and the filter cake was stirred with ethanol (5 mL) for 0.5 hours, filtered, and dried under reduced pressure to obtain 4-[(4-methoxyphenyl)methylamino]-1-methyl-imidazolyl-[1,5-a]quinoline-8-carboxylic acid 17f (110 mg), yield: 45.7%. MS m / z (ESI): 363 [M+1]

[0425] Referring to the synthesis method of step 6 to step 7 of Example 1, ((4-amino-1-methylimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 17 (45 mg) was obtained from 4-[(4-methoxyphenyl)methylamino]-1-methyl-imidazolyl-[1,5-a]quinoline-8-carboxylic acid 17f (60 mg, 0.17 mmol). Yield: 59.3% MS m / z (ESI): 456 [M+1]

[0426] 1 H NMR(400MHz,DMSO)δ8.03(s,1H),7.79(d,3H),7.69(s,2H),7.47(s,2H),7.34(s,2H),5.51( s,1H),4.48(d,1H),3.93(dd,1H),3.82(d,1H),3.67-3.56(m,1H),3.20(s,2H),2.79(s,3H).

[0427] Embodiment 18

[0428]

[0429] Step 1: (E)-2-Methyl-N-(4-(trifluoromethyl)benzylidene)propane-2-sulfenamide

[0430] 4-(Trifluoromethyl)benzaldehyde 18a (1 g, 5.75 mmol) and tert-butylsulfenamide (726 mg, 6 mmol) were dispersed in 10 mL of dichloromethane, cesium carbonate (3.26 g, 10 mmol) was added, and the mixture was stirred at 40°C for 16 hours. The reaction solution was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product (E)-2-methyl-N-(4-(trifluoromethyl)benzylidene)propane-2-sulfenamide 18b (1.5 g) in a yield of 93.8%. MS m / z (ESI): 278 [M+1]

[0431] Step 2: 2-methyl-N-(1-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)propane-2-sulfenamide

[0432] (E)-2-methyl-N-(4-(trifluoromethyl)benzylidene)propane-2-sulfinamide 18b (1.5 g, 5.40 mmol) was dispersed in 20 mL of tetrahydrofuran, and allylmagnesium bromide (6 mL, 6 mmol, 1 M / L tetrahydrofuran solution) was added dropwise at -78°C, and the mixture was stirred at -78°C for 1 hour. 10 mL of water was added to quench the mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title product 2-methyl-N-(1-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)propane-2-sulfinamide 18c (1.58 g) in a yield of 92.2%. MS m / z (ESI): 320 [M+1]

[0433] Step 3: N-allyl-2-methyl-N-(1-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)propane-2-sulfenamide

[0434] 2-Methyl-N-(1-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)propane-2-sulfinamide 18c (1.58 g, 4.98 mmol) was dispersed in 20 mL of tetrahydrofuran, sodium hydride (220 mg, 5.51 mmol, 60% wt) was added at 0°C, and the mixture was stirred at 25°C for 1 hour. Allyl bromide (1.20 g, 9.96 mmol) was added, and the mixture was stirred at 25°C for 16 hours. 10 mL of water was added to quench the mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product N-allyl-2-methyl-N-(1-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)propane-2-sulfinamide 18d (1.05 g). Yield: 58.7%. MS m / z (ESI): 360 [M+1]

[0435] Step 4: 1-(tert-Butylsulfinyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine

[0436] N-allyl-2-methyl-N-(1-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)propane-2-sulfinamide 18d (1.05 g, 2.92 mmol) and 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-yl[2-(isopropoxy-5-(N,N-dimethylaminosulfonyl)phenyl]methylruthenium dichloride (409 mg, 0.56 mmol) were dispersed in 30 mL of dichloromethane and stirred at 40° C. for 4 hours. The reaction solution was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product 1-(tert-butylsulfinyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine 18e (830 mg) in a yield of 86.0%. MS m / z(ESI):332[M+1]

[0437] Step 5: 2-(4-(Trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine

[0438] 1-(tert-Butylsulfinyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine 18e (830 mg, 2.51 mmol) was dispersed in 10 mL of 3M / L hydrochloric acid methanol solution. The mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the title product 1-(tert-Butylsulfinyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine 18f (342 mg) with a yield of 59.8%. MS m / z (ESI): 228 [M+1]

[0439] Step 6: (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)methanone

[0440] 1-(tert-Butylsulfinyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine 18f (50 mg, 0.22 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 18g (60 mg, 0.25 mmol, synthesized by the known method "Patent WO2022169948 A1"), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (114 mg, 0.30 mmol) and N,N-diisopropylethylamine (129 mg, 1 mmol) were dispersed in 3 mL of dichloromethane and stirred at 25 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title product (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)methanone 18 (27 mg) in a yield of 27.2%. MS m / z (ESI): 452 [M+1]

[0441] 1 H NMR (400MHz, DMSO) δ8.67(s,1H),8.57(s,1H),8.30(s,1H),7.84–7.77(m,2H),7.71(d,2H),7. 56(d,2H),5.93(d,1H),5.68(d,1H),4.34(s,3H),3.55(d,1H),3.16(b,2H),2.87-2.68(m,2H).

[0442] Embodiment 19

[0443]

[0444] Step 1: tert-Butyl 3-((tert-butyldimethylsilyl)hydroxy)-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate

[0445] Tert-butyl 5-((tert-butyldimethylsilyl)hydroxy)-2-oxopiperidine-1-carboxylate 19a (3.50 g, 10.64 mmol) was dispersed in 50 mL of tetrahydrofuran, and lithium diisopropylamide (6 mL, 12 mmol, 2M / L tetrahydrofuran solution) was added dropwise at -78°C, and the mixture was stirred at -78°C for 1 hour. Trifluoromethanesulfonic anhydride (3.38 g, 12 mmol) was added at -78°C, and the mixture was stirred at -78°C for 1 hour. The mixture was quenched with 10 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title product tert-butyl 3-((tert-butyldimethylsilyl)hydroxy)-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate 19b (3.21 g), yield: 65.4%. MS m / z(ESI):462[M+1]

[0446] Step 2: tert-Butyl 6-(Benzo[d]thiazol-5-yl)-3-((tert-butyldimethylsilyl)hydroxy)-3,4-dihydropyridine-1(2H)-carboxylate

[0447] tert-Butyl 3-((tert-butyldimethylsilyl)hydroxy)-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate 19b (3.21 g, 6.96 mmol) and 5-benzothiazolylpinacol borate 19c (2.11 g, 8.11 mmol) were dispersed in 40 mL of tetrahydrofuran and 10 mL of water, and sodium carbonate (2.23 g, 21 mmol) and tetrakis(triphenylphosphine)palladium (404 mg, 0.35 mmol) were added, and the reaction was stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title product, tert-butyl 6-(benzo[d]thiazol-5-yl)-3-((tert-butyldimethylsilyl)hydroxy)-3,4-dihydropyridine-1(2H)-carboxylate 19d (2.41 g), yield: 77.6%. MS m / z (ESI): 447 [M+1]

[0448] Step 3: 6-(Benzo[d]thiazol-5-yl)piperidin-3-ol

[0449] Disperse tert-butyl 6-(benzo[d]thiazol-5-yl)-3-((tert-butyldimethylsilyl)hydroxy)-3,4-dihydropyridine-1(2H)-carboxylate 19d (2.41 g, 5.40 mmol) in 30 mL of dichloromethane, add hydrochloric acid (5 mL, 20 mmol, 4M / L 1,4-dioxane solution) at 25°C, and stir to react for 1 hour. Concentrate under reduced pressure, and disperse the residue in 10 mL of methanol. Add sodium borohydride (241 mg, 6.20 mmol), and stir to react at 25°C for 1 hour. The mixture was quenched with 10 mL of water, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 6-(benzo[d]thiazol-5-yl)piperidin-3-ol 19e (1.15 g), yield: 90.9%. MS m / z (ESI): 235 [M+1]

[0450] Step 4: tert-Butyl 2-(Benzo[d]thiazol-5-yl)-5-hydroxypiperidine-1-carboxylate

[0451] 6-(Benzo[d]thiazol-5-yl)piperidin-3-ol 19e (1.15 g, 4.91 mmol) was dispersed in 20 mL of dichloromethane, and di-tert-butyl dicarbonate (1.14 g, 5.21 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product tert-butyl 2-(benzo[d]thiazol-5-yl)-5-hydroxypiperidine-1-carboxylate 19f (1.45 g), yield: 88.3% MS m / z (ESI): 335 [M+1]

[0452] Step 5: tert-Butyl 2-(Benzo[d]thiazol-5-yl)-5-oxopiperidine-1-carboxylate

[0453] 2-(Benzo[d]thiazol-5-yl)-5-hydroxypiperidine-1-carboxylic acid tert-butyl ester 19f (1.45 g, 4.34 mmol) and Dess-Martin periodinane (2.76 g, 6.51 mmol) were dispersed in 20 mL of dichloromethane and stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 2-(benzo[d]thiazol-5-yl)-5-oxopiperidine-1-carboxylic acid tert-butyl ester 19g (1.11 g) in a yield of 77.0%. MS m / z (ESI): 333 [M+1]

[0454] Step 6: tert-Butyl 2-(Benzo[d]thiazol-5-yl)-5-(difluoromethylene)piperidine-1-carboxylate

[0455] 2-(Benzo[d]thiazol-5-yl)-5-oxopiperidine-1-carboxylic acid tert-butyl ester 19g (350 mg, 1.05 mmol) and 2-((difluoromethyl)sulfonyl)pyridine 19h (234 mg, 1.21 mmol) were dispersed in 5 mL of tetrahydrofuran, potassium tert-butoxide (168 mg, 1.50 mmol) was added at -40°C, and the mixture was stirred for 1 hour at -40°C. The mixture was quenched with 10 mL of water, extracted with ethyl acetate (20 mL×3), and the organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product tert-butyl 2-(benzo[d]thiazol-5-yl)-5-(difluoromethylene)piperidine-1-carboxylate 19i (171 mg) in a yield of 44.5%. MS m / z(ESI):367[M+1]

[0456] Step 7: 5-(5-(difluoromethylene)piperidin-2-yl)benzo[d]thiazole

[0457] Tert-butyl 2-(benzo[d]thiazol-5-yl)-5-(difluoromethylene)piperidine-1-carboxylate 19i (171 mg, 0.46 mmol) was dispersed in 4 mL of dichloromethane and 2 mL of trifluoroacetic acid and stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product 5-(5-(difluoromethylene)piperidin-2-yl)benzo[d]thiazole 19j (124 mg) with a yield of 99.8%. MS m / z (ESI): 267 [M+1]

[0458] Step 8: (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(benzo[d]thiazol-5-yl)-5-(difluoromethylene)piperidin-1-yl)methanone

[0459] 5-(5-(Difluoromethylene)piperidin-2-yl)benzo[d]thiazole 19j (50 mg, 0.18 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 19k (60 mg, 0.25 mmol, synthesized by the known method "Patent WO2022169948 A1"), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (114 mg, 0.30 mmol) and N,N-diisopropylethylamine (129 mg, 1 mmol) were dispersed in 3 mL of dichloromethane and stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to give the title product (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(benzo[d]thiazol-5-yl)-5-(difluoromethylene)piperidin-1-yl)methanone 19 (21 mg) in a yield of 23.8%. MS m / z (ESI): 491 [M+1]

[0460] 1 H NMR(400MHz,DMSO)δ9.36(s,1H),8.35(s,1H),8.19(s,1H),8.16(d,1H),8.06(s,1H),7.76-7.4 4(m,5H),5.54(s,1H),4.77(d,1H),4.10(s,3H),3.90-3.75(m,1H),2.39(dd,2H),2.20(d,2H).

[0461] Embodiment 20

[0462]

[0463] Step 1: tert-Butyl 3-methyl-6-(2-methylbenzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0464] (2-2-Methylbenzo[d]thiazol-5-yl)boronic acid 20a (1.00 g, 5.18 mmol) and tert-butyl 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate 20b (2.11 g, 6.11 mmol) were dispersed in 20 mL of tetrahydrofuran and 5 mL of water, and sodium carbonate (1.91 g, 18 mmol) and tetrakis(triphenylphosphine)palladium (300 mg, 0.26 mmol) were added, and the mixture was stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title product tert-butyl 3-methyl-6-(2-methylbenzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate 20c (812 mg) in a yield of 45.6%. MS m / z(ESI):345[M+1]

[0465] Step 2: 2-Methyl-5-(5-methylpiperidin-2-yl)benzo[d]thiazole

[0466] Disperse tert-butyl 3-methyl-6-(2-methylbenzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate 20c (812 mg, 2.36 mmol) in 6 mL of dichloromethane and 3 mL of trifluoroacetic acid, and stir at 25°C for 1 hour. Concentrate under reduced pressure, and disperse the residue in 10 mL of methanol. Add sodium borohydride (112 mg, 3.10 mmol), and stir at 25°C for 1 hour. Quench with 10 mL of water, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title product 2-methyl-5-(5-methylpiperidin-2-yl)benzo[d]thiazole 20d (412 mg), yield: 71.0%. MS m / z(ESI):247[M+1]

[0467] Step 3: (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((2R,5S)-5-methyl-2-(2-methylbenzo[d]thiazol-5-yl)piperidin-1-yl)methanone

[0468] 2-Methyl-5-(5-methylpiperidin-2-yl)benzo[d]thiazole 20d (50 mg, 0.20 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid e (60 mg, 0.25 mmol, synthesized by the known method "Patent WO2022169948A1"), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (114 mg, 0.30 mmol) and N,N-diisopropylethylamine (129 mg, 1 mmol) were dispersed in 3 mL of dichloromethane and stirred at 25 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to give the title product (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((2R,5S)-5-methyl-2-(2-methylbenzo[d]thiazol-5-yl)piperidin-1-yl)methanone 20 (16 mg) in a yield of 17.0%. MS m / z (ESI): 471 [M+1]

[0469] 1 H NMR (400MHz, DMSO) δ8.36(s,1H),8.21(s,1H),8.06(d,1H),7.89-7.66(m,5H),7.43(d,1H),5.57(s,1H),4.17( s,3H),3.89(s,1H),3.19(d,1H),2.81(s,3H),2.25(t,2H),1.87(s,1H),1.68(t,1H),1.37(d,1H),1.05(d,3H).

[0470] Embodiment 21

[0471]

[0472] Step 1: N-methoxy-N-methylbenzo[d]thiazole-5-carboxamide

[0473] Benzo[d]thiazole-5-carboxylic acid 21a (1.5 g, 8.37 mmol), N,O-dimethylhydroxylamine hydrochloride (979 mg, 10.04 mmol), N,N-diisopropylethylamine (4.3 g, 33.48 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.8 g, 10.04 mmol) were dispersed in 15 mL of dimethylformamide and stirred at room temperature for 1 hour. The reaction solution was poured into 100 ml of water and extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product N-methoxy-N-methylbenzo[d]thiazole-5-carboxamide 21b (1.6 g) with a yield of 86.0%. MS m / z (ESI): 223 [M+1]

[0474] Step 2: 1-(Benzo[d]thiazol-5-yl)prop-2-en-1-one

[0475] N-methoxy-N-methylbenzo[d]thiazole-5-carboxamide 21b (1.6 g, 7.20 mmol) was dissolved in 15 mL of tetrahydrofuran, and vinylmagnesium bromide (10.8 ml, 1 M tetrahydrofuran solution) was added under a dry ice ethanol bath. The reaction was stirred at -60°C for 2 hours under nitrogen protection. 50 ml of saturated ammonium chloride solution was added to the reaction solution to quench the reaction. After the reaction solution was warmed to room temperature, it was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1-(benzo[d]thiazol-5-yl)prop-2-en-1-one 21c (156 mg) with a yield of 11.4%. MS m / z (ESI): 190 [M+1]

[0476] Step 3: 1-(Benzo[d]thiazol-5-yl)-3-chloropropane-1-one

[0477] 1-(Benzo[d]thiazol-5-yl)prop-2-en-1-one 21c (156 mg, 0.82 mmol) was dissolved in 6 mL of dichloromethane, and hydrochloric acid (2 ml, 4 M dioxane solution) was added under ice bath, and stirred at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the title product 1-(benzo[d]thiazol-5-yl)-3-chloropropane-1-one 21d (144 mg), with a yield of 77.4%. MS m / z (ESI): 226 [M+1]

[0478] Step 4: 1-(Benzo[d]thiazol-5-yl)-3-chloropropane-1-ol

[0479] 1-(Benzo[d]thiazol-5-yl)-3-chloropropane-1-one 21d (144 mg, 0.64 mmol) was dissolved in 4 mL of methanol, sodium borohydride (120 mg, 3.19 mmol) was slowly added under ice bath, and the mixture was stirred at 0°C for 2 hours. 20 ml of saturated ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1-(Benzo[d]thiazol-5-yl)-3-chloropropane-1-ol 21e (140 mg), with a yield of 96.4%. MS m / z(ESI):228[M+1]

[0480] Step 5: tert-Butyl (3-(Benzo[d]thiazol-5-yl)-3-hydroxypropoxy)carbamate

[0481] 1-(Benzo[d]thiazol-5-yl)-3-chloropropane-1-ol 21e (140 mg, 0.62 mmol) and tert-butyl N-hydroxycarbamate (124 mg, 0.93 mmol) were dissolved in 3 mL of dimethylformamide, and sodium hydride (74 mg, 1.86 mmol, 60% purity) was slowly added under ice bath, and the reaction was stirred at 0°C for 3 hours. 20 ml of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product tert-butyl (3-(benzo[d]thiazol-5-yl)-3-hydroxypropoxy)carbamate 21f (63 mg), with a yield of 31.3%. MS m / z (ESI): 325 [M+1]

[0482] Step 6: tert-Butyl 3-(Benzo[d]thiazol-5-yl)isoxazolidine-2-carboxylate

[0483] Dissolve tert-butyl (3-(benzo[d]thiazol-5-yl)-3-hydroxypropoxy)carbamate 21f (63 mg, 0.19 mmol) in 3 mL of dichloromethane, slowly add methylsulfonyl chloride (26 mg, 0.22 mmol) and triethylamine (30 mg, 0.30 mmol) under ice bath, and stir at 0°C for 2 hours. Add 20 ml of water to the reaction solution to quench the reaction, extract with ethyl acetate (20 mL×2), combine the organic phases, wash with saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system A to obtain the title product tert-butyl 3-(benzo[d]thiazol-5-yl)isoxazolidine-2-carboxylate 21g (23 mg), yield: 38.6%. MS m / z(ESI):307[M+1]

[0484] Step 7: 3-(Benzo[d]thiazol-5-yl)isoxazolidine

[0485] 21 g (23 mg, 0.075 mmol) of tert-butyl 3-(benzo[d]thiazol-5-yl)isoxazolidine-2-carboxylate was dissolved in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then added with 20 ml of saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product 3-(benzo[d]thiazol-5-yl)isoxazolidine 21h (7 mg) in a yield of 45.2%. MS m / z (ESI): 207 [M+1]

[0486] Referring to the synthesis method of the sixth step of Example 1, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(benzo[d]thiazol-5-yl)isoxazolidin-2-yl)methanone 21 (2.7 mg) was obtained from 3-(benzo[d]thiazol-5-yl)isoxazolidine 21h (7 mg, 0.03 mmol). Yield: 18.5% MS m / z (ESI): 431 [M+1]

[0487] Embodiment 22

[0488]

[0489] Step 1: 5-Bromo-2-iodobenzo[d]thiazole

[0490] 5-Bromobenzo[d]thiazoleboronic acid 22a (4.00 g, 18.78 mmol) was dispersed in 50 mL of tetrahydrofuran, and 2,2,6,6-tetramethylpiperidinium magnesium chloride and lithium chloride (20 mL, 20 mmol) were added dropwise at -78°C, and the mixture was stirred at -78°C for 10 minutes. Iodine (5.04 g, 20 mmol) was added, and the mixture was stirred at -78°C for 1 hour. 10 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product. The ethyl acetate reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 5-bromo-2-iodobenzo[d]thiazole 22b (1.88 g), with a yield of 29.5%. MS m / z (ESI): 340 [M+1]

[0491] Step 2: 5-Bromo-2-trifluoromethylbenzo[d]thiazole

[0492] 5-Bromo-2-iodobenzo[d]thiazole 22b (1.88 g, 5.55 mmol), methyl fluorosulfonyl difluoroacetate (1.15 g, 6.00 mmol) and cuprous iodide (2.09 g, 11.00 mmol) were dispersed in 20 mL of N,N-dimethylformamide and stirred at 100°C for 16 hours. The reaction solution was poured into 200 mL of water and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product. The ethyl acetate reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 5-bromo-2-trifluoromethylbenzo[d]thiazole 22c (820 mg) with a yield of 52.6%. MS m / z (ESI): 282 [M+1]

[0493] Step 3: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzo[d]thiazole

[0494] 5-Bromo-2-trifluoromethylbenzo[d]thiazole 22c (820 mg, 2.92 mmol), bipyraclostrobin (762 mg, 3.00 mmol), potassium acetate (882 mg, 9 mmol) and 1,1-bis(diphenylphosphino)diferronichloridopalladium (110 mg, 0.15 mmol) were dispersed in 10 mL 1,4-dioxane and stirred at 100°C for 16 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to give the title product 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzo[d]thiazole 22d (400 mg) in a yield of 41.6%. MS m / z (ESI): 330 [M+1]

[0495] Step 4: tert-Butyl 3-methyl-6-(2-(trifluoromethyl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0496] 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2-(trifluoromethyl)benzo[d]thiazole 22d (400 mg, 1.22 mmol) and tert-butyl 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (518 mg, 1.50 mmol) were dispersed in 4 mL of tetrahydrofuran and 1 mL of water, and sodium carbonate (637 mg, 6 mmol) and tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol) were added, and the reaction was stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title product, tert-butyl 3-methyl-6-(2-(trifluoromethyl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate 22e (200 mg). Yield: 41.2%. MS m / z (ESI): 399 [M+1]

[0497] Step 5: 5-(5-methylpiperidin-2-yl)-2-(trifluoromethyl)benzo[d]thiazole

[0498] Disperse tert-butyl 3-methyl-6-(2-(trifluoromethyl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate 22e (200 mg, 0.50 mmol) in 4 mL of dichloromethane and 1 mL of trifluoroacetic acid, and stir at 25°C for 1 hour. Concentrate under reduced pressure, and disperse the residue in 10 mL of methanol. Add sodium borohydride (112 mg, 3.10 mmol), and stir at 25°C for 1 hour. Quench with 10 mL of water, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title product 5-(5-methylpiperidin-2-yl)-2-(trifluoromethyl)benzo[d]thiazole 22f (50 mg), yield: 33.3%. MS m / z(ESI):301[M+1]

[0499] Step 6: (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((2R,5S)-5-methyl-2-(2-(trifluoromethyl)benzo[d]thiazol-5-yl)piperidin-1-yl)methanone and (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((2S,5R)-5-methyl-2-(2-(trifluoromethyl)benzo[d]thiazol-5-yl)piperidin-1-yl)methanone

[0500] 5-(5-methylpiperidin-2-yl)-2-(trifluoromethyl)benzo[d]thiazole 22f (50 mg, 0.17 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (60 mg, 0.25 mmol, synthesized by the known method "Patent WO2022169948 A1"), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (114 mg, 0.30 mmol) and N,N-diisopropylethylamine (129 mg, 1 mmol) were dispersed in 3 mL of dichloromethane and stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to give a mixture of the title product (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((2R,5S)-5-methyl-2-(2-methylbenzo[d]thiazol-5-yl)piperidin-1-yl)methanone 22-1 and (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)((2S,5R)-5-methyl-2-(2-(trifluoromethyl)benzo[d]thiazol-5-yl)piperidin-1-yl)methanone 22-2 (23 mg) in a yield of 25.8%. MS m / z (ESI): 525 [M+1]

[0501] 1H NMR (400MHz, DMSO) δ8.39(d,1H),8.26(d,2H),8.22(s,1H),7.75(d,1H),7.67-7.52(m,3H),7.34(s,1H),5.66(s,1 H),4.21(s,3H),3.82(s,1H),3.31(m,1H),2.38-2.18(m,2H),1.87(s,1H),1.69(t,1H),1.38(d,1H),1.04(d,3H).

[0502] Embodiment 23

[0503]

[0504] Step 1: Benzyl 4-carbonyl-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate

[0505] Benzyl 4-carbonyl-3,4-dihydropyridine-1(2H)-carboxylate 23a (2.5 g, 10.81 mmol), (4-(trifluoromethyl)phenyl)boric acid 23b (4.11 g, 21.62 mmol), bis(dicyclopentadiene)rhodium tetrafluoroborate (395.6 mg, 1.08 mmol) and potassium hydroxide (1.21 g, 21.62 mmol) were dissolved in a mixed solvent of 24 mL of dioxane and 6 mL of water, and stirred at 20° C. for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give benzyl 4-carbonyl-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate 23c (1.6 g) in a yield of 39.3%.

[0506] MS m / z(ESI):378[M+1]

[0507] Step 2: Benzyl 4-(difluoromethylene)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate

[0508] Benzyl 4-carbonyl-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate 23c (1 g, 2.65 mmol), difluoromethyl (2-pyridyl) sulfone (614 mg, 3.18 mmol) and potassium tert-butoxide (535 mg, 4.77 mmol) were dissolved in 15 mL of N,N-dimethylformamide and stirred at 20°C for 2 hours. 20 mL of water was added to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give benzyl 4-(difluoromethylene)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate 23d (610 mg) in a yield of 56.0%.

[0509] MS m / z(ESI):412[M+1]

[0510] Step 3: 4-(difluoromethylene)-2-(4-(trifluoromethyl)phenyl)piperidine

[0511] Benzyl 4-(difluoromethylene)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate 23d (610 mg, 1.48 mmol) was dissolved in 6 mL of trifluoroacetic acid and stirred at 60° C. for 3 hours. 20 mL of saturated sodium carbonate solution was added to quench the mixture, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated sodium bicarbonate solution (20 mL) and saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain 4-(difluoromethylene)-2-(4-(trifluoromethyl)phenyl)piperidine 23e (350 mg) in a yield of 85.1%.

[0512] MS m / z(ESI):278[M+1]

[0513] Step 4: (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(4-(difluoromethylene)-2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

[0514] 4-(Difluoromethylene)-2-(4-(trifluoromethyl)phenyl)piperidine 23e (125 mg, 0.45 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 23f (100 mg, 0.41 mmol, synthesized by the known method "Patent WO2022169948 A1"), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (312 mg, 0.82 mmol) and N-methylimidazole (135 mg, 1.65 mmol) were dissolved in 3 mL of N,N-dimethylformamide and stirred at 20 °C for 72 hours. 10 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(4-(difluoromethylene)-2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 23 (25 mg). Yield: 12.0%. MS m / z(ESI):502[M+1]

[0515] Embodiment 24

[0516]

[0517] Step 1: Benzyl 2-(Benzo[d]thiazol-5-yl)-4-carbonylpiperidine-1-carboxylate

[0518] Benzyl 4-carbonyl-3,4-dihydropyridine-1(2H)-carboxylate 24a (900 mg, 3.89 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole 24b (1.52 g, 5.84 mmol), (1,5-cyclooctadiene)chlororhodium(I) dimer (191 mg, 0.389 mmol) and triethylamine (1.18 g, 11.68 mmol) were dissolved in a mixed solvent of 10 mL of dioxane and 2 mL of water, and stirred at 90°C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, NH4Cl was added to quench, and then 20 mL of water and 200 mL of ethyl acetate were added to the mixed solution. The organic phase was washed three times with saturated brine, 20 mL each time, and then the organic phase was dried and spin-dried. The residue was purified by silica gel column chromatography with eluent system A to give 2-(benzo[d]thiazol-5-yl)-4-carbonylpiperidine-1-carboxylic acid benzyl ester 24c (450 mg) in a yield of 31.5%. MS m / z (ESI): 367 [M+1]

[0519] Step 2: Benzyl 2-(Benzo[d]thiazol-5-yl)-4-(difluoromethylene)piperidine-1-carboxylate

[0520] Benzyl 2-(Benzo[d]thiazol-5-yl)-4-carbonylpiperidine-1-carboxylate 24c (380 mg, 1.04 mmol), difluoromethyl(2-pyridyl)sulfone (240 mg, 1.24 mmol) and potassium tert-butoxide (232 mg, 2.07 mmol) were dissolved in 4 mL of N,N-dimethylformamide and stirred at 20°C for 2 hours. 20 mL of water was added to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give benzyl 2-(Benzo[d]thiazol-5-yl)-4-(difluoromethylene)piperidine-1-carboxylate 24d (235 mg) in a yield of 56.0%. MS m / z(ESI):401[M+1]

[0521] Step 3: 5-(4-(difluoromethylene)piperidin-2-yl)benzo[d]thiazole

[0522] Benzyl 2-(benzo[d]thiazol-5-yl)-4-(difluoromethylene)piperidine-1-carboxylate 24d (25 mg, 0.062 mmol) was dissolved in 2 mL of trifluoroacetic acid and stirred at 60°C for 3 hours. 20 mL of saturated sodium carbonate solution was added to quench, extracted with dichloromethane (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5-(4-(difluoromethylene)piperidin-2-yl)benzo[d]thiazole 24e (15 mg), yield: 90%. MS m / z(ESI):267[M+1]

[0523] Step 4: (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(benzo[d]thiazol-5-yl)-4-(difluoromethylene)piperidin-1-yl)methanone

[0524] 5-(4-(Difluoromethylene)piperidin-2-yl)benzo[d]thiazole 24e (26 mg, 0.099 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 24f (20 mg, 0.082 mmol, synthesized by the known method "Patent WO2022169948 A1"), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (46 mg, 0.165 mmol) and N-methylimidazole (27 mg, 0.33 mmol) were dissolved in 1 mL of N,N-dimethylformamide and stirred at 50 °C for 1 hour. 10 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(benzo[d]thiazol-5-yl)-4-(difluoromethylene)piperidin-1-yl)methanone 24 (6 mg). Yield: 14.8%. MS m / z(ESI):491[M+1]

[0525] 1 HNMR(400MHz,DMSO)δ9.43(s,1H),8.31(s,1H),8.24-8.20(m,2H),8.01(s,1H),7.67(dd,1H) ,7.62(d,1H),7.50(d,1H),7.16(s,2H),3.19(d,2H),2.95(s,2H),2.69(d,2H),2.32(d,3H).

[0526] Embodiment 25

[0527]

[0528] Step 1: Benzyl 4-cyano-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate

[0529] 4-Carbonyl-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylic acid benzyl ester 25a (150mg, 0.397mmol, synthesized by the known method "Patent WO2022169948 A1"), Tosmic (100mg, 0.52mmol) and t-BuOK (80mg, 0.71mmol) were dissolved in 4mL ethylene glycol dimethyl ether and stirred at -20°C for 2 hours. Cool, add H2O to quench, then add 20mL water and 200mL ethyl acetate to the mixed solution, wash the organic phase with saturated brine three times, 20mL each time, and then dry the organic phase and spin dry. The residue was purified by silica gel column chromatography with eluent system A to obtain 4-cyano-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylic acid benzyl ester 25b (30mg), yield: 19.4%. MS m / z(ESI):389[M+1]

[0530] Step 2: 2-(4-(Trifluoromethyl)phenyl)piperidine-4-carbonitrile

[0531] Benzyl 4-cyano-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate 25b (10 mg, 0.025 mmol) was dissolved in 3 mL of trifluoroacetic acid and stirred at 60°C for 2 hours. After the reaction was completed, it was directly spin-dried to obtain 2-(4-(trifluoromethyl)phenyl)piperidine-4-carbonitrile 25c (5 mg) with a yield of 76%. MS m / z (ESI): 255 [M+1]

[0532] Step 3: 1-(4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carbonyl)-2-(4-(trifluoromethyl)phenyl)piperidine-4-carbonitrile

[0533] 2-(4-(Trifluoromethyl)phenyl)piperidine-4-carbonitrile 25c (17 mg, 0.068 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 25d (15 mg, 0.062 mmol, synthesized by the known method "Patent WO2022169948A1"), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (31 mg, 0.111 mmol) and N-methylimidazole (25 mg, 0.31 mmol) were dissolved in 2 mL of N,N-dimethylformamide and stirred at 50 °C for 1 hour. 10 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain 5-amino-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-c]quinazoline-9-carboxamide 25 (6.4 mg), yield: 21.6%. MS m / z(ESI):479[M+1]

[0534] 1 HNMR (400MHz, DMSO) δ8.51(s,1H),7.81-7.79(m,4H),7.67-7.52(m,3H),3.89-3.76(d,3H),3.66(s,2H),2.86(s,3H),2.33(s,1H),1.93(s,2H).

[0535] Embodiment 26

[0536]

[0537] Step 1: Benzyl 2-(Benzo[d]thiazol-5-yl)-4-oxopiperidine-1-carboxylate

[0538] Benzyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate 26a (1 g, 4.33 mmol), 5-benzothiazolyl pinacol borate (1.57 g, 6 mmol), (1,5-cyclooctadiene)chlororhodium (I) dimer (296 mg, 0.60 mmol) and triethylamine (909 mg, 9 mmol) were dispersed in 20 mL 1,4-dioxane and stirred at 90°C for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product, benzyl 2-(benzo[d]thiazol-5-yl)-4-oxopiperidine-1-carboxylate 26b (600 mg), with a yield of 37.9%. MS m / z (ESI): 367 [M+1]

[0539] Step 2: Benzyl 2-(Benzo[d]thiazol-5-yl)-4-(fluoromethylene)piperidine-1-carboxylate

[0540] Benzyl 2-(Benzo[d]thiazol-5-yl)-4-oxopiperidine-1-carboxylate 26b (600 mg, 1.64 mmol) and 2-[(fluoromethyl)sulfonyl]pyridine (345 mg, 1.97 mmol) were dispersed in 10 mL of N,N-dimethylformamide, potassium tert-butoxide (221 mg, 1.97 mmol) was added at -40°C, and the mixture was stirred at -40°C for 1 hour. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (30 mL×3); the organic phases were combined, washed with saturated brine (200 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product, benzyl 2-(Benzo[d]thiazol-5-yl)-4-(fluoromethylene)piperidine-1-carboxylate 26c (220 mg), with a yield of 35.1%. MS m / z(ESI):383[M+1]

[0541] Step 3: 5-(4-(Fluoromethylene)piperidin-2-yl)benzo[d]thiazole

[0542] Benzyl 2-(Benzo[d]thiazol-5-yl)-4-(fluoromethylene)piperidine-1-carboxylate 26c (220 mg, 0.58 mmol) was dispersed in 10 mL of trifluoroacetic acid and stirred at 60°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title product 5-(4-(fluoromethylene)piperidin-2-yl)benzo[d]thiazole 26d (100 mg) in a yield of 69.5%. MS m / z (ESI): 249 [M+1]

[0543] Step 4: (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(benzo[d]thiazol-5-yl)-4-(fluoromethylene)piperidin-1-yl)methanone

[0544] Reference Example 1, the synthesis method of the fifth step, by 5-(4-(fluoromethylene)piperidin-2-yl)benzo[d]thiazole 26d (100 mg, 0.40 mmol), to obtain the title product (E)-(4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(benzo[d]thiazol-5-yl)-4-(fluoromethylene)piperidin-1-yl)methanone 26-1 (36 mg) and (Z)-(4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(benzo[d]thiazol-5-yl)-4-(fluoromethylene)piperidin-1-yl)methanone 26-2 (23 mg), yield: 31.2%. MS m / z(ESI):473[M+1]

[0545] P1 1 H NMR(400MHz,MeOD)δ9.42(s,1H),9.11–8.26(m,2H),8.16(dd,2H),7.85(d,2H),7. 54(s,1H),7.09–6.73(m,1H),4.16(d,7H),3.00(s,3H),2.70(d,1H),2.29(d,1H).

[0546] P2 1 H NMR(400MHz,MeOD)δ9.64(s,1H),9.42(s,1H),8.67–8.30(m,1H),8.21(d,J=8.4Hz,2H),8.04(s,1H),8.00–7 .82(m,1H),7.52(s,1H),6.83(d,1H),4.38(d,7H),3.57–3.38(m,3H),3.01–2.53(m,1H),2.38–1.88(m,1H).

[0547] Embodiment 27

[0548]

[0549] Step 1: Benzyl 7-(4-(trifluoromethyl)phenyl)-1,4-dithia-8-azaspiro[4.5]decane-8-carboxylate

[0550] 4-Carbonyl-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylic acid benzyl ester 27a (300 mg, 0.79 mmol), 1,2-ethanedithiol (149 mg, 1.59 mmol) and boron trifluoride etherate (22 mg, 0.16 mmol) were dissolved in 5 mL of dichloromethane and stirred at 20°C for 2 hours. 20 mL of water was added to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give 7-(4-(trifluoromethyl)phenyl)-1,4-dithia-8-azaspiro[4.5]decane-8-carboxylic acid benzyl ester 27b (280 mg) in a yield of 77.6%. MS m / z(ESI):454[M+1]

[0551] Step 2: 7-(4-(Trifluoromethyl)phenyl)-1,4-dithia-8-azaspiro[4.5]decane

[0552] Benzyl 7-(4-(trifluoromethyl)phenyl)-1,4-dithia-8-azaspiro[4.5]decane-8-carboxylate 27b (365 mg, 0.8 mmol) was dissolved in 2 mL of trifluoroacetic acid and stirred at 60°C for 2 hours. 20 mL of saturated sodium carbonate solution was added to quench the mixture, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give 7-(4-(trifluoromethyl)phenyl)-1,4-dithia-8-azaspiro[4.5]decane 27c (235 mg) in a yield of 91%. MS m / z(ESI):320[M+1]

[0553] Step 3: (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(7-(4-(trifluoromethyl)phenyl)-1,4-dithia-8-azaspiro[4.5]decane-8-yl)methanone

[0554] 7-(4-(Trifluoromethyl)phenyl)-1,4-dithia-8-azaspiro[4.5]decane 27c (65 mg, 0.20 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 27d (45 mg, 0.19 mmol, synthesized by the known method "Patent WO2022169948 A1"), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (93 mg, 0.24 mmol) and N-methylimidazole (45 mg, 0.55 mmol) were dissolved in 2 mL of N,N-dimethylformamide and stirred at 50 °C for 1 hour. 10 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(7-(4-(trifluoromethyl)phenyl)-1,4-dithia-8-azaspiro[4.5]decane-8-yl)methanone 27 (8.4 mg), yield: 7.6%. MS m / z(ESI):544[M+1]

[0555] 1H NMR(400MHz,DMSO)δ8.16(d,2H),7.75(d,2H),7.65-7.56(m,4H),7.15(s,2H),5.62(s, 1H),4.01(s,2H),3.37(s,1H),3.29-3.06(m,5H),2.83-2.69(m,2H),2.35–2.06(m,3H).

[0556] Embodiment 28

[0557]

[0558] Step 1: 5-(4-difluoromethylpiperidin-2-yl)benzo[d]thiazole

[0559] 5-(4-difluoromethylenepiperidin-2-yl)benzo[d]thiazole 28a (40 mg, 0.15 mmol) was dissolved in isopropanol (5 mL), Pd(OH) / C (40 mg, 5% by mass) was added, and the mixture was stirred at 25°C for 12 h under a hydrogen atmosphere. The reaction was quenched by air, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with eluent system C to give 5-(4-difluoromethylpiperidin-2-yl)benzo[d]thiazole 28b (10 mg) in a yield of 24.8%. MS m / z (ESI): 269 [M+1]

[0560] Referring to the synthesis method of the sixth step of Example 1, 5-(4-difluoromethylpiperidin-2-yl)benzo[d]thiazole 28b (10 mg, 0.04 mmol) was used to obtain the title product (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(benzo[d]thiazol-5-yl)-4-difluoromethylpiperidin-1-yl)methanone 28 (2 mg), yield: 10.9%. MS m / z (ESI): 493 [M+1]

[0561] 1 H NMR(400MHz,MeOD)δ9.26(s,1H),8.16(d,2H),8.11-8.02(m,2H),7.67(s,2H),7.53(d,1H),5. 79(d,1H),5.34(s,1H),4.06(s,3H),2.23–2.15(m,2H),2.02(d,2H),1.31(d,2H),0.89(d,2H).

[0562] Embodiment 29

[0563]

[0564] Step 1: tert-Butyl 5-(diphenyloxyphosphinoyloxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate

[0565] 3-Oxomorpholine-4-carboxylic acid tert-butyl ester 29a (500 mg, 2.48 mmol) was dissolved in 2-methyltetrahydrofuran (10 mL), 1M LiHMDS tetrahydrofuran solution (4 mL) was added at 0°C, the reaction was stirred at 0°C for 1 h, and then diphenyl chlorophosphate (500 mg, 2.48 mmol) was added, and the reaction was stirred at room temperature for 12 h. Saturated ammonium chloride solution was added to quench the reaction, the system was concentrated to dryness, 20 mL of water was added, and it was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography with eluent system C to obtain tert-butyl 5-(diphenoxyphosphinoyloxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate 29b (290 mg), yield: 26.9%. MS m / z (ESI): 434 [M+1]

[0566] Referring to the synthesis method of the first step of Example 15, 5-(diphenyloxyphosphinoyloxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester 29b (290 mg, 0.67 mmol) was used to obtain 5-(benzo[d]thiazol-5-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylic acid tert-butyl ester 29c (173 mg), yield: 80.9%. MS m / z (ESI): 319 [M+1]

[0567] Step 3: tert-Butyl 3-(Benzo[d]thiazol-5-yl)morpholine-4-carboxylate

[0568] Tert-butyl 5-(benzo[d]thiazol-5-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate 29c (115 mg, 0.36 mmol) was dissolved in a mixed solvent of dichloromethane (5 mL) and trifluoroacetic acid (1 mL) and stirred at 25°C for 1 h. The reaction system was concentrated to dryness, 5 mL of methanol was added, cooled to 0°C, and then sodium borohydride (27 mg, 0.72 mmol) was added and stirred at 25°C for 1 h. The reaction system was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate (20 mL×3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in 5 mL of DMF, and Boc2O (157 mg, 0.72 mmol), DIEA (140 mg, 1.08 mmol) and DMAP (12.2 mg, 0.1 mmol) were added and stirred at 25°C for 1 h. The system was concentrated to dryness and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent system C to give tert-butyl 3-(benzo[d]thiazol-5-yl)morpholine-4-carboxylate 29d (80 mg), yield: 69.1%. MS m / z (ESI): 321 [M+1]

[0569] Referring to the synthesis method of the third and fourth steps of Example 5, tert-butyl 3-(benzo[d]thiazol-5-yl)morpholine-4-carboxylate 29d (36 mg, 0.11 mmol) was used to obtain the title product (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(benzo[d]thiazol-5-yl)morpholinyl)methanone 29 (8.1 mg) in a yield of 16.5%. MS m / z (ESI): 445 [M+1]

[0570] 1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.24(s,2H),8.22-8.15(m,2H),7.67-7.55(m,3H),6.92(s,2H),5.58 (s,1H),4.54(d,1H),4.20(s,3H),4.07-3.95(m,2H),3.92–3.85(m,1H),3.70(td,1H),3.39–3.27(m,1H).

[0571] Embodiment 30

[0572]

[0573] Referring to the synthesis method of the sixth step of Example 1, 3-(benzo[d]thiazol-5-yl)morpholine 30e (20 mg, 1 mmol) was used to obtain the title product (4-amino-7-methoxymethyl-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(3-(benzo[d]thiazol-5-yl)morpholinyl)methanone 30 (8.1 mg), yield: 18.3%. MS m / z (ESI): 489 [M+1]

[0574] 1 H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.40-8.15(m,3H),8.15-7.95(m,1H),7.63(s,2H),6.85(s,2H),5.58(s,1 H),4.67-4.57(d,1H),4.57-4.44(s,3H),4.34-3.92(m,4H),3.92-3.78(m,2H),3.72-3.59(m,1H),3.31(m,3H).

[0575] Embodiment 31

[0576]

[0577] Step 1: tert-Butyl 5-methyl-2-carbonylpiperidine-1-carboxylate

[0578] 5-Methylpiperidin-2-one 31a (4.5 g, 39.77 mmol), (Boc)2O (10.41 g, 47.72 mmol) and 4-dimethylaminopyridine (971.66 mg, 7.95 mmol), triethylamine (4.02 g, 39.77 mmol) were dissolved in 40 mL of dichloromethane and stirred at 20 °C for 16 hours. H2O was added to quench the mixture, and then 50 mL of water and 300 mL of ethyl acetate were added to the mixed solution. The organic phase was washed three times with saturated brine, 30 mL each time, and then the organic phase was dried and spin-dried. The residue was purified by silica gel column chromatography with eluent system A to obtain tert-butyl 5-methyl-2-carbonylpiperidine-1-carboxylate 31b (6.56 g) with a yield of 77%. MS m / z (ESI): 236 [M+23]

[0579] Step 2: tert-butyl 6-(diphenoxyphosphino)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate

[0580] 5-Methyl-2-carbonylpiperidine-1-carboxylic acid tert-butyl ester 31b (1 g, 4.69 mmol) and LiHMDS (1.18 g, 7.03 mmol) were dissolved in 3 mL of tetrahydrofuran and stirred at -55°C for 3 hours. 10 mL of saturated ammonium chloride was added to quench the mixture, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined and washed with saturated sodium chloride solution (30 mL×2). After separation, the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain tert-butyl 6-(diphenoxyphosphino)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate 31c (1.36 g) in a yield of 67%. MS m / z(ESI):452[M+23]

[0581] Step 3: 5-Bromo-2-(1-methylpiperidin-4-yl)benzo[d]thiazole

[0582] 2-[(2-amino-4-bromo-phenyl)disulfanyl]-5-bromo-aniline 31d (804 mg, 3.94 mmol), 1-methylpiperidine-4-carboxylic acid 31e (568 mg, 3.94 mmol) and triphenylphosphine (5.17 g, 19.70 mmol) were dissolved in 30 mL of toluene and stirred at 120°C for 48 hours. The mixture was cooled, concentrated, quenched with 10 mL of water, extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give 5-bromo-2-(1-methylpiperidin-4-yl)benzo[d]thiazole 31f (0.47 g) in a yield of 38%. MS m / z(ESI):311[M+1]

[0583] Step 4: 2-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole

[0584] 5-Bromo-2-(1-methylpiperidin-4-yl)benzo[d]thiazole 31f (440 mg, 1.41 mmol), bipyralidin (394 mg, 1.56 mmol), potassium acetate (693 mg, 7.07 mmol), Pd(dppf)Cl2.DCM (229 mg, 0.283 mmol) were dissolved in 10 mL 1,4-dioxane. The reaction was stirred at 90 °C for 16 hours. Cool, filter, and spin dry to obtain 2-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole 31g (520 mg, purity 85%), yield: 87%. MS m / z (ESI): 359 [M+1]

[0585] Step 5: tert-Butyl 3-methyl-6-(2-(1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0586] Tert-butyl 6-diphenoxyphosphino-3-methyl-3,4-dihydro-2H-pyridine-1-carboxylate 31c (1.24 g, 2.79 mmol), 2-(1-methyl-4-piperidinyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole 31g (500 mg, 1.40 mmol), Pd(dppf)Cl2.DCM (226 mg, 0.279 mmol), potassium phosphate (888 mg, 4.19 mmol) were dissolved in 10 mL of 1,4-dioxane and 2 mL of water, and the mixture was stirred at 90 °C for 6 hours. The mixture was cooled, concentrated, quenched by adding 10 mL of water, extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain tert-butyl 3-methyl-6-(2-(1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate 31h (130 mg), yield: 21%. MS m / z(ESI):428[M+1]

[0587] Step 6: 5-(5-methylpiperidin-2-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole

[0588] 3-Methyl-6-(2-(1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 31h (120 mg, 0.28 mmol) was dissolved in 3 mL of trifluoroacetic acid and 1 mL of dichloromethane and stirred at 20°C for 1 hour. The mixture was cooled, concentrated, and methanol (3 mL) was added to dissolve the mixture. Sodium borohydride (10 mg, 0.28 mmol) was added and the mixture was reacted at 20°C for 1 hour. The mixture was spin-dried and the crude product was purified by C18 column chromatography with eluent system A to obtain 5-(5-methylpiperidin-2-yl)-2-(1-methylpiperidin-4-yl)benzo[d]thiazole 31i (80 mg) in a yield of 86%. MS m / z (ESI): 330 [M+1]

[0589] Step 7: (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(5-methyl-2-(2-(1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)methanone

[0590] 4-Aminoimidazole [1,5-a] quinoxaline-8-carboxylic acid 31j (60 mg, 0.263 mmol), 2-(1-methyl-4-piperidinyl)-5-(5-methyl-2-piperidinyl)-1,3-benzothiazole 31i (86 mg, 0.263 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (110 mg, 0.39 mmol), and N-methylimidazole (65 mg, 0.79 mmol) were dissolved in 4 mL of N,N-dimethylformamide and stirred at 50 °C for 2 hours. 10 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(5-methyl-2-(2-(1-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-1-yl)methanone 31 (22.3 mg), yield: 15.7%. MS m / z(ESI):540[M+1]

[0591] 1HNMR(400MHz,DMSO)δ9.19(s,1H),8.31(d,1H),8.14(d,1H),8.10(d,1H),7.91(d,2H),7.45(d,2H),7.41–7.37(m,2H), 3.32(s,5H),2.73(s,2H),2.58(s,3H),2.27(dd,5H),1.97(d,2H),1.85(s,1H),1.68(d,1H),1.36(d,1H),1.02(d,3H).

[0592] Embodiment 32

[0593]

[0594] Step 1: tert-Butyl (6-bromo-2-methyl-3-oxoisoindolin-5-yl)carbamate

[0595] 6-Amino-5-bromo-2-methylisoindolin-1-one (4.82 g, 20 mmol), DMAP (244 mg, 2 mmol), di-tert-butyl carbonate (8.73 g, 40 mmol) and N,N-diisopropylethylamine (5.69 g, 44 mmol) were dissolved in 100 mL of N,N-dimethylformamide and stirred at 60°C for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, 100 mL of water was added, extracted with ethyl acetate (50 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product (6-bromo-2-methyl-3-oxoisoindolin-5-yl)carbamic acid tert-butyl ester 32b (5.22 g) with a yield of 76.5%. MS m / z(ESI):341[M+1]

[0596] Step 2: tert-butyl (2-methyl-3-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-5-yl)carbamate

[0597] Tert-butyl (6-bromo-2-methyl-3-oxoisoindolin-5-yl)carbamate 32b (5.22 g, 15.31 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (1.12 g, 1.53 mmol), potassium acetate (3.01 g, 30.62 mmol) and bispinacol borate (7.78 g, 30.62 mmol) were dispersed in 150 mL of 1,4-dioxane and stirred at 80 °C for 12 hours. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title product (2-methyl-3-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-5-yl)carbamic acid tert-butyl ester 32c (5.01 g) in a yield of 84.3%. MS m / z (ESI): 389 [M+1]

[0598] Step 3: tert-butyl (6-(4-cyano-1-methyl-1H-pyrazol-5-yl)-2-methyl-3-oxaisoindolin-5-yl)carbamate

[0599] Tert-butyl (2-methyl-3-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-5-yl)carbamate 32c (5.01 g, 12.91 mmol), 5-bromo-1-methylpyrazole-4-carbonitrile (2.40 g, 12.91 mmol), tetrakistriphenylphosphine palladium (751 mg, 0.65 mmol) and sodium carbonate (2.74 g, 25.82 mmol) were dissolved in a mixed solvent of 130 mL of dioxane and 26 mL of water, and the reaction was stirred at 80° C. for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, 100 mL of water was added, extracted with ethyl acetate (50 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product (6-(4-cyano-1-methyl-1H-pyrazol-5-yl)-2-methyl-3-oxaisoindolin-5-yl)carbamic acid tert-butyl ester 32d (3.95 g), yield: 83.3%. MS m / z (ESI): 368 [M+1]

[0600] Step 4: 4-amino-1,8-dimethyl-8,9-dihydro-pyrazolo[4,3-c]pyrrolo[3,4-g]quinolin-7(1H)-one

[0601] Tert-butyl (6-(4-cyano-1-methyl-1H-pyrazol-5-yl)-2-methyl-3-oxaisoindolin-5-yl)carbamate 32d (3.95 g, 10.75 mmol) was dissolved in 50 mL of 2M dilute hydrochloric acid and stirred at 50°C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and slurried with ethyl acetate to obtain the title product 4-amino-1,8-dimethyl-8,9-dihydro-pyrazolo[4,3-c]pyrrolo[3,4-g]quinolin-7(1H)-one 32e (2.75 g) with a yield of 95.7%. MS m / z(ESI):268[M+1]

[0602] Step 5: 4-amino-2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester

[0603] 4-Amino-1,8-dimethyl-8,9-dihydro-pyrazolo[4,3-c]pyrrolo[3,4-g]quinolin-7(1H)-one 32e (2.75 g, 10.29 mmol), DMAP (122 mg, 1 mmol), di-tert-butyl carbonate (4.37 g, 20 mmol) and N,N-diisopropylethylamine (2.85 g, 22 mmol) were dissolved in 50 mL of N,N-dimethylformamide and stirred at 60 °C for 12 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, 100 mL of water was added, extracted with ethyl acetate (50 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 4-amino-2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester 32f (4.44 g), yield: 55.5%. MS m / z (ESI): 468 [M+1]

[0604] Step 6: 4-(bis(tert-butoxycarbonyl)amino)-1,8-dimethyl-7-oxo-1,7,8,9-tetrahydro-pyrazolo[4,3-c]pyrrolo[3,4-g]quinoline-9-carboxylic acid

[0605] Methyl 4-amino-2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 32f (4.44 g, 9.50 mmol) was dissolved in 100 mL of tetrahydrofuran, the system was cooled to -78 ° C, 6 mL of 2M lithium diisopropylamine in tetrahydrofuran solution was added under carbon dioxide atmosphere, the system was stirred at -78 ° C for 1 h, and the reaction was continued for 6 h after naturally warming to room temperature. The reaction solution was quenched by adding saturated ammonium chloride solution, concentrated under reduced pressure, 50 mL of water was added to the concentrated residue, extracted with ethyl acetate (50 mL×2), the organic phases were combined, washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 4-(bis(tert-butoxycarbonyl)amino)-1,8-dimethyl-7-oxo-1,7,8,9-tetrahydro-pyrazolo[4,3-c]pyrrolo[3,4-g]quinoline-9-carboxylic acid 32 g (2.90 g), yield: 59.7%. MS m / z(ESI):512[M+1]

[0606] Step 7: (tert-Butyloxycarbonyl)(1,8-dimethyl-9-(methyl(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamoyl)-7-oxo-1,7,8,9-tetrahydro-pyrazolo[4,3-c]pyrrolo[3,4-g]quinolin-4-yl)carbamic acid tert-butyl ester

[0607] 32 g (512 mg, 1 mmol) of methyl 4-amino-2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and N-methyl-2-(trifluoromethyl)-6,8-dihydro-5H-pyran-[3,4-b]pyridin-5-amine (232 mg, 1 mmol, synthesized by the known method "Patent WO2021163344") were dissolved in DMF (10 mL), and N-methylimidazole (46 mg, 3 mmol, 239 μL) and TCFH (561 mg, 2 mmol) were added, and the reaction was stirred at 60 ° C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water (15 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title product (tert-butyloxycarbonyl)(1,8-dimethyl-9-(methyl(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamoyl)-7-oxo-1,7,8,9-tetrahydro-pyrazolo[4,3-c]pyrrolo[3,4-g]quinolin-4-yl)carbamic acid tert-butyl ester 32h (508 mg), yield: 68.9%. MS m / z(ESI):726[M+1]

[0608] Step 8: 4-amino-N,1,8-trimethyl-7-oxo-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-(1,7,8,9-tetrahydro)pyrazolo[4,3-c]pyrrolo[3,4-g]quinoline-9-carboxamide

[0609] Tert-butyl (tert-butyloxycarbonyl)(1,8-dimethyl-9-(methyl(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamoyl)-7-oxo-1,7,8,9-tetrahydro-pyrazolo[4,3-c]pyrrolo[3,4-g]quinolin-4-yl)carbamate 32h (508 mg, 0.70 mmol) was dissolved in 10 mL of 2M dilute hydrochloric acid and stirred at 50°C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title product 4-amino-N,1,8-trimethyl-7-oxo-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-(1,7,8,9-tetrahydro)pyrazolo[4,3-c]pyrrolo[3,4-g]quinoline-9-carboxamide 32 (315 mg, 0.60 mmol) in a yield of 85.7%. MS m / z (ESI): 526 [M+1]

[0610] The preparation of other embodiments of the present invention can refer to the preparation method of any of the above embodiments.

[0611] Biological test evaluation

[0612] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0613] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on the proliferation activity of HCT116 and MTAP Knockout HCT116 cells

[0614] 1.1 Experimental Purpose: The purpose of this test case is to measure the inhibitory effect of compounds on the proliferation activity of HCT116 wild-type and HCT116 MTAP knockout cells.

[0615] 1.2 Experimental instruments: centrifuge (Eppendorf 5810R), microplate reader (BioTek Synergy H1 or PerkinElmer Envision), pipette (Eppendorf or Rainin).

[0616] 1.3 Experimental reagents: HCT116 and MTAP Knockout HCT116 cells were purchased from Nanjing Kebai; Cell Titer-Glo was purchased from Promega, with the catalog number G7573; McCoy`5A was purchased from Gibco, with the catalog number 12330031; FBS was purchased from Gibco, with the catalog number 10091148; PBS was purchased from Gibco, with the catalog number 10010023; trypsin was purchased from Gibco, with the catalog number 25200056; cell culture plates were purchased from Corning, with the catalog number 3610

[0617] 1.4 Experimental method: When HCT116 and MTAP Knockout HCT116 cells were cultured to an appropriate cell density using McCoy'5A medium containing 10% FBS, the cells were collected and adjusted to an appropriate cell concentration using complete medium. The cell suspension was plated on a 96-well plate at 90 μL per well and placed in a 37°C, 5% CO2 incubator to adhere overnight. Compound solutions of different concentrations were prepared using DMSO and culture medium, and a solvent control was set up. The compound solution was added to a 96-well plate at 10 μL per well and placed in a 37°C, 5% CO2 incubator for continued culture for 72 to 240 hours. Then, the CellTiter-Glo solution was added, shaken to mix evenly, incubated in the dark for 10 to 30 minutes, and read using a Synergy H1 or Envision microplate reader.

[0618] 1.5 Experimental data processing method: The inhibition rate was calculated using the luminescence signal value, and the concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC 50 value.

[0619] 1.6 Experimental conclusion: The above scheme shows that the compounds shown in the present invention show about 0.1nM to 100nM (IC 50 ) biological activity; preferably 0.1nM to 50nM (IC 50 ) of biological activity; more preferably 0.1nM to 20nM (IC 50 ) biological activity; most preferably 0.1nM to 10nM (IC 50 )'s biological activity.

[0620] In some embodiments, the IC values ​​of the compounds of the present invention for HCT116 cell proliferation activity are 50 Greater than the IC for proliferation activity of HCT116 MTAP knockout cells 50 About 20 times; preferably greater than about 50 times; more preferably greater than about 70 times; and even more preferably greater than about 100 times.

Claims

1. A compound represented by general formula (II), its stereoisomer or a pharmaceutically acceptable salt thereof: M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -; M3 is selected from -N- or -CR 5e -; Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; Ring D is selected from a saturated or unsaturated 3-8 membered heterocyclic group, a 5-12 membered spiro heterocyclic group, a 5-12 membered bridged heterocyclic group or a 5-12 membered fused heterocyclic group; R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -OR e 、-NR e R f 、-C(O)R e 、-C(O)NR e R f or -P(O)R e R f , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR e 、-NR e R f 、-C(O)R e 、-C(O)NR e R f or -P(O)R e R f , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R 5a , R 5b , R 5c , R 5d and R 5e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -OR j 、-NR j R k 、-C(O)R j 、-C(O)NR j R k or -P(O)R j R k , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR j 、-NR j R k 、-C(O)R j 、-C(O)NR j R k or -P(O)R j R k , the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; or R 5d and R 5e The atoms adjacent to it, R 5c and R 5d The atoms adjacent to it, R 5b and R 5c The adjacent atoms or R 5a and R 5b Each of its neighboring atoms independently links to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n2 -C 3-12 Cycloalkyl, -(CH2) n2 -3-12 membered heterocyclic group, -(CH2) n2 -C 6-12 Aryl, -(CH2) n2 -5-12 membered heteroaryl, -(CH2) n2 OR m 、-(CH2) n2 NR m R n 、-(CH2) n2 C(O)R m 、-(CH2) n2 C(O)NR m R n 、-(CH2) n2 P(O)R m R n or =R m R n , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n2 -C 3-12 Cycloalkyl, -(CH2) n2 -3-12 membered heterocyclic group, -(CH2) n2 -C 6-12 Aryl, -(CH2) n2 -5-12 membered heteroaryl, -(CH2) n2 OR m 、-(CH2) n2 NR m R n 、-(CH2) n2 C(O)R m 、-(CH2) n2 C(O)NR m R n or -(CH2) n2 P(O)R m R n , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R a , R b , R e , R f , R j , R k , R m and R n are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; y is selected from 0, 1, 2, 3, 4, 5 or 6; q is selected from 0, 1, 2, 3, 4, 5 or 6; and n2 is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring D is selected from 3. A compound represented by general formula (A), its stereoisomer or a pharmaceutically acceptable salt thereof: X1 is selected from C or N; X2 is selected from C or N; X3 Selected from CR c or N; X4 Selected from CR d or N; Ring A-1 is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Ring B-1 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; Ring C-1 is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; L 2-1 Select from key, C 2-6 Alkenylene, C 2-6 Alkyne, -(CR aa R bb ) n1 -、-NR cc -、-C(O)-、-NR cc C(O)-、-C(O)NR cc -、-C(O)NR aa NR bb -、-C(O)N=N-、-NR cc C(O)-C 1-3 Alkylene-, -C(O)NR cc -C 1-3 Alkylene-, -S(O) m1 -、-NR cc S(O) m1 -or-S(O) m1 NR cc -; preferably from bond, C 2-6 Alkenylene, C 2-6 Alkyne, -(CR aa R bb ) n1 -、-NR cc -、-C(O)-、-NR cc C(O)-、-C(O)NR cc -、-NR cc C(O)-C 1-3 Alkylene-, -C(O)NR cc -C 1-3 Alkylene-, -S(O) m1 -、-NR cc S(O) m1 -or-S(O) m1 NR cc -; more preferably from a bond, C 2-6 Alkenylene, C 2-6 Alkyne, -(CR aa R bb ) n1 -、-NR cc -、-C(O)-、-NR cc C(O)-、-C(O)NR cc -、-S(O) m1 -、-NR cc S(O) m1 -or-S(O) m1 NR cc -; R 1-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, preferably amino, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R 2-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R 3-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -N=S(O)R a1 R a2 、-S(O)R a1 =NR a2 、-P(O)R a1 R a2 or =CR a1 R a2 , optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =CR e R f and-(CR e R f ) n2 -C≡CR g is substituted by one or more substituents, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -N=S(O)R a1 R a2 、-S(O)R a1 =NR a2 、-P(O)R a1 R a2 or =CR a1 R a2 , optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =CR e R f and-(CR e R f ) n2 -C≡CR g More preferably, it is substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, =CR e R f and-(CR e R f ) n2 -C≡CR g is substituted by one or more substituents; Or any two R 3-1 Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R 4-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -N=S(O)R b1 R b2 、-S(O)R b1 =NR b2 、-P(O)R b1 R b2 、-C(O)NR b1 R b2 or =CR b1 R b2 , optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; preferably selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -N=S(O)R b1 R b2 、-S(O)R b1 =NR b2 、-P(O)R b1 R b2 or =CR b1 R b2 , optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents; more preferably selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-amino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-amino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-amino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R g is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-amino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R a1 and R a2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R b1 and R b2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R aa is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R bb is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; or R aa and R bb Link Form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R cc is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are substituted with one or more substituents, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl and 5-12 membered heteroaryl substituents are optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl and cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; preferably selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; x-1 is selected from 0, 1, 2, 3 or 4; y-1 is selected from 0, 1, 2, 3, 4, 5 or 6; z-1 is selected from 0, 1, 2, 3, 4, 5 or 6; m1 is selected from 0, 1 or 2; n1 is selected from 0, 1, 2, 3 or 4; and n2 is selected from 0, 1, 2, 3 or 4.

4. The compound according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring A-1 is selected from 3-8 membered heterocyclic group or 5-6 membered heteroaryl group; preferably 5. The compound according to claim 3 or 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The The structure is selected from 6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound structure is as follows:

7. A pharmaceutical composition comprising a therapeutically effective dose of a compound as claimed in any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

8. Use of the compound according to any one of claims 1 to 6, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a PRMT5 inhibitor drug.

9. Use of the compound according to any one of claims 1 to 6, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a drug for treating cancer; wherein the cancer is MTAP-related cancer.

10. The use according to claim 9, characterized in that: The cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer, colorectal cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung carcinoma or adenocarcinoma of the lung; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

Images