N-substituted amide derivative inhibitors, methods of making and use thereof

Abstract

An N-substituted amide derivative inhibitor, its preparation method, and its application. In particular, it relates to N-substituted amide derivative compounds, their preparation methods, pharmaceutical compositions containing the compound, and their use in the treatment of cancer.

Description

N-substituted amide derivative inhibitors, preparation method and application thereof Technical Field

[0001] The present invention belongs to the field of drug synthesis, and in particular relates to an N-substituted amide derivative inhibitor, a preparation method and an application thereof. Background Art

[0002] Protein arginase methyltransferases (PRMTs) are divided into three major categories based on catalytic activity and product type: types I, II, and III. Type I primarily includes PRMT1 / 2 / 3 / 4 / 6 / 8, which catalyze the formation of asymmetric dimethylarginine (ADMA) from substrates; type II includes PRMT5 / 9, which catalyze the formation of symmetric dimethylarginine (SDMA) from substrates; and type III, which only includes PRMT7, is responsible for catalyzing the formation of monomethylarginine (MMA) from substrates. PRMT5 uses S-adenosyl-L-methionine (SAM) as a methyl donor to transfer methyl groups to substrates such as DNA, RNA, and histones. Arginine residues on the substrates undergo symmetrical dimethylation to form SDMA, which regulates multiple key cellular processes, including transcription, translation, and DNA repair, maintaining cellular homeostasis. It also participates in regulating tumor cell growth and survival pathways and promotes tumorigenesis and progression. Elevated PRMT5 expression has also been shown to be associated with poor prognosis in various cancers, making it a highly promising epigenetic target.

[0003] Methylthioadenosine phosphorylase (MTAP) catalyzes the conversion of methylthioadenosine (MTA) to methionine, which is essential for maintaining normal cellular function. Loss of the MTAP gene leads to intracellular accumulation of MTA. MTA competes with the PRMT5 substrate SAM, reducing PRMT5 activity and generating a large number of PRMT5-MTA complexes. Loss of the MTAP gene increases tumor dependence on PRMT5. Inhibiting PRMT5 can lead to a "synthetic lethality" effect in MTAP-deficient tumors. PARP inhibitors, based on this "synthetic lethality" theory, have achieved significant success in precision medicine for oncology. The MTAP gene is adjacent to the most common tumor suppressor gene in human cancers, CDKN2A, and is frequently co-deleted with CDKN2A. This co-deletion occurs in 10%-15% of all cancers, primarily in non-small cell lung cancer (12%-20%), glioma (53%), pancreatic cancer (30%), and DLBCL (20%), suggesting significant market potential.

[0004] Currently, there are no PRMT5 inhibitors on the market. Early PRMT5 inhibitors were non-selective, substrate-competitive inhibitors of SAM, which resulted in severe hematologic side effects and a narrow safety window. First-generation PRMT5 inhibitors GSK-3326595, JNJ-64619178, and PF-06939999 have made poor clinical progress. A new generation of PRMT5 inhibitors targeting the PRMT5-MTA complex is only effective against tumors with MTAP deficiency and MTA enrichment, with high selectivity for wild-type MTAP. This mechanistically reduces hematologic toxicity and has been validated in preclinical studies, potentially significantly increasing the safety window.

[0005] This patent relates to a novel, selective PRMT5-MTA inhibitor that is active only against MTAP-deficient cells and exhibits minimal inhibition against wild-type MTAP cells. This approach avoids the hematologic toxicity and other side effects associated with clinically unselective PRMT5 inhibitors. As a novel PRMT5-MTA inhibitor, the highly selective PRMT5-MTA inhibitor 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), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the general formula (I) is as follows:

[0007] M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -; preferably -CR b -; M3 is selected from N or C; preferably N;

[0008] 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;

[0009] Ring B is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; preferably C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Condensed cycloalkyl, 6-10 membered condensed heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0010] L1 is selected from a bond, -(CR aa R bb) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 C(S)-、-(CR aa R bb ) m2 C(NR cc )-、-(CR aa R bb ) m2 NR cc C(O)-、-(CR aa R bb ) m2 S(O) m1 -、-(CR aa R bb ) m2 NR cc -、-(CR aa R bb ) m2 P(O)2-、-(CR aa R bb ) m2 P(O)(OR cc )-、C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 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 Halogenated alkyl, 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; preferably -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ;

[0011] L2 is selected from a bond, -(CR aa Rbb ) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 NR cc C(O),-(CR aa R bb ) m2 S(O) m1 -or-(CR aa R bb ) m2 NR cc -; preferably -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ;

[0012] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6-deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -(CR cc R dd ) n1 -C 3-12 Cycloalkyl, -(CR cc R dd ) n1 -3-12 membered heterocyclic group, -(CR cc R dd ) n1 -C 6-12 Aryl, -(CR cc R dd ) n1 -5-12 membered heteroaryl, -SF5, -OR e 、-NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-N=S(O)R e R f 、-S(O)R e (=NR f ) or -P(O)R e Rf , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 Halogenated alkyl, 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 gg R hh 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 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, -(CR cc R dd ) n1 -C 3-8 Cycloalkyl, -(CR cc R dd ) n1 -3-8 membered heterocyclic group, -(CR cc R dd ) n1 -C 6-10 Aryl, -(CR cc R dd ) n1 -5-10 membered heteroaryl, -OR e 、-NR e R f 、-C(O)Re 、-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 Halogenated alkyl, 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 Halogenated alkyl, 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;

[0013] R2 is selected from hydrogen, 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 Halogenated alkyl, 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) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee Rff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 Halogenated alkyl, 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; 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 Halogenated alkyl, 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 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 1-3Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, 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 Halogenated alkyl, 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;

[0014] R3 is selected from hydrogen, 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 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -Y1-C 3-12 Cycloalkyl, -Y1-3-12 membered heterocyclic group, -Y1-C 6-12 Aryl, -Y1-5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h ),-P(O)R g R h 、-C(=NR i )NR g R h or =R g R h , the amino group, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f 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 Halogenated alkyl, 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 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 Halogenated alkyl, 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 6-10Aryl 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 Halogenated alkyl, 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 and =CR e R f is substituted by one or more substituents;

[0015] Or any two R3 atoms are 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 Halogenated alkyl, 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; 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, 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 Halogenated alkyl, 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;

[0016] R a 、R b 、R c 、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, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 Halogenated alkyl, 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 gg R hh 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 Halogenated alkyl, 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 Halogenated alkyl, 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 Halogenated alkyl, 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;

[0017] or R a With R b 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 Halogenated alkyl, 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] Y1 is selected from a bond, -O-, -S-, -C(O), -NR j -、-C(O)NR j -、-NR j C(O)-、-S(O)2NR j -、-NR j S(O)2-、C 1-6 Alkylene, -OC 1-6 Alkylene-, -C 1-6 Alkylene-O-, -NR j -C 1-6 Alkylene-, -C 1-6 Alkylene-NR j -、C 2-6 Alkenylene or C 2-6 Alkynylidene, the C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne, optionally deuterated, 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 Halogenated alkyl, 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;

[0019] R g 、R h 、R i and R j 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 Halogenated alkyl, 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 Halogenated alkyl, 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 Halogenated alkyl, 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; 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 Halogenated alkyl, C 1-3 Alkoxy, C1-3 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 Halogenated alkyl, 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 Halogenated alkyl, 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;

[0020] R aa 、R bb 、R cc and R dd 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 Halogenated alkyl, 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, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 Halogenated alkyl, 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; 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 Halogenated alkyl, 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 Halogenated alkyl, 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 1-3Alkyl, 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;

[0021] 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 Halogenated alkyl, 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 Halogenated alkyl, 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 Halogenated alkyl, 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 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 Halogenated alkyl, 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 Halogenated alkyl, 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 Halogenated alkyl, 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;

[0022] R gg and R hh 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 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C1-6 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 Halogenated alkyl, 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 Halogenated alkyl, 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; 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 Halogenated alkyl, 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 Halogenated alkyl, C 1-3 Alkoxy, C 1-3Halogenated 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 Halogenated alkyl, 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;

[0023] x is selected from 0, 1, 2, 3, 4, 5 or 6; y is selected from 0, 1, 2, 3, 4, 5 or 6;

[0024] m1 is selected from 0, 1 or 2; n1 is selected from 0, 1, 2, 3 or 4; and

[0025] n2 is selected from 0, 1, 2, 3 or 4.

[0026] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that Selected from

[0027] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (III-C):

[0028] R 1-1 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 Halogenated alkyl, 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)n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 Halogenated alkyl, 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 gg R hh is substituted by one or more substituents;

[0029] R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 Halogenated alkyl, 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 Halogenated alkyl, 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;

[0030] R gg and R hh 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 Halogenated alkyl, 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, 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 Halogenated alkyl, 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 Halogenated alkyl, 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; n2 is selected from 0, 1, 2, 3 or 4;

[0031] Ring A, Ring B, M1, M2, M3, L2, R2, R3, R c , x and y are as defined in any of the above embodiments.

[0032] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that Ring A is selected from a 3-12 membered heterocyclic group or a 5-12 membered heteroaryl group; preferably a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 5-membered heteroaryl group or a 6-membered heteroaryl group; more preferably More preferred

[0033] 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 a 3-6 membered heterocyclyl and phenyl group or a 3-6 membered heterocyclyl and 5-6 membered heteroaryl group; preferably

[0034] 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 a 6-14 membered tricyclic heterocyclic group; preferably a 6-14 membered tricyclic spiro heterocyclic group or a 6-14 membered tricyclic fused heterocyclic group; more preferably

[0035] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (IV-A):

[0036] M4 is selected from N or CR 3a ; M4 is selected from N or CR 3b ;

[0037] R 3a 、R 3c and R 3d are each independently 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 Halogenated alkyl, 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 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 Halogenated alkyl, 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 Halogenated alkyl, C 1-3 Alkoxy, C 1-3Halogenated 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 and =CR e R f is substituted by one or more substituents;

[0038] R 3b 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 Halogenated alkyl, 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 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 Halogenated alkyl, 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 Halogenated alkyl, 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 and =CR e R f substituted by one or more substituents in ; n3 is selected from 0, 1 or 2.

[0039] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized by being further represented by general formula (IV-B):

[0040] M5 is selected from N or C; M6 is selected from N or C;

[0041] Ring C is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0042] R 3e 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 Halogenated alkyl, 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 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 Halogenated alkyl, 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 Halogenated alkyl, 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 and =CR e R fis substituted by one or more substituents;

[0043] R 3f 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 Halogenated alkyl, 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 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 Halogenated alkyl, 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 Halogenated alkyl, 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 and =CR e R f is substituted by one or more substituents;

[0044] n3 is selected from 0, 1 or 2; p is selected from 0, 1, 2, 3 or 4; q is selected from 0, 1 or 2.

[0045] In a preferred embodiment of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt is characterized in that R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl or -C(O)NR ee R ff , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl and C 3-8 Cycloalkyl, optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl and C 3-8 substituted by one or more substituents in the cycloalkyl group;

[0046] R ee and R ff are each independently selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 alkyl;

[0047] Preferred are hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, trifluoromethyl,

[0048] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that R a 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 C substituted with haloalkyl or cyano 1-3 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl or trifluoromethyl.

[0049] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that R b Selected from hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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, --(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, 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 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C1-3 Hydroxyalkyl, cyano substituted C 1- 3 alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl and =CR gg R hh Preferably, hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, 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 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3- 8-membered cycloalkyl or 3-8-membered heterocyclic group or one or more substituents;

[0050] R ee and R ff 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 Halogenated alkyl, 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 or 3-8 membered heterocyclic group, the amino group, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1- 3-hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, 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;

[0051] n2 is selected from 0, 1 or 2;

[0052] Preferred are hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, trifluoromethoxy,

[0053] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that R 1-1 Selected from C 1-3Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl and cyano substituted C 1-3 Alkyl, optionally deuterated, 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 Halogenated alkyl, 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 gg R hh is substituted by one or more substituents.

[0054] The present invention also provides an intermediate, characterized in that the intermediate is a compound represented by the general formula (IV-AI) or (IV-BI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0055] R 1-1 As claimed in claim 3;

[0056] M4, M5, M6, R 1-1 、R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f , p, q, n3 and n4 are as described in any of the above embodiments.

[0057] The present invention also provides a method for preparing a compound represented by general formula (III-C), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that:

[0058] The compound represented by the general formula (III-CI) reacts with the compound represented by the general formula (III-C-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (III-C-III), and the protecting group is further removed to obtain the compound represented by the general formula (III-C);

[0059] Preferably, the method is a method for preparing a compound represented by general formula (IV-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0060] The compound represented by the general formula (IV-AI) reacts with the compound represented by the general formula (IV-A-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (IV-A-III), and the protecting group is further removed to obtain the compound represented by the general formula (IV-A);

[0061] Alternatively, the method is a method for preparing a compound represented by general formula (IV-B), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0062] The compound represented by the general formula (IV-BI) reacts with the compound represented by the general formula (IV-B-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (IV-B-III), and the protecting group is further removed to obtain the compound represented by the general formula (IV-B);

[0063] Pg1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 1,2-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably benzyl, p-methoxybenzyl or tert-butyloxycarbonyl;

[0064] Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably hydrogen, benzyl, p-methoxybenzyl or tert-butyloxycarbonyl;

[0065] Ring A, M1, M2, M3, M4, M5, M6, R a 、R b 、R c , R2, R 1-1 、R 3a 、R 3b 、R 3c、R 3d 、R 3e 、R 3f , x, p, q, n3 and n4 are as described in any of the above embodiments.

[0066] In a preferred embodiment of the present invention, in the preparation method, the condensing agent is selected from thionyl chloride, phosphorus oxychloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyldiimidazole, ethyl chloroformate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetramethyluronium hexafluorophosphate or tetramethylchlorouronium hexafluorophosphonate; preferably phosphorus oxychloride, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetramethyluronium hexafluorophosphate or tetramethylchlorouronium hexafluorophosphonate; the base is selected from potassium carbonate, methylamine, triethylamine, diisopropylamine, pyridine, imidazole, N-methylimidazole or N-methylmorpholine.

[0067] 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.

[0068] 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.

[0069] 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; preferably, the cancer is a cancer with MTAP gene deletion.

[0070] The present invention further relates to a method for preparing a method for treating cancer using the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition; preferably, the cancer is a cancer with MTAP gene deletion.

[0071] 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, colorectal cancer, biliary tract cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung cancer or lung adenocarcinoma; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

[0072] The present invention also relates to a method for preventing and / or treating cancer, comprising 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.

[0073] 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.

[0074] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, has a weight percentage of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof of 0.1% to 95%, preferably 90%, 85%, 80%, 75%, 70%, 60% or 50%.

[0075] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, and preferably further comprises a filler, optionally a disintegrant, or further comprises one or more of a glidant or a lubricant.

[0076] In certain embodiments of the present invention, the pharmaceutical composition is a rapid-release formulation or a sustained-release formulation.

[0077] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, the unit dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is 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.

[0078] In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, can be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition adjusted accordingly.

[0079] In certain embodiments of the present invention, the compound, its stereoisomers or pharmaceutically acceptable salts thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0080] In some embodiments, the present 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, colorectal cancer, biliary tract cancer, or bile duct cancer.

[0081] 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.

[0082] Detailed Description of the Invention

[0083] 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.

[0084] 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". For example, C 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. 1-6 Alkyl groups contain 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-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched chain isomers thereof, etc. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0085] The term "alkylene" refers to an alkyl group with one hydrogen atom further substituted, 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 is an optionally substituted alkyl group as described elsewhere herein.

[0086] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be located at any position within the alkenyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkenyl group is an unsaturated aliphatic hydrocarbon 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 (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 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 Alkenyl groups contain 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.

[0087] The term "alkenylene" refers to an alkenyl group in which one hydrogen atom is further substituted, wherein "alkenyl" is as defined above. In one embodiment, the alkenylene group is an optionally substituted alkyl group as described elsewhere herein.

[0088] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which may be located at any position within the alkynyl group, and which may be optionally substituted with one or more substituents. In a particular 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 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.

[0089] The term "alkynylene" refers to an alkynyl group in which one hydrogen atom is further substituted, wherein "alkynyl" is as defined above. In one embodiment, the alkynylene group is an optionally substituted alkyl group as described elsewhere herein.

[0090] 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 particular embodiment, the cycloalkyl ring contains 3 to 20 (C 3-20 ), 3 to 14 (C 3-14 ), 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 spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl 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 group, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.

[0091] The term "spiroalkyl" refers to an aliphatic hydrocarbon polycyclic group in which the monocyclic rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the spiroalkyl group 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. Spirocycloalkyl is divided into mono-, di-, or poly-spirocycloalkyl according to the number of shared spiro atoms between the rings, and in one embodiment, is mono- and di-spirocycloalkyl. In one embodiment, it is a 4-, 3-, 5-, 4-, 5-, 4-, 6-, 5-, or 5-membered mono-spirocycloalkyl. In one embodiment, the spirocycloalkyl is an optionally substituted spirocycloalkyl described elsewhere herein. Non-limiting examples of spirocycloalkyl include:

[0092] 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 group comprises 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 fused cycloalkyl groups, and in one embodiment, it is bicyclic or tricyclic, and further in one embodiment, it is a 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl group. In one embodiment, the fused cycloalkyl group is an optionally substituted fused cycloalkyl group described elsewhere herein or a fused cycloalkyl group optionally fused with a heterocyclic group, an aryl group or a heteroaryl group. Non-limiting examples of fused cycloalkyl groups include:

[0093] 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 group comprises 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. Depending on the number of constituent rings, the bridged cycloalkyl group may be bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic or tricyclic. In one embodiment, the bridged cycloalkyl group is an optionally substituted bridged cycloalkyl group described elsewhere herein. Non-limiting examples of bridged cycloalkyl groups include:

[0094] The term "cycloalkylene" refers to a divalent cycloalkyl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the cycloalkylene group is optionally substituted or unsubstituted, and the cycloalkyl group is as defined above.

[0095] 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 atoms 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 certain embodiments, the heterocyclyl group contains 3 to 20, 8 to 20, 10 to 20, 3 to 16, 8 to 16, 10 to 16, 3 to 14, 5 to 14, 8 to 14, 3 to 12, 5 to 12, 8 to 12, 3 to 8, or 3 to 6 ring atoms, of which 1-4 are heteroatoms; in one embodiment, the heterocyclyl group 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 group 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 bridged heterocyclic radical.In one embodiment, described 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.

[0096] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the rings, 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 no ring has a completely conjugated π electron system. In a specific embodiment, the spiroheterocyclyl comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; the spiroheterocyclyl is divided into a monospiroheterocyclyl, a bispiroheterocyclyl or a polyspiroheterocyclyl according to the number of spirohetero atoms shared between the rings; monospiroheterocyclyl and bispiroheterocyclyl are preferred; in one embodiment, the spiroheterocyclyl is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl; in one embodiment, the spiroheterocyclyl is an optionally substituted spiroheterocyclyl described elsewhere herein; non-limiting examples of spiroheterocyclyls include:

[0097] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the 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 heterocyclyl is a heterocyclic group containing 5 to 20 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 heterocyclyl; preferably a bicyclic or tricyclic group; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl; in one embodiment, the fused heterocyclyl is an optionally substituted or fused heterocyclyl described elsewhere herein, or a cycloalkyl, heterocyclyl, aryl or heteroaryl group; non-limiting examples of fused heterocyclyls include:

[0098] 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 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 specific embodiments, 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 bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups; preferably bicyclic, tricyclic or tetracyclic; in one embodiment, it is bicyclic or tricyclic; 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:

[0099] 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, aryl or heteroaryl. The definitions of cycloalkyl, heterocyclic, aryl or heteroaryl are as described above. Non-limiting examples thereof are preferably the following tricyclic heterocyclic groups:

[0100] The term "heterocyclylene" refers to a divalent heterocyclic group in which one hydrogen atom of a heterocyclic group is further substituted, wherein the heterocyclic group is optionally substituted or unsubstituted, and the heterocyclic group is as defined above.

[0101] 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 with one or more substituents. In specific embodiments, the aryl group contains 6 to 20, 6 to 14, 6 to 12, 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 aromatic and the other rings may be saturated, partially unsaturated, or contain 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 group, a benzo 3-10 membered cycloalkyl group, or a benzo 3-10 membered heterocyclyl group. In one embodiment, the aryl group is selected from a benzo 5-6 membered heteroaryl group, a benzo 3-6 membered cycloalkyl group, or a benzo 3-6 membered heterocyclyl group, 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),

[0102] The term "arylene group" refers to a divalent aromatic group formed by further replacing one hydrogen atom of an aromatic group, wherein the arylene group is optionally substituted or unsubstituted, and the aromatic group is as defined above.

[0103] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S and N. In particular embodiments, the heteroaryl group contains 5 to 20, 5 to 14, 5 to 12 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 particular 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 a heteroaryl group with 6-10 members, a heteroaryl group with 3-10 members, or a heteroaryl group with 3-10 members, and a heterocyclyl group with 3-10 members. In another embodiment, the heteroaryl group is selected from a 5- or 6-membered heteroaryl group with 6-10 members, a 5- or 6-membered heteroaryl group with 3-6 members, and a 5- or 6-membered heterocyclyl group, 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, benzothienyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl , indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl, acridinyl, benzindolyl, carbazolyl, bibenzofuranyl, phenanthrolinyl, phenanthridinyl, phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,

[0104] 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.

[0105] The term "heteroalkyl" refers to a stable straight or branched chain, or cyclic hydrocarbon radical, 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 is optionally quaternized. In one embodiment, the heteroatoms O, N, and S can be placed at any interior position of the heteroalkyl group. In one embodiment, the heteroatom Si can 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 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 can 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.

[0106] 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.

[0107] The term "alkylacyl" refers to a -C(O)-alkyl group, wherein alkyl is as previously defined.

[0108] 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,

[0109] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.

[0110] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0111] 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.

[0112] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogen groups, wherein alkylthio is as defined above.

[0113] 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.

[0114] The term "aminocarbonyl" refers to NH2-C(O)-.

[0115] The term "alkylaminocarbonyl" refers to an aminocarbonyl (NH2-C(O)-) group in which one or both of the hydrogen atoms are replaced by an alkyl group, wherein the alkyl group is as defined above.

[0116] The term "alkylamino" refers to an amino group in which one or both of the hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.

[0117] The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably in the specification.

[0118] The term "halogen" refers to fluorine, chlorine, bromine or iodine. The term "oxo" or "oxo" refers to =0.

[0119] The term "C(X)" or "C(=X)" refers to When X is O, it represents that the group is a carbonyl group; when X is S, it represents that the group is a thiol group; when X is NR, it represents that the group is When X is CRR, it represents the group

[0120] 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 by appropriately isotopically labeled starting materials obtained from commercial sources or by known literature procedures.

[0121] 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 substituents are 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.

[0122] 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”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0123] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that 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.

[0124] 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 to be 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 a linking alkylene group or arylene group, respectively.

[0125] "Substituted" refers to any one or more hydrogen atoms on a particular atom being 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" refers to being substituted or not substituted, and unless otherwise specified, the type and number of the substituent can be arbitrary on the basis of chemical achievable. It goes without saying that the substituent is only in its 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. The substituent can be selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl.

[0126] "Substituted or unsubstituted" means that it may be substituted or unsubstituted. When it may be substituted, the substituent 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 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -SF5, -C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, C(O)R, C(O)OR, C(O)NRR', N=S(O)RR', S(O)R(=NR'), P(O)RR' or =RR';

[0127] R and 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, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 or 5-12 membered heteroaryl.

[0128] 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.

[0129] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with 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, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0130] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0131] "Stereoisomers" encompass all enantiomerically / diastereomerically / stereomerically pure and enantiomerically / diastereomerically / stereomerically enriched forms of the compounds of the invention.

[0132] "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 comprises 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.

[0133] "Stereoisomerically enriched" refers to a composition comprising greater than about 55% by weight, greater than about 60% by weight, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.

[0134] "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.

[0135] "Optically active" and "enantiomeric active" 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.

[0136] When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about 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 of the optical rotations (+) and (-) have nothing to do with the absolute configuration, R or S, of the molecule. DETAILED DESCRIPTION

[0137] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0138] Example

[0139] 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. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and tetramethylsilane (TMS) as the internal standard.

[0140] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0141] HPLC determination 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).

[0142] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0143] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0144] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0145] 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, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0146] Unless otherwise specified in the examples, the reactions can be carried out under argon atmosphere or nitrogen atmosphere. Argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L, and hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

[0147] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator. The hydrogenation reaction is usually carried out by evacuating the vacuum and filling with hydrogen, and the operation is repeated three times.

[0148] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0149] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0150] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0151] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0152] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound 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.

[0153] Example 1

[0154] (4-Amino-1-methylimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone

[0155] Step 1: Dissolve 2-methyl-1H-imidazole 1a (5 g, 60.89 mmol) in DMSO (50 mL). Slowly add DBU (13.91 g, 91.35 mmol, 14 mL) and methyl 3-fluoro-4-nitrobenzoate (13.34 g, 66.99 mmol). Stir the reaction at 25°C for 2 hours. Add water (200 mL) and extract with ethyl acetate (200 mL x 3). Combine the organic phases, wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using eluent System C to afford 1b (9 g) in a 56.6% yield. MS m / z (ESI): 262 [M+1]. +

[0156] Step 2: 1b (2 g, 7.66 mmol) was dissolved in methanol (20 mL), and Pd / C (816 mg, 766 μmol, 10% purity) was added. The atmosphere was replaced with hydrogen three times. Under hydrogen protection, 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 mixture of methanol:EA = 1:10 (10 mL) for 15 minutes, filtered, and dried under reduced pressure to obtain 1c (1.45 g). Yield: 81.9%. MS m / z (ESI): 232 [M+1]. +

[0157] Step 3: 1c (1 g, 4.32 mmol) was dissolved in DCM (15 mL), and DMAP (265 mg, 2.16 mmol) and 1-(isocyanatomethyl)-4-methoxybenzene (1.06 g, 6.49 mmol, 926 μL) were added. The reaction was stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane (10 mL) and methyl tert-butyl ether (10 mL) were added to the residue. The mixture was stirred for 15 minutes, filtered, and the filter cake was collected and dried under reduced pressure to afford 1 g (750 mg). Yield: 45.8%. MS m / z (ESI): 380 [M+1] +

[0158] Step 4: Dissolve 1g (600mg, 1.52mmol) in pyridine (2mL) and add phosphorus oxychloride (280mg, 1.83mmol, 171μL). Stir the reaction at 120°C for 16 hours. Concentrate the reaction mixture under reduced pressure, add water (50mL) to the residue, and extract with ethyl acetate (50mL x 3). Combine the organic phases, wash with saturated brine (50mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography using eluent System C to afford 1d (250mg) in a 43.7% yield. MS m / z (ESI): 377[M+1]. +

[0159] Step 5: 1d (250 mg, 664 μmol) was dissolved in water (2 mL) / methanol (2 mL) / tetrahydrofuran (6 mL). Lithium hydroxide (32 mg, 1.33 mmol) was added and stirred at 80°C for 3 hours. The 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 afford 1h (110 mg). Yield: 45.7%. MS m / z (ESI): 363 [M+1]. +

[0160] Step 6: 1h (50 mg, 138 μmol) and N-methyl-2-(trifluoromethyl)-6,8-dihydro-5H-pyran-[3,4-b]pyridin-5-amine (39 mg, 166 μmol, synthesized by the known method "Patent WO2021163344") were dissolved in DMF (2 mL), and N-methylimidazole (46 mg, 552 μmol, 44 μL) and TCFH (58 mg, 207 μmol) were added. The reaction was stirred at 25 ° C for 1.5 hours; the reaction solution was concentrated under reduced pressure, and water (15 mL) was added to the concentrated residue, and 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 concentrated residue was separated by high performance liquid chromatography to obtain 1i (55 mg), with a yield of 68.9%.

[0161] Step 7: 1i (45 mg, 78 μmol) was dissolved in trifluoroacetic acid (3 mL). The reaction was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated by HPLC to afford Example 1 (20 mg). Yield: 56.2%. MS m / z (ESI): 458 [M+1]. +

[0162] 1H NMR (400MHz, DMSO) δ8.23-8.11(m,2H),7.86(d,2H),7.60-7.38(m,4H),5.80(s,1H),4.81(dd,2H),4.20(d,2H),2.97(s,3H),2.87-2.71(m,3H).

[0163] Example 1 Preparation of Chiral Isomers

[0164] P1: (R)-(4-amino-1-methylimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone

[0165] P2: (S)-(4-amino-1-methylimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone

[0166] Example 1 (20 mg, 0.044 mmol) was separated by Chiral-HPLC to give Example 1-P1 (9.5 mg) with a yield of 47.5%. MS m / z (ESI): 487 [M+1] + Example 1-P2 (9.8 mg), yield: 49.0%. MS m / z (ESI): 487 [M+1] +

[0167] Example 2

[0168] 4-Amino-N-(2-(3,3-difluoroazetidin-1-yl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0169] Step 1: Disperse methyl 6-methoxy-2-methylnicotinate 2a (15.00 g, 82.87 mmol), N-bromosuccinimide (29.00 g, 162.92 mmol), and azobisisobutyronitrile (2.60 g, 15.85 mmol) in 150 mL of carbon tetrachloride and stir at 80°C for 16 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure to yield 2b (30.50 g, crude product). MS m / z (ESI): 338 [M+1] +

[0170] Step 2: Disperse 2b (30.50 g, crude), diethyl phosphite (14.00 g, 101.45 mmol), and N,N-diisopropylethylamine (26.00 g, 201.55 mmol) in 400 mL of dichloromethane and stir at 25°C for 2 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent System B to afford 2c (12.00 g) in a 55.9% yield. MS m / z (ESI): 260 [M+1] +

[0171] Step 3: Disperse methyl 2-hydroxyacetate (8.50 g, 94.44 mmol) in 200 mL of N,N-dimethylformamide. Add sodium hydride (5.70 g, 142.48 mmol, 60% dispersion in mineral oil) at 0°C and stir for 1 hour. Add 2c (12.00 g, 46.33 mmol) and stir at 25°C for 16 hours. The reaction mixture is poured into 2000 mL of water and extracted with ethyl acetate (300 mL x 3). The organic phases are combined, washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 2d (22.00 g, crude product). MS m / z (ESI): 238 [M+1] +

[0172] Step 4: Disperse 2d (22.00 g, crude) in 100 mL of ethanol and 100 mL of concentrated hydrochloric acid, and stir at 100°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to afford 2e (4.00 g) in a 52.3% yield. MS m / z (ESI): 166 [M+1] +

[0173] Step 5: Disperse 2e (4.00 g, 24.24 mmol) in 30 mL of phosphorus oxychloride and stir at 90°C for 2 hours. Concentrate under reduced pressure, and the residue is dispersed in 300 mL of dichloromethane. Wash with saturated sodium bicarbonate solution (200 mL x 2) and sodium chloride solution (200 mL x 2), sequentially, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give 2f (4.30 g) in a 96.9% yield. MS m / z (ESI): 184 [M+1] +

[0174] Step 6: Disperse 2f (300 mg, 1.64 mmol), 3,3-difluorotrimethyleneimine hydrochloride (260 mg, 2.02 mmol), and N,N-diisopropylethylamine (800 mg, 6.20 mmol) in 5 mL of acetonitrile and stir at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent System B to yield 2g (240 mg), in a 61.0% yield. MS m / z (ESI): 241 [M+1] +

[0175] Step 7: Disperse 2g (240 mg, 1.00 mmol) and methylamine (310 mg, 3.00 mmol, 30% methanol solution) in 3 mL of trifluoroethanol and stir at 25°C for 16 hours. Add sodium cyanoborohydride (130 mg, 2.06 mmol) and stir 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 afford 2h (150 mg) in a 58.8% yield. MS m / z (ESI): 256 [M+1] +

[0176] Referring to the synthesis method of step 6 of Example 1, Example 2 (9 mg) was obtained by 2h (50 mg, 0.20 mmol), with a yield of 9.3%. MS m / z (ESI): 480 [M+1] +

[0177] Example 3

[0178] 4-amino-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide

[0179] Step 1: 4-Amino-3-nitro-benzoic acid methyl ester 3a (5 g, 25.49 mmol) was dissolved in dichloromethane (50 mL), and DIEA (3.95 g, 30.59 mmol, 5.5 mL), DMAP (155.70 mg, 1.27 mmol), and di-tert-butyl dicarbonate (6.68 g, 30.59 mmol) were added in sequence. The reaction was stirred at 25°C for 2 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified with eluent system C to obtain 3b (6.5 g) in a yield of 86.0%.

[0180] Step 2: Dissolve 3b (5 g, 16.88 mmol) in methanol (60 mL) and add Pd / C (2.05 g, 1.69 mmol, 10% purity). Stir the reaction at 50°C for 16 hours. Filter the reaction mixture through a diatomaceous earth filter funnel. The filtrate is collected and concentrated under reduced pressure to afford 3c (4 g) in an 89.0% yield. MS m / z (ESI): 267 [M+1] +

[0181] Step 3: 3c (1 g, 3.76 mmol) was dissolved in N,N-dimethylformamide (12 mL), and ethyl 2-oxoacetate 3d (575.05 mg, 5.63 mmol, 559 μL) was added. The reaction was stirred in a microwave at 100°C for 10 minutes. The reaction was completed to obtain 3e, which was used directly in the next step.

[0182] Step 4: 3e (600 mg, 1.78 mmol) was dissolved in N,N-dimethylformamide (7 mL), and tosylmethyl isocyanate 3f (417.95 mg, 2.14 mmol) and potassium carbonate (493.11 mg, 3.57 mmol) were added. The reaction was stirred in a microwave at 80°C for 10 minutes. Water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed with saturated brine (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3g (700 mg), which was used directly in the next step.

[0183] Step 5: Dissolve 3g (600mg, 1.54mmol) in 1,2-dichloroethane (6mL) / trifluoroacetic acid (0.6mL) and stir in a microwave at 80°C for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was stirred with dichloromethane (10mL) for 15 minutes, filtered, and the filter cake was dried under reduced pressure to obtain 3h (200mg). Yield: 53.4%. MS m / z (ESI): 244[M+1] +

[0184] Step 6: Dissolve 3h (200 mg, 822 μmol) in phosphorus oxychloride (3 mL) and stir at 180°C for 8 hours. The reaction mixture was concentrated under reduced pressure, and water (15 mL) was added to the concentrated residue to separate the organic phase. The aqueous layer was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3i (100 mg), which was used directly in the next step. MS m / z (ESI): 262 [M+1] +

[0185] Step 7: Dissolve 3i (100 mg, 383 μmol) in N,N-dimethylformamide (2 mL), and add 4-methoxybenzylamine (99.52 mg, 726 μmol) and potassium carbonate (150.40 mg, 1.09 mmol) in this order. The reaction is stirred at 120°C for 2 hours. Water (20 mL) is added to the reaction solution, and the organic phase is separated. The aqueous layer is extracted with ethyl acetate (20 mL × 3). The organic phases are combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3j (200 mg), which is used directly in the next step. MS m / z (ESI): 363 [M+1] +

[0186] Step 8: Dissolve 3j (100 mg, 276 μmol) in water (1 mL) / methanol (1 mL) / tetrahydrofuran (3 mL) and add lithium hydroxide (25.45 mg, 1.06 mmol). Stir the reaction at 80°C for 3 hours. Adjust the pH to 5 with 0.5 M hydrochloric acid, filter, rinse the filter cake with water (5 mL), and dry under reduced pressure to obtain 3k (60 mg). Yield: 62.4%. MS m / z (ESI): 349 [M+1]. +

[0187] Step 9: 3k (50 mg, 144 μmol) and N-(cyclopropylmethyl)-2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-amine 3l (40 mg, 172 μmol) were dissolved in N,N-dimethylformamide. N-methylpyrazole (45.31 mg, 552 μmol, 46 μL) and TCFH (58.07 mg, 207 μmol) were added. The reaction was stirred at 25°C for 16 hours. The reaction solution was directly separated and purified by Pre-HPLC to obtain 3m (18 mg) in a yield of 22.3%. MS m / z (ESI): 563 [M+1]+

[0188] Step 10: 3m (18 mg, 32 μmol) was dissolved in trifluoroacetic acid (2 mL). The reaction was stirred at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by Pre-HPLC (acid method) to obtain Example 3 (6 mg). Yield: 42.4%. MS m / z (ESI): 443 [M+1]. +

[0189] 1H NMR(400MHz,DMSO)δ9.21(s,2H),8.38(s,1H),8.12(d,1H),7.94(s,1H),7.87(d, 1H),7.62–7.44(m,3H),5.83(s,1H),4.93–4.61(m,2H),4.21(s,2H),2.81(s,3H).

[0190] Example 4

[0191] 4-amino-N-(cyclopropylmethyl)-3-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5-pyrano[3,4-b]]pyridin-5-yl]imidazolyl-[1,5-a]quinoxaline-8-carboxamide

[0192] Step 1: Dissolve 2-(Trifluoromethyl)-8H-pyrano[3,4-b]pyridin-5-one 4a (500 mg, 2.30 mmol) and cyclopropylmethylamine (1.31 g, 18.42 mmol, 1.6 mL) in methanol (15 mL). Add tetraisopropyl titanate (1.96 g, 6.91 mmol, 2 mL). Stir the reaction at 25°C for 16 hours. Then add sodium acetate borohydride (732.02 mg, 3.45 mmol) and stir at 25°C for 30 minutes. Add saturated aqueous sodium bicarbonate (8 mL) to the reaction mixture, filter, collect the filtrate, and concentrate under reduced pressure. The residue is separated by Pre-TLC to afford 4b (52 mg) in an 8.3% yield. MS m / z (ESI): 273 [M+1]. +

[0193] Step 2: 4c (5 g, 25.49 mmol) was dissolved in dichloromethane (50 mL), and DIEA (3.95 g, 30.59 mmol, 5.5 mL), DMAP (155.70 mg, 1.27 mmol), and di-tert-butyl dicarbonate (6.68 g, 30.59 mmol) were added in sequence. The reaction was stirred at 25°C for 2 h. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified with eluent System C to give 4d (6.5 g) in a yield of 86.0%.

[0194] Step 3: Dissolve 4d (5 g, 16.88 mmol) in methanol (60 mL) and add Pd / C (2.05 g, 1.69 mmol, 10% purity). Stir the reaction at 50°C for 16 hours. Filter the reaction mixture through a diatomaceous earth filter funnel. The filtrate is collected and concentrated under reduced pressure to afford 4e (4 g) in an 89.0% yield. MS m / z (ESI): 267 [M+1] +

[0195] Step 4: 4e (1 g, 3.76 mmol) was dissolved in N,N-dimethylformamide (12 mL), and ethyl 2-oxoacetate (575.05 mg, 5.63 mmol, 559 μL) was added. The reaction was stirred in a microwave at 100°C for 10 min. After the reaction was completed, the product was used directly in the next step.

[0196] Step 5: 4f (500 mg, 1.49 mmol) was dissolved in N,N-dimethylformamide (7 mL), and 1-methyl-1-toluenesulfonylmethyl isocyanate (373.30 mg, 1.78 mmol) and potassium carbonate (410.92 mg, 2.97 mmol) were added. The reaction was stirred in a microwave at 80°C for 10 minutes. Water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL×3). The organic phases were combined, washed with saturated brine (60 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4 g, which was used directly in the next step.

[0197] Step 6: Dissolve 4g (600mg, 1.49mmol) in 1,2-dichloroethane (6mL) / trifluoroacetic acid (0.6mL). The reaction was stirred at 80°C in a microwave oven for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was stirred with dichloromethane (10mL) for 15 minutes, filtered, and the filter cake was dried under reduced pressure to obtain 4h (200mg). Yield: 52.3%. MS m / z (ESI): 258[M+1] +

[0198] Step 7: Dissolve 4h (200 mg, 778 μmol) in phosphorus oxychloride (3 mL) and stir at 180°C for 8 hours. The reaction mixture was concentrated under reduced pressure, and water (15 mL) was added to the concentrated residue to separate the organic phase. The aqueous layer was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 4i (100 mg), which was used directly in the next step. MS m / z (ESI): 276 [M+1] +

[0199] Step 8: Dissolve 4i (100 mg, 363 μmol) in N,N-dimethylformamide (2 mL), and add 4-methoxybenzylamine (99.52 mg, 726 μmol) and potassium carbonate (150.40 mg, 1.09 mmol) in this order. The reaction is stirred at 120°C for 2 hours. Water (20 mL) is added to the reaction solution, and the organic phase is separated. The aqueous layer is extracted with ethyl acetate (20 mL × 3). The organic phases are combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4j (200 mg), which is used directly in the next step. MS m / z (ESI): 377 [M+1] +

[0200] Step 9: Dissolve 4j (100 mg, 266 μmol) in water (1 mL) / methanol (1 mL) / tetrahydrofuran (3 mL). Add lithium hydroxide (25.45 mg, 1.06 mmol). Stir the reaction at 80°C for 3 hours. Adjust the pH to 5 with 0.5 M hydrochloric acid, filter, rinse the filter cake with water (5 mL), and dry under reduced pressure to obtain 4k (60 mg). Yield: 62.3%. MS m / z (ESI): 363 [M+1]. +

[0201] Step 10: 4k (50 mg, 138 μmol) and 4b (45.08 mg, 166 μmol) were dissolved in N,N-dimethylformamide. N-methylpyrazole (45.31 mg, 552 μmol, 46 μL) and TCFH (58.07 mg, 207 μmol) were added. The reaction was stirred at 25°C for 16 hours. The reaction solution was directly purified by Pre-HPLC to afford 4 (18 mg) in a 21.2% yield. MS m / z (ESI): 617 [M+1]. +

[0202] Step 11: 4 (18 mg, 29 μmol) was dissolved in trifluoroacetic acid (2 mL) and the reaction was stirred at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative HPLC (acid method) to give Example 4 (6 mg) in a 41.4% yield. MS m / z (ESI): 497 [M+1]. +

[0203] 1H NMR(400MHz,DMSO)δ9.07(s,1H),8.25(d,2H),7.81(d,1H),7.41(s,2H),6.88(s,2H),5.32(t,1H),4.94 –4.63(m,2H),4.28(s,2H),2.63(s,3H),2.00(q,1H),1.26–1.21(m,2H),1.09–0.73(m,2H),0.32(d,2H).

[0204] Example 5

[0205] 4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0206] Referring to steps 9 to 10 of Example 3, 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid 5a (90 mg) and N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine 5c (40 mg, synthesized using the known method "Patent WO2022169948") were used to obtain Example 5 (10.9 mg) in a yield of 26%. MS m / z (ESI): 428 [M+1] +

[0207] 1 HNMR(400MHz,DMSO)δ9.16(s,1H),8.32(s,1H),7.91(s,1H),7.64(d,1H),7.48(s,2H) ,7.41(s,2H),7.33(d,1H),7.24(s,1H),4.82–4.65(m,2H),2.68(s,3H),1.99(s,1H).

[0208] Example 6

[0209] 4-amino-N,7-dimethyl-N-(8-methyl-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0210] Step 1: Dissolve methyl 2-chloro-6-methoxy-pyridine-3-carboxylate 6a (9 g, 44.64 mmol), potassium vinyl fluoroborate (11.96 g, 89.28 mmol), and potassium carbonate (12.34 g, 89.28 mmol) in water (20 mL) and 1'4-dioxane (100 mL). The mixture was purged with nitrogen three times. 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (3.27 g, 4.46 mmol) was added, and the reaction system was stirred at 90°C for 15 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography using eluent System B to afford 6b (6 g) in a 69.6% yield. MS m / z (ESI): 194 [M+1] +

[0211] Step 2: Dissolve 6b (6 g, 31.06 mmol) in methanol (100 mL). The atmosphere was purged with nitrogen three times. Palladium on carbon (377 mg, 0.31 mmol, 10% purity) was added. The reaction system was stirred at 25°C under a hydrogen balloon for 2 hours. The reaction mixture was filtered and concentrated to afford 6c (5.90 g, crude product). MS m / z (ESI): 196 [M+1] +

[0212] Step 3: Dissolve 6c (5.9 g, 30.22 mmol), azobisisobutyronitrile (496 mg, 3.02 mmol), and N-bromosuccinimide (8.61 g, 48.36 mmol) in carbon tetrachloride (60 mL). The atmosphere was purged with nitrogen three times and heated to 90°C for reaction. The reaction mixture was cooled to room temperature, concentrated, and water was added. The mixture was washed with ethyl acetate (100 mL x 3), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 6d (7.50 g) in a 90.5% yield. MS m / z (ESI): 275 [M+1]. +

[0213] Referring to the synthesis method from the third to the fourth step of Example 2, 2-hydroxy-8-methyl-6H-pyrano[3,4-b]pyridin-5(8H)-one 6f (2.60 g) was obtained from 6d (7.80 g, 28.46 mmol). Yield: 51.0% MS m / z (ESI): 180 [M+1] +

[0214] Step 6: Dissolve 6f (0.5 g, 2.79 mmol) in dichloromethane (40 mL), purge the nitrogen atmosphere three times, cool to 0°C, add triethylamine (339 mg, 3.35 mmol, 0.47 mL) and trifluoromethanesulfonic anhydride (866 mg, 3.07 mmol), and react at 25°C for 2 hours. Sodium iodide (2.09 g, 13.95 mmol) and concentrated hydrochloric acid (12 M, 0.28 mL) were then added to the mixture, and the reaction was continued at 20°C for 15 hours. Filter and concentrate. The residue was purified by silica gel column chromatography using eluent System B to afford 6g (0.35 g) in a 43.4% yield. MS m / z (ESI): 290 [M+1] +

[0215] Step 7: Dissolve 6g (0.32g, 1.11mmol) and cuprous iodide (527mg, 2.77mmol) in N,N-dimethylformamide (5mL), add methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (532mg, 2.77mmol), purge with nitrogen three times, and heat to 100°C for 2 hours. The reaction mixture was cooled to room temperature, concentrated, added with water, washed with ethyl acetate (5mL×3), washed with brine (3mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent System B to give 6h (0.14g) in a yield of 54.7%. MS m / z (ESI): 232[M+1] +

[0216] Step 8: Dissolve 6h (0.14 g, 0.61 mmol) and methylamine alcohol solution (314 mg, 3.03 mmol, 30% purity) in trifluoroethanol (10 mL). The atmosphere was purged with nitrogen three times and the reaction was allowed to proceed at 25°C for 2 hours. Sodium cyanoborohydride (76 mg, 1.21 mmol) was added and the reaction was allowed to proceed at 25°C for 1 hour. 10 mL of saturated sodium bicarbonate solution was added to the reaction, and the system was stirred at room temperature for one hour. The product was extracted with dichloromethane / methanol = 10 / 1 (50 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System A to afford 6i (80 mg) in a 53.6% yield. MS m / z (ESI): 247 [M+1]. +

[0217] Referring to the synthesis method of steps 9 to 10 of Example 3, Example 6 was obtained by using 4-[(3,5-dimethoxyphenyl)methylamino]-7-methyl-imidazo[1,5-a]quinoxaline-8-carboxylic acid 6j (160 mg, 0.41 mol) and 6i (100 mg, 0.41 mmol), and further separation gave Example 6-1 (23 mg) and Example 6-2 (10 mg). Yield: 9.5%

[0218] Example 6-1: MS m / z (ESI): 471 [M+1] +

[0219] 1 H NMR(400MHz,DMSO)δ9.05(s,1H),8.12(s,2H),7.89(s,2H),7.36(s,1H),7.12(s,2H),5. 96(s,1H),4.96(s,1H),4.31(s,1H),4.08(s,1H),2.73(d,3H),2.38(s,3H),1.50(d,3H).

[0220] Example 6-2: MS m / z (ESI): 471 [M+1] +

[0221] 1 H NMR(400MHz,DMSO)δ9.05(s,1H),8.11(d,2H),7.98–7.78(m,2H),7.36(s,1H),7.21( s,2H),5.93(s,1H),4.85(s,1H),4.26(d,2H),2.68(s,3H),2.36(s,3H),1.59(d,3H).

[0222] Example 7

[0223] 4-Amino-N-(2-bromo-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0224] Step 1: Dissolve methyl 2-chloro-3-methyl-pyridine-4-carboxylate 7a (5 g, 26.94 mmol), diphenylmethaneimine (5.37 g, 29.63 mmol), tris(dibenzylideneacetone)dipalladium (2.47 g, 2.69 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (3.12 g, 5.39 mmol), and cesium carbonate (13.17 g, 40.41 mmol) in dioxane (25 mL). The mixture was reacted at 100°C for 16 hours, resulting in a yellowish color. After completion of the reaction, the mixture was quenched by addition of H2O. 50 mL of water and 300 mL of ethyl acetate were then added to the mixture. The organic phase was washed three times with 30 mL of saturated brine, dried, and spin-dried. The resulting residue was purified by silica gel column chromatography using eluent system A to afford 7b (1.9 g) in a 42% yield. MS m / z(ESI):167[M+1] +

[0225] Step 2: Dissolve 7b (1.4 g, 8.42 mmol), 2-bromo-1,1-dimethoxyethane (1.42 g, 8.42 mmol), and p-toluenesulfonic acid (725 mg, 4.21 mmol) in N,N-dimethylformamide (15 mL) and react at 100°C for 16 hours. The reaction solution turns yellow. After completion, the reaction is quenched by the addition of 10 mL of saturated ammonium chloride. The mixture is extracted with ethyl acetate (100 mL x 3). The organic phases are combined and washed with saturated sodium chloride solution (30 mL x 2). The organic phases are separated, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using eluent System A to afford 7c (0.64 g) in a 39% yield. MS m / z (ESI): 191 [M+1]. +

[0226] Step 3: Dissolve 7c (60 mg, 0.315 mmol), N-bromosuccinimide (56 mg, 0.31 mmol), and azobisisobutyronitrile (15 mg, 0.094 mmol) in carbon tetrachloride (4 mL) and react at 80°C for 16 hours. The reaction solution turns yellow. After completion, cool, concentrate, and quench with 10 mL of water. Extract with ethyl acetate (50 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using eluent System A to afford 7d (0.06 g) in a 70% yield. MS m / z (ESI): 269 [M+1]. +

[0227] Step 4: Dissolve 7d (30 mg, 0.11 mmol), N-bromosuccinimide (20 mg, 0.11 mmol), and azobisisobutyronitrile (6 mg, 0.034 mmol) in carbon tetrachloride (3 mL). React at 80°C for 16 hours. The reaction solution turns yellow. Stir at 90°C for 16 hours. After completion of the reaction, cool, filter, and spin dry to obtain 7e (25 mg). Yield: 64%. MS m / z (ESI): 349 [M+1]. +

[0228] Step 5: Dissolve 7e (380 mg, 1.09 mmol), methyl glycolate (216 mg, 2.40 mmol), and sodium hydride (65 mg, 2.73 mmol) in N,N-dimethylformamide (8 mL) and react at 20°C for 16 hours. After completion, the reaction was quenched by adding 10 mL of water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford 7f (180 mg) in a 46% yield. MS m / z (ESI): 357 [M+1]. +

[0229] Step 6: Dissolve 7f (50 mg, 0.14 mmol) and lithium bis(trimethylsilyl)amide (46 mg, 0.28 mmol) in tetrahydrofuran (2 mL) and react at -55°C for 1 hour. The reaction solution turns yellow. After the reaction is complete, the crude product is purified by C 18 The residue was purified by column chromatography using eluent system A to give 7 g (35 mg) of the product in a 76% yield. MS m / z (ESI): 325 [M+1] +

[0230] Step 7: Dissolve 7g (26mg, 0.08mmol) and hydrochloric acid (2mL) in ethanol (2mL) and react at 80℃ for 16 hours. The reaction solution turns yellow. After the reaction is completed, cool, concentrate, and dry. The crude product is purified by C 18 The residue was purified by column chromatography using eluent system A to give 7h (8 mg) in a 37% yield. MS m / z (ESI): 267 [M+1] +

[0231] Step 8: 7h (30 mg, 0.11 mmol), methylamine (7 mg, 0.225 μmol) and trifluoroethanol (2 mL) were reacted at 60 ° C for 2 hours. The reaction solution turned yellow. After the reaction was completed, it was cooled, concentrated, and dried by rotary evaporation. The crude product was purified by C 18 The residue was purified by column chromatography using eluent system A to give 7i (15 mg) in 47% yield. MS m / z (ESI): 282 [M+1] +

[0232] Step 9: 7i (24 mg, 0.086 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (36 mg, 0.13 mmol), and N-methylimidazole (21 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (4 mL) and reacted at 40°C for 1 hour. The reaction solution turned yellow. After completion, the reaction was quenched by the addition of 10 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford Example 7 (16.8 mg) in a 38% yield. MS m / z (ESI): 506 [M+1]. +

[0233] 1 HNMR (400MHz, DMSO) δ8.35(d,1H),8.27(d,2H),7.72-7.61(m,3H),7.15(s,3H),4.94(d,3H),4.42(s,3H),4.30(dd,1H),4.16(s,1H),2.84(s,3H).

[0234] Example 8

[0235] 4-amino-N,7-dimethyl-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0236] Step 1: Disperse 2-amino-3-methylisothiazolinone 8a (5 g, 30.12 mmol) and bromoacetaldehyde dimethyl acetal (10.12 g, 60.24 mmol) in 50 mL of ethanol and 10 mL of 2 M / L hydrochloric acid. Stir and react at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to afford 8b (3.2 g) in a 55.9% yield. MS m / z (ESI): 191 [M+1] +

[0237] Step 2: Disperse 8b (3.2 g, 16.84 mmol) in 50 mL of acetonitrile and add N-iodosuccinimide (4.5 g, 20 mmol). Stir and react for 1 hour. The reaction mixture is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography using eluent System A to afford 8c (2.80 g) in a 52.6% yield. MS m / z (ESI): 317 [M+1] +

[0238] Step 3: Disperse 8c (2.80 g, 8.86 mmol), cuprous iodide (8.42 g, 44.30 mmol), and potassium fluoride (1.54 g, 26.58 mmol) in 30 mL of N,N-dimethylformamide. Add (trifluoromethyl)trimethylsilane (3.77 g, 26.58 mmol). Stir and react at 90°C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to afford 8d (830 mg) in a 36.3% yield. MS m / z (ESI): 259 [M+1] +

[0239] Referring to the synthesis method of steps 3 to 8 of Example 6 and steps 9 to 10 of Example 3, Example 8 (19 mg) was obtained from 8d (400 mg, 1.55 mmol) with a yield of 2.5%. MS m / z (ESI): 496 [M+1] +

[0240] 1 H NMR (400MHz, DMSO) δ9.29(s,1H),8.87(s,2H),8.31(dd,4H),7.50(s,1H),7.16(s,1H),5.93–4.56(m,3H),4.27(s,2H),2.79(d,3H),2.42(s,3H).

[0241] The following example is reference 4:

[0242] The following examples are synthesized with reference to Example 8:

[0243] Example 112

[0244] 4-amino-N-(3-((dimethyl(carbonyl)-16-sulfaneylidene)amino)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-N,7-dimethylimidazo[1,5-a]quinoxaline-8-carboxamide

[0245] Step 1: Dissolve 3-bromo-N-methyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridine-7-amine (220 mg, 0.78 mmol), di-tert-butyl dicarbonate (218 mg, 1.17 mmol), and diisopropylethylamine (302 mg, 2.34 mmol) in dichloromethane and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent System A to afford 112a (240 mg) in an 80.5% yield. MS m / z (ESI): 382 [M+1]. +

[0246] Step 2: Dissolve 112a (100 mg, 0.26 mmol), imino-dimethyl-carbonyl-sulfane (37 mg, 0.39 mmol), cesium carbonate (127 mg, 0.39 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28 mg, 0.5 mmol), and tris(dibenzylideneacetone)palladium (24 mg, 0.03 mmol) in 5 mL of dioxane. Stir and react at 80°C under nitrogen for 2 hours. Ethyl acetate (50 mL) was added to the reaction mixture for extraction, followed by washing with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 112b (57 mg) in a 55.1% yield. MS m / z (ESI): 395 [M+1]. +

[0247] Step 3: Dissolve 112b (57 mg, 0.13 mmol) in 5 mL of 2M hydrochloric acid in dioxane and stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to afford 112c (33 mg) in an 85.7% yield. MS m / z (ESI): 295 [M+1] +

[0248] Referring to the ninth step of Example 306, Example 112 (4.2 mg) was obtained from 112c (33 mg, 0.11 mmol). Yield: 7.4%. MS m / z (ESI): 519 [M+1] +

[0249] 1H NMR(400MHz,DMSO)δ9.08(s,1H),8.13–8.06(m,2H),7.88(s,1H),7.34(d,2H),7.32(s,1H),7.00(d,1H),6.78(d ,1H),5.74(s,1H),5.07(d,1H),4.78(d,1H),4.23(d,1H),4.15(dd,1H),3.30(d,6H),2.63(s,3H),2.33(s,3H).

[0250] Alternatively, the synthesis of Examples 9, 10, and 66 may be performed by referring to the following preparation method:

[0251] Example 9

[0252] 4-amino-N-methoxy-7-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0253] Step 1: Dissolve 2-(trifluoromethyl)-6H-pyrano[3,4-b]pyridin-5(8H)-one 1f (500 mg, 2.30 mmol, synthesized using the known method described in Patent WO2022169948 A1) in methanol. Add sodium borohydride (435 mg, 11.51 mmol) portionwise under ice-cooling, and stir at 0°C for 1 hour. Quench the reaction mixture with saturated ammonium chloride solution (30 mL) and extract with ethyl acetate (30 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using eluent System B to afford 9b (470 mg) in a 93.1% yield. MS m / z (ESI): 220 [M+1]. +

[0254] Step 2: Dissolve 9b (470 mg, 2.14 mmol) and triethylamine (651 mg, 6.43 mmol) in 10 mL of dichloromethane. Add methylsulfonic anhydride (560 mg, 3.22 mmol) and stir at room temperature for 1 hour. Quench the reaction mixture with saturated ammonium chloride solution (30 mL) and extract with ethyl acetate (30 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to afford 9c (430 mg) in a 66.8% yield. MS m / z (ESI): 298 [M+1] +

[0255] Step 3: Dissolve 9c (220 mg, 0.74 mmol) in 10 mL of acetonitrile, add potassium carbonate (511 mg, 3.7 mmol), and stir at 80°C in a sealed tube for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford 9d (139 mg) in a 75.7% yield. MS m / z (ESI): 249 [M+1] +

[0256] Step 4: Dissolve 9d (139 mg, 0.56 mmol) and 4-((3,4-dimethylbenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid 9e (241 mg, 0.62 mmol) in 5 mL of dichloromethane. Phosphorus oxychloride (257 mg, 1.68 mmol) and pyridine (265 mg, 3.36 mmol) were added sequentially and stirred at room temperature for 2 hours. The reaction mixture was quenched by adding 2M hydrochloric acid (30 mL) and extracted with dichloromethane (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford 9f (67 mg) in a 19.2% yield. MS m / z (ESI): 623 [M+1]. +

[0257] Referring to the seventh step of Example 1, 9f (67 mg, 0.11 mmol) was used to obtain Example 9 (20.2 mg) in a yield of 38.9%. MS m / z (ESI): 473 [M+1] +

[0258] 1 H NMR (400MHz, DMSO) δ9.24(s,1H),8.32(s,1H),8.20(s,1H),8.13(d,1H),7.90(d,1H),7.38( s,1H),5.70(s,1H),4.90(d,1H),4.78(d,1H),4.37–4.15(m,2H),3.43(s,3H),2.38(s,3H).

[0259] Example 10

[0260] 4-amino-7-fluoro-N-methoxy-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0261] Referring to the fourth step of Example 9 and the seventh step of Example 1, 4-((3,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid 10a (88 mg, 0.24 mmol) was used to obtain Example 10 (20 mg) in a 17.4% yield. MS m / z (ESI): 477 [M+1]. +

[0262] 1 H NMR(400MHz,DMSO)δ9.14(s,1H),8.44(d,1H),8.07(d,1H),7.95–7.89(m,2H),7.65(s ,2H),7.23(d,1H),5.68(s,1H),4.89(d,1H),4.78(d,1H),4.25(qd,2H),3.47(s,3H).

[0263] Example 66

[0264] 4-amino-7-fluoro-N-methoxy-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0265] Referring to the first to fourth steps of Example 9 and the seventh step of Example 1, 3-(trifluoromethyl)-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7(10H)-one 66a (300 mg, 0.24 mmol) was used to obtain Example 66 (12 mg) in a 2.0% yield. MS m / z (ESI): 516 [M+1]. +

[0266] 1 H NMR(400MHz,DMSO)δ9.15(s,1H),8.53(d,1H),8.45(d,1H),8.20(s,1H),7.93(s,1H),7.64(s,2H),7.2 4(d,1H),7.14(d,1H),5.64(s,1H),5.13(d,1H),4.92(d,1H),4.32(dd,1H),4.21(d,1H),3.45(s,3H).

[0267] Example 66-P1 & 66-P2

[0268] Example 66 (12 mg, 0.023 mmol) was separated by chiral preparative HPLC to give (S)-4-amino-7-fluoro-N-methoxy-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 66-P1 (5.1 mg) in a yield of 42.5% and 4-amino-7-fluoro-N-methoxy-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 66-P2 (5.5 mg) in a yield of 45.8%.

[0269] Chiral preparation conditions:

[0270] Chiral analysis conditions:

[0271] 66-P1(t R :4.343min): 1 H NMR(400MHz,DMSO)δ9.15(s,1H),8.53(d,1H),8.45(d,1H),8.20(s,1H),7.93(s,1H),7.64(s,2H),7.2 4(d,1H),7.14(d,1H),5.64(s,1H),5.13(d,1H),4.92(d,1H),4.32(dd,1H),4.21(d,1H),3.45(s,3H).

[0272] 66-P2(t R :5.530min): 1 H NMR(400MHz,DMSO)δ9.15(s,1H),8.53(d,1H),8.45(d,1H),8.20(s,1H),7.93(s,1H),7.64(s,2H),7.2 4(d,1H),7.14(d,1H),5.64(s,1H),5.13(d,1H),4.92(d,1H),4.32(dd,1H),4.21(d,1H),3.45(s,3H).

[0273] The following examples can be synthesized with reference to Example 5:

[0274] The following examples can be synthesized with reference to Example 2:

[0275] The following examples can be synthesized with reference to Example 112:

[0276] The following examples can be synthesized with reference to Example 10:

[0277] Example 154

[0278] 4-Amino-7-fluoro-N-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0279] Step 1: 4-((2,4-Dimethoxyphenyl)amino)-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid 154a (160 mg, 0.40 mmol), O-(2-butynyl)hydroxylamine (344 mg, 4.04 mmol), DIEA (156 mg, 1.21 mmol), HOBT (109 mg, 0.80 mmol), and HATU (305 mg, 0.81 mmol) were dissolved in 5 mL of N,N-dimethylformamide and stirred at 20°C for 1 hour. The system was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to afford 154b (150 mg) in an 80.2% yield. MS m / z (ESI): 464 [M+1]. +

[0280] Step 2: 154b (160 mg, 0.40 mmol), 5-trifluoromethyl-12-oxa-3,6-diazatricyclo[7.4.0.02,6]tridec-1(9),2,4,7-tetraen-10-yl] methanesulfonate (148 mg, 0.44 μmol), and Cs2CO3 (215 mg, 0.66 mmol) were dissolved in 15 mL of N,N-dimethylformamide and stirred at 60°C for 12 hours. The system was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using eluent System A to afford 154c (43 mg) in a 17.8% yield. MS m / z (ESI): 704 [M+1]. +

[0281] Step 3: Disperse 154c (30 mg, 0.04 mmol) and DDQ (19 mg, 0.09 mmol) in 2 mL of water and 10 mL of dichloromethane. Stir the mixture at room temperature for 12 hours. The system was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to afford Example 154 (18 mg) in a 76.2% yield. MS m / z (ESI): 554 [M+1].+

[0282] 1 H NMR(400MHz,DMSO)δ9.11(s,1H),8.52(dd,2H),8.21(d,1H),7.95(s,1H),7.72(s,2H),7.30(d,1H),7.1 6(d,1H),5.23(s,1H),5.16(d,1H),4.81(d,1H),4.62(q,2H),4.19(dd,1H),3.90(dd,1H),1.83(t,3H).

[0283] Biological test evaluation

[0284] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0285] Test Example 1: Determination of the ability of the compounds of the present invention to enhance the thermal stability (melting temperature) of the PRMT5 / MEP50-MTA protein complex.

[0286] 1 Experimental purpose: To measure the ability of compounds to enhance the thermal stability of the PRMT5 / MEP50-MTA protein complex and increase the protein melting temperature.

[0287] 2 Experimental instruments: Quantitative PCR instrument (Quantstudio6 Flex) was purchased from Life Science; pipettes were purchased from Eppendorf or Rainin.

[0288] 3 Experimental reagents and consumables: PRMT5 / MEP50 protein was prepared by Via Biotechnology; HEPES was purchased from Thermo Fisher, catalog number 15630080; DTT was purchased from Sigma, catalog number 43816-10ml; sodium chloride was purchased from Invitrogen, catalog number AM9760G; Protein Thermal ShiftTMDye Kit was purchased from Thermo Fisher, catalog number 4461146; methylthioadenosine (MTA) was purchased from Sigma, catalog number D5011.

[0289] 4 Experimental Methods: This study characterizes the ability of compounds to enhance the thermal stability of the PRMT5 / MEP50-MTA protein complex by measuring the change in melting temperature (Tm) of the complex before and after compound binding using the thermal shift method. A solution containing 50 mM HEPES, 10 mM DTT, 2 μM MTA, SYPRO Orange, and 250 mM NaCl was prepared as the experimental buffer. Human PRMT5 / MEP50 protein was added to a final concentration of 2 μM and incubated at room temperature for 30 minutes. The reaction mixture was aliquoted into 8 PCR tube strips, 19.5 μL per tube. 0.5 μL of test compound or DMSO was added, resulting in a total reaction volume of 20 μL and a final compound concentration of 8 μM. A 2.5% DMSO control was used as the vehicle. After incubation at room temperature for 10 minutes, the PCR tube was placed in a PCR instrument, and the melt curve function was selected to detect the melting temperature of the PRMT5 / MEP50-MTA protein complex in different treatment groups (heating from 25°C to 95°C, 0.03°C / s).

[0290] 5. Experimental Data Processing and Results: The PCR instrument experimental data file was imported into the thermal shift software to obtain the melting temperature (Tm) of each treatment group. The Tm of the DMSO solvent control group was subtracted to obtain the melting temperature change value (ΔTm) shown in the following table:

[0291] 6 Experimental conclusion: The compound of the present invention has good binding ability with PRMT5 / MEP50-MTA protein.

[0292] Test Example 2: Determination of the inhibitory effect of the compounds of the present invention on the proliferation activity of HCT116 and MTAP Knockout HCT116 cells

[0293] 1 Experimental purpose: To measure the inhibitory effect of compounds on the proliferation activity of HCT116 wild-type and HCT116 MTAP knockout cells.

[0294] 2 Experimental instruments: centrifuge (Eppendorf 5810R); microplate reader (BioTek Synergy H1 or PerkinElmer Envision); pipette (Eppendorf or Rainin).

[0295] 3 Experimental reagents: HCT116 and MTAP Knockout HCT116 cells were purchased from Nanjing Kebai; Cell Titer-Glo was purchased from Promega, catalog number G7573; McCoy`5A was purchased from Gibco, catalog number 12330031; FBS was purchased from Gibco, catalog number 10091148; PBS was purchased from Gibco, catalog number 10010023; trypsin was purchased from Gibco, catalog number 25200056; cell culture plates were purchased from Corning, catalog number 3610.

[0296] 4 Experimental method: When HCT116 and MTAP knockout HCT116 cells were cultured to an appropriate cell density in 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 into 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. A solvent control was set up and the compound solution was added to a 96-well plate at 10 μL per well. The plate was placed in a 37°C, 5% CO2 incubator and continued to be cultured for 72 to 240 hours. Then, CellTiter-Glo solution was added, the plate was shaken to mix evenly, and the plate was incubated in the dark for 10 to 30 minutes. The plate was read using a Synergy H1 or Envision microplate reader.

[0297] 5 Experimental data processing and results: 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 values ​​shown in the following table. 50 value:

[0298] 6 Experimental Conclusion: The compounds shown in the present invention have good proliferation inhibitory activity against HCT116 MTAP knockout cells and have good selectivity for wild-type HCT116 cells.

[0299] Test Example 3: Pharmacokinetics of the compounds of the present invention in mice (plasma) after oral administration

[0300] 1. Study purpose: Balb / c mice were used as test animals to study the pharmacokinetic behavior of the compound in mice (plasma) after oral administration.

[0301] 2 Experimental plan

[0302] 2.1 Test drugs: Compounds of the present invention, homemade.

[0303] 2.2 Experimental animals: Balb / c male mice were purchased from Shanghai JXJ Laboratory Animal Co., Ltd., with animal production license number (SCXK (Shanghai) 2013-0006, No. 311620400001794).

[0304] 2.3 Drug preparation: Oral administration drug preparation: 0.5% CMC-Na (1% Tween 80).

[0305] Weigh 5 g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200 cps), dissolve it in 1000 mL of purified water, add 10 g of Tween 80, and mix well to form a clear solution.

[0306] 4 mg of the example compound was weighed and dissolved in the solution, shaken, broken with a cell disrupter for 1 min, and ultrasonicated for 10 minutes to obtain a suspension solution with a concentration of 3 mg / mL.

[0307] The example compound was weighed and first added with 5% DMSO in proportion to the total volume of the dosage. Vortex and sonicate for 2 minutes to completely dissolve it. Then, 10% Solutol HS15 was added and vortexed and sonicate for 2 minutes to completely dissolve it. Finally, 85% PBS was added and vortexed and sonicated for 5 minutes. The solution was filtered through a 0.22 μm filter to obtain a colorless, transparent, clear solution with a concentration of 0.2 mg / mL.

[0308] 2.4 Administration: Three male Balb / c mice were fasted overnight and administered PO at a dose of 30 mg / kg in a volume of 10 mL / kg.

[0309] 2.5 Sample collection: 0.04 mL of blood was collected from the orbital cavity at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood was placed in an EDTA-2K tube and centrifuged at 6000 rpm for 6 min at 4°C to separate the plasma. The blood was stored at -20°C and the patient was fed 4 h after administration.

[0310] 3. Determination results: The final determination results were obtained using the LCMS / MS method, which showed that the example compound had a higher oral exposure.

[0311] Test Example 4: Pharmacokinetics of the compounds of the present invention in rats (plasma) after oral administration

[0312] 1. Study purpose: SD rats were used as test animals to study the pharmacokinetic behavior of the following compound examples in rat plasma after oral administration at a dose of 5 mg / kg.

[0313] 2 Experimental plan

[0314] 2.1 Test Drugs: Solvent formulation: 0.5% CMC-Na (1% Tween 80); Examples of the present invention, homemade.

[0315] 2.2 Experimental Animals: Three male Sprague-Dawley rats per group. Shanghai Bikeway Biotechnology Co., Ltd., Animal License No. (SCXK (Shanghai) 2018-0006, No. 20180006037467).

[0316] 2.3 Administration: 3 male SD rats per group were fasted overnight and administered orally at a dose of 5 mg / kg in a volume of 10 mL / kg.

[0317] 2.4 Sample collection: Before and after administration, rats were given blood (0.2 mL) from the jugular vein at 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. The blood was placed in an EDTA-K2 tube and centrifuged at 6000 rpm for 6 min at 4°C to separate the plasma. The plasma was stored at -80°C and fed 4 hours after administration.

[0318] 2.5 Sample processing

[0319] 1) 40 μL of plasma sample was added to 160 μL of acetonitrile for precipitation, mixed and centrifuged at 3500 × g for 5-20 minutes.

[0320] 2) Take 100 μL of the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the test compound.

[0321] 2.6 Liquid phase analysis

[0322] Liquid phase conditions: Shimadzu LC-20AD pump

[0323] ●Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0324] ●Chromatographic column: phenomenex Gemiu 5um C 18 50×4.6mm

[0325] ●Mobile phase: Liquid A is 0.1% formic acid in water, Liquid B is methanol Flow rate: 1.0 mL / min

[0326] Elution time: 0-4.0 minutes, eluent is as follows:

[0327] 3 Experimental results and analysis: The main pharmacokinetic parameters were calculated using WinNonlin 8.2 to obtain the results of the rat pharmacokinetic experiment. The results are shown in the following table:

[0328] 4 Experimental conclusion: Oral administration of 5 mg / kg dose, the example compounds of the present invention showed good metabolic properties, exposure AUC and maximum blood concentration C max All performed well.

[0329] Test Example 5: hERG potassium channel inhibitory activity test

[0330] 1. Research purpose: To investigate the inhibitory ability of compounds on hERG potassium channel activity.

[0331] 2 Experimental instruments and reagents:

[0332] 2.1 Reagents

[0333] 2.2 Instruments and consumables

[0334] 3 Experimental methods

[0335] 3.1 Cell Culture: CHO cells stably expressing the hERG potassium channel (CHO-hERG) were obtained from Sophion Biosciences (Ballerup, Denmark) and cryopreserved at Shanghai WuXi AppTec. CHO-hERG cells were cultured and passaged in Ham's F-12 medium supplemented with 1× GlutaMAX, 10% fetal bovine serum, 100 μg / mL G418, and 100 μg / mL hygromycin B in 5% CO2 at 37°C.

[0336] 3.2 Preparation of Extracellular and Intracellular Fluids: Extracellular fluid was prepared monthly and stored in 1L aliquots. Intracellular fluid was prepared every three months and stored frozen at -20°C. Thaw the intracellular fluid in a 37°C water bath before the start of the experiment and place it in an ice bath until use.

[0337] 3.3 Compound Preparation: Compounds were prepared in 100% DMSO (Sigma-Aldrich, D2650) to a 10 mM or 30 mM stock solution. Prior to the experiment, the stock solution of the test compound was diluted 1000-fold or 333-fold with DMSO to the desired concentration, and then diluted 1000-fold or 333-fold with extracellular fluid to the desired concentration.

[0338] 3.4 Preliminary cell preparation: CHO-hERG cells used in the experiment were cultured for at least two days. When the cell density reached above 75%, the cells were digested with TrypLE, resuspended in extracellular solution, and centrifuged. After removing the supernatant, 2 mL of extracellular solution was added to resuspend the cells for later use.

[0339] 3.4 Experimental data processing: In data processing, when judging the blocking effect on hERG, the peak value of the tail current and its baseline are corrected. The inhibition rate of the tail current is used to represent the effect of each compound at different concentrations. IC 50 The values ​​are obtained by fitting the Hill equation: I / Icontrol=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0340] Top: maximum effect; Bottom: minimum effect; Hillslope: slope; X: test sample concentration.

[0341] IC 50 : The half-maximal inhibitory concentration of the test compound on hERG. If the inhibition rate at the lowest concentration exceeds half inhibition or the inhibition rate at the highest concentration does not reach half inhibition, the corresponding IC 50 Below minimum concentration or IC 50 The value is greater than the highest concentration.

[0342] 4 Experimental conclusion: The superior compounds of the present invention have inhibitory activity on cardiac hERG potassium ion channels (IC 50 ) is greater than 5 μM, even greater than 15 μM, and the inhibitory activity (IC 50 ) greater than 30 μM, which can avoid the cardiac toxicity at high doses.

[0343] Test Example 6: In vivo pharmacodynamic study of the compound of the present invention in a subcutaneous transplant tumor model of human lung cancer cell line LU99 nude mice

[0344] 1. Study purpose: To evaluate the in vivo efficacy of the compound in the subcutaneous transplant tumor model of nude mice with human lung cancer cell line LU99.

[0345] 2 Experimental instruments and reagents

[0346] 2.1 Instruments: Refrigerator (BCD-268TN, Haier); Biosafety Cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory); Clean Bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.); Electric pipette assistant (Easypet 3, Eppendorf); Constant temperature water bath (HWS-12, Shanghai Yiheng Science); CO2 incubator (Thermo-311, Thermo); Centrifuge (Centrifuge 5720R, Eppendorf); Automatic cell counter (Countess II, Life Sciences) Technologies); vernier caliper (CD-6" AX, Mitutoyo, Japan); cell culture flasks (T25 / T75 / T225, Corning); electronic balance (CPA2202S, Sartorius); electronic balance (BSA2202S-CW, Sartorius); ultrasonic cleaner (115F0032, Shanghai Kedao); water purifier (Pacific TII, Thermo); magnetic stirrer (08-2G, Chijiu).

[0347] 2.2 Reagents: RPMI-1640 medium (22400-089, Gibco); fetal bovine serum (FBS) (A5669701, Gibco); phosphate-buffered saline (PBS) (10010-023, Gibco); Matrigel (356234, Corning); sodium carboxymethylcellulose (30036365, Sinopharm Group); Tween-80 (30189828, Sinopharm Group).

[0348] 3 Experimental operation and data processing

[0349] 3.1 Animals: BALB / c nude mice, 6-8 weeks old, female, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0350] 3.2 Cell culture and cell suspension preparation

[0351] a) Take out a strain of LU99 cells from the cell bank, resuscitate the cells with RPMI-1640 medium (RPMI-1640 + 10% FBS), and place the resuscitated cells in a cell culture flask in a CO2 incubator (incubator temperature: 37°C, CO2 concentration: 5%).

[0352] b) Subculture the cells every three days and continue to culture them in a CO2 incubator. Repeat this process until the cell count meets the in vivo efficacy requirement.

[0353] c) Cells in the exponential growth phase were collected and counted using an automatic cell counter. Based on the count results, the cells were resuspended in PBS and mixed with Matrigel in a 1:1 ratio to a concentration of 5 × 10 7 cells / mL and placed in an ice box until use.

[0354] 3.3 Cell seeding

[0355] a) Before inoculation, nude mice were marked with disposable ear tags for both rats and mice;

[0356] b) Mix the cell suspension thoroughly during inoculation, draw out 0.1-1 mL of cell suspension with a 1 mL syringe, remove any air bubbles, and place the syringe on an ice pack until ready to use.

[0357] c) Secure the nude mouse with your left hand and disinfect the right side of the mouse's back near the right shoulder (inoculation site) with a 75% alcohol cotton ball. After 30 seconds, begin inoculation.

[0358] d) The nude mice were inoculated sequentially (0.1 mL of cell suspension per mouse).

[0359] 3.4 Tumor measurement, grouping, and drug administration in tumor-bearing mice

[0360] a) Based on tumor growth, the tumor was measured and the tumor size was calculated on days 9-12 after inoculation; Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) × width (mm) × width (mm) / 2;

[0361] b) Tumor-bearing mice were randomly divided into groups according to their weight and tumor size;

[0362] c) According to the grouping results, the test drug was started to be administered (administration method: oral administration; administration volume: 10 mL / kg; administration frequency: once or twice a day; administration cycle: 28 days; solvent: 0.5% CMC-Na (1% Tween 80)).

[0363] d) Tumors were measured and weighed twice a week after the start of administration of the test drug.

[0364] e) Euthanize the animals after the experiment.

[0365] f) Data were processed using Excel or other software. Calculation of compound tumor inhibition rate (TGI) (%): If tumors did not regress, TGI (%) = [1 - (average tumor volume at the end of dosing for a given treatment group - average tumor volume at the start of dosing for that treatment group) / (average tumor volume at the end of treatment for the solvent control group - average tumor volume at the start of treatment for the solvent control group)] × 100%. If tumors regressed, TGI (%) = [1 - (average tumor volume at the end of dosing for a given treatment group - average tumor volume at the start of dosing for that treatment group) / average tumor volume at the start of dosing for that treatment group] × 100%.

[0366] 4 Experimental conclusions:

[0367] The advantageous compounds of the present invention have a tumor inhibition rate (TGI) greater than 80% or even greater than 90% at low doses, showing a significant tumor growth inhibition effect. At high doses, the compounds have a tumor inhibition rate (TGI) greater than 100% or even greater than 150%, showing a significant tumor regression effect.

Claims

1. A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -; preferably -CR b -; M3 is selected from N or C; preferably N; 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 B is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; preferably C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Condensed cycloalkyl, 6-10 membered condensed heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; L1 is selected from a bond, -(CR aa R bb ) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 C(S)-、-(CR aa R bb ) m2 C(NR cc )-、-(CR aa R bb ) m2 NR cc C(O),-(CR aa R bb ) m2 S(O) m1 -、-(CR aa R bb ) m2 NR cc -、-(CR aa R bb ) m2 P(O)2-、-(CR aa R bb ) m2 P(O)(OR cc )-、C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene or 5-12 membered heteroarylene, the C 3-12 Cycloalkylene, 3-12 membered heterocyclylene, C 6-12 Arylene and 5-12 membered heteroarylene, 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; preferably -CR aa R bb -、-C(O)-、-S(O) m1 -or-NR cc -; L2 is selected from a bond, -(CR aa R bb ) m2 -、-(CR aa R bb ) m2 C(O)-、-(CR aa R bb ) m2 NR cc C(O),-(CR aa R bb ) m2 S(O) m1 -or-(CR aa R bb ) m2 NR cc -; preferably -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ; R1 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, -(CR cc R dd ) n1 -C 3-12 Cycloalkyl, -(CR cc R dd ) n1 -3-12 membered heterocyclic group, -(CR cc R dd ) n1 -C 6-12 Aryl, -(CR cc R dd ) n1 -5-12 membered heteroaryl, -SF5, -OR e 、-NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-N=S(O)R e R f 、-S(O)R e (=NR 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, 5-12 membered heteroaryl and =CR gg R hh Preferably, the substituted amine group is 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, -(CR cc R dd ) n1 -C 3-8 Cycloalkyl, -(CR cc R dd ) n1 -3-8 membered heterocyclic group, -(CR cc R dd ) n1 -C 6-10 Aryl, -(CR cc R dd ) n1 -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; 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, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , 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 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; 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, -Y1-C 3-12 Cycloalkyl, -Y1-3-12 membered heterocyclic group, -Y1-C 6-12 Aryl, -Y1-5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h )、-P(O)R g R h 、-C(=NR i )NR g R h or =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 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f Preferably, the substituted amine group is 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 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 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents; Or any two R3 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 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, 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 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R a , R b , R c , 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, 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) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , 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, 5-12 membered heteroaryl and =CR gg R hh Preferably, the substituted amine group is 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; or R a With R b 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, 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; Y1 is selected from a bond, -O-, -S-, -C(O), -NR j -、-C(O)NR j -、-NR j C(O)-、-S(O)2NR j -、-NR j S(O)2-、C 1-6 Alkylene, -OC 1-6 Alkylene-, -C 1-6 Alkylene-O-, -NR j -C 1-6 Alkylene-, -C 1-6 Alkylene-NR j -、C 2-6 Alkenylene or C 2-6 Alkyne, the C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne, optionally deuterated, 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, 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 , R h , R i and R j 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; Or, R g With R h 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, 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 , R bb , R cc and R dd 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; 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 6-12 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; R gg and R hh 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; x is selected from 0, 1, 2, 3, 4, 5 or 6; y 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.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Said Selected from 3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Further as shown in general formula (III-C): 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, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , 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, 5-12 membered heteroaryl and =CR gg R hh is substituted by one or more substituents; preferably C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl and cyano substituted C 1-3 Alkyl, optionally deuterated, 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, 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 gg R hh is substituted by one or more substituents; 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 6-12 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 gg and R hh 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; n2 is selected from 0, 1, 2, 3 or 4; Ring A, Ring B, M1, M2, M3, L2, R2, R3, R c , x and y are as defined in claim 1.

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from 3-12 membered heterocyclic group or 5-12 membered heteroaryl group; preferably 5 membered heterocyclic group, 6 membered heterocyclic group, 5 membered heteroaryl group or 6 membered heteroaryl group; more preferably 5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring B is selected from 3-6 membered heterocyclyl and phenyl or 3-6 membered heterocyclyl and 5-6 membered heteroaryl; preferably Or, Ring B is selected from a 6-14 membered tricyclic heterocyclic group; preferably a 6-14 membered tricyclic spiro heterocyclic group or a 6-14 membered tricyclic fused heterocyclic group; more preferably 6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Further as shown in general formula (IV-A): M4 is selected from N or CR 3a ; M4 is selected from N or CR 3b ; R 3a , R 3c and R 3d are each independently 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 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted 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 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents; R 3b 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 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted 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 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents; n3 is selected from 0, 1 or 2.

7. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Further as shown in general formula (IV-B): M5 is selected from N or C; M6 is selected from N or C; Ring C is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 3e 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 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted 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 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents; R 3f 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 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted 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 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents; n3 is selected from 0, 1 or 2 p is selected from 0, 1, 2, 3 or 4; q is selected from 0, 1 or 2.

8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R2 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, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl or -C(O)NR ee R ff , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl and C 3-8 Cycloalkyl, optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl and C 3-8 The cycloalkyl group is substituted by one or more substituents; Preferred are hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, trifluoromethyl, R c 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 C substituted with haloalkyl or cyano 1-3 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl or trifluoromethyl; R a 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 C substituted with haloalkyl or cyano 1-3 Alkyl; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl or trifluoromethyl; R b Selected from hydrogen, deuterium, halogen, cyano, 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, --(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, 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 and 3-8 membered heterocyclic groups, optionally substituted by 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 heterocyclyl and =CR gg R hh Preferably, hydrogen, deuterium, halogen, cyano, 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, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff or -(CH2) n2 P(O)R ee R ff , the amino group, 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 and 3-8 membered heterocyclic groups, optionally substituted by 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-membered cycloalkyl or 3-8-membered heterocyclic group or one or more substituents; R ee and R ff 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, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, 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 and 3-8 membered heterocyclic groups, optionally substituted by 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; n2 is selected from 0, 1 or 2; Preferred are hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, trifluoromethoxy, 9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound structure is as follows:

10. A compound represented by the general formula (IV-AI) or (IV-BI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: R 1-1 As claimed in claim 3; M4, R 3a , R 3b , R 3c , R 3d and n3 as claimed in claim 6; M5, M6, R 3e , R 3f , p, q and n4 as described in claim 7.

11. The compound according to claim 10, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound structure is as follows:

12. A method for preparing a compound represented by general formula (III-C), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by the general formula (III-CI) reacts with the compound represented by the general formula (III-C-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (III-C-III), and the protecting group is further removed to obtain the compound represented by the general formula (III-C); Preferably, the method is a method for preparing a compound represented by general formula (IV-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: The compound represented by the general formula (IV-AI) reacts with the compound represented by the general formula (IV-A-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (IV-A-III), and the protecting group is further removed to obtain the compound represented by the general formula (IV-A); Or, the method is a method for preparing a compound represented by general formula (IV-B), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: The compound represented by the general formula (IV-BI) reacts with the compound represented by the general formula (IV-B-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (IV-B-III), and the protecting group is further removed to obtain the compound represented by the general formula (IV-B); Pg1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 4-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 4-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; Ring A, M1, M2, M3, R a , R b , R c , R2 and x as described in claim 1; R 1-1 As claimed in claim 3; M4, R 3a , R 3b , R 3c , R 3d and n3 as claimed in claim 6; M5, M6, R 3e , R 3f , p, q and n4 as described in claim 7.

13. A pharmaceutical composition comprising a therapeutically effective dose of a compound as claimed in any one of claims 1 to 9, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

14. Use of the compound according to any one of claims 1 to 9, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in the preparation of a PRMT5 inhibitor drug.

15. Use of the compound according to any one of claims 1 to 9, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in the preparation of a drug for treating cancer.

16. The use according to claim 15, 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, colon cancer, colorectal cancer, biliary tract cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung cancer or adenocarcinoma of the lung; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.