Tri-fused ring derivative inhibitor as well as preparation method and application thereof

Abstract

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

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and in particular relates to a tricyclic 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), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) has the following structure:

[0007]

[0008] M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -; M3 is selected from N or C; preferably N;

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

[0010] Ring B is selected from C 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;

[0011] L1 is selected from self-bond, -CR aaR bb -、-C(O)-、-NR cc C(O), -S(O) m1 - or NR cc ; Preferred -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ;

[0012] L2 is selected from a bond, -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ; Preferred -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ;

[0013] Alternatively, R1 and L2 are linked to form a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, 5 or 6 R 1a replaced by;

[0014] 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, -OR e 、-NR e R f 、-C(O)R e 、-C(O)NR e R f or-P(O)R e R f, the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 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 in aryl and 5-12 membered heteroaryl; more 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)R e 、-C(O)NR e R for-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;

[0015] 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 R ff or -(CH2) n2 P(O)R eeR 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 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, C1-3 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] Or R2 and R c 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 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;

[0017] R3 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 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, 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, 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 6-10Aryl 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 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents in;

[0018] 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, C2-4 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;

[0019] R 1a 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, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n3 -3-12 membered heterocyclic group, -(CH2) n3 -C 6-12 Aryl, -(CH2) n3 -5-12 membered heteroaryl, -(CH2) n3 OR g 、-(CH2) n3 NR g R h 、-(CH2) n3 C(O)R g 、-(CH2) n3 C(O)NR g R h 、-(CH2) n3 P(O)R 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 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6Hydroxyalkyl, 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;

[0020] Or any two R 1a Linked to its adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 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;

[0021] 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 C1-6 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 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 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 3-8Cycloalkyl, 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] Either R2 and L1 or R2 and R1 are linked to form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally further 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 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 or 3-8 membered heterocyclic group, optionally further substituted by 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, C1-3 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] R g and R h are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 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, C1-3 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 1-3 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;

[0024] 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 1-6Alkyl, -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 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 1-3Alkyl, 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;

[0025] 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 1-6Alkoxy, 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 1-3 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;

[0026] 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; n2 is selected from 0, 1, 2, 3 or 4; and n3 is selected from 0, 1, 2, 3 or 4.

[0027] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (II), its stereoisomer or pharmaceutically acceptable salt thereof:

[0028]

[0029] Ring D is selected from C 3-8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclyl, phenyl or 5-6 membered heteroaryl;

[0030] L1, L2, R1, R2, R3, R a 、R b 、R c , x and y are as described in any of the above embodiments.

[0031] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that Selected from

[0032] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (III), its stereoisomer or pharmaceutically acceptable salt thereof:

[0033]

[0034] Ring A, Ring B, L1, R1, R2, R3, R a 、R b 、R c , x and y are as described in any of the above embodiments.

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

[0036]

[0037] M5 is selected from N or CR 3d ;

[0038] R 3a 、R 3b 、R 3c and R 3d are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 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, 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 Aryl, 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, C2-6 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 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents in;

[0039] or R 3a and R 3b The adjacent atoms, R 3b and R 3c The adjacent atoms or R 3c and R 3d Each of its neighboring atoms independently links to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 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 6-10Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 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;

[0040] R4 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 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, C6-12 Aryl, 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 6-10 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 in;

[0041] Or any two R4 atoms are linked to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 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;

[0042] z is selected from 0, 1, 2, 3 or 4;

[0043] Ring A, R1, R2, R a 、R b 、R c 、R e 、R f and x is as described in any of the above embodiments.

[0044] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (VI-1), its stereoisomer or pharmaceutically acceptable salt thereof:

[0045]

[0046] M4 is selected from N or CR 6a ;

[0047] L3 is selected from a bond, -C(O)-, -C(O)NR cc -、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 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 bond, -C(O)-, -C(O)NR cc -、C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the 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, 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;

[0048] R4 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 heterocyclic group, C6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Deuterated alkyl, C 1-6 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 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 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 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 in;

[0049] Or any two R4 atoms are linked to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 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;

[0050] R 6a 、R 6b and R 6care 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, 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, C6-10 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;

[0051] R7 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 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 6-12Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 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 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 6-10 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 3-8Cycloalkyl, 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 in;

[0052] R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 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 1-3Halogenated 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 1-3 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;

[0053] R cc 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 2-6Alkynyl, 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 1-3 Alkyl, C 2-4 Alkenyl, C 2-4Alkynyl, 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;

[0054] z is selected from 0, 1, 2, 3 or 4.

[0055] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (VI-2), its stereoisomer or pharmaceutically acceptable salt thereof:

[0056]

[0057] M4 is selected from N or CR 6a ;

[0058] L4 is selected from CR 8a 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 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 8a 、C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0059] R4 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 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 Aryl, 5-12 membered heteroaryl and =CR e R f Preferably, hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C1-3 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 1-3 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 in;

[0060] Or any two R4 atoms are linked to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C1-6 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;

[0061] R 6a 、R 6b and R 6c 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 6-12Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 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 1-3 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 6-10substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0062] R 8a 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, 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 Aryl, 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 1-3Hydroxyalkyl, 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 1-3 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 in;

[0063] R 8b and R 8c 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, 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, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 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 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 6-10 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, C1-3 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 in;

[0064] R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 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 6-12Aryl 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 1-3 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;

[0065] z is selected from 0, 1, 2, 3 or 4.

[0066] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (III-A), its stereoisomer or pharmaceutically acceptable salt thereof:

[0067]

[0068] Ring B is selected from C6-10 Aryl or 5-10 membered heteroaryl; preferably phenyl, 5-membered heteroaryl or 6-membered heteroaryl;

[0069] Ring C is selected from 3-10 membered heterocyclic groups; preferably 5-membered heterocyclic groups, 6-membered heterocyclic groups or 7-membered heterocyclic groups; more preferably More preferred

[0070] p is selected from 0, 1, 2, 3, 4, 5 or 6.

[0071] 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

[0072] Further optimization

[0073] Further optimization Best

[0074] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (V):

[0075]

[0076] M5 is selected from N or CR 3d ;

[0077] R 2a 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 C1-3 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;

[0078] R 2b 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 substituted by one or more substituents in the cycloalkyl group;

[0079] 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;

[0080] R 3a 、R 3b 、R 3c and R 3dare each independently selected from hydrogen, 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 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 1-3 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 in;

[0081] or R 3a and R 3b The adjacent atoms, R 3b and R 3c The adjacent atoms or R 3c and R 3d Each of its neighboring atoms independently links to form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 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;

[0082] R4 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 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 1-3 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 eR f is substituted by one or more substituents in;

[0083] Or any two R4 atoms are linked to form 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;

[0084] z is selected from 0, 1, 2, 3 or 4; n4 is selected from 0, 1, 2 or 3.

[0085] 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

[0086]

[0087] 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, 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 3-8Cycloalkyl, 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;

[0088] 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;

[0089] Preferred are hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, trifluoromethyl,

[0090] 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.

[0091] 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) n2OR 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 substituted by one or more substituents in a cycloalkyl group or a 3-8 membered heterocyclic group;

[0092] 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, C1-3 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 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;

[0093] n2 is selected from 0, 1 or 2;

[0094] Preferred are hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, trifluoromethoxy,

[0095] In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that R1 is selected from hydrogen, deuterium, 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, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the 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 3-8Cycloalkyl, 3-8 membered heterocyclic group, -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 , optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 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 gg R hh is substituted by one or more substituents; preferably selected from hydrogen, deuterium, 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, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the 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 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, C1-3 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 in aryl and 5-10 membered heteroaryl; preferably methyl, ethyl, deuterated methyl, deuterated ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, acetyl,

[0096] The present invention also provides a method for preparing the compound represented by general formula (V), its stereoisomers or pharmaceutically acceptable salts thereof, comprising the following steps:

[0097]

[0098] The compound represented by general formula (V-1) reacts with the compound represented by general formula (V-2) in the presence of a base to obtain the compound represented by general formula (V-3), and the protecting group is further removed to obtain the compound represented by general formula (V);

[0099] Pg1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 1,2-dimethoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl;

[0100] Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 1,2-dimethoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl;

[0101] R1, R a 、R b 、R c , M5, R 2a 、R 2b 、R 3a 、R 3b 、R 3c , R4, n4 and z are as defined in any of the above embodiments.

[0102] In a preferred embodiment of the present invention, the base in the method for preparing the compound represented by general formula (V), its stereoisomers or pharmaceutically acceptable salts thereof is selected from N-methylpyrazole, imidazole, trimethylamine, triethylamine, methylamine, ethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine or diisopropylethylamine; preferably N-methylpyrazole.

[0103] 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.

[0104] 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.

[0105] The present invention further relates to the use of the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating cancer, wherein the cancer is selected from MTAP-related cancers.

[0106] The present invention further relates to a method for preparing a compound, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as shown in any embodiment for treating cancer, wherein the cancer is selected from MTAP-related cancers.

[0107] 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, colorectal cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung carcinoma or lung adenocarcinoma; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

[0108] 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.

[0109] 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.

[0110] 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%.

[0111] 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.

[0112] In certain embodiments of the present invention, the pharmaceutical composition is a rapid-release formulation or a sustained-release formulation.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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, colon cancer, colorectal cancer, or bile duct cancer.

[0117] 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.

[0118] Detailed Description of the Invention

[0119] 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.

[0120] 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. 1-6Alkyl 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.

[0121] 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.

[0122] 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 (C3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 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.

[0123] 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.

[0124] 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. 2-6Alkynyl 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.

[0125] 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.

[0126] 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.

[0127] 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:

[0128]

[0129] 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:

[0130]

[0131] 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:

[0132]

[0133] 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.

[0134] 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 with oxygen, but does not include the ring portion of -OO- or -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, 3 to 14, 3 to 12, 3 to 8, or 3 to 6 ring atoms, of which 1 to 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.

[0135] 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:

[0136]

[0137] 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:

[0138] 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:

[0139]

[0140] 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.

[0141] 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),

[0142] The term "arylene group" refers to a divalent aromatic group formed by further replacing one hydrogen atom of an aryl group, wherein the arylene group is optionally substituted or unsubstituted, and the aryl group is as defined above.

[0143] 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,

[0144] 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.

[0145] 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.

[0146] 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.

[0147] The term "alkylacyl" refers to a -C(O)-alkyl group, wherein alkyl is as previously defined.

[0148] 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,

[0149] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.

[0150] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0151] 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.

[0152] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogen groups, wherein alkylthio is as defined above.

[0153] 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.

[0154] The term "aminocarbonyl" refers to NH2-C(O)-.

[0155] 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.

[0156] 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.

[0157] The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably in the specification.

[0158] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0159] The term "oxo" or "oxo" refers to =0.

[0160] 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

[0161] 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.

[0162] 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.

[0163] 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.

[0164] "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.

[0165] 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.

[0166] "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.

[0167] "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';

[0168] 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.

[0169] 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.

[0170] 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.

[0171] "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.

[0172] "Stereoisomers" encompass all enantiomerically / diastereomerically / stereomerically pure and enantiomerically / diastereomerically / stereomerically enriched forms of the compounds of the invention.

[0173] "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.

[0174] "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.

[0175] "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.

[0176] "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.

[0177] 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

[0178] 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.

[0179] Example

[0180] 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), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0181] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0182] 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 18150×4.6mm chromatographic column).

[0183] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0184] Thin-layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for thin-layer chromatography (TLC) are 0.15mm to 0.2mm in size, and the sizes used for TLC separation and purification products are 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0185] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0186] Unless otherwise specified in the examples, reactions can be carried out under an argon or nitrogen atmosphere. Argon or nitrogen atmosphere refers to the reaction flask being connected to an approximately 1 L argon or nitrogen balloon. Hydrogen atmosphere refers to the reaction flask being connected to an approximately 1 L hydrogen balloon. Pressurized hydrogenation reactions were performed using a Parr 3916EKX hydrogenator and a Clear Blue QL-500 hydrogen generator or HC2-SS hydrogenator. Hydrogenation reactions were typically performed by evacuating the sample, filling it with hydrogen, and repeating this process three times. Microwave reactions were performed using a CEM Discover-S908860 microwave reactor.

[0187] Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0188] 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.

[0189] 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.

[0190] The compounds in the embodiments of the present invention are prepared by referring to the following example preparation steps:

[0191] Example 1

[0192]

[0193] 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 residue is purified by silica gel column chromatography using eluent System C to afford methyl 3-(2-methylimidazol-4-yl)-4-nitrobenzoate 1b (9 g) in a 56.6% yield. MS m / z (ESI): 262 [M+1].

[0194] Step 2: Compound 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 methyl 4-amino-3-(2-methylimidazol-1-yl)benzoate 1c (1.45 g) in an 81.9% yield. MS m / z (ESI): 232 [M+1].

[0195] Step 3: Compound 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 obtain methyl 4-[(4-methoxyphenyl)methylcarbamoylamino]-3-(2-methylimidazol-1-yl)benzoate (1 g, 750 mg). Yield: 45.8%. MS m / z (ESI): 380 [M+1].

[0196] Step 4: Compound 1g (600 mg, 1.52 mmol) was dissolved in pyridine (2 mL), and phosphorus oxychloride (280 mg, 1.83 mmol, 171 μL) was added. The reaction was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue, which was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System C to afford methyl 4-[(4-methoxyphenyl)methylamino]-1-methyl-imidazolyl-[1,5-a]quinoxaline-8-carboxylate 1d (250 mg) in a 43.7% yield. MS m / z (ESI): 377 [M+1].

[0197] Step 5: Compound 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 and filtered. The filter cake was stirred with ethanol (5 mL) for 0.5 hours, filtered, and dried under reduced pressure to afford 4-[(4-methoxyphenyl)methylamino]-1-methyl-imidazolyl-[1,5-a]quinoline-8-carboxylic acid 1h (110 mg) in a 45.7% yield. MS m / z (ESI): 363 [M+1].

[0198] Step 6: Compound 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. Water (15 mL) was added to the concentrated residue, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was separated by high performance liquid chromatography to obtain 4-[(4-methoxyphenyl)methylamino]-N,1-dimethyl-N-[2-(trifluoromethyl)-5,6,8,8-tetrahydro-4aH-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoline-8-carboxamide 1i (55 mg) in a yield of 68.9%.

[0199] Step 7: Compound 1i (45 mg, 78 μmol) was dissolved in trifluoroacetic acid (3 mL), and the reaction was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated by preparative HPLC to obtain 4-amino-N,1-dimethyl-N-[2-(trifluoromethyl)-5,6,8,8a-tetrahydro-4aH-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoline-8-carboxamide 1 (20 mg) in a yield of 56.2%. MS m / z (ESI): 458 [M+1].

[0200] 1 H 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).

[0201] Example 1 Preparation of Chiral Isomers

[0202]

[0203] Compound 1 (20 mg, 0.044 mmol) was separated by Chiral-HPLC to give 1-P1: (R)-4-amino-N,1-dimethyl-N-[2-(trifluoromethyl)-5,6,8,8a-tetrahydro-4aH-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoline-8-carboxamide (9.5 mg), yield: 47.5%; MS m / z (ESI): 458[M+1]; 1-P2: (S)-4-amino-N,1-dimethyl-N-[2-(trifluoromethyl)-5,6,8,8a-tetrahydro-4aH-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoline-8-carboxamide (9.8 mg), yield: 49.0%. MS m / z(ESI):458[M+1]

[0204] The preparation of the following examples is described in Example 1:

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211] Example 17

[0212] 4-amino-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-[1,2,3]triazolo[1,5-a]quinoxaline-8-carboxamide

[0213]

[0214] Step 1: Disperse 6-bromo-2-chloro-3-methylquinoxaline 17a (1.5 g, 5.82 mmol) and cesium carbonate (2.85 g, 8.47 mmol) in 15 mL of dimethylformamide. Add 4-methoxybenzylamine (799 mg, 5.82 mmol) and stir at 100°C for 2 hours. The reaction mixture was poured into 50 mL of ethyl acetate, washed with saturated sodium chloride solution (50 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 provide 7-bromo-3-((4-methoxybenzyl)amino)quinoxaline-2-carbaldehyde 17b (1.5 g) in a 71.9% yield. MS m / z (ESI): 358 [M+1].

[0215] Step 2: Dissolve 17b (1.5 g, 4.19 mmol) in 10 mL of dioxane and 1 mL of water. Add selenium dioxide (929 mg, 8.37 mmol) and stir at 85°C for 2 hours. Add water (100 mL) to the reaction mixture, extract with ethyl acetate (100 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to afford 6-bromo-N-(4-methoxybenzyl)-3-methylquinoxalin-2-amine 17c (1.43 g) in a 91.7% yield. MS m / z (ESI): 372 [M+1].

[0216] Step 3: Dissolve 17c (1.43 g, 3.84 mmol) and 4-methylbenzenesulfonylhydrazide (1.07 g, 5.76 mmol) in 10 mL of methanol and stir at 60°C for 3 hours. Add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to afford 6-bromo-3-(hydrazinylidenemethyl)-N-(4-methoxybenzyl)quinoxalin-2-amine 17d (1.43 g) in a 96.2% yield. MS m / z (ESI): 386 [M+1].

[0217] Step 4: Dissolve 17d (1.43 g, 3.70 mmol) and sodium ethoxide (1.01 g, 14.80 mmol) in 10 mL of dioxane and 10 mL of cyclohexane. Stir the reaction at 60°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to afford 8-bromo-N-(4-methoxybenzyl)-[1,2,3]triazolo[1,5-a]quinoxalin-4-amine 17e (560 mg) in a 41.2% yield. MS m / z (ESI): 384 [M+1].

[0218] Step 5: Dissolve 17e (250 mg, 0.65 mmol), triethylamine (131 mg, 1.30 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (48 mg, 0.07 mmol) in 10 mL of ethanol. Stir the reaction mixture at 80°C under a carbon monoxide atmosphere for 72 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 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 A to afford methyl 4-((4-methoxybenzyl)amino)-[1,2,3]triazolo[1,5-a]quinoxaline-8-carboxylate 17f (91 mg) in a 37.1% yield. MS m / z (ESI): 363 [M+1].

[0219] Referring to the synthesis method of steps 5 to 7 of Example 1, 17f (91 mg) was used to obtain 4-amino-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-[1,2,3]triazolo[1,5-a]quinoxaline-8-carboxamide 17 (6 mg) in a yield of 5.6%. MS m / z (ESI): 444 [M+1].

[0220] 1 H NMR(400MHz,DMSO)δ8.60(s,1H),8.44(d,1H),8.17(d,1H),7.86(d,3H),7.75( s,1H),7.55(d,1H),5.84(s,1H),5.02-4.71(m,2H),4.18(d,2H),2.76(d,3H).

[0221] Example 30

[0222]

[0223] Step 1: Disperse methyl 6-methoxy-2-methylnicotinate 30a (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 methyl 2-(dibromomethyl)-6-methoxy hydrochloride 30b (30.50 g, crude product). MS m / z (ESI): 338 [M+1]

[0224] Step 2: Disperse 30b (30.50 g crude product), 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 using eluent System B to afford methyl 2-(bromomethyl)-6-methoxy ester hydrochloride 30c (12.00 g) in a 55.9% yield. MS m / z (ESI): 260 [M+1].

[0225] 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 30c (12.00 g, 46.33 mmol) and stir at 25°C for 16 hours. The reaction solution 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 methyl 2-methoxy-5-oxo-5,8-dihydro-6H-pyrano[3,4-b]pyridine-6-carboxylate 30d (22.00 g, crude product). MS m / z (ESI): 238 [M+1]

[0226] Step 4: Disperse 30d (22.00 g crude product) 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 with eluent System A to afford 2-hydroxy-6H-pyrano[3,4-b]pyridin-5(8H)-one 30e (4.00 g) in a 52.3% yield. MS m / z (ESI): 166 [M+1]

[0227] Step 5: Disperse 30e (4.00 g, 24.24 mmol) in 30 mL of phosphorus oxychloride and stir at 90°C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dispersed in 300 mL of dichloromethane. The mixture was washed sequentially with saturated sodium bicarbonate solution (200 mL x 2) and sodium chloride solution (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 2-chloro-6H-pyrano[3,4-b]pyridin-5(8H)-one 30f (4.30 g) in a 96.9% yield. MS m / z (ESI): 184 [M+1]

[0228] Step 6: Disperse 30f (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 obtain 30 g (240 mg) of the title product, 2-(3,3-difluoroazetidin-1-yl)-6H-pyrano[3,4-b]pyridin-5(8H)-one, in a 61.0% yield. MS m / z (ESI): 241 [M+1]

[0229] Step 7: Disperse 30 g (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 obtain 2-(3,3-difluoroazetidin-1-yl)-N-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine 30h (150 mg) in a yield of 58.8%. MS m / z (ESI): 256 [M+1]

[0230] Referring to the synthesis method of step 6 of Example 1, 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 30 (9 mg) was obtained by 30 h (50 mg, 0.20 mmol) in a yield of 9.3%. MS m / z (ESI): 480 [M+1].

[0231] Example 31

[0232]

[0233] Referring to the synthesis method of Example 30, 4-amino-N-(2-(3-(difluoromethylene)heterocyclobutane-1-yl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 31 (11 mg) was obtained from 2-chloro-6H-pyrano[3,4-b]pyridin-5(8H)-one 31a and 3-(difluoromethylene)azetidine. MS m / z (ESI): 492 [M+1]

[0234] 1 H NMR (400MHz, CD3OD) δ8.53(s,1H),8.49(s,1H),8.07-7.78(m,3H),6.87(d,1H),5.76(s,1H),5.00-3.92(m,11H),2.94(s,3H).

[0235] Example 45

[0236]

[0237] Step 1: Dissolve 1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine 45a (700 mg, 2.76 mmol), 4-(trifluoromethyl)benzoic acid (629 mg, 3.31 mmol), (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.56 g, 4.13 mmol) and diisopropylethylamine (1.07 g, 8.27 mmol) in 10 mL of dimethylformamide and allow the reaction to stir at room temperature for 2 h. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 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 A to afford N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(trifluoromethyl)benzamide 45b (850 mg) in a 72.4% yield. MS m / z (ESI): 426 [M+1].

[0238] Step 2: Disperse 45b (850 mg, 1.99 mmol) and cesium carbonate (975 mg, 3 mmol) in 10 mL of dimethylformamide. Add iodomethane (849 mg, 5.98 mmol) dropwise and stir the reaction at room temperature for 1 hour. The reaction mixture was poured into 50 mL of ethyl acetate, washed with saturated sodium chloride solution (50 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 N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-4-(trifluoromethyl)benzamide 45c (790 mg) in a 90.0% yield. MS m / z (ESI): 440 [M+1].

[0239] Step 3: Dissolve 45c (790 mg, 1.79 mmol), tert-butyl carbamate (315 mg, 2.69 mmol), tris(dibenzylideneacetone)palladium (164 mg, 0.18 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (208 mg, 0.36 mmol), and cesium carbonate (585 mg, 1.79 mmol) in 10 mL of dioxane. Stir the reaction at 100°C under nitrogen for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to give tert-butyl (N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-4-(trifluoromethyl)benzamide)carbamate 45d (600 mg) in a 70.1% yield. MS m / z (ESI): 477 [M+1].

[0240] Step 4: Dissolve 45d (600 mg, 1.26 mmol) in 1 mL of trifluoroacetic acid and 5 mL of dichloromethane. Stir the reaction at room temperature for 1 hour. Add saturated sodium bicarbonate solution (50 mL) to the reaction mixture, extract with dichloromethane (50 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to afford N-(1-(4-aminophenyl)-2,2,2-trifluoroethyl)-N-methyl-4-(trifluoromethyl)benzamide 45e (330 mg) in a 69.6% yield. MS m / z (ESI): 377 [M+1].

[0241] Step 5: Dissolve 45e (100 mg, 0.27 mmol) in 3 mL of dichloromethane. Add N-bromosuccinimide (50 mg, 0.28 mmol) under ice-cooling, and stir the reaction for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to afford N-(1-(4-amino-3-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-4-(trifluoromethyl)benzamide 45f (101 mg) in 83.5% yield. MS m / z (ESI): 455 [M+1].

[0242] Step 6: Disperse 45f (90 mg, 0.20 mmol), bis(pinacolato)diboron (315 mg, 2.69 mmol), DPPF palladium dichloride (14 mg, 0.02 mmol), and potassium pivalate (56 mg, 0.40 mmol) in 3 mL of 2-methyltetrahydrofuran. Stir the reaction at 80°C under nitrogen for 16 hours. Pour the reaction solution into 30 mL of ethyl acetate, wash with saturated sodium chloride solution (30 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 45 g (81 mg) of (2-amino-5-(2,2,2-trifluoro-1-(N-methyl-4-(trifluoromethyl)benzamido)ethyl)phenyl)boronic acid in a yield of 96.2%. MS m / z (ESI): 421 [M+1].

[0243] Step 7: Disperse 45 g (81 mg, 0.19 mmol), 5-bromo-1-methyl-pyrazole-4-carbonitrile (34 mg, 0.18 mmol), tetrakistriphenylphosphine palladium (22 mg, 0.02 mmol), and sodium carbonate (41 mg, 0.39 mmol) in 4 mL of dioxane and 1 mL of water. Stir the reaction at 105°C under nitrogen for 16 hours. The reaction mixture was poured into 30 mL of ethyl acetate, washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System C to give N-(1-(4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)-2,2,2-trifluoroethyl)-N-methyl-4-(trifluoromethyl)benzamide 45 (17 mg) in 18.3% yield. MS m / z(ESI):482[M+1]

[0244] 1H NMR(400MHz,DMSO)δ8.40(s,1H),8.27(s,1H),7.87(d,2H),7.73(d,2H),7.67( d,1H),7.63–7.58(m,1H),7.15(s,2H),6.85(s,1H),4.41(s,3H),1.24(s,3H).

[0245] Example 65

[0246]

[0247] Step 1: Dissolve (2-amino-5-(carbomethoxy)phenyl)boronic acid 65a (1 g, 3.61 mmol, synthesized using the known method "Patent WO2022169948 A1"), 4-bromoimidazole (530 mg, 3.61 mmol), Pd(dppf)Cl2.DCM (292 mg, 0.36 mmol), and K2CO3 (997 mg, 7.22 mmol) in a mixed solvent of 10 mL of dioxane and 2 mL of water. Stir and react at 90°C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure and quenched by adding NH4Cl. Then, 20 mL of water and 200 mL of ethyl acetate were added to the mixed solution. The organic phase was washed three times with saturated brine, each time with 20 mL, and then the organic phase was dried and spin-dried. The resulting residue was purified by silica gel column chromatography using eluent System A to afford methyl 4-amino-3-(1H-imidazol-5-yl)benzoate 65b (300 mg) in 38.3% yield. MS m / z (ESI): 218 [M+1]

[0248] Step 2: Dissolve 65b (190 mg, 0.874 mmol) and BrCN (96 mg, 0.874 mmol) in 3 mL of methanol and stir at 20°C for 16 hours. Add an appropriate amount of ethyl acetate and filter to afford methyl 5-aminoimidazo[1,5-c]quinazoline-9-carboxylate 65c (70 mg) in a 33% yield. MS m / z (ESI): 243 [M+1].

[0249] Step 3: Dissolve 65c (60 mg, 0.247 mmol) and LiOH (30 mg, 1.24 mmol) in 1 mL of methanol / 1 mL of tetrahydrofuran / 1 mL of water and stir at 50°C for 2 hours. Dry the mixture, add an appropriate amount of ethyl acetate, and filter to afford 5-aminoimidazo[1,5-c]quinazoline-9-carboxylic acid 65d (45 mg) in a 79% yield. MS m / z (ESI): 229 [M+1].

[0250] Step 4: 65d (50 mg, 219.10 μmol), N-methyl-2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-amine 65e (50.88 mg, 219.10 μmol, synthesized by the known method "Patent WO2022169948A1"), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (123 mg, 0.438 mmol) and N-methylimidazole (90 mg, 1.1 mmol) were dissolved in 3 mL of N,N-dimethylformamide and stirred at 50 ° C for 1 hour. The mixture was quenched by adding 10 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were 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 with eluent System A to afford 5-amino-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-c]quinazoline-9-carboxamide 65 (5 mg) in a 5.16% yield. MS m / z (ESI): 443 [M+1].

[0251] 1 HNMR(400MHz,DMSO)δ9.43(s,1H),8.31(s,1H),8.24–8.20(m,2H),8.01(s,1H),7.67(dd,1H) ,7.62(d,1H),7.50(d,1H),7.16(s,2H),3.19(d,1H),2.95(s,1H),2.69(d,2H),2.32(d,3H).

[0252] Example 67

[0253]

[0254] Referring to the synthesis of Example 1, compound 5-fluoro-2-methyl-4-nitrobenzoic acid methyl ester 67a (5 g, 23.46 mmol) was used to obtain 4-amino-N,1,7-trimethyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazolyl[1,5-a]quinoxaline-8-carboxamide (2.5 mg) in a yield of 0.02%. MS m / z (ESI): 471 [M+1].

[0255] 1H NMR (400 MHz, DMSO) δ 8.11–8.02 (m, 3H), 7.89 (dd, 2H), 7.47 (s, 2H), 5.90 (s, 1H), 4.89 (d, 2H), 4.77 (d, 2H), 3.03 (s, 3H), 2.61 (s, 3H), 2.41 (s, 3H). Alternatively, Example 75 was synthesized according to the following method:

[0256]

[0257] Step 1: Methyl 4-amino-2-methylbenzoate 75a (9.91 g, 60 mmol) was dissolved in acetonitrile (100 mL). NBS (10.89 g, 61.20 mmol) was added portionwise at 25°C and stirred at 25°C for 10 minutes. The reaction mixture was quenched by adding 1 mL of water, concentrated to dryness, and the residue was purified by silica gel column chromatography using eluent System C to afford methyl 4-amino-5-bromo-2-methylbenzoate 75b (9 g) in a 61.7% yield. MS m / z (ESI): 244 [M+1]

[0258] Step 2: 75b (976 mg, 4 mmol), Pd(dppf)Cl2 (293 mg, 0.4 mmol), bis(pinacolato)boronate (2.03 g, 8 mmol), and potassium acetate (824 mg, 8.4 mmol) were dispersed in toluene (20 mL). The mixture was deoxygenated by bubbling nitrogen and stirred in a microwave oven at 100°C for 5 hours. The reaction mixture was cooled, quenched by purging with air, filtered, and the filtrate was concentrated to dryness under reduced pressure and pumped dry to obtain a mixture of methyl 4-amino-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 75c and (2-amino-5-methoxyacyl-4-methylphenyl)boronic acid 75d (2.15 g, crude product). This crude product was used in the next step without further purification. MS m / z (ESI): 292 [M+1], 210 [M+1].

[0259] Step 3: A mixture of crude products 75c and 75d (2.15 g), tetrakistriphenylphosphine palladium (231 mg, 0.2 mmol), sodium carbonate (848 mg, 8 mmol), and 5-bromo-1-methylpyrazole-4-carbonitrile (744 mg, 4 mmol) were dispersed in a mixture of 10 mL of water and 10 mL of dioxane. The mixture was stirred at 120°C for 24 hours. The reaction mixture was cooled to room temperature, concentrated to dryness, and thoroughly dissolved in 20 mL of water. The mixture was filtered and washed with a small amount of water. The resulting solid was thoroughly dissolved in 20 mL of ethyl acetate, filtered, and washed with a small amount of ethyl acetate to obtain methyl 4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 75e (313 mg) in a yield of 28.9%. MS m / z (ESI): 271 [M+1].

[0260] Step 4: Dissolve 75e (313 mg, 1.15 mmol), DMAP (28 mg, 0.23 mmol), N,N-diethylisopropylamine (398 mg, 3.45 mmol), and di-tert-butyl dicarbonate (502 mg, 2.30 mmol) in DMF (10 mL) and stir at 20°C for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System C to afford methyl 4-(bis(tert-butoxycarbonyl)imino)-1,7-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 75f (480 mg) in 88.6% yield. MS m / z (ESI): 471 [M+1].

[0261] Step 5: Dissolve 75f (236 mg, 0.50 mmol), dibenzoyl peroxide (12 mg, 0.05 mmol), and N-bromosuccinimide (182 mg, 1.02 mmol) in carbon tetrachloride (20 mL) and stir at 80°C under nitrogen for 12 hours. The reaction system was cooled to room temperature and quenched by the addition of 1 mL of water. The system was concentrated to dryness, and the residue was purified by silica gel column chromatography with eluent System C to afford 75 g (205 mg) of methyl 7-bromomethyl-4-(bis(tert-butoxycarbonyl)imino)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate in a 74.7% yield. MS m / z (ESI): 549 [M+1].

[0262] Step 6: Disperse 75 g (205 mg, 0.37 mmol) of the product in 5 mL of methanol, add 1 mL of a 2 M sodium methoxide-methanol solution, and react at 20°C for 3 hours. The reaction system was concentrated to dryness, and the residue was purified by reverse-phase chromatography using acetonitrile and water as eluents to obtain methyl 4-tert-butoxyformamido-7-methoxymethyl-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 75h (103 mg) in a 69.4% yield. MS m / z (ESI): 401 [M+1]

[0263] Step 7: Dissolve 75h (103 mg, 0.26 mmol) in a mixed solvent of tetrahydrofuran-methanol-water (volume ratio 1:1:1, 3 mL), add lithium hydroxide (31 mg, 1.30 mmol), and stir at 60°C for 3 hours. The reaction system was quenched by adding 2M dilute hydrochloric acid (2 mL) and concentrated to dryness to obtain 4-amino-7-methoxymethyl-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 75i (150 mg, crude product), which was directly used in the next step. MS m / z (ESI): 387 [M+1]

[0264] Step 8: Disperse crude product 75i (150 mg) in a hydrogen chloride-dioxane solution (3 mL), add 3 mL of methanol, and stir at 20°C for 1 hour. The reaction system is concentrated to dryness, and the resulting residue is purified by reverse-phase chromatography using acetonitrile and water as eluents to afford 4-amino-7-methoxymethyl-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 75j (70 mg) in a 93.8% yield. MS m / z (ESI): 287 [M+1]

[0265] Step 9: 75j (29 mg, 0.10 mmol), N-methyl-2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine (23 mg, 0.10 mmol), TCFH (56 mg, 0.2 mmol), and N-methylimidazole (41 mg, 0.5 mmol) were dissolved in DMF (5 mL) and stirred at 80°C for 3 hours. The reaction solution was cooled to room temperature to quench, concentrated to dryness, and the residue was purified by silica gel column chromatography with eluent System C. The resulting residue was then purified by preparative HPLC to afford 4-amino-7-methoxymethyl-N,1-dimethyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 75 (6.0 mg) in 11.8% yield. MS m / z(ESI):501[M+1]

[0266] 1H NMR(400MHz,DMSO-d6)δ8.34–8.10(m,3H),7.93(d,1H),7.61(d,1H),7.12(s,2H),5 .93(s,1H),4.97-4.47(m,4H),4.41(s,3H),4.25(d,2H),3.34(s,3H),2.65(s,3H).

[0267] Example 75 Preparation of Chiral Isomers

[0268]

[0269] Step 1: Dissolve 75 (200 mg, 0.40 mmol), 4-dimethylaminopyridine (12 mg, 0.08 mmol), di-tert-butyl dicarbonate (198 mg, 1.20 mmol), and triethylamine (124 mg, 1.20 mmol) in N,N-dimethylformamide (12 mL) and react at 20°C for 3 h. After completion, the system was concentrated to dryness. The resulting mixture was purified by silica gel column chromatography using eluent System B to afford tert-butyl (7-ethoxymethyl-1-methyl-8-(methyl(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamoyl)-1H-pyrazolo[4,3-c]quinolin-4-yl)carbamate 75k (260 mg) in a 92.9% yield. MS m / z (ESI): 701 [M+1].

[0270] Step 2: 75k (260 mg, 0.37 mmol) was separated by Chiral-HPLC to give P1: (R)-tert-butyl (7-methoxymethyl-1-methyl-8-(methyl (2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamoyl)-1H-pyrazolo[4,3-c]quinolin-4-yl)carbamate (120 mg), yield: 46.2%; P2: (S)-tert-butyl (7-methoxymethyl-1-methyl-8-(methyl (2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamoyl)-1H-pyrazolo[4,3-c]quinolin-4-yl)carbamate (130 mg), yield: 50.0%. MS m / z(ESI):701[M+1],P1; 701[M+1],P2

[0271] Step 3: P1 (120 mg) and P2 (130 mg) were dissolved in 4 M hydrochloric acid (10 mL), stirred at room temperature for 3 h, concentrated to dryness, and purified by preparative HPLC to obtain P1: (R)-4-amino-7-ethoxymethyl-N,1-dimethyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyridin-2-yl ...4-amino-7-ethoxymethyl-N,1-dimethyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyridin-2-yl P2: (S)-4-amino-7-ethoxymethyl-N,1-dimethyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 75-2 (92 mg), yield: 99.0%.

[0272] MS m / z(ESI):501[M+1],P1; 501[M+1],P2

[0273] 1 H NMR(400MHz,DMSO-d6,P1)δ8.34-8.10(m,3H),7.93(d,1H),7.61(d,1H),7.12(s,2H) ,5.93(s,1H),4.97-4.47(m,4H),4.41(s,3H),4.25(d,2H),3.34(s,3H),2.65(s,3H).

[0274] 1 H NMR(400MHz,DMSO-d6,P2)δ8.34-8.10(m,3H),7.93(d,1H),7.61(d,1H),7.12(s,2H) ,5.93(s,1H),4.97-4.47(m,4H),4.41(s,3H),4.25(d,2H),3.34(s,3H),2.65(s,3H).

[0275] Example 76

[0276]

[0277] Step 1: Disperse methyl 2-hydroxy-4-nitrobenzoate 76a (1.1 g, 5.58 mmol), sodium difluorochloroacetate (1.02 g, 6.70 mmol), and sodium carbonate (768 mg, 7.25 mmol) in 15 mL of dimethylformamide. Stir the reaction mixture at 100°C under nitrogen for 16 hours. Pour the reaction mixture into 100 mL of water and extract with ethyl acetate (50 mL x 2). The combined organic phases are washed with saturated sodium chloride solution (50 mL x 2), 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 methyl 2-(difluoromethoxy)-4-nitrobenzoate 76b (330 mg) in a 23.9% yield. MS m / z (ESI): 248 [M+1].

[0278] Step 2: Dissolve 76b (330 mg, 1.34 mmol) in 8 mL of methanol, add palladium on carbon (284 mg, 0.13 mmol, 5% purity), and stir at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through celite to remove the palladium on carbon, and then concentrated under reduced pressure to afford methyl 4-amino-2-(difluoromethoxy)benzoate 76c (250 mg) in an 86.2% yield. MS m / z (ESI): 218 [M+1]

[0279] Step 3: Dissolve 76c (250 mg, 1.15 mmol) and N-bromosuccinimide (204 mg, 1.15 mmol) in 6 mL of dichloromethane and stir at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to provide methyl 4-amino-5-bromo-2-(difluoromethoxy)benzoate 76d (160 mg) in a 47.0% yield. MS m / z (ESI): 296 [M+1]

[0280] Step 4: Dissolve 76d (160 mg, 0.54 mmol), 1,1-bis(diphenylphosphino)diborane iron palladium chloride (40 mg, 0.05 mmol), potassium acetate (106 mg, 1.08 mmol), and bis(pinacol boronate) (292 mg, 1.15 mmol) in 5 mL of dioxane and stir at 90°C for 16 hours. Filter the reaction mixture, pour the filtrate into 100 mL of water, and extract with ethyl acetate (50 mL x 2). The combined organic phases are washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to afford methyl 4-amino-2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 76e (71 mg) in a yield of 38.3%. MS m / z(ESI):344[M+1]

[0281] Step 5: Dissolve 76e (71 mg, 0.21 mmol), 5-bromo-1-methylpyrazole-4-carbonitrile (38 mg, 0.21 mmol), tetrakistriphenylphosphine palladium (24 mg, 0.02 mmol), and sodium carbonate (44 mg, 0.41 mmol) in 5 mL of dioxane and 1 mL of water. Stir the reaction at 90°C for 16 hours. Filter the reaction mixture, pour the filtrate into 100 mL of water, and extract with ethyl acetate (50 mL x 2). The combined organic phases are washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to afford methyl 4-amino-2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 76f (37 mg) in a 55.5% yield. MS m / z (ESI): 323 [M+1].

[0282] Referring to the synthesis method of steps 5 to 6 of Example 1, 4-amino-7-(difluoromethoxy)-N,1-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 76 (7.1 mg) was obtained from 76f (37 mg, 0.11 mmol) in an 11.8% yield. MS m / z (ESI): 523 [M+1].

[0283] The preparation of the following examples refers to Example 76:

[0284]

[0285]

[0286] Example 77

[0287]

[0288] Step 1: Disperse 2-methoxy-6H-pyrano[3,4-b]pyridin-5(8H)-one 77a (500 mg, 2.79 mmol) in 10 mL of concentrated hydrochloric acid and stir at 100°C for 1 hour. The reaction mixture was concentrated under reduced pressure to afford 2-hydroxy-6H-pyrano[3,4-b]pyridin-5(8H)-one 77b (440 mg) in a 95.6% yield. MS m / z (ESI): 166 [M+1]

[0289] Step 2: Disperse 77b (440 mg, 2.67 mmol) in 5 mL of phosphorus oxychloride and stir at 90°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 2-chloro-6H-pyrano[3,4-b]pyridin-5(8H)-one 77c (300 mg) in a 61.4% yield. MS m / z (ESI): 184 [M+1]

[0290] Step 3: Disperse 77c (300 mg, 1.64 mmol), tributyl propargyl stannane (658 mg, 2 mmol), and bistriphenylphosphine palladium dichloride (112 mg, 0.16 mmol) in 5 mL of 1,4-dioxane 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 with eluent System A to afford 2-(propyn-1-yl)-6H-pyrano[3,4-b]pyridin-5(8H)-one 77d (300 mg) in a 97.9% yield. MS m / z (ESI): 188 [M+1]

[0291] Step 4: Disperse 77d (300 mg, 1.60 mmol) in methylamine (30% methanol solution) and 10 mL of methanol. Stir and react at 60°C for 3 hours. The reaction mixture was cooled to 25°C, and sodium cyanoborohydride (201 mg, 3.20 mmol) was added. Stir and react at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to afford N-methyl-2-(propyn-1-yl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine 77e (60 mg) in 18.6% yield. MS m / z (ESI): 203 [M+1]

[0292] Step 5: Referring to the synthesis method of Step 6 of Example 1, 4-amino-N,1-dimethyl-N-(2-(propyn-1-yl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 77 (8 mg) was obtained from 77e (60 mg, 0.30 mmol). Yield: 6.3%. MS m / z (ESI): 427 [M+1]. 1 H NMR(400MHz,MeOD)δ8.33(d,1H),8.26(s,1H),7.81(d,1H),7.70–7.57(m,2H),7. 40(d,1H),7.18(s,2H),5.76(s,1H),4.75–4.04(m,7H),2.77(s,3H),2.07(s,3H).

[0293] Example 80

[0294]

[0295] Step 1: Disperse 5-amino-1-(2-hydroxyethyl)-1H-pyrazole-4-cyano 80a (5 g, 32.89 mmol), tert-butyldiphenylsilyl chloride (9.62 g, 35 mmol), and imidazole (3.40 g, 50 mmol) in 50 mL of dichloromethane and stir at 25°C for 1 hour. 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 5-amino-1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-1H-pyrazole-4-cyano 80b (11.3 g) in 88.1% yield. MS m / z (ESI): 391 [M+1]

[0296] Step 2: Disperse 80b (5 g, 12.82 mmol) and tert-butyl nitrite (1.55 g, 15 mmol) in 50 mL of diiodomethane and stir at 50°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 1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-iodo-1H-pyrazole-4-cyano 80c (4.10 g) in a 63.8% yield. MS m / z (ESI): 502 [M+1].

[0297] Step 3: Disperse 80c (4.10 g, 8.18 mmol) in 50 mL of tetrahydrofuran, add tetrabutylammonium fluoride (1 M / L tetrahydrofuran solution, 10 mL, 10 mmol), and stir at 25°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 1-(2-hydroxyethyl)-5-iodo-1H-pyrazole-4-cyano 80d (1.21 g) in a 56.2% yield. MS m / z (ESI): 264 [M+1]

[0298] Step 4: Disperse 80d (1.21 g, 4.60 mmol), methyl 4-amino-2-hydroxy-3-iodobenzoate (1.90 g, 6.50 mmol), and potassium carbonate (1.38 g, 10 mmol) in 10 mL of N,N-dimethylformamide and stir at 50°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 methyl 4-amino-2-(2-(4-cyano-5-iodo-1H-pyrazol-1-yl)ethoxy)-3-iodobenzoate 80e (1.11 g) in a 44.9% yield. MS m / z (ESI): 539 [M+1].

[0299] Step 5: Disperse 80e (1.1 g, 2.06 mmol), palladium acetate (45 mg, 0.20 mmol), and potassium acetate (392 mg, 4 mmol) in 10 mL of N,N-dimethylformamide and stir at 100°C for 16 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to obtain the title product, methyl 10-amino-3,4-dihydro-5-oxo-2,2a,9-triazolato[2,1,8-cde]azulene-6-carboxylate 80f (230 mg) in a yield of 39.3%. MS m / z (ESI): 285 [M+1].

[0300] With reference to the synthesis method of the fifth and sixth steps of Example 1, 10-amino-N-methyl-N-(2-trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3,4-dihydro-5-oxo-2,2a,9-triazolato[2,1,8-cde]azulene-6-carboxamide (5.5 mg) was obtained.

[0301] Example 82-1 & Example 82-2

[0302]

[0303] Step 1: Dissolve 5-bromo-1H-pyrazole-4-carbonitrile 82a (1.9 g, 11.05 mmol) in dichloromethane (30 mL). The atmosphere was purged with nitrogen three times and cooled to 0°C. p-Toluenesulfonic acid (380 mg, 2.21 mmol) and 3,4-dihydro-2H-pyran (1.12 g, 13.26 mmol, 1.21 mL) were added and the mixture was allowed to react at 0°C for 2 hours. The reaction was quenched with water and extracted with dichloromethane (80 mL x 3). The mixture was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbonitrile 82b (2.30 g) in an 81.3% yield. MS m / z (ESI): 257 [M+1].

[0304] Step 2: Dissolve (2-amino-5-methoxycarbonyl-phenyl)boronic acid (2.10 g, 10.78 mmol, synthesized by the known method "WO2022 / 132914"), 82b (2.3 g, 8.98 mmol), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (446 mg, 629 μmol) and potassium phosphate (3.81 g, 17.96 mmol) in water (4 mL) and 1'4-dioxane (16 mL), replace nitrogen three times, and stir the reaction at 90 ° C for 18 hours. The mixture was cooled to room temperature, filtered, and the residue was washed with a small amount of ethyl acetate. The combined filtrates were dried and spin-dried to afford methyl 4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 82c (2.30 g). Yield: 78.5%. MS m / z (ESI): 327 [M+1].

[0305] Step 3: Dissolve 82c (0.4 g, 1.23 mmol) in ethanolic hydrochloric acid solution (10 mL) and stir the reaction at 0°C for 1 hour. The reaction mixture was dried to give methyl 4-amino-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 82d (0.30 g, crude product). MS m / z (ESI): 243 [M+1]

[0306] Step 4: 82d (300 mg, 1.24 mmol), 1-bromo-2-methoxy-ethane (207 mg, 1.49 mmol, 0.14 mL), and cesium carbonate (1.21 g, 3.72 mmol) were dissolved in N,N-dimethylformamide (10 mL), purged with nitrogen three times, and the reaction was stirred at 25°C for 15 hours. The reaction was filtered, the filtrate was added with water, extracted with ethyl acetate (50 mL × 3), washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture of methyl 4-amino-1-(2-methoxyethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 82e and methyl 4-amino-2-(2-methoxyethyl)-2H-pyrazolo[4,3-c]quinoline-8-carboxylate 82f (0.34 g, crude), which was directly used in the next step. MS m / z(ESI):301[M+1]

[0307] Step 5: A mixture of 82e and 82f (340 mg, 1.13 mmol) and lithium hydroxide (54 mg, 2.26 mmol) were dissolved in tetrahydrofuran (5 mL) / water (5 mL) / methanol (5 mL). The reaction system was stirred at 25°C for 15 hours, concentrated, and extracted with 5 mL of ethyl acetate. 1M hydrochloric acid was added to the aqueous phase to adjust the pH to 5-6, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield a mixture of 4-amino-1-(2-methoxyethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 82g and 4-amino-2-(2-methoxyethyl)-2H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 82h (0.24 g, crude product). MS m / z (ESI): 287 [M+1]

[0308] Step 6: A mixture of 82g and 82h (200 mg, 0.70 mmol), N-methyl-2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridine-5-amine (162 mg, 0.70 mmol, obtained by the known method "WO2022 / 169948A1"), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (316. mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (271 mg, 2.10 mmol, 0.37 mL) was added. The nitrogen was evacuated three times, and the reaction system was stirred at 25 ° C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by alkaline preparative HPLC with eluent System A. The resulting first peak was lyophilized to give (4-amino-1-(2-methoxyethyl)-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 82-2 (55 mg) in a yield of 31.5%. MS m / z (ESI): 502 [M+1].

[0309] 1 H NMR (400MHz, DMSO) δ8.52(s,1H),8.22(d,1H),8.12(s,1H),7.88(d,1H),7.58(d,1H),7.49(d,1H),7. 11(s,2H),5.83(s,1H),4.84(t,2H),4.60(t,2H),4.20(s,2H),3.82(t,2H),3.26(s,3H),2.80(s,3H).

[0310] The residue was purified by basic preparative HPLC with eluent system A to obtain the second peak. The lyophilized residue was purified by basic preparative HPLC with eluent system B to give (4-amino-1-(2-methoxyethyl)-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 82-1 (13 mg) in 7.4% yield. MS m / z (ESI): 502 [M+1]

[0311] 1 H NMR(400MHz,DMSO)δ8.39-8.30(m,2H),8.20(s,1H),7.88(d,1H),7.64(q,2H),7.16( s,2H),5.83(s,1H),4.89(d,4H),4.21(s,2H),3.82(s,2H),3.14(s,3H),2.80(s,3H).

[0312] Example 83

[0313]

[0314] Step 1: Disperse N-benzyl-2-carbonylacetamide 83a (294 mg, 1.80 mmol) and methyl 3-amino-4-[di(tert-butoxycarbonyl)amino]benzoate (600 mg, 1.64 mmol) in 7 mL of dimethylformamide and microwave-react at 100°C for 10 minutes under nitrogen. 1-(1-Isocyanoethylsulfonyl)-4-methylbenzene (411 mg, 1.97 mmol) and potassium carbonate (339 mg, 2.46 mmol) were added to the reaction solution and microwave-reacted at 80°C for 10 minutes under nitrogen. The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (50 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 methyl 3-(5-(benzylcarbamoyl)-4-methyl-1H-imidazol-1-yl)-4-((tert-butoxycarbonyl)amino)benzoate 83b (338 mg) in a yield of 44.5%. MS m / z (ESI): 465 [M+1].

[0315] Step 2: Dissolve 83b (338 mg, 0.73 mmol) in 5 mL of dichloroethane and 0.5 mL of trifluoroacetic acid and microwave the reaction at 90°C for 10 minutes. The reaction solution was concentrated under reduced pressure to afford methyl 3-methyl-4-carbonyl-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate 83c (147 mg) in a 78.5% yield. MS m / z (ESI): 258 [M+1]

[0316] Step 3: Dissolve 83c (147 mg, 0.57 mmol) in 5 mL of phosphorus oxychloride and heat at 160°C for 2 hours. The reaction solution was concentrated under reduced pressure. 30 mL of sodium bicarbonate solution was added to the reaction solution under ice bath to quench the phosphorus oxychloride. The solution was extracted with dichloromethane (30 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give methyl 4-chloro-3-methylimidazo[1,5-a]quinoxaline-8-carboxylate 83d (39 mg) in a yield of 24.8%. MS m / z (ESI): 276 [M+1].

[0317] Step 4: 83d (39 mg, 0.14 mmol), p-methoxybenzylamine (29 mg, 0.21 mmol), and cesium carbonate (92 mg, 0.28 mmol) were dispersed in 3 mL of dimethylformamide and microwave-treated at 110°C for 1.5 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 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 methyl 4-((4-methoxybenzyl)amino)-3-methylimidazo[1,5-a]quinoxaline-8-carboxylate 83e (31 mg) in a 58.2% yield. MS m / z (ESI): 377 [M+1].

[0318] Referring to the synthesis methods of steps 5 to 7 of Example 1, 4-amino-N,3-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 83 (8 mg) was obtained from 83e (31 mg, 0.08 mol) in a yield of 21.9%. MS m / z (ESI): 457 [M+1].

[0319] 1H NMR(400MHz,DMSO)δ9.08(s,1H),8.30(s,1H),8.11(s,1H),7.87(d,1H),7.52-7.38(m,2 H),6.96(s,2H),5.82(s,1H),4.95-4.71(m,2H),4.20(d,2H),2.78(d,3H),2.63(s,3H).

[0320] Example 83 Preparation of Chiral Isomers Reference Example 1 Preparation of Chiral Isomers

[0321]

[0322] Example 84

[0323]

[0324] Step 1: Compound 4-amino-3-nitro-benzoic acid methyl ester 84a (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 4-(tert-butoxycarbonylamino)-3-nitro-benzoic acid methyl ester 84b (6.5 g) in a yield of 86.0%.

[0325] Step 2: Compound 84b (5 g, 16.88 mmol) was dissolved in methanol (60 mL) and Pd / C (2.05 g, 1.69 mmol, 10% purity) was added. The reaction was stirred at 50°C for 16 hours. A filtration funnel was lined with celite and the reaction mixture was filtered. The filtrate was collected and concentrated under reduced pressure to afford methyl 3-amino-4-(tert-butoxycarbonylamino)benzoate 84c (4 g) in an 89.0% yield. MS m / z (ESI): 267 [M+1]

[0326] Step 3: Compound 84c (1 g, 3.76 mmol) was dissolved in N,N-dimethylformamide (12 mL), and ethyl 2-oxoacetate 84d (575.05 mg, 5.63 mmol, 559 μL) was added. The reaction was stirred at 100°C in a microwave for 10 minutes. After the reaction was completed, the product was used directly in the next step.

[0327] Step 4: Compound 4-(tert-butoxycarbonylamino)-3-[(E)-(2-methoxy-2-oxo-ethylidene)amino]benzoic acid methyl ester 84e (600 mg, 1.78 mmol) was dissolved in N,N-dimethylformamide (7 mL), and tosylmethyl isocyanate 84f (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 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 give 1-(2-((tert-butoxycarbonyl)amino)-5-(methoxycarbonyl)phenyl)-1H-imidazole-4-carboxylic acid ethyl ester 84g (700 mg), which was used directly in the next step.

[0328] Step 5: Compound 84g (600 mg, 1.54 mmol) was dissolved in 1,2-dichloroethane (6 mL) / trifluoroacetic acid (0.6 mL). 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 (10 mL) for 15 minutes, filtered, and the filter cake was dried under reduced pressure to obtain methyl 4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate 84h (200 mg) in a yield of 53.4%. MS m / z (ESI): 244 [M+1]

[0329] Step 6: Compound 84h (200 mg, 822 μmol) was dissolved in phosphorus oxychloride (3 mL). The reaction was stirred at 180°C for 8 hours. The reaction solution was concentrated under reduced pressure, and water (15 mL) was added to the concentrated residue. The organic phase was separated, and 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 obtain methyl 4-chloroimidazo[1,5-a]quinoxaline-8-carboxylate 84i (100 mg), which was used directly in the next step. MS m / z (ESI): 262 [M+1]

[0330] Step 7: Compound 84i (100 mg, 383 μmol) was dissolved in N,N-dimethylformamide (2 mL). 4-Methoxybenzylamine (99.52 mg, 726 μmol) and potassium carbonate (150.40 mg, 1.09 mmol) were added sequentially. The reaction was stirred at 120°C for 2 hours. Water (20 mL) was added to the reaction solution, and the organic phase was separated. The aqueous layer was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 4-(4-(methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 84j (200 mg), which was used directly in the next step. MS m / z (ESI): 363 [M+1].

[0331] Step 8: Compound 84j (100 mg, 276 μmol) was dissolved in water (1 mL) / methanol (1 mL) / tetrahydrofuran (3 mL). Lithium hydroxide (25.45 mg, 1.06 mmol) was added and stirred at 80°C for 3 hours. The pH was adjusted to 5 with 0.5 M hydrochloric acid, and the mixture was filtered. The filter cake was rinsed with water (5 mL) and dried under reduced pressure to afford 4-(4-(methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid 84k (60 mg) in a 62.4% yield. MS m / z (ESI): 349 [M+1].

[0332] Step 9: Compound 84k (50 mg, 144 μmol) and N-(cyclopropylmethyl)-2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-amine 84l (40 mg, 172 μmol) were dissolved in N,N-dimethylformamide, and N-methylpyrazole (45.31 mg, 552 μmol, 46 μL) and TCFH (58.07 mg, 2 The reaction was stirred at 25°C for 16 hours. The reaction solution was directly separated and purified by Pre-HPLC to obtain 4-((4-methoxybenzyl)amino)-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 84m (18 mg) in a yield of 22.3%. MS m / z (ESI): 563 [M+1].

[0333] Step 10: Compound 84m (18 mg, 32 μmol) was dissolved in trifluoroacetic acid (2 mL). The reaction was stirred at 90°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated by preparative HPLC (acid method) to give 4-amino-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (6 mg) in a yield of 42.4%. MS m / z (ESI): 443 [M+1].

[0334] 1 H 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).

[0335] Example 84 Preparation of Chiral Isomers Refer to Example 1 for the preparation of chiral isomers.

[0336]

[0337] Example 97

[0338]

[0339] Step 1: 2-Methyl-thiophene-3-carboxylic acid methyl ester 97a (8.00 g, 51.22 mmol) was dissolved in carbon tetrachloride (100 mL). NBS (10.03 g, 56.34 mmol) and AIBN (841 mg, 5.12 mmol) were added. The reaction was stirred at 80°C for 16 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using eluent system C to afford 2-(bromomethyl)thiophene-3-carboxylic acid methyl ester 97b (8.60 g) in a 71.4% yield. MS m / z (ESI): 235 [M+1]. +

[0340] Step 2: Sodium hydride (510 mg, 12.76 mmol, 60% purity) was added to a solution of methyl 2-hydroxyacetate (766 mg, 8.51 mmol) in DMF (3 mL) at 0°C. After stirring at 0°C for 20 minutes, compound 97b (1.00 g, 4.25 mmol) was added to the reaction mixture and stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and the organic phase was concentrated. The residue was purified using eluent system C to afford methyl 4-oxo-4,7-dihydro-5H-thieno[2,3-c]pyran-5-carboxylate 97c (430 mg) in a yield of 47.6%. MS m / z (ESI): 213 [M+1]. + .

[0341] Step 3: Compound 97c (3.10 g, 14.61 mmol) was dissolved in dioxane (15 mL) and concentrated hydrochloric acid (15 mL, 12 M). The reaction mixture was heated to 100°C and stirred for 2 hours. The reaction mixture was concentrated and extracted with dichloromethane (80 mL × 3). The organic phases were combined, washed with saturated brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with eluent system C to give 5H-thieno[2,3-c]pyran-4(7H)-one 97d (1.80 g) in a yield of 79.9%. MS m / z (ESI): 155 [M+1]. + .

[0342] Step 4: Compound 97d (800 mg, 5.19 mmol) and NIS (1.20 g, 6.75 mmol) were dissolved in acetonitrile (20 mL) and acetic acid (5 mL). The reaction was stirred at 30°C for 6 hours. The reaction was diluted with ethyl acetate, washed with water and brine, and the organic phase was concentrated. The concentrated residue was purified using eluent System C to afford 2-iodo-5H-thieno[2,3-c]pyran-4(7H)-one 97e (680 mg) in a 54.6% yield. MS m / z (ESI): 281 [M+1] + .

[0343] Step 5: Compound 97e (850 mg, 3.03 mmol), methyl 2,2-difluoro-2-fluorosulfonylacetate (2.33 g, 12.14 mmol), and cuprous iodide (1.73 g, 9.10 mmol) were dispersed in DMF (10 mL), purged with nitrogen, and stirred at 90°C for 16 hours. The reaction mixture was diluted with ethyl acetate, filtered to remove solids, and the organic phase was washed with water and brine, then concentrated. The residue was purified with eluent System C to afford 2-(trifluoromethyl)-5H-thieno[2,3-c]pyran-4(7H)-one 97f (520 mg) in a 77.1% yield.

[0344] Step 6: Compound 97f (100 mg, 0.43 mmol) and methylamine (237 mg, 2.15 mmol, 28% methanol solution) were dissolved in trifluoroethanol (3 mL). The reaction solution was stirred at room temperature for 3 hours. Sodium borohydride (16 mg, 0.49 mmol) was added to the reaction solution and stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and brine, and the organic phase was concentrated. The concentrated residue was purified with eluent system C to give 2-trifluoromethyl-N-methyl-4,7-dihydro-5H-thieno[2,3-c]pyran-4-amine 97 g (58 mg) in a yield of 46.9%. MS m / z (ESI): 238 [M+1] + .

[0345] Step 7: Compound 97g (20 mg, 0.08 mmol) and 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (39 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N-methylpyrazole (20 mg, 0.24 mmol) and TCFH (45 mg, 0.16 mmol) were added. The reaction was stirred at 25°C for 16 hours. The reaction solution was directly separated and purified by Pre-HPLC to give 4-amino-N-(2-trifluoromethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 97 (16 mg) in a yield of 42.0%. MS m / z (ESI): 462 [M+1].

[0346] 1 H NMR (400MHz, CD3OD) δ8.54(d,1H),8.49(s,1H),7.93(d,1H),7.81(d,1H),7.61(d,1H),5. 76(s,1H),4.99(s,1H),4.79(d,1H),4.54(s,3H),4.38(d,1H),4.10(d,1H),2.91(s,3H).

[0347] Example 100

[0348]

[0349] Step 1: Disperse 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine 100a (1.20 g, 5.66 mmol) and sodium nitrite (700 mg, 10.14 mmol) in 10 mL of 2N dilute hydrochloric acid. Stir and react at 25°C for 1 hour. Filter to obtain 6-bromo-1-nitroso-1,2,3,4-tetrahydro-1,5-naphthyridine 100b (950 mg, crude product). MS m / z (ESI): 242 [M+1]

[0350] Step 2: Disperse 100b (950 mg, crude) in 10 mL of tetrahydrofuran and add diisobutylaluminum hydride (6 mL, 6 mmol, 1 M / L tetrahydrofuran solution) dropwise at 0°C. Stir and react at 0°C for 1 hour. Add 20 mL of water and 30 mL of ethyl acetate to quench the reaction. Filter, separate, and concentrate the organic phase under reduced pressure to obtain 6-bromo-3,4-dihydro-1,5-naphthyridine-1(2H)-amine 100c (900 mg, crude). MS m / z (ESI): 228 [M+1]

[0351] Step 3: Disperse 100c (900 mg, crude) and paraformaldehyde (300 mg, 10 mmol) in 10 mL of methanol and stir at 25°C for 1 hour. Add sodium borohydride (760 mg, 20 mmol) and stir at 60°C for 2 hours. Quench the reaction by adding 10 mL of water and 40 mL of ethyl acetate. The mixture is separated, and the organic phase is washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography with eluent System A to give 6-bromo-N-methyl-3,4-dihydro-1,5-naphthyridin-1(2H)-amine 100d (320 mg) in 23.4% yield. MS m / z (ESI): 242 [M+1]

[0352] Referring to the synthesis method of step 6 of Example 1, 4-amino-N-(6-bromo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 100 (2 mg) was obtained from 100d and 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid. MS m / z (ESI): 466 [M+1].

[0353] 1 H NMR (400MHz, DMSO) δ8.28(dd,2H),7.62-7.45(m,2H),7.37(d,1H),7.28–7.17(m,3H),4.28(s,1H),4.05(s,1H),3.24-2.54(m,10H).

[0354] Example 101

[0355]

[0356] Referring to the synthesis method of Example 75, 75 g (548 mg, 1 mmol) of 4-amino-7-ethoxymethyl-N,1-dimethyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 101 (8 mg) was obtained in a yield of 1.6%. MS m / z (ESI): 515 [M+1].

[0357] 1 H NMR(400MHz,DMSO-d6)δ8.24(m,2H),8.13(s,1H),7.91(d,1H),7.61(s,1H),7.10(s,2H),5.92(s,1 H),4.62(dt,2H),4.41(s,3H),4.23(dd,2H),3.45(tt,2H),2.79(s,2H),2.66(s,3H),1.06(t,3H).

[0358] Example 101 Preparation of Chiral Isomers

[0359]

[0360] Referring to the method for preparing chiral isomers in Example 75, 101 (470 mg, 0.66 mmol) was used to obtain P1: (R)-4-amino-7-ethoxymethyl-N,1-dimethyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 101-P1 (170 mg), yield: 36.2% and P2: (S)-4-amino-7-ethoxymethyl-N,1-dimethyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 101-P2 (195 mg), yield: 41.5%. MS m / z(ESI):515[M+1],P1; 515[M+1],P2

[0361] 1H NMR(400MHz,DMSO-d6,P1)δ8.24(m,2H),8.13(s,1H),7.91(d,1H),7.61(s,1H),7.10(s,2H),5.92(s ,1H),4.62(dt,2H),4.41(s,3H),4.23(dd,2H),3.45(tt,2H),2.79(s,2H),2.66(s,3H),1.06(t,3H).

[0362] 1 H NMR(400MHz,DMSO-d6,P1)δ8.24(m,2H),8.13(s,1H),7.91(d,1H),7.61(s,1H),7.10(s,2H),5.92(s ,1H),4.62(dt,2H),4.41(s,3H),4.23(dd,2H),3.45(tt,2H),2.79(s,2H),2.66(s,3H),1.06(t,3H).

[0363] Example 102

[0364]

[0365] Step 1: Methyl 4-amino-2-methylbenzoate 102a (10 g, 60.58 mmol) was dispersed in 200 mL of acetonitrile. N-bromosuccinimide (13 g, 73.03 mmol) was added and stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to afford methyl 4-amino-5-bromo-2-methylbenzoate 102b (13 g) in 88.3% yield. MS m / z (ESI): 244 [M+1]

[0366] Step 2: Disperse 102b (6 g, 24.69 mmol), bis(pinacolato)boronate (12.7 g, 50 mmol), potassium acetate (4.9 g, 50 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2 g, 2.74 mmol) in 100 mL of toluene and microwave-heat the mixture at 100°C for 5 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was concentrated to dryness under reduced pressure to afford (2-amino-5-(methoxycarbonyl)-4-methylphenyl)boronic acid 102c (11.5 g). MS m / z (ESI): 210 [M+1].

[0367] Step 3: Disperse 102c (11.5 g crude product), 5-bromo-1-methyl-1H-pyrazole-4-carbonitrile (4.65 g, 25 mmol), sodium carbonate (4.3 g, 50 mmol), and tetrakis(triphenylphosphine)palladium (2.88 g, 2.50 mmol) in 150 mL of 1,4-dioxane and 50 mL of water. The mixture was reacted at 120°C for 16 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was concentrated to dryness under reduced pressure to afford methyl 4-amino-1,7-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 102d (15 g). MS m / z (ESI): 271 [M+1].

[0368] Step 4: Disperse 102d (15 g crude product), di-tert-butyl dicarbonate (13.08 g, 60 mmol), and 4-dimethylaminopyridine (366 mg, 3 mmol) in 50 mL of N,N-dimethylformamide and react at 50°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 methyl 4-(N,N-di-tert-butoxycarbonylamino)-1,7-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 102e (1.81 g) in a 15.6% yield. MS m / z (ESI): 471 [M+1].

[0369] Step 5: Disperse 102e (400 mg, 0.85 mmol), N-bromosuccinimide (178 mg, 1 mmol), and azobisisobutyronitrile (33 mg, 0.21 mmol) in 10 mL of carbon tetrachloride 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 the title product, methyl 4-(N,N-di-tert-butoxycarbonylamino)-7-(bromomethyl)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 102f (400 mg) in 85.8% yield. MS m / z (ESI): 549 [M+1].

[0370] Step 6: 102f (200 mg, 0.36 mmol) and trifluoromethoxysilver (1 M / L acetonitrile solution, 1 mL, 1 mmol, synthesized by the known method "Organic Letters (2019), 21 (19), 8003-8007") were dispersed in 5 mL of acetonitrile and reacted at 40°C for 16 hours. The reaction solution was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A to obtain 102 g (150 mg) of methyl 4-(N,N-di-tert-butyloxycarbonylamino)-1-methyl-7-(trifluoromethoxymethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylate in a yield of 75.2%. MS m / z (ESI): 555 [M+1]

[0371] Step 7: Disperse 102g (150mg, 0.27mmol) in 4mL of concentrated hydrochloric acid and react at 100°C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain 4-amino-1-methyl-7-(trifluoromethoxymethyl)-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 102h (80mg, crude product). MS m / z (ESI): 341[M+1]

[0372] Step 8: Referring to the synthesis method of Step 6 of Example 1, the title product, 4-amino-N,1-dimethyl-7-((trifluoromethoxy)methyl)-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 102 (11 mg), was obtained in a yield of 16.5%. MS m / z (ESI): 555 [M+1].

[0373] 1 H NMR(400MHz,MeOD)δ8.36(s,1H),8.21(d,1H),8.14(s,1H),7.88(d,1H),7.82–7.51(m,4 H),5.90(s,1H),5.38(s,1H),4.84(dd,2H),4.45(s,3H),4.34–4.13(m,2H),2.71(s,3H).

[0374] The preparation of the following examples refers to Example 100:

[0375]

[0376]

[0377] Example 105

[0378]

[0379] Step 1: Methyl 4-amino-2-bromobenzoate 105a (1 g, 4.35 mmol), cyclopropylboronic acid (0.41 g, 4.78 mmol), potassium carbonate (1.2 g, 8.69 mmol), and Pd(dppf)Cl2.DCM (352 mg, 0.435 mmol) were dissolved in 10 mL of 1,4-dioxane and 2 mL of water. The mixture was stirred at 80°C for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure. 40 mL of water and 200 mL of ethyl acetate were added to the mixture. The organic phase was washed three times with 20 mL of saturated brine, dried, and spin-dried. The resulting residue was purified by silica gel column chromatography using eluent System A to afford methyl 4-amino-2-cyclopropylbenzoate 105b (0.56 g) in a 67.3% yield. MS m / z (ESI): 192 [M+1].

[0380] Step 2: Dissolve 105b (400 mg, 2.09 mmol) and N-bromosuccinimide (372 mg, 2.09 mmol) in 10 mL of acetonitrile and stir at 5°C for 2 hours. Quench with 10 mL of water and extract with ethyl acetate (50 mL x 3). The combined organic phases are washed with saturated sodium chloride solution (10 mL x 2). The organic phases are separated and 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 methyl 4-amino-5-bromo-2-cyclopropylbenzoate 105c (490 mg) in 86% yield. MS m / z (ESI): 270 [M+1].

[0381] Step 3: Dissolve 105c (490 mg, 1.81 mmol), pinacol diboronate (506 mg, 2.00 mmol), Pd(dppf)Cl2.DCM (147 mg, 0.18 mmol), and potassium acetate (890 mg, 9.07 mmol) in 10 mL of 4-dioxane and stir at 90°C for 6 hours. Cool, filter, and spin dry to obtain methyl 4-amino-2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 105d (600 mg, 75% purity) in a 78% yield. MS m / z (ESI): 318 [M+1].

[0382] Step 4: Dissolve 105d (575 mg, 1.81 mmol), 5-bromo-4-cyano-1-methylpyrazole (337 mg, 1.81 mmol), tetrakistriphenylphosphine palladium (314 mg, 0.272 mmol), and sodium carbonate (384 mg, 3.63 mmol) in 10 mL of 1,4-dioxane and 2 mL of water. Stir the mixture at 90°C for 3 hours. Cool the mixture and quench with 10 mL of saturated ammonium chloride solution. Extract the mixture 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 methyl 4-amino-7-cyclopropyl-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 105e (570 mg, 75% purity) in a yield of 79.5%. MS m / z (ESI): 297 [M+1].

[0383] Step 5: Dissolve 105e (100 mg, 0.337 mmol) and lithium hydroxide (24 mg, 1.01 mmol) in 1 mL of methanol, 1 mL of tetrahydrofuran, and 1 mL of water. Stir and react at 50°C for 2 hours. Cool and spin dry to obtain 4-amino-7-cyclopropyl-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 105f (75 mg) in 78% yield. MS m / z (ESI): 283 [M+1]

[0384] Step 6: 105f (40 mg, 0.142 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (33 mg, 0.142 mmol, synthesized by the known method "Patent WO2022169948 A1"), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (71 mg, 0.255 mmol) and N-methylimidazole (35 mg, 0.425 mmol) were dissolved in 3 mL of N,N-dimethylformamide and stirred at 50 °C for 2 h. The mixture was quenched by adding 10 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were 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 4-amino-7-cyclopropyl-N,1-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 105 (25 mg) in a 35.5% yield. MS m / z (ESI): 497 [M+1].

[0385] 1HNMR(400MHz,DMSO)δ8.22(d,1H),8.08(d,1H),7.93–7.84(m,1H),7.14–7.00(m,1H),6.97(d,2H),5.98(d,1H),4.89(d,1H),4.83–4. 75(m,1H),4.38(d,3H),4.32(s,1H),4.22(t,1H),4.15–4.02(m,1H),2.83(d,1H),2.63(s,2H),2.09–1.93(m,1H),1.17–0.85(m,4H).

[0386] Example 105 Preparation of Chiral Isomers

[0387]

[0388] Step 1: Dissolve 105 (50 mg, 0.1 mmol), 4-dimethylaminopyridine (3 mg, 0.02 mmol), di-tert-butyl dicarbonate (66 mg, 0.3 mmol), and triethylamine (31 mg, 0.3 mmol) in N,N-dimethylformamide (3 mL) and react at 20°C for 3 h. After completion, the system was concentrated to dryness. The resulting mixture was purified by silica gel column chromatography using eluent System B to afford tert-butyl (7-cyclopropyl-1-methyl-8-(methyl(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamoyl)-1H-pyrazolo[4,3-c]quinolin-4-yl)carbamate 105h (46 mg) in a 65.5% yield.

[0389] With reference to the method for preparing chiral isomers in Example 1, 105h (46 mg, 0.066 mmol) was used to obtain P1: (R)-(tert-butoxycarbonyl)(7-cyclopropyl-1-methyl-8-(methyl(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamoyl)-1H-pyrazolo[4,3-c]quinolin-4-yl)carbamate (15 mg) in a yield of 30%. P2: (R)-4-amino-7-cyclopropyl-N,1-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (20 mg) in a yield of 40%.

[0390] MS m / z (ESI): 497 [M+1], P1 MS m / z (ESI): 497 [M+1], P2 The preparation of the following examples refers to Example 75:

[0391]

[0392] The preparation of the following examples refers to Example 84:

[0393]

[0394] The preparation of the following examples is described in Example 1:

[0395]

[0396]

[0397] The preparation of the following examples refers to Example 80:

[0398]

[0399] Example 107

[0400]

[0401] Step 1: Dissolve 1-(4-bromo-3-nitrophenyl)ethan-1-ol 107a (2.46 g, 10 mmol) in 20 mL of methanol, followed by the addition of sodium borohydride (567 mg, 15 mmol). Stir the reaction at 20°C for 3 hours. Saturated ammonium chloride solution was added to quench the reaction, and the system was concentrated to dryness and extracted with ethyl acetate (50 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 C to afford crude 1-bromo-4-(1-methoxyethyl)-2-nitrobenzene 107b (2.56 g), which was used directly in the next step. MS m / z (ESI): 246 [M+1].

[0402] Step 2: 107b (1.97 g, 7.57 mmol), zinc powder (2.97 g, 45.45 mmol), and ammonium chloride (3.65 g, 68.17 mmol) were dispersed in a mixture of 30 mL of ethanol and 6 mL of water. The mixture was stirred at 80°C for 2 hours. The mixture was concentrated to dryness and extracted with ethyl acetate (50 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 C to afford 2-bromo-5-(1-methoxyethyl)aniline 107c (847 mg) in a 48.6% yield. MS m / z (ESI): 230 [M+1].

[0403] Step 3: Dissolve 107c (847 mg, 3.68 mmol) and NIS (855 mg, 3.80 mmol) in acetonitrile (20 mL) and stir at 20°C for 3 hours. The reaction mixture was diluted with 50 mL of ethyl acetate, washed with water and brine, and the organic phase was concentrated. The residue was purified by silica gel column chromatography using eluent System C to afford 2-bromo-4-iodo-5-(1-methoxyethyl)aniline 107d (500 mg) in a 38.2% yield. MS m / z (ESI): 356 [M+1] + .

[0404] Step 4: Dissolve 107d (500 mg, 1.40 mmol), Pd(dppf)Cl2.DCM (113 mg, 0.14 mmol), and triethylamine (568 mg, 5.62 mmol) in 5 mL of N,N-dimethylformamide and stir at 65°C under a CO atmosphere for 6 hours. Cool, quench with 10 mL of water, and 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 with eluent System A to afford methyl 4-amino-5-bromo-2-(1-methoxyethyl)benzoate 107e (220 mg) in 54% yield. MS m / z (ESI): 288 [M+1].

[0405] Step 5: Dissolve 107e (80 mg, 0.277 mmol), pinacol diboronate (70 mg, 0.277 mmol), palladium acetate (6 mg, 0.0278 mmol), tert-butyldiphenylphosphine (13 mg, 0.055 mmol), and potassium acetate (136 mg, 1.39 mmol) in 3 mL of 1,4-dioxane. Stir and react at 80°C for 16 hours. Cool, filter, and spin dry to obtain methyl 4-amino-2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 107f (100 mg, 85% purity) in a 91% yield. MS m / z (ESI): 335 [M+1].

[0406] Step 6: 107f (80 mg, 0.24 mmol), 5-bromo-1-methyl-pyrazole-4-carbonitrile 107g (44 mg, 0.24 mmol), tetrakistriphenylphosphine palladium (55 mg, 0.048 mmol), and sodium carbonate (76 mg, 0.716 mmol) were dissolved in 4 mL of 1,4-dioxane and 1 mL of water. The reaction was stirred at 100°C for 16 hours. The mixture was cooled, concentrated, and quenched with 10 mL of water. The mixture was extracted with ethyl acetate (50 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 methyl 4-amino-7-(1-methoxyethyl)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 107h (26 mg) in a 34% yield. MS m / z (ESI): 315 [M+1].

[0407] Step 7: Dissolve 107h (26 mg, 0.083 mmol) and LiOH (6 mg, 0.025 mmol) in 1 mL of tetrahydrofuran, 1 mL of methanol, and 1 mL of water. Stir and react at 50°C for 2 hours. Cool and spin dry to obtain 4-amino-7-(1-methoxyethyl)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 107i (25 mg) in 85% yield. MS m / z (ESI): 301 [M+1]

[0408] Step 8: 107i (26 mg, 0.087 mmol), N-methyl-2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-amine 107j (20 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 2 mL of N,N-dimethylformamide and stirred at 40°C for 2 h. The mixture was quenched by the addition of 10 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were 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 4-amino-7-(1-methoxyethyl)-N,1-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 107 (12.2 mg) in a 27.3% yield. MS m / z (ESI): 515 [M+1].

[0409] 1HNMR(400MHz,DMSO)δ8.59(d,1H),8.34–8.19(m,1H),7.96–7.90(m,1H),7.82(q,2H),5.95–5.71(m,1H),4.92–4.80(m,2H), 4.73(dd,1H),4.49(s,1H),4.03–3.91(m,2H),3.21(d,2H),2.80(d,3H),2.67–2.57(m,2H),2.17(d,3H),1.51–1.23(m,3H).

[0410] Or Example 109 was synthesized by referring to the following method:

[0411]

[0412] Step 1: Disperse 75 g (275 mg, 0.50 mmol) and potassium carbonate (207 mg, 1.50 mmol) in 5 mL of DMF. Add TMSCN (99 mg, 1.50 mmol) and react at 80°C for 12 hours. Cool, filter, and concentrate the filtrate to dryness. The resulting residue is purified by silica gel column chromatography using eluent System C to afford methyl 7-cyanomethyl-4-(bis(tert-butoxycarbonyl)imino)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 109a (240 mg) in a 96.9% yield. MS m / z (ESI): 496 [M+1].

[0413] Referring to the synthesis method of steps 7 to 9 of Example 75, 4-amino-7-cyanomethyl-N,1-dimethyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 109 (5.5 mg) was obtained using 109a (240 mg, 0.48 mmol) in a 2.3% yield. MS m / z (ESI): 496 [M+1].

[0414] 1 H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.34(s,1H),8.31(d,1H),7.93(s,1H),7.90(d,1H ),5.92(s,1H),4.84(dd,2H),4.91(s,3H),4.42-4.16(m,4H),2.84(s,1H),2.70(s,2H).

[0415] Or Example 110 was synthesized by referring to the following method:

[0416]

[0417] Step 1: Methyl 4-amino-2-bromobenzoate 110a (1 g, 4.37 mmol), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (980 mg, 5 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (366 mg, 0.50 mmol), and potassium carbonate (2.07 g, 15 mmol) were dispersed in 20 mL of 1,4-dioxane and 5 mL of water. The mixture was stirred at 100°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 methyl 4-amino-2-(2,5-dihydrofuran-3-yl)benzoate 110b (650 mg) in a 67.6% yield. MS m / z (ESI): 220 [M+1]

[0418] Step 2: Disperse 110b (650 mg, 2.97 mmol) and palladium on carbon (5%, 100 mg) in 10 mL of ethyl acetate and react at 25°C under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to afford methyl 4-amino-2-(tetrahydrofuran-3-yl)benzoate 110c (600 mg) in a 91.0% yield. MS m / z (ESI): 222 [M+1]

[0419] Referring to the synthesis method of Example 75, compound 110c (200 mg, 0.90 mmol) was used to obtain 4-amino-N,1-dimethyl-7-(tetrahydrofuran-3-yl)-N-((S)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 110 (1.5 mg) in a yield of 0.3%. MS m / z (ESI): 527 [M+1].

[0420] Example 114

[0421]

[0422] Step 1: Dissolve cyclopropylhydrazine hydrochloride 114a (1.24 g, 17.20 mmol) and 2-(ethoxymethylene)malononitrile 114b (2.1 g, 17.20 mmol) in 20 mL of ethanol and stir at 80°C for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure and quenched by adding NaCO. Then, 20 mL of water and 200 mL of dichloromethane were added to the mixture. The organic phase was washed three times with 20 mL of saturated brine, then dried and spin-dried. The resulting residue was purified by silica gel column chromatography using eluent System A to afford 5-amino-1-cyclopropyl-1H-pyrazole-4-carbonitrile 114c (1.25 g) in a 49% yield. MS m / z (ESI): 149 [M+1].

[0423] Step 2: 114c (700 mg, 2.19 mmol), allylmagnesium bromide (250 mg, 1.69 mmol), tert-butyl nitrite (261 mg, 2.53 mmol), and CuBr2 (452 ​​mg, 2.02 mmol) were dissolved in 5 mL of acetonitrile and stirred at 0°C for 2 hours. The mixture was quenched by the addition of 10 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL x 2). The organic phases were separated, 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 5-bromo-1-cyclopropyl-1H-pyrazole-4-carbonitrile 114d (250 mg) in 29% yield. MS m / z (ESI): 212 [M+1].

[0424] Step 3: 114d (230 mg, 1.08 mmol), (2-amino-5-methylcarbomethoxy-phenyl)boronic acid 114e (420 mg, 2.17 mmol, synthesized by the known method "Patent WO2022169948 A1"), tetrakistriphenylphosphine palladium (251 mg, 217 μmol) and Na2CO3 (345 mg, 3.25 mmol) were dissolved in 4 mL of 1,4-dioxane and 1 mL of water, and the reaction was stirred at 90 ° C for 2 hours. The mixture was cooled, quenched by the addition of 10 mL of saturated ammonium chloride solution, and extracted with ethyl acetate (50 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 methyl 4-amino-1-cyclopropyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 114f (200 mg) in a 65% yield. MS m / z (ESI): 283 [M+1].

[0425] Step 4: Dissolve 114f (20 mg, 0.071 mmol) and lithium hydroxide (5.1 mg, 0.212 mmol) in 0.5 mL of methanol, 0.5 mL of tetrahydrofuran, and 0.5 mL of water. Stir and react at 50°C for 2 hours. Cool and spin dry to obtain 4-amino-1-cyclopropyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 114 g (20 mg, 90% purity) in a 94% yield. MS m / z (ESI): 269 [M+1]

[0426] Step 5: 114 g (20 mg, 0.07 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 114h (19 mg, 0.08 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (31 mg, 0.111 mmol) and N-methylimidazole (31 mg, 0.372 mmol) were dissolved in 2 mL of N,N-dimethylformamide and stirred at 50°C for 2 hours. The mixture was quenched by the addition of 10 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were 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 4-amino-1-cyclopropyl-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 114 (8 mg) in a 22.2% yield. MS m / z (ESI): 483 [M+1].

[0427] 1 HNMR(400MHz,DMSO)δ8.24(s,2H),8.14–7.86(m,1H),7.70–7.67(m,1H),7.65–7.61(m,1H),7.16(s,2H),4.91–4.86(m, 1H),4.30–4.22(m,2H),4.14–4.10(m,1H),3.78–3.76(m,1H),2.85–2.80(m,3H),2.33–2.30(m,1H),1.32–1.25(m,4H).

[0428] Or Example 115 is synthesized by referring to the following method:

[0429]

[0430] By referring to the synthetic methods of Steps 1 to 2 of Example 84 and Step 3 of Example 76, methyl 5-amino-2-bromo-4-(tert-butoxycarbonylamino)benzoate 115d (6.0 g) was obtained from methyl 4-amino-3-nitrobenzoate 115a (6 g) in a 56.8% yield. MS m / z (ESI): 346 [M+1].

[0431] Step 4: Compound 115d (1 g, 2.90 mmol) was dissolved in 25 mL of 1'4-dioxane and 5 mL of water. Cyclopropylboronic acid (746.52 mg, 8.69 mmol) and potassium carbonate (1.20 g, 8.69 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and under nitrogen protection, Pd(dppf)Cl2 (211.97 mg, 290 μmol) was quickly added. The reaction was stirred at 90°C for 16 hours. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (60 mL x 3). The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using Purification System C to afford methyl 5-amino-4-(tert-butoxycarbonylamino)-2-cyclopropylbenzoate 115e (540 mg) in a 55.3% yield. MS m / z (ESI): 307 [M+1].

[0432] Referring to the synthesis method of Example 84, 115e (540 mg, 1.76 mmol) was used to obtain 4-amino-7-cyclopropyl-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 115 (12.0 mg) in a 1.4% yield. MS m / z (ESI): 483 [M+1].

[0433] 1 H NMR(400MHz,DMSO)δ9.03(s,1H),8.18(d,2H),7.89(s,2H),7.38–6.85(m,3H),5.97(s,1H) ,4.95–4.54(m,2H),4.18(d,2H),2.76(d,3H),2.00(s,1H),1.23–0.94(m,2H),0.75(d,2H).

[0434] Example 123

[0435]

[0436] Step 1: 2-(Trifluoromethyl)-8H-pyrano[3,4-b]pyridin-5-one 123a (500 mg, 2.30 mmol) and cyclopropylmethylamine (1.31 g, 18.42 mmol, 1.6 mL) were dissolved in methanol (15 mL). Tetraisopropyl titanate (1.96 g, 6.91 mmol, 2 mL) was added and the reaction was stirred at 25°C for 16 hours. Sodium acetate borohydride (732.02 mg 3.45 mmol) was added and stirred at 25°C for 30 minutes. Saturated aqueous sodium bicarbonate (8 mL) was added to the reaction solution, which was filtered and the filtrate was collected and concentrated under reduced pressure. The residue was separated by Pre-TLC to give N-(cyclopropylmethyl)-2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-amine 123b (52 mg) in a yield of 8.3%. MS m / z(ESI):273[M+1]

[0437] Step 2: 4-Amino-3-nitro-benzoic acid methyl ester 123c (5 g, 25.49 mmol) was dissolved in dichloromethane (50 mL), and DIEA (3.95 g, 30.59 mmol, 5.5 mL) was added, followed by DMAP (155.70 mg, 1.27 mmol) and di-tert-butyl dicarbonate (6.68 g, 30.59 mmol). 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 combined organic phases were washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using eluent System C to afford 4-(tert-butoxycarbonylamino)-3-nitro-benzoic acid methyl ester 123d (6.5 g) in 86.0% yield.

[0438] Step 3: 123d (5 g, 16.88 mmol) was dissolved in methanol (60 mL) and Pd / C (2.05 g, 1.69 mmol, 10% purity) was added. The reaction was stirred at 50°C for 16 hours. A layer of celite was laid on the filter funnel, and the reaction solution was filtered. The filtrate was collected and concentrated under reduced pressure to give methyl 3-amino-4-(tert-butoxycarbonylamino)benzoate 123e (4 g) in an 89.0% yield. MS m / z (ESI): 267 [M+1]

[0439] Step 4: 123e (1 g, 3.76 mmol) was dissolved in N,N-dimethylformamide (12 mL), and ethyl 2-oxoacetate 7 (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.

[0440] Step 5: 4-(tert-Butoxycarbonylamino)-3-[(E)-(2-methoxy-2-oxo-ethylidene)amino]benzoic acid methyl ester 123f (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 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 give compound 1-[2-(tert-Butoxycarbonylamino)-5-methoxycarbonyl-phenyl]-5-methylimidazole-4-carboxylic acid ethyl ester 123 g, which was used directly in the next step.

[0441] Step 6: Dissolve 123g (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 methyl 3-methyl-4-oxo-5H-imidazo[1,5-a]quinoxaline-8-carboxylate 123h (200mg). Yield: 52.3%. MS m / z (ESI): 258[M+1].

[0442] Step 7: Compound 123h (200 mg, 778 μmol) was dissolved in phosphorus oxychloride (3 mL). The reaction was stirred at 180°C for 8 hours. The reaction solution was concentrated under reduced pressure, and water (15 mL) was added to the concentrated residue. The organic phase was separated; 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 obtain methyl 4-chloro-3-methylimidazo[1,5-a]quinoxaline-8-carboxylate 123i (100 mg), which was used directly in the next step. MS m / z (ESI): 276 [M+1]

[0443] Step 8: 123i (100 mg, 363 μmol) was dissolved in N,N-dimethylformamide (2 mL), and 4-methoxybenzylamine (99.52 mg, 726 μmol) and potassium carbonate (150.40 mg, 1.09 mmol) were added sequentially. The reaction was stirred at 120°C for 2 hours. Water (20 mL) was added to the reaction solution, and the organic phase was separated. The aqueous layer was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 4-[(4-methoxyphenyl)methylamino]-3-methylimidazo[1,5-a]quinoxaline-8-carboxylate 123j (200 mg), which was used directly in the next step. MS m / z (ESI): 377 [M+1]

[0444] Step 9: 123j (100 mg, 266 μmol) was dissolved in water (1 mL) / methanol (1 mL) / tetrahydrofuran (3 mL). Lithium hydroxide (25.45 mg, 1.06 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 rinsed with water (5 mL). The filter cake was dried under reduced pressure to afford 4-[(4-methoxyphenyl)methylamino]-3-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid 123k (60 mg) in a 62.3% yield. MS m / z (ESI): 363 [M+1].

[0445] Step 10: 123k (50 mg, 138 μmol) and 123b (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 separated and purified by Pre-HPLC to obtain N-(cyclopropylmethyl)-4-[(4-methoxyphenyl)methylamino]-3-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 123l (18 mg) in a yield of 21.2%. MS m / z (ESI): 617 [M+1].

[0446] Step 11: 123l (18 mg, 29 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 preparative HPLC (acid method) to give 4-amino-N-(cyclopropylmethyl)-3-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5-pyrano[3,4-b]pyridin-5-yl]imidazol-[1,5-a]quinoxaline-8-carboxamide (6 mg) in a yield of 41.4%. MS m / z (ESI): 497 [M+1].

[0447] 1 H 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).

[0448] Example 123 Preparation of Chiral Isomers

[0449]

[0450] With reference to Example 1, Preparation of Chiral Isomers was performed using 123 to obtain P1: (S)-4-amino-N-(cyclopropylmethyl)-3-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5-pyrano[3,4-b]]pyridin-5-yl]imidazol-[1,5-a]quinoxaline-8-carboxamide 123-P1 and P2: (R)-4-amino-N-(cyclopropylmethyl)-3-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5-pyrano[3,4-b]]pyridin-5-yl]imidazol-[1,5-a]quinoxaline-8-carboxamide 123-P2 (195 mg). MS m / z (ESI): 497 [M+1], P1; 497 [M+1], P2

[0451] The preparation of the following examples refers to Example 83:

[0452]

[0453]

[0454] The preparation of the following examples refers to Example 84:

[0455]

[0456]

[0457] The preparation of the following examples is described in Example 1:

[0458]

[0459]

[0460] The preparation of the following examples refers to Example 97:

[0461]

[0462]

[0463] The preparation of the following examples refers to Example 77:

[0464]

[0465] Example 163

[0466]

[0467] Step 1: 7-Bromoisochroman-4-one 163a (100 mg, 440 μmol) was dissolved in 1,4-dioxane (2 mL), and tributyl(3,3,3-trifluoroprop-1-ynyl)stannane 163b (506.15 mg, 1.32 mmol) was added. The atmosphere was replaced with nitrogen three times and protected with nitrogen. Pd(PPh3)4 (101.79 mg, 88 μmol) was quickly added. The reaction was stirred at 130°C in a microwave for 2 hours. The reaction solution was concentrated under reduced pressure, and the concentrated residue was separated and purified by Pre-TLC to give 7-(3,3,3-trifluoroprop-1-ynyl)isochroman-4-one 163c (94 mg) in a yield of 88.9%.

[0468] 1 H NMR(400MHz, CDCl3)δ8.06(d,1H),7.59(dd,1H),7.45(d,1H),4.88(s,2H),4.39(s,2H)

[0469] Step 2: 163c (94 mg, 391.38 μmol) and methylamine (291.72 mg, 2.35 mmol) were dissolved in DCE (1 mL). Titanium tetraisopropoxide (333.70 mg, 1.17 mmol, 348 μL) was added. The reaction was stirred at 25°C for 16 h. NaBH(OAc)3 (124 mg, 587 μmol) was added and stirred at 25°C for 30 min. Saturated aqueous sodium bicarbonate (8 mL) was added to the reaction mixture, which was filtered, collected, and concentrated under reduced pressure. The residue was separated by Pre-TLC to afford 7-(3,3,3-trifluoropropyl-1-ynyl)isochroman-4-amine 163d (17 mg) in a 15.5% yield. MS m / z (ESI): 256 [M+1].

[0470] Step 3: 163d (17 mg, 66.61 μmol) was dissolved in DMF (2 mL), and N-methylimidazole (21.87 mg, 266 μmol, 22 μL) and TCFH (28.03 mg, 100 μmol) were added. The reaction was stirred at 25°C for 16 hours. The reaction solution was filtered and separated by Pre-HPLC to give 4-amino-N,1-dimethyl-N-[7-(3,3,3-trifluoroprop-1-ynyl)isochroman-4-yl]pyrazolo[4,3-c]quinoline-8-carboxamide 163 (7 mg) in a yield of 22.0%. MS m / z (ESI): 480 [M+1].

[0471] 1 H NMR(400MHz,DMSO)δ8.62(s,1H),8.44(s,1H),7.94-7.81(m,2H),7.65(d,1H) ,7.57(d,2H),4.91-4.59(m,3H),4.48(s,3H),4.22-4.08(m,2H),2.77(s,3H).

[0472] Example 165

[0473]

[0474] Step 1: 7-Bromoisochroman-4-one 165a (0.20 g, 0.88 mmol), diethylamine (64 mg, 0.88 mmol, 0.1 mL) and cuprous iodide (34 mg, 0.18 mmol) were dissolved in triethylamine (10 mL). The mixture was purged with nitrogen three times. Cyclopropylacetylene (291 mg, 4.40 mmol, 0.37 mL) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (124 mg, 0.18 mmol) were added and the system was reacted at 25 °C for 15 h. The reaction mixture was cooled to room temperature, quenched by addition of water, and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford 7-(cyclopropylethynyl)isochroman-4-one 165b (120 mg) in a 64.2% yield. MS m / z (ESI): 213 [M+1].

[0475] Step 2: 165b (130 mg, 0.61 mmol) and ethanolic methylamine (317 mg, 3.06 mmol, 30% purity) were dissolved in methanol (10 mL). The atmosphere was purged with nitrogen three times, and tetraisopropyl titanate (174 mg, 0.61 mmol, 0.18 mL) was added. The reaction was allowed to proceed at 25°C for 15 h. Sodium cyanoborohydride (44 mg, 1.23 mmol) was added and the mixture was allowed to react at 25°C for 1 h. The reaction was quenched by addition of saturated aqueous sodium bicarbonate and extracted with methanol / dichloromethane (1 / 10) (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford 7-(cyclopropylethynyl)-N-methylisochroman-4-amine 165c (55 mg) in a 39.5% yield. MS m / z(ESI):228[M+1]

[0476] Step 3: 165c (50 mg, 0.22 mmol) and (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (100 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (85 mg, 0.66 mmol) was added, and the atmosphere was purged with nitrogen three times. The reaction system was stirred at 25°C for 2 hours. The reaction was quenched with water, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to afford 4-amino-N-(7-(cyclopropylethynyl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 165 (35 mg) in a 35.2% yield. MS m / z (ESI): 452 [M+1].

[0477] 1 H NMR(400MHz,DMSO)δ8.31(d,1H),8.25(s,1H),7.68–7.59(m,2H),7.33(d,2H),7.16(s,3H),5.71(s,1H),4.75(s,1H) ,4.66-4.47(m,1H),4.39(s,3H),4.16(dd,1H),4.08(s,1H),2.74(s,3H),1.53(tt,1H),0.88(dt,2H),0.72(dt,2H).

[0478] Example 166

[0479]

[0480] Step 1: 2-Chloro-8H-pyrano[3,4-b]pyridin-5-one 166a (0.3 g, 1.63 mmol) and cuprous iodide (62 mg, 0.33 mmol) were dissolved in triethylamine (827 mg, 8.17 mmol, 1.14 mL) and N,N-dimethylformamide (10 mL). The mixture was purged with nitrogen three times, and cyclopropylacetylene (540 mg, 8.17 mmol, 0.69 mL) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (115 mg, 0.16 mmol) were added. The system was heated to 80 °C in a microwave reactor for 3 h. The reaction mixture was cooled to room temperature, quenched by the addition of water, and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford 2-(cyclopropylethynyl)-6H-pyrano[3,4-b]pyridin-5(8H)-one 7b (260 mg) in a yield of 74.6%. MS m / z (ESI): 214 [M+1].

[0481] Referring to the synthesis method from steps 2 to 3 of Example 165, 4-amino-N-(2-(cyclopropylethynyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 166 (17 mg) was obtained from 166b (130 mg, 0.61 mmol) in a 6.1% yield. MS m / z (ESI): 453 [M+1].

[0482] 1H NMR(400MHz,DMSO)δ8.26(d,1H),8.19(s,1H),7.72(d,1H),7.62-7.51(m,2H),7.31(d,1H),7.08(s,2H),5.68 (s,1H),4.65(d,2H),4.33(s,3H),4.19-3.99(m,2H),2.70(s,3H),1.51(tt,1H),0.86(dq,2H),0.71(dq,2H).

[0483] The preparation of the following examples refers to Example 77:

[0484]

[0485]

[0486] Example 181

[0487]

[0488] Step 1: Referring to the synthesis method of Step 2 of Example 165, 7-bromoisochroman-4-one 181a (0.20 g, 0.88 mmol) was used to obtain 7-bromo-N-methylisochroman-4-amine 181b (100 mg). Yield: 46.9%. MS m / z (ESI): 243 [M+1].

[0489] Step 2: 181b (100 mg, 0.41 mmol), potassium acetate (81 mg, 0.83 mmol), and pinacol diboronate (210 mg, 0.83 μmol) were dissolved in 1'4-dioxane (10 mL). The atmosphere was purged with nitrogen three times, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (34 mg, 41 μmol) was added. The reaction system was stirred at 100°C for 2 h. The mixture was filtered and concentrated under reduced pressure to afford N-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-4-amine 181c (400 mg, crude). MS m / z (ESI): 290 [M+1].

[0490] Step 3: 181c (670 mg, 2.32 mmol), potassium phosphate (294 mg, 1.38 mmol) and 2-bromo-3,3,3-trifluoropropene (605 mg, 3.46 mmol, 0.36 mL) were dissolved in water (1 mL) and 1,4-dioxane (10 mL). The nitrogen atmosphere was purged three times and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (50 mg, 69 μmol) was added. The reaction system was heated to 90 ° C in a microwave reactor for 1.5 hours. The reaction was quenched with water and extracted with methanol / dichloromethane (1 / 10) (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent System A to afford N-methyl-7-(3,3,3-trifluoroprop-1-en-2-yl)isochroman-4-amine 181d (60 mg) in a 10.1% yield. MS m / z (ESI): 258 [M+1].

[0491] Referring to the synthesis method of the third step of Example 165, 4-amino-N,1-dimethyl-N-(7-(3,3,3-trifluoroprop-1-en-2-yl)isochroman-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 181 (3 mg) was obtained from 8d (10 mg, 39 μmol). Yield: 16.0%. MS m / z (ESI): 482 [M+1].

[0492] 1 H NMR (400MHz, DMSO) δ13.20(s,1H),8.52(s,1H),8.38(d,1H),7.80(d,2H),7.53–7.34(m,2H),7. 24(d,1H),6.05(s,2H),5.69(s,1H),4.91-4.60(m,3H),4.41(d,3H),4.11(d,2H),2.69(d,3H).

[0493] Example 182

[0494]

[0495] Step 1: 7-Bromoisochroman-4-one 182a (250 mg, 1.11 mmol), dimethylphosphine oxide (41 mg, 0.53 mmol), tris(dibenzylideneacetone)palladium (35 mg, 0.04 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (41 mg, 0.07 mmol) and cesium carbonate (150 mg, 0.71 mmol) were dissolved in 10 mL of dioxane and the reaction was microwaved at 100 °C under nitrogen atmosphere for 2 h. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 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 A to afford 8-bromo-N-(4-methoxybenzyl)-[1,2,3]triazolo[1,5-a]quinoxalin-4-amine 182b (71 mg) in a 28.6% yield. MS m / z (ESI): 225 [M+1].

[0496] Referring to the synthesis method of Step 7 of Example 30 and Step 6 of Example 1, 182b (71 mg) was used to obtain 4-amino-N-(7-(dimethylphosphino)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 182 (6 mg) in a 4.2% yield. MS m / z (ESI): 464 [M+1].

[0497] 1 H NMR(400MHz,DMSO)δ8.63(d,2H),8.47(d,1H),7.94(t,1H),7.86(d,1H),7.70(q,1H),7.65-7.50(m,2H) ,4.89(d,1H),4.84-4.57(m,2H),4.49(d,3H),4.26-4.05(m,2H),2.82-2.68(m,3H),1.71-1.56(m,6H).

[0498] The preparation of the following examples refers to Example 77:

[0499]

[0500] The preparation of the following examples refers to Example 75:

[0501]

[0502] The preparation of Example 190 is referred to Example 65, the preparation of Example 191 is referred to Example 80, and the preparation of Example 192 is referred to Example 45:

[0503]

[0504]

[0505] The preparation of the following examples refers to Example 77:

[0506]

[0507] Or Example 186 was synthesized by the following method:

[0508]

[0509] Step 1: 1-(4-(Methylamino)isochroman-7-yl)ethan-1-one 186a (0.20 g, 0.97 mmol) and difluoromethyl(2-pyridyl)sulfone (169 mg, 0.88 mmol) were dissolved in N,N-dimethylformamide (5 mL). The mixture was purged with nitrogen three times and cooled to -40°C. Potassium tert-butoxide (142 mg, 1.27 mmol) was added and the reaction was allowed to react at -40°C for 1 hour. 1 mL of saturated ammonium chloride solution and 1 mL of 2M hydrochloric acid solution were added to the reaction. The system was stirred at room temperature for 1 hour and extracted with dichloromethane / methanol = 10 / 1 (50 mL x 3). The mixture was 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 give 7-(1,1-difluoroprop-1-en-2-yl)-N-methylisochroman-4-amine 186b (140 mg) in a 60.0% yield. MS m / z (ESI): 240 [M+1]

[0510] Step 2: Referring to the synthesis method of Step 3 of Example 165, 4-amino-N-(7-(1,1-difluoroprop-1-en-2-yl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 186 (22 mg) was obtained from 186b (10 mg, 39 μmol). Yield: 14.4%. MS m / z (ESI): 464 [M+1].

[0511] 1 H NMR(400MHz,DMSO)δ8.29(d,2H),7.64(q,2H),7.40(d,2H),7.15(s,3H),5.73( s,1H),4.88–4.57(m,2H),4.40(s,3H),4.13(d,2H),2.77(s,3H),1.95(s,3H).

[0512] Or Example 188 was synthesized by the following method:

[0513]

[0514] Step 1: Disperse 75 g (300 mg, 0.59 mmol) of methyl 7-bromomethyl-4-(bis(tert-butoxycarbonyl)imino)-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate and TMSN3 (126 mg, 1.09 mmol) in 10 mL of DMF and react at 70°C for 12 hours. The mixture was cooled, concentrated to dryness, and the residue was purified by silica gel column chromatography using eluent System C to afford methyl 7-azidomethyl-4-tert-butoxycarbonylamino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate 188a (230 mg) in a 95.3% yield. MS m / z (ESI): 412 [M+1].

[0515] Referring to the synthesis method of steps 2 to 3 of Example 109, tert-butyl (7-azidomethyl-1-methyl-8-(methyl(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamoyl)-1H-pyrazolo[4,3-c]quinolin-4-yl)carbamate 188c (160 mg) was obtained in a yield of 46.8%. MS m / z (ESI): 612 [M+1].

[0516] Step 4: 188c (160 mg, 0.26 mmol) and Pd(OH)2 / C (32 mg, 5% by mass) were dispersed in 10 mL of EA and reacted at 20°C under a hydrogen atmosphere for 6 h. The mixture was filtered, concentrated to dryness, and the residue was purified by silica gel column chromatography using eluent System C to afford tert-butyl (7-aminomethyl-1-methyl-8-(methyl(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamoyl)-1H-pyrazolo[4,3-c]quinolin-4-yl)carbamate 188d (140 mg) in a 91.4% yield. MS m / z (ESI): 586 [M+1].

[0517] Step 5: Disperse 188d (140 mg, 0.24 mmol), paraformaldehyde (41 mg, 1.20 mmol) and sodium triacetoxyborohydride (102 mg, 0.48 mmol) in 10 mL of tetrahydrofuran and react at 20°C for 12 h. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (2 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent System C to afford tert-butyl (7-dimethylaminomethyl-1-methyl-8-(methyl(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamoyl)-1H-pyrazolo[4,3-c]quinolin-4-yl)carbamate 188e (70 mg) in a 47.7% yield. MS m / z (ESI): 614 [M+1].

[0518] Step 6: Disperse 188e (70 mg) in 4M HCl / dioxane solution (3 mL) and react at 20°C for 3 hours. The system was concentrated to dryness, and the resulting residue was purified by preparative HPLC to afford 4-amino-N,1-dimethyl-7-methylaminomethyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 188 (7.3 mg) in a 12.4% yield. MS m / z (ESI): 514 [M+1].

[0519] 1 H NMR(400MHz,DMSO-d6)δ8.75-8.20(m,5H),7.90-7.75(m,2H),5.98(s,1H),5.08-4 .67(m,2H),4.51-3.99(m,4H),4.41(s,3H),2.99-2.80(m,3H),2.75-2.55(m,6H).

[0520] Or Example 189 was synthesized by the following method:

[0521]

[0522] Referring to the synthesis methods of Example 109, Step 1, and Steps 7 to 9 of Example 75, 75 g (110 mg, 0.20 mmol) of 4-amino-N,1-dimethyl-7-methylaminomethyl-N-(2-trifluoromethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 189 (6 mg) was obtained in a 6.0% yield. MS m / z (ESI): 500 [M+1].

[0523] 1 H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.27(s,1H),8.21(d,1H),7.90-7.78(m,2H),6.00(s,1H) ,4.90(dd,2H),4.49(s,3H),4.43(s,1H),4.30(s,2H),3.87(d,2H),2.99(s,3H),2.81(s,2H).

[0524] Or Example 191 was synthesized by the following method:

[0525]

[0526] Step 1: 1-(Chloromethyl)-1H-pyrazol-4-cyano 191a (649 mg, 4.60 mmol), methyl 4-amino-2-hydroxy-3-iodobenzoate (1.90 g, 6.50 mmol), and potassium carbonate (1.38 g, 10 mmol) were dispersed in 10 mL of N,N-dimethylformamide and stirred at 50°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 methyl 4-amino-2-((4-cyano-1H-pyrazol-1-yl)methoxy)-3-iodobenzoate 191b (1.21 g) in a 66.1% yield. MS m / z (ESI): 399 [M+1]

[0527] Step 2: 191b (600 mg, 1.51 mmol), palladium acetate (34 mg, 0.15 mmol), n-butyldi(1-adamantyl)phosphine (111 mg, 0.31 mmol), and potassium acetate (296 mg, 3.02 mmol) were dispersed in 10 mL of N,N-dimethylacetamide and reacted at 100°C for 48 hours. The reaction solution was poured into 100 mL of water and filtered to afford methyl 9-amino-3H-4-oxo-2,2a,8-triazolecyclopenta[cd]phenalene-5-carboxylate 191c (210 mg) in a 51.6% yield. MS m / z (ESI): 271 [M+1].

[0528] The synthesis method of the fifth and sixth steps of Reference Example 1 was used to obtain 9-amino-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-3H-4-oxo-2,2a,8-triazolecyclopenta[cd]phenazone-5-carboxamide (21 mg).

[0529] 1 H NMR(400MHz,DMSO)δ13.06(s,1H),10.08(s,1H),8.89(d,1H),8.07–7.71(m,3H),7.43 (d,1H),6.66–6.45(m,2H),5.41(d,1H),4.91–4.60(m,2H),4.19(d,2H),2.76(d,3H).

[0530] Example 197

[0531]

[0532] Step 1: Dissolve 4-fluoro-2-methyl-5-nitro-benzoic acid methyl ester 197a (20 g, 93.83 mmol) in 1,4-dioxane and add aqueous ammonia (2 M, 93.8 mL). The reaction is stirred at 25°C for 16 hours. The reaction solution is concentrated under reduced pressure to obtain the crude product. The crude product is stirred with dichloromethane (100 mL) for 15 minutes, filtered, and the filter cake is dried under reduced pressure to obtain 4-amino-2-methyl-5-nitro-benzoic acid methyl ester 197b (22 g, crude product). MS m / z (ESI): 211 [M+1]

[0533] Step 2: 197b (22 g, 104.67 mmol) was dissolved in DMF (150 mL). The reaction system was cooled to 0°C, and BocO (34.27 g, 157.00 mmol, 36.0 mL), DIEA (16.23 g, 125.60 mmol, 21.9 mL), and DMAP (1.28 g, 10.47 mmol) were added sequentially. The reaction was stirred at 25°C for 2 h. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL×3). The combined organic phases were washed with saturated brine (200 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with eluent System C to afford methyl 4-(tert-butoxycarbonylamino)-2-methyl-5-nitrobenzoate 197c (18 g) in a yield of 55.4%.

[0534] 1H NMR (400MHz, DMSO) δ9.82(s,1H),8.42(s,1H),7.80(s,1H),3.85(s,3H),2.58(s,3H),1.48(s,9H).

[0535] Step 3: Compound 197c (10 g, 32.23 mmol) was dissolved in carbon tetrachloride (100 mL), and NBS (17.21 g, 96.68 mmol) and BPO (1.12 g, 3.22 mmol, 70% purity) were added. The reaction was stirred at 80°C for 16 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (200 mL × 3). The organic phases were combined, washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was added to tetrahydrofuran (120 mL). Diethyl phosphite (7.03 g, 51.27 mmol, 6.6 mL) and DIEA (6.63 g, 51.27 mmol, 9.0 mL) were added and stirred at 25°C for 1 hour. Water (100 mL) was added and the mixture was extracted with ethyl acetate (120 mL × 3). The combined organic phases were washed with saturated brine (120 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified with eluent System C to give methyl 2-(bromomethyl)-4-(tert-butoxycarbonylamino)-5-nitro-benzoate 197d (9 g) in a yield of 90.2%.

[0536] 1H NMR (400MHz, DMSO) δ9.93(s,1H),8.44(s,1H),8.03(s,1H),5.05(s,2H),3.89(s,3H),1.47(s,9H).

[0537] Step 4: 197d (4.8 g, 12.33 mmol) was dissolved in DMF (50 mL), and sodium methoxide (5 M, 9.9 mL, 30% purity) in DMF (20 mL) was added dropwise. The reaction was stirred at 25°C for 2 h. Water (150 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL×3). The combined organic phases were washed with saturated brine (150 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with eluent System C to give methyl 4-(tert-butoxycarbonylamino)-2-(methoxymethyl)-5-nitrobenzoate 197e (1.3 g) in a yield of 31.0%.

[0538] Referring to the synthesis method of steps 3 to 11 of Example 123, compound 197e (500 mg) was used to obtain 4-amino-7-(methoxymethyl)-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 197 (5.5 mg) in a yield of 1%. MS m / z (ESI): 487 [M+1].

[0539] 1 H NMR(400MHz,DMSO)δ9.07(s,1H),8.15(s,2H),7.96–7.78(m,2H),7.48(s,1H),7.16(s,2 H),5.92(s,1H),4.83(d,2H),4.52(d,2H),4.22(s,2H),3.33(s,3H),2.86–2.60(m,3H).

[0540] Example 197 Preparation of Chiral Isomers

[0541]

[0542] Step 1: 4-amino-7-(methoxymethyl)-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 197 was separated by Chiral-HPLC to obtain 197-P1: (R)-4-amino-7-(methoxymethyl)-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H- [3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide (4.5 mg), yield: 45.0%; 197-P2: (S)-4-amino-7-(methoxymethyl)-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide (5.0 mg), yield: 50.0%.

[0543] MS m / z(ESI):487[M+1],P1 MS m / z(ESI):487[M+1],P2

[0544] 1H NMR(400MHz,DMSO,P1)δ9.07(s,1H),8.15(s,2H),7.96–7.78(m,2H),7.48(s,1H),7.16(s ,2H),5.92(s,1H),4.83(d,2H),4.52(d,2H),4.22(s,2H),3.33(s,3H),2.86–2.60(m,3H).

[0545] 1 H NMR(400MHz,DMSO,P2)δ9.07(s,1H),8.15(s,2H),7.96–7.78(m,2H),7.48(s,1H),7.16(s ,2H),5.92(s,1H),4.83(d,2H),4.52(d,2H),4.22(s,2H),3.33(s,3H),2.86–2.60(m,3H).

[0546] Example 198

[0547]

[0548] Step 1: 5-Nitrophthalide 198a (5 g, 27.93 mmol) was dispersed in 20 mL of 2N / L aqueous sodium hydroxide solution and stirred at 25°C for 1 hour. The reaction solution was adjusted to neutral pH with 6N hydrochloric acid. A white solid precipitated and was filtered to afford 2-(hydroxymethyl)-4-nitrobenzoic acid 198b (4 g) in a 72.7% yield. MS m / z (ESI): 198 [M+1]

[0549] Step 2: Disperse 198b (1 g, 5.08 mmol), di-tert-butyl dicarbonate (3.27 g, 15 mmol), and 4-dimethylaminopyridine (122 mg, 1 mmol) in 10 mL of tetrahydrofuran and stir at 25°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 tert-butyl 2-(hydroxymethyl)-4-nitrobenzoate 198c (500 mg) in a 38.8% yield. MS m / z (ESI): 254 [M+1]

[0550] Step 3: Disperse 198c (500 mg, 1.97 mmol) and potassium bifluoride (468 mg, 6 mmol) in 10 mL of dichloromethane and 10 mL of water. Add difluorobromomethyltrimethylsilane (1.22 g, 6 mmol) at 0°C, and stir at 25°C for 1 hour. Add 30 mL of dichloromethane to the reaction mixture, separate the layers, and concentrate the organic phase under reduced pressure. The resulting residue is purified by silica gel column chromatography using eluent System A to afford tert-butyl 2-(difluoromethoxymethyl)-4-nitrobenzoate 198d (450 mg) in a 75.4% yield. MS m / z (ESI): 304 [M+1].

[0551] Step 4: Disperse 198d (450 mg, 1.49 mmol), zinc powder (960 mg, 15 mmol), and ammonium chloride (795 mg, 15 mmol) in 10 mL of ethanol and 5 mL of water. Stir and react at 60°C for 3 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford tert-butyl 4-amino-2-(difluoromethoxymethyl)benzoate 198e (400 mg) in a 98.8% yield. MS m / z (ESI): 274 [M+1].

[0552] Referring to the synthesis methods of Steps 1 to 3 and Step 7 of Example 102 and Step 6 of Example 1, the title product 4-amino-N,1-dimethyl-7-((difluoromethoxy)methyl)-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (21 mg) was obtained.

[0553] 1 H NMR(400MHz,MeOD)δ8.70-8.41(m,3H),8.36(s,1H),8.22(d,1H),7.92(dd,2H),6.92(dd,1H) ,5.91(s,1H),5.22-5.02(m,2H),4.84(dd,2H),4.51(s,3H),4.40–4.16(m,2H),2.68(s,3H).

[0554] Example 199

[0555]

[0556] Step 1: Dissolve 7-bromoisochroman-4-one 199a (200 mg, 0.88 mmol), bis(pinacol)boronate (671 mg, 2.64 mmol), and potassium acetate (259 mg, 2.64 mmol) in 1,4-dioxane (5 mL). The mixture was purged with nitrogen three times. [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (72 mg, 88 μmol) was added and the system was heated to 80°C in a microwave reactor for 2 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to afford (4-carbonylisochroman-7-yl)boronic acid 199b (1.1 g, crude product). MS m / z (ESI): 193 [M+1].

[0557] Step 2: 199b (1.17 g, 3.05 mmol), (E)-2-fluorovinyl-4-methylbenzenesulfonate (0.6 g, 2.77 mmol, synthesized by the known method "[Organic Letters, 2011, vol. 13, #4, p. 560–563"), tricyclohexylphosphine fluoroborate (204 mg, 555 μmol), and potassium phosphate (1.00 g, 4.72 mmol) were dissolved in water (2 mL) and 1,4-dioxane (10 mL). The mixture was purged with nitrogen three times, and tris(dibenzylideneacetone)palladium (254 mg, 277 μmol) was added. The system was heated to 110 °C in a microwave reactor for 2 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford (E)-7-(2-fluorovinyl)isochroman-4-one 199c (130 mg) in a 24.4% yield. MS m / z (ESI): 193 [M+1].

[0558] Step 3: 199c (110 mg, 572 μmol) and ethanolic methylamine (296 mg, 2.86 mmol, 30% purity) were dissolved in trifluoroethanol (10 mL). The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 25°C for 15 hours. Sodium cyanoborohydride (54.00 mg, 1.50 mmol) was added and the mixture was allowed to react at 25°C for 1 hour. The reaction was quenched by adding saturated aqueous sodium bicarbonate and extracted with methanol / dichloromethane (1 / 10 volume ratio) (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System A to afford (E)-7-(2-fluorovinyl)-N-methylisochroman-4-amine 199d (35 mg) in a 29.5% yield. MS m / z (ESI): 208 [M+1].

[0559] Step 4: 4-Amino-1-methyl-pyrazolo[4,3-c]quinoline-8-carboxylic acid 199e (41 mg, 0.17 mmol), 199d (35 mg, 0.17 mmol), and (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (76 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-Diisopropylethylamine (65 mg, 0.51 mmol) was added, and the atmosphere was purged with nitrogen three times. The reaction system was stirred at 25 °C for 2 h. The reaction mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography using eluent System A to afford (E)-4-amino-N-(7-(2-fluorovinyl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 4 (18 mg) in a 24.7% yield. MS m / z (ESI): 432 [M+1].

[0560] 1 H NMR (400MHz, DMSO) δ8.37-8.24(m,2H),7.71-7.45(m,3H),7.34(d,2H),7.15(s,1H),7.01-6.90(m,2H ),6.49(dd,1H),5.39(s,1H),4.78(d,1H),4.62(d,1H),4.40(s,3H),4.20-4.04(m,2H),2.78(s,3H).

[0561] Example 200

[0562]

[0563] Referring to the synthetic methods of steps 4 and 6 of Example 97, 2-bromo-N-methyl-4,7-dihydro-5H-thieno[2,3-c]pyran-4-amine 200b was obtained from 5H-thieno[2,3-c]pyran-4(7H)-one 97d. MS m / z (ESI): 233 [M+1] + .

[0564] Step 3: Compound 200b (20 mg, 0.08 mmol) and 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (39 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL). N-methylpyrazole (20 mg, 0.24 mmol) and TCFH (45 mg, 0.16 mmol) 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 4-amino-N-(2-bromo-4,7-dihydro-5H-thieno[2,3-c]pyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 200 (16 mg) in a yield of 42.0%. MS m / z (ESI): 472 [M+1]. +

[0565] 1 H NMR(400MHz,CD3OD)δ8.45(s,1H),8.32(s,1H),7.76(s,2H),7.14(s,1H),5.66(s, 1H),4.83(s,1H),4.66(d,1H),4.50(s,3H),4.30(d,1H),4.07(d,1H),2.95(s,3H).

[0566] Example 201

[0567]

[0568] Step 1: 7-bromoisochroman-4-one (560 mg, 2.47 mmol), triazole (341 mg, 4.93 mmol), (1S, 2S)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (175 mg, 1.23 mmol), cuprous iodide (469 mg, 2.47 mmol), and potassium carbonate (510 mg, 3.70 mmol) were dissolved in dimethyl sulfoxide (6 mL), purged with nitrogen, sealed in a microwave tube, and stirred at 100°C for 2 hours. The reaction mixture was diluted with ethyl acetate, and the solids were removed by filtration. The filtrate was washed with water and brine, and the organic phase was concentrated. The concentrated residue was purified with eluent System C to afford 7-(2H-1,2,3-triazol-2-yl)isochroman-4-one 201b (120 mg) in a 24.5% yield and 7-(1H-1,2,3-triazol-1-yl)isochroman-4-one 2-2 (160 mg) in a 26.4% yield. MS m / z (ESI): 216 [M+1]

[0569] Referring to the synthesis method of steps 6 and 7 of Example 97, N-(7-(2H-1,2,3-triazol-2-yl)isochroman-4-yl)-4-amino-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 201 (30 mg) was obtained from 7-(2H-1,2,3-triazol-2-yl)isochroman-4-one 201b in a yield of 30.8%. MS m / z (ESI): 455 [M+1].

[0570] 1 H NMR (400MHz, DMSO) δ8.55(s,1H),8.49(s,1H),9.90(m,6H),7.61(m,1H),5. 89(s,1H),4.98(m,1H),4.77(d,1H),4.55(d,3H),4.2(m,2H),2.94(d,3H).

[0571] Example 202

[0572]

[0573] Referring to the synthesis method of steps 6 and 7 of Example 97, N-(7-(1H-1,2,3-triazol-1-yl)isochroman-4-yl)-4-amino-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (33 mg) was obtained from 7-(1H-1,2,3-triazol-1-yl)isochroman-4-one 201c in a yield of 41.8%. MS m / z (ESI): 455 [M+1].

[0574] 1 H NMR(400MHz,CD3OD)δ8.56(d,2H),8.49(s,1H),7.88(m,4H),7.71(m,2H),5. 92(s,1H),4.97(s,1H),4.73(d,1H),4.55(d,3H),4.30(m,2H),2.95(d,3H).

[0575] Example 203

[0576]

[0577] Referring to the seventh to thirteenth steps of Example 197, 4-amino-7-(methoxymethyl)-N,3-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 203 (22.6 mg) was obtained by reaction with (E)-4-((tert-butoxycarbonyl)amino)-5-((2-ethoxy-2-carbonylethylidene)amino)-2-(methoxymethyl)benzoate 203a (470 mg). Yield: 3.8%. MS m / z (ESI): 501 [M+1].

[0578] 1 HNMR(400MHz,DMSO)δ9.00(s,1H),8.13(d,2H),7.92(d,1H),7.41(d,1H),6.86(s,2H),5.89(d,1H),4.89 (d,1H),4.78(d,1H),4.62(d,1H),4.45–4.38(m,1H),4.20(d,2H),3.28(s,3H),2.77(s,1H),2.63(s,5H).

[0579] Example 203 Preparation of Chiral Isomers

[0580]

[0581] Reference Example 1 Preparation of Chiral Isomers, P1 was obtained by 4-amino-7-(methoxymethyl)-N,3-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 203: (S)-4-amino-7-(methoxymethyl)-N,3-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide ,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 203-P1; P2: (R)-4-amino-7-(methoxymethyl)-N,3-dimethyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 203-P2.

[0582] MS m / z(ESI):501[M+1],P1; 501[M+1],P2

[0583] Example 204-1 & Example 204-2

[0584]

[0585] Step 1: 7-Bromo-N-methyl-isochroman-4-amine 204a (870 mg, 3.59 mmol) and tributyl(1-ethoxyethylene)tin (1.56 g, 4.31 mmol) were dissolved in 1'4-dioxane (10 mL). The nitrogen atmosphere was purged three times, and bis(triphenylphosphine)palladium(II) dichloride (252 mg, 0.36 mmol) was added. The reaction was allowed to proceed at 100°C for 5 hours. After cooling to room temperature, HCl (2 M, 3.59 mL) was added to the system and the reaction was continued at 25°C for 5 hours. The reaction was quenched with sodium bicarbonate solution, 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 give 1-(4-(methylamino)isochroman-7-yl)ethan-1-one 204b (600 mg) in 81.4% yield. MS m / z (ESI): 206 [M+1]

[0586] Step 2: Dissolve 204b (0.2 g, 0.97 mmol) and 2-[(fluoromethyl)sulfonyl]pyridine (154 mg, 0.88 mmol) in N,N-dimethylformamide (5 mL). The mixture was purged with nitrogen three times and cooled to -40°C. Potassium tert-butoxide (142 mg, 1.27 mmol) was added and the reaction was allowed to react at -40°C for 1 hour. 1 mL of saturated ammonium chloride solution and 1 mL of 2M hydrochloric acid solution were added to the reaction mixture. The system was stirred at room temperature for 1 hour, 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 7-(1-fluoroprop-1-en-2-yl)-N-methylisochroman-4-amine 204c (150 mg) in a 69.6% yield. MS m / z(ESI):222[M+1]

[0587] Step 3: 4-Amino-1-methyl-pyrazolo[4,3-c]quinoline-8-carboxylic acid 204d (60 mg, 248 μmol), 204c (60 mg, 272 μmol), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (83 mg, 297 μmol) were dissolved in N,N-dimethylformamide (5 mL). N-Methylimidazole (64 mg, 0.77 mmol) was added, and the atmosphere was purged with nitrogen three times. The reaction system was heated to 25 °C for 2 h. The reaction was quenched with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System A to give (Z)-4-amino-N-(7-(1-fluoroprop-1-en-2-yl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 204-1 (3 mg) in a yield of 2.3%; (E)-4-amino-N-(7-(1-fluoroprop-1-en-2-yl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide 204-2 (10 mg) in a yield of 9.1%. MS m / z (ESI): 446 [M+1], 204-1; 446 [M+1], 204-2

[0588] 1 H NMR(400MHz,DMSO,204-1)δ8.38–8.21(m,3H),7.64(t,2H),7.43(s,2H),7.15(s,2H),7. 08(s,1H),5.73(s,1H),4.80(s,2H),4.40(s,3H),4.13(d,2H),2.77(s,3H),1.88(s,3H).

[0589] 1 H NMR(400MHz,DMSO,204-2)δ8.22(d,2H),7.62–7.53(m,2H),7.33(d,2H),7.11(d,4H) ,5.65(s,1H),4.78–4.47(m,2H),4.33(s,3H),4.05(d,2H),2.69(s,3H),1.91(s,3H).

[0590] Synthesis of Example 205 Reference Example 123:

[0591]

[0592] The following examples are synthesized with reference to Example 65:

[0593]

[0594] The synthesis of the following examples is described in Example 97:

[0595]

[0596]

[0597] The synthesis of the following examples is described in Example 163:

[0598]

[0599]

[0600] The synthesis of the following examples is described in Example 1:

[0601]

[0602] The synthesis of the following examples is described in Example 197:

[0603]

[0604]

[0605] Or Example 225 is synthesized by reference to the following method:

[0606]

[0607] From steps 9 to 10 of Example 84, 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid 225a (90 mg) and N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine 225c (40 mg, synthesized using the known method "Patent WO2022169948 A1") were used to obtain 4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (10.9 mg) in a 26% yield. MS m / z (ESI): 428 [M+1].

[0608] 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).

[0609] Or Example 240 was synthesized by the following method:

[0610]

[0611] Step 1: 2,4-Difluoro-5-nitro-benzoic acid methyl ester 240a (112 g, 55.27 mmol) was dissolved in tetrahydrofuran (50 mL). Ammonia (2 M, 10.4 mL) was added under ice-cooling. The reaction was stirred at 0°C for 0.5 h. THF (50 mL) was then added and the reaction was stirred at 25°C for 16 h. The reaction solution was concentrated under reduced pressure. Water (100 mL) was added to the residue, stirred for 15 min, filtered, and the filter cake was dried under reduced pressure to afford 4-amino-2-fluoro-5-nitro-benzoic acid methyl ester 240b (12 g, crude product). MS m / z (ESI): 214 [M+1]

[0612] Referring to the synthesis method of steps 1 to 10 of Example 84, 240b (500 mg, 2.33 mmol) was used to obtain 4-amino-N,7-dimethyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide (10 mg) in a yield of 0.9%. MS m / z (ESI): 461 [M+1].

[0613] 1 H NMR(400MHz,DMSO)δ9.06(s,1H),8.32(s,1H),8.19–7.68(m,3H),7.38(s,1 H),7.24(d,1H),5.89(s,1H),4.83(d,2H),4.32–3.99(m,2H),2.78(s,3H).

[0614] Example 240 Preparation of Chiral Isomers

[0615]

[0616] Reference Example 197 Preparation of Chiral Isomers: P1: (R)-4-amino-N,7-dimethyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 240-P1; P2: (S)-4-amino-N,7-dimethyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 240-P2 were obtained through 4-amino-N,7-dimethyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide. MS m / z(ESI):461[M+1],P1; 461[M+1],P2

[0617] Or Example 242 was synthesized by the following method:

[0618]

[0619] Referring to Example 225, 4-amino-7-(methoxymethyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (3 mg) was obtained from 4-((4-methoxybenzyl)amino)-7-(methoxymethyl)imidazo[1,5-a]quinoxaline-8-carboxylic acid 242a (40 mg). Yield: 11%. MS m / z (ESI): 472 [M+1].

[0620] 1 HNMR(400MHz,DMSO)δ9.12(s,1H),8.15(d,1H),7.95(s,1H),7.63(d,1H),7.47(s,1H),7.37(d,1H),7.32 –7.21(m,2H),6.50(d,1H),5.53(s,1H),4.89(t,1H),4.67(d,1H),4.48(d,2H),3.27(s,3H),2.68(s,3H).

[0621] Or Example 244 was synthesized by the following method:

[0622]

[0623] Step 1: Deuterated methanol (523 mg, 14.94 mmol) was dispersed in 20 mL of tetrahydrofuran. Sodium hydride (597 mg, 14.94 mmol, 60% wt) was added at 0°C and stirred at 0°C for 1 hour. Potassium (bromomethyl) trifluoroborate 244a (1 g, 4.98 mmol) was added and stirred at 25°C for 16 hours. Potassium bifluoride (3.90 g, 50 mmol) and 5 mL of water were added to quench the reaction. The reaction solution was concentrated to dryness under reduced pressure, and the residue was recrystallized from acetone to obtain the title product, (methoxy(d-3)methyl) trifluoroborate 244b (560 mg), in a yield of 72.6%.

[0624] By referring to the synthetic methods of steps 1 to 2 of Example 197 and steps 3 to 8 of Example 123, methyl 2-bromo-4-fluoro-5-nitrobenzoate 244c (10 g, 35.97 mmol) was used to obtain methyl 7-bromo-4-(2,4-dimethoxybenzylamino)imidazo[1,5-a]quinoxaline-8-carboxylate 244k (5 g) in a 31.7% yield. MS m / z (ESI): 439 [M+1].

[0625] Step 10: 244k (300 mg, 0.64 mmol), 244b (198 mg, 1.28 mmol), tris(dibenzylideneacetone)dipalladium (55 mg, 0.06 mmol), n-butyldi(1-adamantyl)phosphine (43 mg, 0.12 mmol), and cesium carbonate (626 mg, 1.92 mmol) were dispersed in 10 mL of 1,4-dioxane and 2 mL of water and reacted at 100°C for 3 hours. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to give the title product, methyl 4-((2,4-dimethoxybenzyl)amino)-7-((methoxy-d3)methyl)imidazo[1,5-a]quinoxaline-8-carboxylate 244l (80 mg) in a 28.5% yield. MS m / z (ESI): 408 [M+1].

[0626] Referring to the synthesis methods of steps 9 to 11 of Example 123, 2441 (80 mg, 0.18 mmol) was used to obtain 4-amino-7-(methoxy-d3)methyl-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 244 (15 mg) in a 16.8% yield. MS m / z (ESI): 490 [M+1].

[0627] 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.21(s,1H),7.94-7.75(m,3H),7.50-7.39(m,3H),5.9 1(t,1H),5.00-4.76(m,2H),4.75-4.25(m,2H),4.25-3.85(m,2H),2.77(s,1H),2.66(s,2H).

[0628] Example 241

[0629]

[0630] Step 1: Dissolve 4-fluoro-2-methyl-5-nitro-benzoic acid methyl ester 241a (10 g, 46.92 mmol) in 1,4-dioxane and add aqueous ammonia (2 M, 46.9 mL). The reaction is stirred at 25°C for 16 hours. The reaction solution is concentrated under reduced pressure to obtain a crude product. The crude product is stirred with dichloromethane (50 mL) for 15 minutes, filtered, and the filter cake is dried under reduced pressure to obtain 4-amino-2-methyl-5-nitro-benzoic acid methyl ester 241b (11 g, crude product). MS m / z (ESI): 211 [M+1]

[0631] Referring to the synthesis method of steps 1 to 10 of Example 84, 241b (500 mg, 1.78 mmol) was used to obtain 4-amino-N,7-dimethyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 241 (9.8 mg) in a yield of 1.2%. MS m / z (ESI): 458 [M+1].

[0632] 1 H NMR(400MHz,DMSO)δ9.02(s,1H),8.25–7.95(m,2H),7.88(s,2H),7.40(d,1H),7. 10(s,2H),5.94(s,1H),4.92–4.66(m,2H),4.22(s,2H),2.74(d,3H),2.39(d,3H).

[0633] Example 241 Preparation of Chiral Isomers

[0634]

[0635] Reference Example 197 Preparation of Chiral Isomers: P1 was obtained by 4-amino-N,7-dimethyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 241: (R)-4-amino-N,7-dimethyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide [2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 241-P1; P2: (S)-4-amino-N,7-dimethyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 241-P2.

[0636] Example 247

[0637]

[0638] Referring to the synthesis method of steps 1 to 12 of Example 115, 4-amino-7-(2-methoxyethyl)-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 247 (21 mg) was obtained from 4-amino-3-nitrobenzoic acid methyl ester 247a (2 g, 10.20 mmol) in a 0.4% yield. MS m / z (ESI): 501 [M+1].

[0639] 1 H NMR(400MHz,DMSO)δ9.05(s,1H),8.09(s,2H),7.88(d,2H),7.42(s,1H),7.12(s,2H) ,5.93(s,1H),4.85(d,2H),4.24(s,2H),3.62(s,2H),3.25(s,3H),2.98–2.59(m,5H).

[0640] Synthesis of Example 248 Refer to Example 247, isomer separation Refer to Example 1 isomer separation:

[0641]

[0642] Example 249

[0643]

[0644] Step 1: Methyl 7-bromo-4-(2,4-dimethoxybenzylamino)imidazo[1,5-a]quinoxaline-8-carboxylate 234 (94 mg, 0.20 mmol) and CuCN (54 mg, 0.60 mmol) were dispersed in 10 mL of DMF and reacted at 70°C for 12 hours. The reaction mixture was cooled, concentrated to dryness, and the resulting residue was purified by silica gel column chromatography using eluent System C to afford methyl 7-cyano-4-(2,4-dimethoxybenzylamino)imidazo[1,5-a]quinoxaline-8-carboxylate 249a (67 mg) in an 80.5% yield. MS m / z (ESI): 386 [M+1].

[0645] Referring to the synthesis methods of steps 8 to 10 of Example 84, 249a (67 mg, 0.16 mmol) was used to obtain 4-amino-7-cyano-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 249 (4.5 mg) in a 6.0% yield. MS m / z (ESI): 468 [M+1].

[0646] 1 H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.49(s,1H),8.10(d,1H),7.97(d,1H),7.92(d,2H), 7.74(d,2H),5.90(t,1H),5.00-4.66(m,2H),4.27-4.10(m,2H),2.84(s,1H),2.75(s,2H).

[0647] Example 250

[0648]

[0649] Referring to the synthesis method of steps 9 to 10 of Example 84, 4-amino-N,7-dimethyl-N-[6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl]imidazo[1,5-a]quinoxaline-8-carboxamide (56 mg) was obtained from 4-[(2,4-dimethoxyphenyl)methylamino]-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid 250a (150 mg, 382 μmol) in a yield of 24.4%. MS m / z (ESI): 442 [M+1].

[0650] 1 H NMR(400MHz,DMSO)δ9.02(s,1H),8.12(d,1H),7.88(s,1H),7.67(d,1H),7. 34(s,2H),7.15(d,2H),6.53(s,1H),4.77(d,2H),2.59(s,3H),2.33(s,3H).

[0651] Example 251

[0652]

[0653]

[0654] Referring to the synthesis method of steps 1 to 10 of Example 84, 4-amino-7-chloro-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 251 (30 mg) was obtained from 4-amino-2-chloro-5-nitrobenzoic acid methyl ester 251a (2 g, 8.70 mmol) in a 0.7% yield. MS m / z (ESI): 477 [M+1].

[0655] 1 H NMR (400MHz, DMSO) δ9.11(d,1H),8.61–7.31(m,7H),5.94(s,1H),4.78(dt,2H),4.16(d,2H),2.76(d,3H).

[0656] Example 251 Preparation of Chiral Isomers

[0657]

[0658] Reference Example 197 Preparation of Chiral Isomers: P1 was obtained by 251: (R)-4-amino-7-chloro-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 251-P1; P2: (S)-4-amino-7-chloro-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 251-P2.

[0659] The synthesis of Example 252 is referred to Example 197, and the synthesis of Examples 253 to 258 is referred to Example 247:

[0660]

[0661]

[0662] Example 259

[0663]

[0664] The first step: 4-fluoro-2-(trifluoromethyl)benzoic acid methyl ester 259a (5.40 g, 24.30 mmol, 4.2 mL) was dissolved in concentrated sulfuric acid (4.2 mL) and fuming nitric acid (9.95 g, 157.92 mmol, 7.9 mL) was gradually added dropwise. The reaction was stirred at 25 ° C for 30 minutes, then warmed to 45 ° C and stirred at 45 ° C for 16 hours. The reaction mixture was dropwise added to ice water (30 mL), diluted with ethyl acetate (30 mm L) and stirred for 30 minutes. The mixture was extracted with ethyl acetate (50 mL × 3), washed with water and saturated sodium bicarbonate solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue was purified with eluent System C to give 4-fluoro-5-nitro-2-(trifluoromethyl)benzoic acid methyl ester 259b (6 g) in a yield of 92.5%.

[0665] 1 H NMR (400MHz, CDCl3) δ7.87(ddd,1H),7.46(dd,1H),7.29(td,1H),3.93(s,3H).

[0666] Referring to the synthesis method of steps 1 to 10 of Example 240, 259b (2 g, 7.49 mmol) was used to obtain 4-amino-N-methyl-7-(trifluoromethyl)-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide (60 mg) in a 1.6% yield. MS m / z (ESI): 511 [M+1].

[0667] 1 H NMR (400MHz, DMSO) δ9.16(s,1H),8.35(s,1H),7.94(d,3H),7.73(s,1H),7.46(s,2H),5.91(s,1H),4.84(d,2H),4.21(s,2H),2.74(d,3H).

[0668] The following examples are synthesized with reference to Example 84:

[0669]

[0670] Example 262

[0671]

[0672] 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 262a (70 mg, 158 μmol) was dissolved in N,N-dimethylformamide (5 mL). N-chlorosuccinimide (25 mg, 0.19 mmol) was added, and the atmosphere was purged with nitrogen three times. The reaction system was stirred at 25°C for 48 hours. After concentration, the residue was purified by silica gel column chromatography using eluent System A to afford 4-amino-3-chloro-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 262 (5 mg) in a 6.6% yield. MS m / z(ESI):477[M+1]

[0673] 1 H NMR(400MHz,DMSO)δ9.21(s,1H),8.36(s,1H),8.14(d,1H),7.87(d,1H),7.56(dd,1H) ,7.47(d,1H),7.10(s,2H),5.82(s,1H),4.97–4.61(m,2H),4.20(s,2H),2.80(s,3H).

[0674] The following examples are synthesized with reference to Example 84:

[0675]

[0676]

[0677] The synthesis of the following examples is described in Example 247:

[0678]

[0679] The synthesis of the following examples is described in Example 197:

[0680]

[0681]

[0682] Or Example 275 was synthesized by the following method:

[0683]

[0684] Step 1: Dissolve 7-bromo-4-[(3,5-dimethoxyphenyl)methylamino]-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 275a (250 mg, 0.37 mmol) in trifluoroacetic acid (5 mL). The atmosphere was purged with nitrogen three times, and the reaction system was stirred at 90°C for 0.5 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography using eluent System B to afford 4-amino-7-bromo-N-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 275b (180 mg) in a 92.7% yield. MS m / z(ESI):521[M+1]

[0685] Step 2: 275b (0.15 g, 0.29 mmol), 4,4,5,5-tetramethyl-2-(oxetane-3-yl)-1,3,2-dioxaborolane (106 mg, 0.58 mmol) and [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridyl] nickel(II) dichloride (34 mg, 86 μmol) were dissolved in N,N-dimethylformamide (10 mL). The nitrogen atmosphere was purged three times, and morpholine (38 mg, 0.43 mmol) and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridyl]iridium bis(hexafluorophosphate) (9 mg, 9 μmol) were added. The system was irradiated in a blue light reactor (8W, 456 nm) for 2 h. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (50 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System A to afford 4-amino-N-methyl-7-(oxetan-3-yl)-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 275 (10 mg) in a 7.0% yield. MS m / z (ESI): 499 [M+1].

[0686] 1 H NMR(400MHz,DMSO)δ9.22(d,1H),8.39–8.05(m,2H),7.85(td,2H),7.77–7.60(m,2H),7.47(d,2H),6.57(s,1H), 4.87(d,1H),4.79–4.63(m,2H),4.56(ddd,1H),4.36(d,1H),4.28–4.11(m,2H),3.98–3.72(m,3H),3.58(t,3H).

[0687] Example 281-1 & Example 281-2

[0688]

[0689]

[0690] Step 1: 2-Chloro-6-methoxy-pyridine-3-carboxylic acid methyl ester 281a (9 g, 44.64 mmol), potassium vinyl fluoroborate (11.96 g, 89.28 mmol), and potassium carbonate (12.34 g, 89.28 mmol) were dissolved in water (20 mL) and 1,4-dioxane (100 mL). The mixture was purged with nitrogen three times, and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (3.27 g, 4.46 mmol) was added. The reaction system was stirred at 90°C for 15 hours. The reaction 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 with eluent system B to afford 6-methoxy-2-vinylnicotinic acid methyl ester 281b (6 g) in a yield of 69.6%. MS m / z(ESI):194[M+1]

[0691] Step 2: Dissolve 281b (6 g, 31.06 mmol) in methanol (100 mL). The atmosphere was purged with nitrogen three times, and 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 methyl 2-ethyl-6-methoxynicotinate 281c (5.90 g, crude). MS m / z (ESI): 196 [M+1]

[0692] Step 3: Dissolve 281c (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 the system was heated to 90°C for reaction. The reaction mixture was cooled to room temperature, concentrated, added with water, and washed with ethyl acetate (100 mL x 3), then with 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 methyl 2-(1-bromoethyl)-6-methoxynicotinate 281d (7.50 g) in a 90.5% yield. MS m / z (ESI): 275 [M+1].

[0693] Step 4 to Step 5: Referring to the synthesis method of Step 3 to Step 4 of Example 30, 2-hydroxy-8-methyl-6H-pyrano[3,4-b]pyridin-5(8H)-one 281f (2.60 g) was obtained from 281d (7.80 g, 28.46 mmol). Yield: 51.0% MS m / z (ESI): 180 [M+1]

[0694] Step 6: Dissolve 281f (0.5 g, 2.79 mmol) in dichloromethane (40 mL), evacuate nitrogen 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 system, and the system was reacted at 20°C for 15 hours. Filter and concentrate. The residue was purified by silica gel column chromatography with eluent System B to give 281 g (0.35 g) of 2-iodo-8-methyl-6H-pyrano[3,4-b]pyridin-5(8H)-one in a yield of 43.4%. MS m / z (ESI): 290 [M+1]

[0695] Step 7: Dissolve 281g (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 8-methyl-2-(trifluoromethyl)-6H-pyrano[3,4-b]pyridin-5(8H)-one 281h (0.14g) in a yield of 54.7%. MSm / z(ESI):232[M+1]

[0696] Step 8: Dissolve 281h (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 mixture was then 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 N,8-dimethyl-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine 281i (80 mg) in a 53.6% yield. MS m / z(ESI):247[M+1]

[0697] Step 9 to Step 10: Referring to the synthesis method of Step 9 to Step 10 of Example 84, 4-amino-N,7-dimethyl-N-(8-methyl-2-(trifluoromethyl)-5,8-dimethoxyphenyl)methylamino]-7-methyl-imidazo[1,5-a]quinoxaline-8-carboxylic acid 281j (160 mg, 0.41 mol) and 281i (100 mg, 0.41 mmol) were obtained. dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 281-1 (23 mg) & 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 281-2 (10 mg), yield: 9.5%

[0698] Example 281-1: MS m / z (ESI): 471 [M+1]

[0699] 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).

[0700] Example 281-2: MS m / z (ESI): 471 [M+1]

[0701] 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).

[0702] Example 282

[0703]

[0704] Step 1: 2-Bromo-N-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine 282a (0.64 g, 2.63 mmol) was dissolved in methanol (10 mL) and water. Sodium bicarbonate (221.16 mg, 2.63 mmol) and tert-butyl dicarbonate (575 mg, 2.63 mmol) were added and the reaction was carried out at 25°C for 1 hour. The methanol was removed by concentration, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent System B to afford tert-butyl (2-bromo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)(methyl)carbamate 282b (540 mg) in a yield of 59.8%. MS m / z (ESI): 344 [M+1].

[0705] Step 2: Tert-butyl (2-bromo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)(methyl)carbamate 282b (540 mg, 1.57 mmol) and cuprous iodide (60 mg, 0.1 mmol) were dissolved in diisopropylamine (159 mg, 1.57 mmol, 1 mL) and N,N-dimethylformamide (10 mL). The nitrogen atmosphere was replaced three times, and methyl 1-ethynylcyclopropanecarboxylate (273 mg, 2.20 mmol, 0.25 mL) and bistriphenylphosphine palladium dichloride (110 mg, 0.15 mmol) were added. The system was heated to 60 ° C in a microwave reactor for 2 hours. The reaction mixture was cooled to room temperature, concentrated, and water was added. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent System B to afford methyl 1-((5-((tert-butoxycarbonyl)(methyl)amino)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-2-yl)ethynyl)cyclopropane-1-carboxylate 282c (500 mg) in 82.2% yield. MS m / z (ESI): 387 [M+1].

[0706] Step 3: Methyl 1-((5-((tert-Butoxycarbonyl)(methyl)amino)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-2-yl)ethynyl)cyclopropane-1-carboxylate 282c (500 mg, 1.29 mmol) was dissolved in methanol (10 mL) and water (5 mL), and lithium hydroxide (62 mg, 2.59 mmol) was added. The system was reacted at 25°C for 2 hours. The reaction was concentrated, and the pH was adjusted to 5-6 by adding dilute hydrochloric acid. The mixture was washed with ethyl acetate (60 mL × 3) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-((5-((tert-Butoxycarbonyl)(methyl)amino)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-2-yl)ethynyl)cyclopropane-1-carboxylic acid 282d (440 mg, crude). MS m / z(ESI):373[M+1]

[0707] Step 4: 1-((5-((tert-Butoxycarbonyl)(methyl)amino)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-2-yl)ethynyl)cyclopropane-1-carboxylic acid 282d (400 mg, 1.07 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (76 mg, 0.32 mmol), 1,3-dihydro-3,3-dimethyl-1-(trifluoromethyl)-1,2-benzimidazole (443 mg, 1.34 mmol) and cuprous cyanide (20 mg, 0.21 mmol) was dissolved in ethyl acetate (40 mL) and water (580 mg, 32.22 mmol), the nitrogen was replaced three times, 2-tert-butyl-1,1,3,3-tetramethyl-guanidine (92 mg, 0.54 mmol) and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium hexafluorophosphate (22 mg, 21 μmol) were added, and the system was reacted in a blue light reactor (425 nm, 18 W) at 25 ° C for 24 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent System B to afford tert-butyl methyl (2-((1-(trifluoromethyl)cyclopropyl)ethynyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate 282e (160 mg) in a 37.6% yield. MS m / z (ESI): 397 [M+1].

[0708] Step 5: To tert-butyl methyl (2-((1-(trifluoromethyl)cyclopropyl)ethynyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate 282e (160 mg, 0.40 mmol) and ethyl acetate (5 mL) was added ethyl acetate hydrochloride (4 M, 5 mL) and the system was reacted at 25°C for 0.5 hours. The reaction was concentrated to give N-methyl-2-((1-(trifluoromethyl)cyclopropyl)ethynyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine 282f (110 mg, crude). MS m / z (ESI): 297 [M+1]

[0709] Step 6 to Step 7: Referring to the synthesis method of Step 9 to Step 10 of Example 84, 4-amino-N,7-dimethyl-N-(2-((1-(trifluoromethyl)cyclopropyl)ethynyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 282 (22 mg) was obtained by reacting 4-[(3,5-dimethoxyphenyl)methylamino]-7-methyl-imidazo[1,5-a]quinoxaline-8-carboxylic acid 282g (83 mg, 0.21 mmol) and N-methyl-2-((1-(trifluoromethyl)cyclopropyl)ethynyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine 282f (60 mg, 0.22 mmol). Yield: 20.1% MS m / z(ESI):521[M+1]

[0710] 1 H NMR(400MHz,DMSO)δ9.08(s,1H),8.11(s,1H),7.97(s,1H),7.81(s,1H),7.51(s,1 H),7.37(s,2H),4.77(s,2H),4.17(s,2H),2.71(d,3H),2.35(s,3H),1.46(d,4H).

[0711] Synthesis of Example 283 Reference Example 282:

[0712]

[0713] Example 284-1 & Example 284-2

[0714]

[0715] Step 1: Dissolve 2-hydroxy-8-methyl-6H-pyrano[3,4-b]pyridin-5(8H)-one 284a (1 g, 5.58 mmol) in phosphorus oxychloride (855.78 mg, 5.58 mmol, 5 mL). The atmosphere was purged with nitrogen three times and heated to 90°C for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent System B to afford 2-chloro-8-methyl-6H-pyrano[3,4-b]pyridin-5(8H)-one 284b (0.38 g) in a 34.5% yield. MS m / z (ESI): 199 [M+1].

[0716] Step 2: Referring to the synthesis method of Step 8 of Example 281, 2-chloro-N,8-dimethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine 284c (160 mg) was obtained from 284b (0.38 g, 1.92 mmol). Yield: 39.1%. MS m / z (ESI): 213 [M+1].

[0717] Step 3: Referring to the synthesis method of Example 166, step 1, 2-(cyclopropylethynyl)-N,8-dimethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine 284d (110 mg) was obtained from 284c (0.14 g, 0.66 mmol) in a 68.9% yield. MS m / z (ESI): 243 [M+1].

[0718] Step 4 to Step 5: Referring to the synthesis method of Step 9 to Step 10 of Example 84, 4-amino-N-(2-(cyclopropylethynyl)-8-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,7-dimethylimidazo[1,5-a]quinoxaline-8-carboxamide 284-1 (27 mg) was obtained by using 4-[(3,5-dimethoxyphenyl)methylamino]-7-methyl-imidazo[1,5-a]quinoxaline-8-carboxylic acid 284e (170 mg, 0.62 mmol) and 284d (100 mg, 0.41 mmol). Yield: 14.0%. &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 284-2 (15 mg), yield: 7.8%.

[0719] Example 284-1: MS m / z (ESI): 467 [M+1]

[0720] 1H NMR (400MHz, DMSO) δ9.05(s,1H),8.24–8.06(m,1H),7.91(d,1H),7.69(s,1H),7.51–7.32(m,2H),7.18(s,1H),5.90(s,1H),4.80( d,1H),4.24(s,1H),3.97(s,1H),3.74(d,1H),2.66(d,3H),2.35(s,3H),1.55(d,3H),1.34(s,1H),1.00–0.90(m,2H),0.80(s,2H).

[0721] Example 284-2: MS m / z (ESI): 467 [M+1]

[0722] 1 H NMR(400MHz,DMSO)δ9.03(s,1H),8.10(d,1H),7.95–.85(m,1H),7.73(s,1H),7.37(d,2H),7.10(s,2H),5.81(s,1 H),4.70(s,1H),4.25(s,1H),4.12(s,1H),2.74(d,3H),2.33(s,3H),1.64–1.30(m,4H),0.94(d,2H),0.81(s,2H).

[0723] The synthesis of Examples 285 to 289 and 289 to 292 is described with reference to Example 84, and the synthesis of Example 290 is described with reference to Example 282:

[0724]

[0725] Example 293

[0726]

[0727] With reference to the synthesis method of steps 9 to 10 of Example 84, 4-amino-N-methyl-N-(2-((1-(trifluoromethyl)cyclopropyl)ethynyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 293 (5 mg) was obtained from 4-[(3,5-dimethoxyphenyl)methylamino]imidazo[1,5-a]quinoxaline-8-carboxylic acid 293b (34 mg, 131 μmol) and N-methyl-2-((1-(trifluoromethyl)cyclopropyl)ethynyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine 293a (25 mg, 84 μmol). Yield: 11.7%. MS m / z (ESI): 507[M+1].

[0728] 1 H NMR(400MHz,DMSO)δ9.12(s,1H),8.28(s,1H),7.84(s,1H),7.75(s,1H),7.48– 7.30(m,4H),5.70(s,1H),4.64(d,2H),4.09(d,2H),2.69(s,3H),1.39(d,4H).

[0729] The synthesis of the following examples is described in Example 282:

[0730]

[0731]

[0732] Example 302

[0733]

[0734] Step 1: 2-Chloro-8H-pyrano[3,4-b]pyridin-5-one 302a (500 mg, 2.72 mmol) was dissolved in acetonitrile (10 mL). Tri(o-tolyl)phosphine (165.78 mg, 545 μmol) and palladium acetate (61.15 mg, 273 μmol) were added sequentially. The atmosphere was purged with nitrogen three times and protected with nitrogen. Acrylic acid (392.52 mg, 5.45 mmol) was added. The reaction was stirred at 100°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC (acid method) to afford 3-(5-oxo-8H-pyrano[3,4-b]pyridin-2-yl)prop-2-enoic acid 302b (350 mg) in a 58.6% yield. MS m / z (ESI): 220 [M+1].

[0735] Step 2: 302b (140 mg, 639 μmol) was dissolved in 1,2-dichloroethane (4 mL). Sodium trifluoromethanesulfonate (302.88 mg, 1.92 mmol), cuprous chloride (12.65 mg, 128 μmol), silver carbonate (105.67 mg, 3838 μmol), and tert-butyl hydroperoxide (287.80 mg, 3.19 mmol, 309 μL) were added sequentially. The reaction was stirred at 70°C for 24 hours. A filtration funnel was covered with celite and the reaction mixture was filtered. The filtrate was collected and concentrated under reduced pressure. The residue was purified by Pre-TLC to afford 2-(3,3,3-trifluoropropyl-1-enyl)-8H-pyrano[3,4-b]pyridin-5-one 302c (150 mg) in a 71.0% yield. MS m / z (ESI): 244 [M+1].

[0736] Step 3: 302c (30 mg, 124 μmol) and methylamine (22.99 mg, 740 μmol, 35 μL) were dissolved in 1,2-dichloroethane (2 mL). Tetraisopropyl titanate (106 mg, 370 μmol, 110 μL) was added. The reaction was stirred at 25°C for 16 h. Sodium cyanoborohydride (15.50 mg, 247 μmol) was added and stirred at 25°C for 30 min. Water (5 mL) was added and the mixture was filtered, dried over anhydrous sodium sulfate, filtered, dried, and concentrated under reduced pressure to afford N-methyl-2-(-3,3,3-trifluoropropyl-1-enyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-amine 302d (30 mg) in 94.2% yield. MS m / z (ESI): 259 [M+1].

[0737] Referring to the synthesis method of step 9 of Example 84, N-methyl-2-(-3,3,3-trifluoropropyl-1-enyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-amine 302d (30 mg, 120 μmol) was used to obtain 4-[(2,4-dimethoxyphenyl)methylamino]-N,7-dimethyl-N-[2-(-3,3,3-trifluoropropyl-1-enyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide (16 mg) in a yield of 28.6%. MS m / z (ESI): 483 [M+1].

[0738] 1 H NMR(400MHz,DMSO)δ9.09(s,1H),8.13(s,1H),7.99(s,1H),7.88(s,1H),7.70(d,1H),7.53(s,1 H),7.40(d,2H),6.94(s,1H),5.90(s,1H),4.78(q,2H),4.19(s,2H),2.73(d,3H),2.35(s,3H).

[0739] The synthesis of the following examples refers to Example 107:

[0740]

[0741] The following examples are synthesized with reference to Example 30:

[0742]

[0743]

[0744]

[0745] Example 356

[0746]

[0747] Step 1: Methyl 3,4-diaminobenzoate 356a (2 g, 12.04 mmol) was dissolved in ethanol (50 mL). Ethyl glyoxylate (50% in toluene) (5.04 M, 2.8 mL) was added. The nitrogen atmosphere was purged three times. The reaction system was heated to 90°C and stirred for 3 hours. The mixture was cooled to room temperature, filtered, and the residue was washed with a small amount of ethyl acetate and dried to afford a mixture of methyl 2-carbonyl-1,2-dihydroquinoxaline-6-carboxylate 356b-1 and methyl 3-carbonyl-3,4-dihydroquinoxaline-6-carboxylate 356b-2 (1.80 g) in a 73.2% yield. MS m / z (ESI): 205 [M+1].

[0748] Step 2: A mixture of 356b-1 and 356b-2 (1.6 g, 7.84 mmol) was dissolved in N,N-dimethylformamide (20 mL), and p-toluenesulfonylmethyl isocyanide (1.91 g, 9.80 mmol) and potassium carbonate (2.17 g, 15.67 mmol) were added. The system was heated to 180°C in a microwave reactor for 10 minutes. The mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System C to obtain a mixture of methyl 4-carbonyl-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate 356c-1 and methyl 4-carbonyl-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylate 356c-2 (0.30 g) in a yield of 31.5%. MS m / z (ESI): 244 [M+1].

[0749] Step 3: A mixture of 356c-1 and 356c-2 (300 mg, 1.23 mmol) was dissolved in trichlorophosphine (189 mg, 1.23 mmol, 5 mL), and nitrogen was evacuated three times. The reaction system was heated to 130°C and stirred for 2 hours. The system was cooled to room temperature and concentrated. The residue was poured into saturated sodium carbonate and quenched. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture of methyl 4-chloroimidazo[1,5-a]quinoxaline-8-carboxylate 356d-1 and methyl 4-chloro-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylate 356d-2 (0.25 g, crude product). MS m / z (ESI): 262 [M+1]

[0750] Step 4: A mixture of 356d-1 and 356d-2 (0.20 g, 0.76 mmol) and potassium carbonate (317 mg, 2.29 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 4-methoxybenzylamine (210 mg, 1.53 mmol, 0.2 mL) was added. The reaction system was heated in a microwave reactor at 120°C for 1.5 hours. The mixture was cooled to room temperature, filtered, concentrated, quenched with water, and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent System A to afford a mixture of methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate 356e-1 and methyl 4-((4-methoxybenzyl)amino)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylate 356e-2 (0.15 g) in a 54.2% yield. MS m / z (ESI): 363 [M+1].

[0751] Step 5: A mixture of 356e-1 and 356e-2 (0.22 g, 0.61 mmol) and lithium hydroxide monohydrate (29 mg, 1.21 mmol) were dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). The reaction system was heated to 50°C and stirred for 2 hours. The reaction was cooled to room temperature, concentrated, and the pH was adjusted to approximately 5-6 with 2M hydrochloric acid. The mixture was filtered, and the residue was washed with a small amount of water and petroleum ether. The residue was dried to afford a mixture of 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid 356f-1 and 4-((4-methoxybenzyl)amino)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid 356f-2 (0.11 g, crude). MS m / z (ESI): 349 [M+1].

[0752] Step 6: A mixture of 356f-1 and 356f-2 (108 mg, 0.31 mmol), 3-(4-(trifluoromethyl)phenyl)morpholine (60 mg, 0.26 mmol, obtained by a known method "Chemical Science, 2019, vol. 10, #41, p. 9591-9596"), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (117.48 mg, 311.40 μmol) were dissolved in N,N-dimethylformamide (6 mL), and N,N-diisopropylethylamine (134 mg, 1.04 mmol, 0.18 mL) was added. The nitrogen atmosphere was evacuated three times, and the reaction system was stirred at 25 ° C for 12 hours. The reaction was quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent System C to afford (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 356h-1 (15 mg) in a 10.3% yield. (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxalin-7-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 356h-2 (40 mg) in a 27.5% yield. MS m / z (ESI): 562 [M+1].

[0753] Step 7: 356h-1 (15 mg, 27 μmol) was dissolved in trifluoroacetic acid (3 mL), the atmosphere was purged with nitrogen three times, and the reaction system was heated to 80°C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography using eluent System C to afford (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxalin-7-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 356-1 (5 mg) in a 50.7% yield. MS m / z (ESI): 442 [M+1].

[0754] 1 H NMR(400MHz,DMSO)δ9.11(s,1H),8.23(d,1H),7.84(s,1H),7.76-7.56(m,4H) ,7.45-7.28(m,4H),5.54(s,1H),4.43(d,1H),3.87(d,1H),3.79-3.48(m,3H).

[0755] Step 8: 4-aminoimidazo[1,5-a]quinoxalin-7-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[0756] Referring to the synthesis method of step 8 of Example 1, 356h-2 (40 mg, 71 μmol) was used to obtain (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxalin-7-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 356-2 (24 mg) in a yield of 76.2%. MS m / z (ESI): 442 [M+1].

[0757] 1 H NMR(400MHz,DMSO)δ9.12(s,1H),8.22(d,1H),7.91(s,1H),7.79(d,2H),7.42(d,3H),7.3 0(d,1H),5.70(s,1H),4.49(s,1H),3.93(dd,1H),3.80(d,1H),3.60(t,2H),3.18(s,1H).

[0758] Example 357

[0759]

[0760] Step 1: 4-(Trifluoromethyl)benzaldehyde 357a (1 g, 5.75 mmol) and tert-butylsulfenamide (726 mg, 6 mmol) were dispersed in 10 mL of dichloromethane. Cesium carbonate (3.26 g, 10 mmol) was added and stirred at 40°C for 16 hours. The reaction mixture was filtered to remove insoluble material, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford (E)-2-methyl-N-(4-(trifluoromethyl)benzylidene)propane-2-sulfenamide 357b (1.5 g) in a 93.8% yield. MS m / z (ESI): 278 [M+1]

[0761] Step 2: 357b (1.5 g, 5.40 mmol) was dispersed in 20 mL of tetrahydrofuran. Allylmagnesium bromide (6 mL, 6 mmol, 1 M / L tetrahydrofuran solution) was added dropwise at -78°C and stirred at -78°C for 1 hour. The mixture was quenched by the addition of 10 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 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 2-methyl-N-(1-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)propane-2-sulfenamide 357c (1.58 g) in 92.2% yield. MS m / z (ESI): 320 [M+1].

[0762] Step 3: Disperse 357c (1.58 g, 4.98 mmol) in 20 mL of tetrahydrofuran. Add sodium hydride (220 mg, 5.51 mmol, 60% wt) at 0°C and stir at 25°C for 1 hour. Add allyl bromide (1.20 g, 9.96 mmol) and stir at 25°C for 16 hours. Quench with 10 mL of water and extract with ethyl acetate (20 mL x 3). The combined organic phases are washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography with eluent System A to give N-allyl-2-methyl-N-(1-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)propane-2-sulfinamide 357d (1.05 g) in 58.7% yield. MS m / z (ESI): 360 [M+1].

[0763] Step 4: 357d (1.05 g, 2.92 mmol) and 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-yl[2-(isopropyloxy-5-(N,N-dimethylsulfamoyl)phenyl]methylruthenium dichloride (409 mg, 0.56 mmol) were dispersed in 30 mL of dichloromethane and stirred at 40°C for 4 hours. The reaction mixture was filtered to remove insoluble material, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System A to give 1-(tert-butylsulfinyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine 357e (830 mg) in 86.0% yield. MS m / z (ESI): 332 [M+1]

[0764] Step 5: Disperse 357e (830 mg, 2.51 mmol) in 10 mL of 3M / L methanolic hydrochloric acid solution and stir at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to afford 1-(tert-butylsulfinyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine 357f (342 mg) in a 59.8% yield. MS m / z (ESI): 228 [M+1]

[0765] Step 6: 357f (50 mg, 0.22 mmol), 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid 357g (60 mg, 0.25 mmol, synthesized by the known method "Patent WO2022169948 A1"), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (114 mg, 0.30 mmol) and N,N-diisopropylethylamine (129 mg, 1 mmol) were dispersed in 3 mL of dichloromethane and stirred at 25 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to afford the title product, (4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)(2-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)methanone 357 (27 mg) in a 27.2% yield. MS m / z (ESI): 452 [M+1].

[0766] 1 H NMR (400MHz, DMSO) δ8.67(s,1H),8.57(s,1H),8.30(s,1H),7.84–7.77(m,2H),7.71(d,2H),7. 56(d,2H),5.93(d,1H),5.68(d,1H),4.34(s,3H),3.55(d,1H),3.16(b,2H),2.87-2.68(m,2H).

[0767] The synthesis of Examples 358 to 359 is referred to Example 356, the synthesis of Examples 360 to 367 is referred to Example 357, the synthesis of Examples 368 to 373 is referred to Example 232, the synthesis of Examples 374 to 379 is referred to Example 281, the synthesis of Examples 380 to 382 is referred to Example 241, and the synthesis of Examples 383 to 384 is referred to Example 31:

[0768]

[0769]

[0770]

[0771] Example 385

[0772]

[0773] Referring to the synthetic method of the first to tenth steps of Example 240, 2-bromo-4-fluoro-5-nitrobenzoic acid methyl ester 385a (2 g, 3.60 mmol) was used to obtain compound 7-bromo-4-[(2,4-dimethoxyphenyl)methylamino]-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 385j (600 mg) in a yield of 0.1%.

[0774] Step 10: Compound 385j (100 mg, 149 μmol) and iminodimethylsulfonamide (16.65 mg, 179 μmol) were dissolved in DMSO (8 mL), and Pd2(dba)3 (19.43 mg, 20 μmol), Xantphos (24.55 mg, 40 μmol), and sodium tert-butoxide (30.59 mg, 319 μmol) were added in sequence. The atmosphere was replaced with nitrogen three times and protected with nitrogen. The reaction was stirred at 80°C for 16 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was analyzed by Pre-HPLC to obtain 4-[(2,4-dimethoxyphenyl)methylamino]-7-[[dimethyl(oxo)-sulfinyl]amino]-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 385k (61 mg) in a 60% yield. MS m / z (ESI): 534 [M+1].

[0775] Step 11: (61 mg, 89 μmol) was dissolved in TFA (3 mL) and the reaction was stirred at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the concentrated residue was separated and purified by Pre-HPLC to obtain 4-amino-7-[[dimethyl(oxo)-sulfinyl]amino]-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxylic acid (15 mg) in a yield of 31.5%. MS m / z (ESI): 535 [M+1]

[0776] 1H NMR(400MHz,DMSO)δ8.96(d,1H),8.11(d,2H),7.97(d,1H),7.87(s,1H),7.22(s,1H),7. 07(s,2H),5.95(s,1H),4.92–4.73(m,2H),4.28–4.13(m,2H),3.23(d,6H),2.67(s,3H).

[0777] Example 386

[0778]

[0779] Step 1: Add THF (70 mL) to a three-necked flask, replace the atmosphere with nitrogen three times, and cool to 0°C. Quickly add dibromo(difluoro)methane (20.72 g, 98.74 mmol, 9.02 mL). Stir in an ice bath for 10 minutes, and slowly add HMPT (16.12 g, 98.74 mmol, 18 mL) dropwise. A white solid is formed. After the addition was completed, stirring was continued at 0°C for 1 hr, and tert-butyl 3-oxocyclobutanecarboxylate (3.86 g, 22.7 mmol) in THF (10 mL) was slowly added dropwise. The temperature was raised to 25°C and stirred for 1 hour. Zinc powder (3.86 g, 90.8 mmol) was added, and 0.3 mL of HMPT was added. The temperature was transferred to 75°C and stirred for 5 hours. Water (100 mL) was added to the reaction solution, and the organic phase was separated. The aqueous layer was extracted with ethyl acetate (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 by Purification System C to give tert-butyl 3-(difluoromethylene)cyclobutanecarboxylate 386b (2 g) in a yield of 43.1%.

[0780] Step 2: 386b (1.5 g, 7.35 mmol) was dissolved in DCM (15 mL) and TFA (10 mL). The reaction was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to afford 3-(difluoromethylene)cyclobutanecarboxylic acid 386c (1 g, crude).

[0781] Step 3: 386c (1 g, crude product) and 2-hydroxyisoindole-1,3-dione (1.21 g, 7.43 mmol) were dissolved in DCM (10 mL), DMAP (82.49 mg, 675.19 μmol) was added, and N,N-diisopropylcarbodiimide (937.29 mg, 7.43 mmol, 1.2 mL) was added dropwise. The atmosphere was replaced with nitrogen three times and protected with nitrogen. The reaction was carried out at 25 °C. The mixture was stirred for 16 hours, and water (20 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was separated and purified using Purification System C to obtain (1,3-dioxoisoindol-2-yl) 3-(difluoromethylene)cyclobutanecarboxylate 386d (1.92 g) in a yield of 96.9%. MS m / z (ESI): 294 [M+1].

[0782] Step 4: 386d (1.92 g, 6.55 mmol) and 2,2-bis-1,3,2-benzodioxaborol (1.95 g, 8.18 mmol) were dissolved in DMA (120 mL), and the atmosphere was replaced with nitrogen three times. The mixture was stirred under a blue light reactor (18w, 456 nm) for 15 h, and then Pinacol (3.10 g, 26.19 mmol) and TEA (4.18 g, 41.32 mmol, 5.8 mL) were added in sequence. The atmosphere was replaced with nitrogen three times. The reaction mixture was stirred at 25°C for 1 hour under nitrogen protection. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was separated and purified by Purification System C to obtain 2-[3-(difluoromethylene)cyclobutyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 386e (540 mg) in a yield of 35.9%.

[0783] Referring to the synthesis method of the first to tenth steps of Example 240, compound 7-bromo-4-[(2,4-dimethoxyphenyl)methylamino]-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 386o (600 mg) was obtained using compound 2-bromo-4-fluoro-5-nitrobenzoate 386f (2 g, 3.60 mmol) in a yield of 0.1%.

[0784] Step 14: 386o (100 mg, 149 μmol) and 386e (137.05 mg, 596 μmol) were dissolved in DMF (5 mL), and Ni(dtbppy)Cl2 (29.64 mg, 75 μmol), [Ir(dtbbpy)[dF(CF3)ppy]2]PF6 (7.52 mg, 8 μmol), and morpholine (19.46 mg, 224 μmol) were added in sequence. The atmosphere was replaced with nitrogen three times and protected with nitrogen. The reaction was stirred at 25°C for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7-[3-(difluoromethylene)cyclobutyl]-4-[(2,4-dimethoxyphenyl)methylamino]-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 386p (100 mg, crude). MS m / z (ESI): 545 [M+1].

[0785] Step 15: 386p (100 mg, crude) was dissolved in TFA (1 mL) and the reaction was stirred at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure and the concentrated residue was separated and purified by Pre-HPLC to give 4-amino-7-[3-(difluoromethylene)cyclobutyl]-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide 386 (7.5 mg). MS m / z (ESI): 545 [M+1].

[0786] 1 H NMR(400MHz,DMSO)δ9.07(s,1H),8.32–8.03(m,2H),8.02–7.79(m,2H),7.54(s,1H),7.23(s,2H) ,5.90(s,1H),5.00–4.70(m,2H),4.24(s,2H),3.98–3.69(m,3H),2.92–2.73(m,3H),2.66(s,2H).

[0787] Example 387

[0788]

[0789] Referring to the synthesis method from the first step to the second step of Example 386, tert-butyl 4-oxopiperidine-1-carboxylate 387a (5 g, 25.09 mmol) was used to obtain 4-(difluoromethylene)piperidinamine 387c (1.5 g) in a yield of 44.9%.

[0790] Referring to the synthetic method of the first to tenth steps of Example 240, 4-fluoro-2-methyl-5-nitrobenzoic acid methyl ester 387e (2 g, 9.38 mmol) was used to obtain N-(2-bromo-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl)-4-[(2,4-dimethoxyphenyl)methylamino]-N,7-dimethylimidazo[1,5-a]quinoxaline-8-carboxamide 387n (600 mg) in a yield of 12%.

[0791] Step 12: 387n (120 mg, 195 μmol) and 387c (51.75 mg, 389 μmol) were dissolved in DMF (3 mL), and Xphos-Pd-G2 (15.27 mg, 20 μmol) and t-BuoNa (112.05 mg, 1.17 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times and protected with nitrogen. The reaction was stirred at 110° C. in a microwave oven for 3 hours. Water (10 mL) was added to the reaction solution and ethyl acetate was added. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-[2-[4-(difluoromethylene)-1-piperidinyl]-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]-4-[(2,4-dimethoxyphenyl)methylamino]-N,7-dimethylimidazo[1,5-a]quinoxaline-8-carboxamide 387o (100 mg, crude product). MS m / z (ESI): 670 [M+1]

[0792] Step 13: 387o (100 mg, 150 μmol) was dissolved in TFA (3 mL), replaced with nitrogen three times, and protected with nitrogen. The reaction was stirred at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the concentrated residue was separated and purified by Pre-HPLC to obtain 4-amino-N-[2-[4-(difluoromethylene)-1-piperidinyl]-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]-N,7-dimethyl-imidazo[1,5-a]quinoxaline-8-carboxamide 387 (18 mg). MS m / z (ESI): 520 [M+1]

[0793] 1H NMR(400MHz,DMSO)δ9.03(s,1H),8.08(d,1H),7.89(s,1H),7.50(s,1H),7.33(s,1H),7.11(s,2H),6. 85(d,1H),5.71(s,1H),4.54(q,2H),4.09(d,2H),3.62(s,4H),2.60(s,3H),2.32(s,3H),2.22(s,4H).

[0794] Example 388

[0795]

[0796] Referring to the synthesis method of the first to fourth steps of Example 386, 2-[4-(difluoromethylene)cyclohexyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 387e (1.5 g) was obtained from tert-butyl 4-oxocyclohexanecarboxylate 388a (5 g, 25.09 mmol) with a yield of 23.0%.

[0797] Referring to the synthetic method of the first to tenth steps of Example 240, 4-fluoro-2-methyl-5-nitrobenzoic acid methyl ester 388f (2 g, 9.38 mmol) was used to obtain N-(2-bromo-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl)-4-[(2,4-dimethoxyphenyl)methylamino]-N,7-dimethylimidazo[1,5-a]quinoxaline-8-carboxamide 388o (600 mg) in a yield of 12%.

[0798] Step 14: 388o (100 mg, 162 μmol) and 387e (167.20 mg, 648 μmol) were dissolved in DMF (5 mL), and Ni(dtbppy)Cl2 (32.23 mg, 81 μmol), [Ir(dtbbpy)[dF(CF3)ppy]2]PF6 (8.18 mg, 9 μmol), and morpholine (21.16 mg, 243 μmol, 22 μL) were added in sequence. The atmosphere was replaced with nitrogen three times and protected with nitrogen. The reaction was stirred at 25°C for 16 hours under a blue light reactor (14w, 456 nm). Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was separated and purified by Pre-HPLC to obtain N-[2-[4-(difluoromethylene)cyclohexyl]-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]-4-[(2,4-dimethoxyphenyl)methylamino]-N,7-dimethylimidazo[1,5-a]quinoxaline-8-carboxamide 388p (35 mg) in a yield of 32.3%. MS m / z (ESI): 670 [M+1].

[0799] Step 15: 388p (35 mg, 53 μmol) was dissolved in TFA (3 mL), replaced with nitrogen three times, and protected with nitrogen. The reaction was stirred at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the concentrated residue was separated and purified by Pre-HPLC to ...

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; Ring G is selected from a 5-membered heterocyclyl or a 5-membered heteroaryl; L1 is selected from a bond, -CR aa R bb -、-C(O)-、-NR cc C(O), -S(O) m1 -or-NR cc -; preferably -CR aa R bb -、-C(O)-、-S(O) m1 -or-NR cc -; L2 is selected from a bond, -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ; Preferred -CR aa R bb -、-C(O)-、-S(O) m1 - or NR cc ; Alternatively, R1 and L2 are linked to form a 3-10 membered heterocyclic group, wherein the 3-10 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, 5 or 6 R 1a replaced by; 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, -OR e 、-NR e R f 、-C(O)R e 、-C(O)NR e R f or -P(O)R e R f , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; more 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 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)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 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; Or R1 and R a , R b or R c 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 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, 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 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; 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 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 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 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 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 R2 and R c 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 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, 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 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; R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, 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 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 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl 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 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, 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 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; R 1a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n1 -C 3-12 Cycloalkyl, -(CH2) n3 -3-12 membered heterocyclic group, -(CH2) n3 -C 6-12 Aryl, -(CH2) n3 -5-12 membered heteroaryl, -(CH2) n3 OR g 、-(CH2) n3 NR g R h 、-(CH2) n3 C(O)R g 、-(CH2) n3 C(O)NR g R h 、-(CH2) n3 P(O)R 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 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; Or any two R 1a Linked with its neighboring atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; 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)NR ee R 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 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 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 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 R2 and R c Link Form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally further 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 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, one or more substituents; preferably forming C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; Either R2 and L1 or R2 and R1 are linked to form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally further 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 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, one or more substituents; preferably forming C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R g and R h are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 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 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 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 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 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 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 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 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 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 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; n2 is selected from 0, 1, 2, 3 or 4; and n3 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 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Further, the compound represented by the general formula (III), its stereoisomer or its pharmaceutically acceptable salt:

4. The compound according to any one of claims 1 to 3, 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 5. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Further, the compound represented by the general formula (IV), its stereoisomer or a pharmaceutically acceptable salt thereof: M5 is selected from N or CR 3d ; R 3a , R 3b , R 3c and R 3d are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 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 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 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 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents; or R 3a and R 3b The atoms adjacent to it, R 3b and R 3c The adjacent atoms or R 3c and R 3d Each of its neighboring atoms independently links to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, one or more substituents; preferably forming C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 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; R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 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 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 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 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents; Or any two R4 atoms are linked to their adjacent atoms to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 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 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; z is selected from 0, 1, 2, 3 or 4.

6. The compound according to any one of claims 1 to 3 or 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Further, the compound represented by the general formula (VI-2), its stereoisomer or a pharmaceutically acceptable salt thereof: M4 is selected from N or CR 6a ; L4 is selected from CR 8a , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 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 8a , C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, 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; R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 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 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 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 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents; Or any two R4 atoms are linked to their adjacent atoms to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 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 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; R 6a , R 6b and R 6c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 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 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 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 8a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl and =CR 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 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 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents; R 8b and R 8c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 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 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 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 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents; R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, thio, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 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 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 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; z is selected from 0, 1, 2, 3 or 4.

7. The compound according to any one of claims 1 to 6, 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 Further optimization 8. The compound according to any one of claims 1 to 3 or 5 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Further, the compound represented by the general formula (V), its stereoisomer or a pharmaceutically acceptable salt thereof: M5 is selected from N or CR 3d ; R 2a 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; R 2b 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; R ee and R ff are each independently selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 alkyl; R 3a , R 3b , R 3c and R 3d are each independently selected from hydrogen, 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 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 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents; or R 3a and R 3b The atoms adjacent to it, R 3b and R 3c The adjacent atoms or R 3c and R 3d Each of its neighboring atoms independently links to form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 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; R4 is selected from hydrogen, 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 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 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and =CR e R f is substituted by one or more substituents; Or any two R4 atoms are linked to their adjacent atoms to form a C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, oxo, thio, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; z is selected from 0, 1, 2, 3 or 4; n4 is selected from 0, 1, 2 or 3.

9. The compound according to any one of claims 1 to 8, 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; R ee and R ff are each independently selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 alkyl; Preferred are hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, trifluoromethyl, 10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: 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)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 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 is substituted by one or more substituents in a cycloalkyl group or a 3-8 membered heterocyclic group; 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 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, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl 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 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 are substituted with one or more substituents; preferably hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, trifluoromethoxy, n2 is selected from 0, 1 or 2; R1 is selected from hydrogen, deuterium, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 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 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 are substituted with one or more substituents; preferably methyl, ethyl, deuterated methyl, deuterated ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, acetyl, 11. The compound according to any one of claims 1 to 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 (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps: The compound represented by the general formula (V-1) reacts with the compound represented by the general formula (V-2) in the presence of a base to obtain the compound represented by the general formula (V-3), and the protecting group is further removed to obtain the compound represented by the general formula (V); Pg1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 2,4-dimethoxycarbonyl, 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, nitrobenzenesulfonyl, trityl, 2-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; R1, R a , R b and R c The definition of is as in claim 1; M5, R 2a , R 2b , R 3a , R 3b , R 3c , R4, n4 and z are as defined in claim 8.

13. A pharmaceutical composition comprising a therapeutically effective dose of a compound as claimed in any one of claims 1 to 11, 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 11, 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 a compound according to any one of claims 1 to 11, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13 in the preparation of a method for treating cancer; wherein the cancer is an MTAP-related cancer; the cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer, colorectal cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung cancer or lung adenocarcinoma; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

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